RTOG Address
Search  
HomeMember InfoProtocolsResearcherMeetingsVisitorsFAQSite Map




Committee Minutes - Brain Tumor
BRAIN TUMOR COMMITTEE (JANUARY 2008)
Minesh P. Mehta, M.D., Chair

Active Trials

  1. RTOG 0227-This is a Phase I/II trial of pre-radiation methotrexate, rituximab, and temozolomide and post-radiation temozolomide for primary central nervous system lymphoma. The primary phase I goal is to assess the MTD of temozolomide in combination with methotrexate and rituximab when administered prior to twice-daily fractionated whole brain radiation therapy and this has been completed. The phase II portion is now open to accrual. A total of 26/64 patients have been accrued.

  2. RTOG 0320-This is a Phase III protocol in patients with 1-3 brain metastases (from NSCLC) eligible for radiosurgery. The protocol allows for randomization to radiosurgery with whole brain radiation therapy and either Temozolomide or Tarceva. The protocol has accrued 78/381 patients, which is a significant improvement since the last meeting. Barriers to accrual were discussed.

  3. RTOG 0424-This is a Phase II study for patients with high-risk low grade glioma, receiving temozolomide during and post-radiation. The protocol has enrolled 97/97 patients and an amendment to expand accrual has been submitted to CTEP. No undue toxicities have been reported. Replacement strategies and studies were discussed.

  4. RTOG 0513-This is a Phase I/II trial of the radiosensitizer MGd with standard XRT and temozolomide for GBM. The trial has has accrued 24/113 patients and in the phase I portion and the phase II will be opened soon.

  5. RTOG 0525-This is a phase III randomized trial of low-dose temozolomide plus radiotherapy followed by either standard monthly temozolomide (x up to 12 months) or dose-intense temozolomide (21 days on, 7 days off x upto12 months) for GBM patients, including stratification by MGMT status (which requires submission of a tissue block as part of study eligibility). The study is accruing very rapidly, with 834/1154 patients accrued. Tissue analysis for MGMT status is proceeding well. In addition, a recent grant was obtained for performing QOL/NC analysis on a subset of patients, and a protocol amendment for this has been developed and approved and is available to individual institutions.

  6. RTOG 0614-A neuroprotection pharmacologic trial in patients with brain metastases undergoing whole brain radiotherapy has been developed, using the agent Memantine. CTEP approval has been received and the trial will open shortly.

  7. RTOG 0625-This is a phase I/II trial of continuous temozolomide and bevacizumab in recurrent GBM. 101/121 patients have been enrolled; the trial is on hold for toxicity monitoring on the temozolomide arm and will be reactivated shortly.

  8. RTOG 0627-This is the second trial in recurrent GBM as part of a new portfolio of trials to investigate targeted agents. The protocol, using the multi-tyrosine kinase inhibitor Dasatinib has just been initiated and 29/83 patients have been enrolled; patients having specific tumor markers will be eligible for study; Drs. Lassman and Aldape have developed a mechanism to pre-evaluate marker status on patients such this would be available at initial diagnosis, so at recurrence patients could rapidly be enrolled to this trial. Accrual is on hold to monitor responses, prior to opening Step 2.

  9. NCCTG 0574-This is an RTOG-endorsed Phase III trial of radiosurgery with or without whole brain radiotherapy in patients with up to 3 brain metastases. The RTOG membership is encouraged to enroll patients with other than non-small cell lung cancer on this trial, and enrollment from RTOG sites has formally begun.

Developing Trials

  1. RTOG 0539-This is a Phase II proposal for patients with meningioma, with the end-point being 3-year progression free survival. This protocol continues to be developed with feedback from CTEP.

    2. Action Items: Dr. Rogers will develop the statistics for the redraft with Dr. Pajak and this will be submitted to CTEP. The QOL subcommittee will develop QOL and neurocognitive/endocrine endpoints. Central path review endpoints are also being developed, with potential collaboration with EORTC.

  2. EORTC 26053/RTOG 0634-This is a phase III 2 x 2 randomized trials in patients with non co-deleted Grade 3 glioma. RTOG HQ has received the trial from EORTC and it is being finalized for CTEP submission.

    3. Action Items: RTOG HQ personnel will continue to work with EORTC and NCI-CTEP.

  3. NCCTG NO577/RTOG 0670-This is a phase III trial in patients with co-deleted Grade 3 glioma. The finalized protocol has been submitted by NCCTG to CTEP.

  4. RTOG 0716-Gliadel and 06BG for recurrent GBM: The design incorporates a contemporary arm of rec GBM patients treated without the experimental treatment, i.e. Gliadel alone, in a 2:1 randomization.

    5. Action Items: Dr. Tatter will complete the protocol for CTEP submission with RTOG HQ.

  5. RTOG 0824-EGFRViii vaccine for recurrent GBM: Dr. Vogelbaum; the protocol is in development

    6. Action Items: Dr. Vogelbaum will begin protocol development.

  6. RTOG 0825-Phase III trial of radiotherapy plus temozolomide with or without Bevacuzimab for GBM: Dr. Gilbert: the protocol is in development.

  7. RTOG Developing Phase I/II trial of the PARP1 inhibitor ABT-888 for recurrent malignant glioma, using 2 temozolomide schedules; Dr. Robins.

    8. Action Items: Dr. Robins has submitted the LOI to Abbott and a response is awaited.

  8. RTOG 0722-Dr. Weil: SRS trial for pituitary adenomas (GH secreting). This was approved by Research Strategy on 6/24/07.

    9. Action Items: Dr. Weil will work with Dr. Pajak to complete statistical design (already nearly done), and will submit to CTEP; the QOL subcommittee will develop QOL and cost-effectiveness endpoints.

  9. RTOG Developing Several antiangiogenic agents are potentially available for testing in the high grade glioma population; a subcommittee of individuals (Gilbert, Bachelor, Wen, and others) has begun a rationale protocol development strategy to incorporate these agents in future RTOG trials.

  10. RTOG Developing LGG: Dr. Brown is working with a subcommittee to develop a three-tiered approach, based on risk, for LGG patients. These protocols are in development.

  11. RTOG 0820-This is a subprotocol of RTOG 0525, evaluating the electronic Smartphone technology for prescription management within a co-operative group setting and will be initiated shortly.

  12. RTOG is developing a subcommittee to evaluate the development of re-radiation protocols or recurrent GBM; several novel ideas will be incorporated, including advanced imaging for the definition of the target, as well as incorporation of targeted agents with radiotherapy in the recurrent setting.

  13. RTOG is developing a proposal for combining targeted agents (e.g. Sorafenib) with WBRT for brain metastases was discussed; Drs. Dicker and Khuntia will begin developing the proposal.
BRAIN TUMOR COMMITTEE (JUNE 2007)
Minesh P. Mehta, M.D., Chair

ACTIVE TRIALS

  1. RTOG 0227-This is a Phase I/II trial of pre-radiation methotrexate, rituximab, and temozolomide and post-radiation temozolomide for primary central nervous system lymphoma. The primary phase I goal is to assess the MTD of temozolomide in combination with methotrexate and rituximab when administered prior to twice-daily fractionated whole brain radiation therapy and this has been completed. The phase II portion is now open to accrual. A total of 23/64 patients have been accrued.


  2. RTOG 0320-This is a Phase III protocol in patients with 1-3 brain metastases (from NSCLC) eligible for radiosurgery. The protocol allows for randomization to radiosurgery with whole brain radiation therapy and either Temozolomide or Tarceva. The protocol has accrued 52/381 patients, which is a significant improvement since the last meeting. Barriers to accrual were discussed and Dr. Sperduto has already made amendments allowing the use of chemotherapy of choice following radiotherapy.


  3. RTOG 0424-This is a Phase II study for patients with high-risk low grade glioma, receiving temozolomide during and post-radiation. The protocol has enrolled 78/97 patients. No undue toxicities have been reported. Replacement strategies and studies were discussed.


  4. RTOG 0513-This is a Phase I/II trial of the radiosensitizer MGd with standard XRT and temozolomide for GBM. The trial has just been opened and has accrued 14/113 patients and is currently on hold for toxicity monitoring.


  5. RTOG 0525-This is a phase III randomized trial of low-dose temozolomide plus radiotherapy followed by either standard monthly temozolomide (x upto12 months) or dose-intense temozolomide (21 days on, 7 days off x upto12 months) for GBM patients, including stratification by MGMT status (which requires submission of a tissue block as part of study eligibility). The study is accruing very rapidly, with 469/834 patients accrued. Tissue analysis for MGMT status is proceeding well, especially after screening out patients with "inadequate" tissue. In addition, a recent grant was obtained for performing QOL/NC analysis on a subset of patients, and a protocol amendment for this is being developed. The protocol will be amended to increase accrual to account for patients whose MGMT status remains indeterminate.


  6. RTOG 0611-Dr. Kevin Camphausen initiated this surrogate predictive marker (using urinary and serum MMPs and VEGF levels) trial which has accrued 130/130 patients. An amendment to increase accrual has been developed.


  7. RTOG 0625-With the recent suggestion of possible activity of Bevacizumab in recurrent GBM, in co-operation with CTEP, Genentech and Pfizer, a phase I/II trial of continuous temozolomide and bevacizumab was initiated; this is a high priority trial with very significant emphasis on rapid accrual, which was discussed extensively. The protocol is just being initiated at various sites. There is a useful and innovative imaging section which was discussed in detail. ACRIN representatives promised all possible assistance to make this process as smooth as possible.


  8. RTOG 0627-This is the second trial in recurrent GBM as part of a new portfolio of trials to investigate targeted agents. The protocol, using the multi-tyrosine kinase inhibitor Dasatinib has just been initiated and 3/83 patients have been enrolled; patients having specific tumor markers will be eligible for study; Drs. Lassman and Aldape have developed a mechanism to pre-evaluate marker status on patients such that this would be available at initial diagnosis, so at recurrence patients could rapidly be enrolled to this trial.


  9. NCCTG 0574-This is an RTOG-endorsed Phase III trial of radiosurgery with or without whole brain radiotherapy in patients with upto 3 brain metastases. The RTOG membership is encouraged to enroll patients with other than non-small cell lung cancer on this trial, and enrollment from RTOG sites has formally begun.


DEVELOPING TRIALS

  1. RTOG 0539-This is a Phase II proposal for patients with meningioma, with the end-point being 3-year progression free survival. This protocol continues to be developed with feedback from CTEP.

    Action Items: Dr. Rogers will develop the statistics for the redraft with Dr. Pajak and this will be submitted to CTEP. The QOL Subcommittee will develop QOL and neurocognitive/endocrine endpoints. Central path review endpoints are also being developed.


  2. RTOG 0614-A neuroprotection pharmacologic trial in patients with brain metastases undergoing whole brain radiotherapy is under formulation, using the agent Memantine. Research Strategy approved this in 11/05 and a protocol is being finalized.

    Action Items: Dr. Brown will finalize protocol development and submission with HQ personnel and will work with Dr. Khuntia to develop a possible biomarker study, including the possibility of utilizing metabolomic profiling, as an exploratory endpoint.


  3. EORTC 26053/RTOG 0670-This is a phase III 2 x 2 randomized trial in patients with non co-deleted Grade 3 glioma. RTOG HQ has received the trial from EORTC and discussions are ongoing to coordinate data capture, drug supply and submission by RTOG HQ to CTEP as a sponsoring group.

    Action Items: RTOG HQ personnel will continue to liase with EORTC, NCI-CTEP, NCI-C (if necessary), and Schering Plough.


  4. NCCTG NO577/RTOG 0634- This is a phase III trial in patients with co-deleted Grade 3 glioma. We are awaiting a finalized protocol from NCCTG.

    Action Items: Dr. Pajak will work with the NCCTG statisticians regarding several statistical questions and concerns.


  5. RTOG 0716-Gliadel and RTOG 06BG for recurrent GBM: Dr. Tatter; the design incorporates a contemporary arm of rec GBM patients treated without the experimental treatment, i.e. Gliadel alone, in a 2:1 randomization.

    Action Items: Dr. Tatter will complete the protocol for CTEP submission.


  6. RTOG 0717-EGFRViii vaccine for recurrent GBM: Dr. Vogelbaum; the protocol was approved by Research Strategy approved the concept on 5/24/07.

    Action Items: Dr. Vogelbaum will begin LOI submission to CTEP.


  7. RTOG 0721-HDAC inhibitor SAHA and CPT-11 for recurrent GBM: Dr. Chinnaiyan; the protocol was approved by Research Strategy approved the concept on 6/24/07.

    Action Items: Dr. Chinnaiyan will begin LOI submission to CTEP as soon as contractual issues are resolved.


  8. RTOG 0722-Dr. Weil: SRS trial for pituitary adenomas (GH secreting). This was approved by Research Strategy on 6/24/07.

    Action Items: Dr. Weil will work with Dr. Pajak to complete statistical design (already nearly done), and will submit to CTEP; the QOL subcommittee will develop QOL and cost-effectiveness endpoints.


  9. MR spectroscopy based treatment planning: Dr. Stieber. This is being developed as a subset protocol to be appended to RTOG 0525; the plan will be to evaluate a number of MR parameters and monitor failure patterns. Protocol is in development.

    Action Items: Dr. Stieber will work with Dr. Pajak to develop appropriate statistics and also with IGRT committee for data-capture issues; he will also begin a dialog with ACRIN, to include them, and develop a methodology for covering the MRS component of the trial; Research Strategy approval will be obtained after that.


BRAIN TUMOR COMMITTEE (FEBRUARY 2007)
Minesh Mehta, M.D., Chair

Active Trials

  1. RTOG 0227- This is a Phase I/II trial of pre-radiation methotrexate, rituximab, and temozolomide and post-radiation temozolomide for primary central nervous system lymphoma. The primary phase I goal is to assess the MTD of temozolomide in combination with methotrexate and rituximab when administered prior to twice-daily fractionated whole brain radiation therapy and this has been completed. The phase II portion is now open to accrual. A total of 21/64 patients have been accrued.


  2. RTOG 0320- This is a Phase III protocol in patients with 1-3 brain metastases (from NSCLC) eligible for radiosurgery. The protocol allows for randomization to radiosurgery with whole brain radiation therapy and either Temozolomide or Tarceva. The protocol has accrued 43/381 patients, which is a significant improvement since the last meeting. Barriers to accrual were discussed and Dr. Sperduto has already made amendments allowing the use of chemotherapy of choice following radiotherapy.


  3. RTOG 0424- This is a Phase II study for patients with high-risk low grade glioma, receiving temozolomide during and post-radiation. The protocol has enrolled 72/97 patients. No undue toxicities have been reported. An amendment requiring tissue submission for MGMT and 1p19q analysis has been made.


  4. RTOG 0513- This is a Phase I/II trial of the radiosensitizer MGd with standard XRT and temozolomide for GBM. The trial has just been opened and has accrued 14/113 patients and is currently on hold for toxicity monitoring.


  5. RTOG 0525- This is a phase III randomized trial of low-dose temozolomide plus radiotherapy followed by either standard monthly temozolomide (x upto12 months) or dose-intense temozolomide (21 days on, 7 days off x upto12 months) for GBM patients, including stratification by MGMT status (which requires submission of a tissue block as part of study eligibility). The study is accruing very rapidly, with 312/834 patients accrued. Over 500 patients have been screened centrally by Dr. Aldape. Tissue analysis for MGMT status is proceeding well, especially after screening out patients with "inadequate" tissue. In addition, a recent grant was obtained for performing QOL/NC analysis on a subset of patients, and a protocol amendment for this is being developed.


  6. RTOG 0611- Dr. Kevin Camphausen initiated this surrogate predictive marker (using urinary and serum MMPs and VEGF levels) trial which has accrued 88/130 patients.


  7. RTOG 0625- With the recent suggestion of possible activity of Bevacizumab in recurrent GBM, in co-operation with CTEP, Genentech and Pfizer, a phase I/II trial of continuous temozolomide and bevacizumab was initiated at this meeting; this is a high priority trial with very significant emphasis on rapid accrual, which was discussed extensively.


  8. RTOG 0627- This is the second trial in recurrent GBM as part of a new portfolio of trials to investigate targeted agents. The protocol, using the multi-tyrosine kinase inhibitor Dasatinib was launched at this meeting; patients having specific tumor markers will be eligible for study; Drs. Lassman and Aldape are developing a mechanism to pre-evaluate marker status on patients such this would be available at initial diagnosis, so at recurrence patients could rapidly be enrolled to this trial.


  9. RTOG 9813- This is a Phase III randomized study of radiation therapy and temozolomide vs. radiation therapy and BCNU vs. radiation therapy and temozolomide + BCNU for anaplastic astrocytoma. A total of 223/484 patients have now been enrolled on the trial. The recent shortage of BCNU has now been resolved. Further, an amendment allowing the use of CCNU has been activated, thus allowing a randomization to 2 arms with oral drugs. To perform MGMT methylation analysis, all patients will be required to have tissue submitted henceforth. The DSMC reviewed accrual and the current recommendation is to keep the trial open.


  10. NCCTG 0574: This is an RTOG-endorsed Phase III trial of radiosurgery with or without whole brain radiotherapy in patients with up to 3 brain metastases. The RTOG membership is encouraged to enroll patients with other than non-small cell lung cancer on this trial, and enrollment from RTOG sites has formally begun.


Developing Trials

  1. RTOG 0539- This is a Phase II proposal for patients with meningioma, with the end-point being 3-year progression free survival. Patients were to be stratified by risk level; low risk patients to be observed, intermediate and high risk patients to be treated with IMRT. The protocol was submitted to CTEP which has requested a phase III design. At this meeting, a redraft was developed so intermediate risk patients would be randomized to radiotherapy (either IMRT, 3D or radiosurgery, based on local preference) or observation. Significant discussion was held about this; some quarters have expressed concern we do not have a track record in meningioma and a phase III question should not be asked; CTEP will not permit a study without a phase III question. Others expressed concern there might not be enough patients for this trial. We reviewed data suggesting the incidence of this tumor is in fact equal to or greater than GBM and major centers are willing to provide support letters; further, the Canadian institutions reported a strong desire to participate in this trial, as the EORTC meningioma trial is not open, and hence there is no competing protocol. There was also concern expressed by some a "no radiotherapy" arm will fail to accrue; in this context, we discussed the recent SWOG trial of radiotherapy versus observation which in fact accrued rather well, belying the assumption that no radiotherapy arm trials are doomed to failed.

    Action Items: Dr. Rogers will develop the statistics for this design with Dr. Pajak and we will present this idea at the next Research Strategy teleconference. The QOL subcommittee will develop QOL and neurocognitive/endocrine endpoints. Central path review endpoints are also being developed.


  2. RTOG 0614- A neuroprotection pharmacologic trial in patients with brain metastases undergoing whole brain radiotherapy is under formulation, using the agent Memantine. Research Strategy approved this in 11/05 and a protocol is being finalized.

    Action Items: Dr. Brown will finalize protocol development and submission with HQ personnel and will work with Dr. Khuntia to develop a possible biomarker study, including the possibility of utilizing metabolomic profiling, as an exploratory endpoint.


  3. EORTC 26053- This is a phase III 2 x 2 randomized trial in patients with non co-deleted Grade 3 glioma. RTOG HQ has received the trial from EORTC and discussions are ongoing to coordinate data capture, drug supply and submission by RTOG HQ to CTEP as a sponsoring group.

    Action Items: RTOG HQ personnel will continue to liase with EORTC, NCI-CTEP, NCI-C (if necessary), and Schering Plough.


  4. NCCTG NO577- This is a phase III trial in patients with co-deleted Grade 3 glioma. We are awaiting a finalized protocol from NCCTG.

    Action Items: None.


  5. MR spectroscopy based treatment planning: Dr. Stieber. This is being developed as a subset protocol to be appended to RTOG 0525; the plan will be to evaluate a number of MR parameters and monitor failure patterns. The protocol is in development.

    Action Items: Dr. Stieber will work with Dr. Pajak to develop appropriate statistics and also with IGRT committee for data-capture issues; he will also begin a dialog with ACRIN, to include them, and develop a methodology for covering the MRS component of the trial; Research Strategy approval will be obtained after that.


  6. SRS trial for pituitary adenomas (GH secreting). This was presented on the Research Strategy call 4/06 but was not approved. Research Strategy requested documentation stating institutions will be able to enroll patients. Study Chairs are compiling documentation for this. At this meeting, significant interest was re-expressed for this trial.

    Action Items: Dr. Weil will work with Dr. Pajak to complete statistical design (already nearly done), and will compile support letters which will be forwarded to Research Strategy; the QOL subcommittee will develop QOL and cost-effectiveness endpoints.


  7. Dr. Howard Coleman presented a concept for "personalized treatment selection" using a 38 gene metagene analysis strategy as a PhaseI/II adaptive design strategy as a possible next GBM protocol; this will be developed further.


  8. A Phase II concept of radiation therapy plus temozolomide plus R115777 (a farnesyl transferase inhibitor) for GBM has previously been considered. Dr. Ian Robins has worked with headquarters to submit an LOI, which has been approved by CTEP and a protocol has been developed. We are awaiting the DLT from the NABTC trial.


  9. Other developing concepts for recurrent GBM include:


    10. a. Leading edge image guided radiosurgery: Dr. Duma; in development.

    Action Items: Drs. Duma and Steiber will complete concept development and will discuss with Dr. Gilbert.


    b. Gliadel and 06BG for recurrent GBM: Dr. Tatter; This was presented on Research Strategy call 4/06 but was not approved. Research Strategy requested documentation of commitment from MGI. The study chair is compiling documentation. Further, the recurrent GBM task force recommended that the design incorporate a contemporary arm of rec GBM patients treated without the experimental treatment, i.e. Gliadel alone, possibly in a 2:1 randomization.

    Action Items: Dr. Tatter will compile institutional support letters, discuss drug-replacement as a strategy with MGI Pharma and finalize study design for resubmission to Research Strategy.


    c. PARP-1 inhibitors and temozolomide for recurrent GBM; in development by Drs. Robins and Gilbert, with preclinical work by Dr. Chakravarti. This study was discussed and it was felt tissue correlates for PARP suppression would be useful, and perhaps this could be done ither in NABTC or NABTT; RTOG will continue further protocol development beyond this.

    Action Items: Dr. Vogelbaum will determine whether NABTT will perform the tissue correlative study; Drs. Mehta and Robins will continue study development discussions with Abbott.


    d. HDAC-inhibitors plus a topotecan trial for recurrent GBM: Chinnaiyan; in development.


  10. Spine mets radiosurgery trial (Sam Ryu): This was presented on Research Strategy 4/06 call and was not approved. It was suggested this could be a CCOP study. CCOP has supported this and is developing it further; the Brain Tumor Committee supports the concept.


  11. A protocol for carcinomatous meningitis was previously developed (to be run through the Medical Oncology Committee); the protocol has now been referred to the Brain Tumor Committee to be run through us. This was approved and after a final design becomes available, it will be represented to Research Strategy.

    Action Items: Drs. Robins and Khuntia will work with Dr. Pajak to complete statistical design and protocol revisions and will be forwarded to Research Strategy.


  12. A replacement protocol for low grade glioma was discussed; Dr. Brown will host a teleconference to further develop this.

    Action Items: Dr. Brown will continue development with a working group that was organized at this meeting.
BRAIN TUMOR COMMITTEE (June 2006)
Minesh P. Mehta, M.D., Chair

Active Trials

RTOG 9813 – This is a Phase III randomized study of radiation therapy and temozolomide vs. radiation therapy and BCNU vs. radiation therapy and temozolomide + BCNU for anaplastic astrocytoma. A total of 203/454 patients have now been enrolled on the phase III arm. The recent shortage of BCNU has now been resolved. Further, an amendment is in progress to allow the use of CCNU. To perform MGMT methylation analysis, all patients will be required to have tissue submitted henceforth.

RTOG 0227 – This is a Phase I/II trial of pre-radiation methotrexate, rituximab, and temozolomide and post-radiation temozolomide for primary central nervous system lymphoma. The primary phase I goal is to assess the MTD of temozolomide in combination with methotrexate and rituximab when administered prior to twice-daily fractionated whole brain radiation therapy and this has been completed. The phase II portion is now open to accrual. A total of 4/52 patients on the phase II arm have been accrued. Dr. Glass received several recommendations for amendments to make the protocol more user-friendly, which he will pursue.

RTOG 0320 – This is a Phase III protocol in patients with 1-3 brain metastases (from NSCLC) eligible for radiosurgery. The protocol allows for randomization to radiosurgery with whole brain radiation therapy and either Temozolomide or Tarceva. The protocol has accrued 18/381 patients. Barriers to accrual were discussed and Dr Sperduto will make suggested amendments.

RTOG 0424 – This is a Phase II study for patients with high-risk low grade glioma, receiving temozolomide during and post-radiation. The protocol has enrolled 45/97 patients. No undue toxicities have been reported. An amendment requiring tissue submission for MGMT and possibly 1p19q analysis has been made.

RTOG 0525 - This is a phase III randomized trial of low-dose temozolomide plus radiotherapy followed by either standard monthly temozolomide (x upto12 months) or dose-intense temozolomide (21 days on, 7 days off x upto12 months) for GBM patients, including stratification by MGMT status (which requires submission of a tissue block as part of study eligibility). The study was recently activated and is accruing very rapidly, with 72/834 patients accrued. Tissue analysis for MGMT status is yielding close to 100% results. In addition, a recent grant was obtained for performing QOL/NC analysis on a subset of patients, and a protocol for this is being developed.

RTOG 0513 - This is a Phase I/II trial of the radiosensitizer MGd with standard XRT and temozolomide for GBM. The trial has just been opened and has accrued 7/113 patients.

RTOG 0611 - Dr. Kevin Camphausen has initiated a surrogate predictive marker (using urinary and serum MMPs and VEGF levels) trial which has accrued 14/ 130 patients.

Developing Trials

RTOG 0539 - This is a Phase II proposal (presented by Dr. Lee Rogers), for patients with meningioma, with the end-point being 3-year progression free survival. Patients will be stratified by risk level; low risk patients will be observed, intermediate and high risk patients will be treated with IMRT. The protocol has been submitted to CTEP (6/06).

RTOG 0614 – A neuroprotection pharmacologic trial in patients with brain metastases undergoing whole brain radiotherapy is under formulation, using the agent Memantine. Research Strategy approved this in 11/05 and a protocol is being finalized.

RTOG 0625 - With the recent suggestion of possible activity of Bevacizumab in recurrent GBM, in co-operation with CTEP, Genentech and Pfizer, a phase I/II trial of continuous temozolomide and bevacizumab will be initiated shortly; the concept has been approved by CTEP and a full protocol is being developed.

RTOG 0627 - This is the second trial in recurrent GBM as part of a new portfolio of trials to investigate targeted agents. In response to a CTEP RFA, the LOI for Dasatinib was submitted by Dr. Lassman and has been approved by CTEP and protocol development is ongoing.

Other developing concepts for recurrent GBM include:

Leading edge image guided radiosurgery: Duma; in development.

Gliadel and 06BG for recurrent GBM: Tatter; This was presented on Research Strategy call 4/06 but was not approved. Research Strategy requested documentation of commitment from MGI. The study chair is compiling documentation.

PARP-1 inhibitors and temozolomide for recurrent GBM; in development by Dr Robins and Gilbert, with preclinical work by Dr. Chakravarti.

HDAC-inhibitors plus a topotecan trial for recurrent GBM: Chinnaiyan; in development.

Other agents being explored include Sorafenib and ZD6474.

MR spectroscopy based treatment planning: Stieber. This is being developed as a subset protocol to be appended to RTOG 0525; the plan will be to evaluate a number of MR parameters and monitor failure patterns. Protocol is in development.

This is a Phase II concept of radiation therapy plus temozolomide plus R115777 (a farnesyl transferase inhibitor) for GBM. Dr. Ian Robins has worked with headquarters to submit an LOI, which has been approved by CTEP and a protocol has been developed. We are awaiting the DLT from the NABTC trial.

SRS trial for pituitary adenomas (GH secreting). This was presented on the Research Strategy call 4/06 but was not approved. Research Strategy requested documentation stating that institutions will be able to enroll pts. Study Chairs are compiling documentation for this.

Spine mets radiosurgery trial (Sam Ryu): This was presented on Research Strategy 4/06 call and was not approved. It was suggested that this could be a CCOP study.

EORTC 26053 – This is a Phase III study for patients with non co-deleted anaplastic gliomas, being coordinated by EORTC and RTOG would like to participate in this trial. The protocol needs to be approved by Research Strategy. As long as RTOG 9813 is open, RTOG will not enroll grade 3 AA patients on this trial.

NCCTG N0577 – This is a Phase III study for patients with co-deleted anaplastic gliomas, being coordinated by NCCTG and RTOG would like to participate in this trial, with Dr. Vogelbaum from RTOG recommended as a joint-PI at a recent cooperative group meeting with CTEP. The protocol needs to be approved by Research Strategy.

NCCTG 0574 - This phase III trial was previously an ACOSOG radiosurgery trial in brain metastases patients in whom whole brain radiotherapy would be withheld. RTOG would like to endorse this trial, specifically recommending it to its membership for the non-lung cancer patients. Dr. Asher will be designated the RTOG PI. The protocol needs to be approved by Research Strategy.

Concepts

Dr. Ali Choucair provided an update on developing a concept for LGG with a molecular profiling based strategy, which will be developed further.

Dr. Arnab Chakravarti chaired the third meeting of the Brain Tumor Committee TRP, which will now be responsible for developing biological questions and endpoints for various trials, and moving forward with a PO1.

Dr. Mark Gilbert chaired a workshop on recurrent GBMs, leading to several new ideas.

Manuscripts

The following is a list of primary manuscripts that need to be completed:


STUDY PI
RTOG 9006: Phase III GBM Trial Walter Curran
RTOG 9803: Phase I/II GBM 3-D dose-escalation Jeff Michalski
RTOG 9806: Phase II GBM Trial (+ Thalidomide) Alfred Yung
RTOG 0113: Phase II GBM Trial (+ Bleomycin) Roy Patchell
RTOG 0118: Phase III Mets Trial (+ Thalidomide) Jonathan Knisley
RTOG 0119: Phase IIR Mets Trial (+ Melatonin) Larry Berk
RTOG 9802: Phase III LGG RT +/- PCV Ed Shaw
RTOG 0227: Phase I PCNSL component Jon Glass
RTOG 0420: Phase I component F. Lieberman
RTOG 0211: Ph I/II Gefitinib + RT for GBM A. Chakravarti
RTOG 0131: Ph II Pre-RT temozolomide for AO M. Vogelbaum


The following is a list of secondary manuscripts that need to be completed:


STUDY PI
RTOG 8315/8806: EBV status in PCNSL Chris Schultz
RTOG 9802: Observation arm Ed Shaw
GBM: Impact of race on outcome Ed Shaw
GBM: Modified RPA Ed Shaw
GBM: RPA-matched analysis of MGd Judith Ford
Gliomas: her2neu expression Ian Robins
Predictive value of early radiographic failure R. Lustig
Impact of RT delay on GBM outcome D. Blumenthal
RTOG 0118 QOL S. Fox
RTOG 9803 QOL S. Fox


We discussed reassigning manuscript authorship away from primary authors for those manuscripts that become inordinately delayed.

BRAIN TUMOR COMMITTEE (January 2006)
Minesh Mehta, M.D., Chair

Ongoing Protocols

RTOG 0214 - This is a phase I/II trial in patients with central nervous system lymphoma. The trial is currently in the phase I component.

RTOG 0320 - This phase III trial of radiosurgery in lung cancer patients with brain metastases is being opened nationwide. Currently 8 patients are enrolled. Significant effort needs to be focused on enhancing accrual to this trial.

RTOG 0420 - This phase II trial in patients who have high-risk low-grade gliomas is accruing well. Two recent study amendments have been made including tissue acquisition and quality of life/neurocognitive evaluation.

RTOG 0513 - This phase II protocol of MGd plus Temozolomide will be activated shortly.

RTOG 0525 - This major phase III randomized trial in patients with glioblastoma multiforme was activated just prior to the RTOG meeting and is now available to all centers.

RTOG 0611 - This urinary VEGF evaluation protocol will be activated next week.

RTOG 9813 - For patients with anaplastic astrocytoma is currently on hold because of a shortage of BCNU. The trial will be amended to allow the use of CCNU and will be reactivated.

Developing Trials and Concepts

Glioblastoma Multiforme - Dr. Mike Vogelbaum will lead a team of individuals to develop a set of clinical trials that will test administration of targeted agents to patients with recurrent malignant glioma followed by surgical resection to obtain tissue to quantify intratumor drug concentration and target binding. This will be focused primarily on recurrent GBM patients from RTOG 0525.

Dr. Mark Gilbert will assemble a team to start developing a series of phase I/II clinical trials using molecularly targeted agents in molecularly stratified populations of patients with recurrent GBM primarily from RTOG 0525. Several agents are potentially available for evaluation including sorafinib, gefitinib, avastin, pan-tyrosine kinase inhibitors, etc.

Discussions regarding the next generation phase III GBM trial were initiated.

A proposal was made by Dr. Chris Duma to consider leading edge radiosurgery for recurrent glioblastoma multiforme. He and Dr. Volker Stieber will continue to develop this proposal.

A proposal for evaluating O6BG and BCNU in recurrent glioblastoma multiforme was presented. It was recommended this should be developed for recurrent GBM.

Anaplastic Astrocytoma

RTOG 9813 will continue accrual with a modification to allow the use of CCNU. In addition the data safety monitoring committee will be asked to look at an early analysis performed by the statistical office and to inform the Brain Tumor Committee if significant results are observed.

Anaplastic Gliomas.

A committee decision was made to provide full support to the developing EORTC concept of a 2 by 2 randomized design for patients with non co-deleted anaplastic gliomas.

The NCCTG randomized phase III proposal for this was discussed at great length. There was substantial enthusiasm in developing a collaborative project for this disease as it is extremely rare and collaboration is necessary to be successful. After an extensive discussion of the scientific merit and statistical design of the phase III concept the unanimous opinion of the Brain tumor Committee was this trial would be extremely difficult to conduct and there would be high probability of not completing the trial in a timely fashion. In view of this, the committee's decision was to approach NCCTG and discuss with them the possibility of working together on a different approach and study design for this disease.

Low grade glioma RTOG 0420 is continuing accrual as mentioned above. We discussed at great length the proposal from ECOG for a phase III randomized study in low-grade glioma. The unanimous committee opinion was an obvious phase III question is not apparent for testing at this point and we will therefore continue our efforts to enroll to RTOG 0420 and study future options.

Brain metastases. The ACOSOG radiosurgery brain metastases trial was discussed. The committee gave full support to joining this trial, by collaborating with NCCTG.

Meningioma. An IMRT proposal for meningioma is progressing through committee development and has previously been approved. It is anticipated this protocol will open shortly.

Growth hormone secreting pituitary adenoma. A proposal for stereotactic radiosurgery only was presented by Dr. Robert Weil. There was great enthusiasm for proceeding further and concept development will be pursued.

Radiosurgery for spine metastases. Dr. Sam Ryu presented a concept for single fraction radiosurgery for spine metastases. There was general enthusiasm for conducting this study with significant questions about the development of a specific endpoint could reproducibly be measured in patients. Dr. Ryu will continue to work and develop this project in greater detail.

BRAIN TUMOR COMMITTEE (June 2005)
Minesh P. Mehta, M.D., Chair

Active Trials

1. RTOG 0227–This is a Phase I/II trial of pre-radiation methotrexate, rituximab, and temozolomide and post-radiation temozolomide for primary central nervous system lymphoma. The primary phase I goal is to assess the MTD of temozolomide in combination with methotrexate and rituximab when administered prior to twice-daily fractionated whole brain radiation therapy. The Arm 1 dose of temozolomide is 100 mg/m2, and the first 6 patients have been enrolled at this dose level, and toxicity review has been completed. The second dose level has opened, two patients have been accrued, and, 1 Grade 3 renal toxicity has been encountered. Accrual continues at this dose level.

2. RTOG 0320–This is a Phase III protocol in patients with 1-3 brain metastases (from NSCLC) eligible for radiosurgery. The concept allows for randomization to radiosurgery with whole brain radiation therapy and either Temozolomide or Iressa. With the recent results from the Iressa ISEL trial, the Iressa arm was dropped. Recently, with input from CTEP, this arm has now been substituted by Tarceva. The protocol is ready for site activation.

3. RTOG 0420- This is a phase II study of radiation therapy plus low dose temozolomide followed by 1 year of temozolomide plus irinotecan for glioblastoma multiforme. The protocol has rapidly enrolled 99/104 patients. Because a higher than expected proportion of patients are failing to continue on to adjuvant therapy, an amendment requesting an increase in the enrollment target has been submitted to CTEP.

4. RTOG 0424–This is a Phase II study for patients with high-risk low grade glioma, receiving temozolomide during and post-radiation. The protocol has enrolled 8/72 patients. No undue toxicities have been reported. An amendment requiring tissue submission for MGMT and possibly 1p19q analysis is about to be circulated.

5. RTOG 9813–This is a Phase III randomized study of radiation therapy and temozolomide vs. radiation therapy and BCNU vs. radiation therapy and temozolomide + BCNU for anaplastic astrocytoma. A total of 155/454 patients have now been enrolled on the phase III arm. A shortage of BCNU has now been resolved. To perform MGMT methylation analysis, all patients will be required to have tissue submitted in the future.

Developing Trials

1. RTOG 0217–This is a Phase II concept of radiation therapy plus temozolomide plus R115777 (a farnesyl transferase inhibitor) for GBM. Dr. Ian Robins has worked with headquarters to submit an LOI, which has been approved by CTEP and a protocol has been developed. We are awaiting the DLT from the NABTC trial.

2. RTOG 0242-This is a pilot feasibility study of new technologies in GBM. Dr. Stieber presented the recent NABTT data with gliasite; this resulted in a proposal to consider a “high-tech” feasibility trial consisting of resection, gliasite, external beam therapy plus temozolomide and MRS directed boosting. Drs. Stieber and Tsien will continue the development of this proposal, in collaboration with Dr. Tome and funding from GE and Proxima will be sought for this proposal.

3. RTOG 0425–This is a Phase II study for patients with anaplastic oligodendroglioma, receiving temozolomide during and post-radiation. Dr. Vogelbaum is completing trial development. 1p19q status will be determined prospectively, but will not be used as a stratification variable.

4. RTOG 0426–This is a Phase II concept of radiation therapy plus temozolomide plus Sarasar (a farnesyl transferase inhibitor) for GBM. Phase I data for combining this regimen do not exist,; further, the experience with Sarasar alone in recurrent glioma has been modestly encouraging, and this trial will be dropped from further development.

5. RTOG 0512- This was a Phase II proposal (presented by Dr. Lee Rogers), for patients with meningioma, with the end-point being 3-year progression free survival. Patients will be stratified by risk level; low risk patients will be observed, intermediate and high risk patients will be treated with IMRT.

6. RTOG 0513-This is a Phase II trial of the radiosensitizer MGd with standard XRT and temozolomide for GBM. The protocol was submitted to CTEP and a recommendation as been made to resubmit as a PhaseI/II design and the appropriate changes have been made by Brian Berkey and Dr. Dave Brachman and the revised version has been resubmitted to CTEP.

7. RTOG 0525- This is a phase III randomized trial of low-dose temozolomide plus radiotherapy followed by either standard monthly temozolomide (x up to 12 months) or dose-intense temozolomide (21 days on, 7 days off x up to 12 months) for GBM patients, including stratification by MGMT status (which will require submission of a tissue block as part of study eligibility). The study is estimated to require 840 patients. The protocol has submitted with revisions to CTEP. EORTC shall partner with us in the conduct of this trial. Several translational research opportunities were identified and will be pursued.

Concepts

1. A neuroprotection pharmacologic trial in patients with brain metastases undergoing whole brain radiotherapy was discussed. Research Strategy supported further concept development by Dr. Paul Brown.

2. Dr. Martin VandenBent from the EORTC presented a phase III concept for 1p19q non-deleted anaplastic gliomas; this will be developed further; Dr. David MacDonald will represent the RTOG on this project.

3. Terri Armstrong presented a concept to evaluate symptoms and symptomatic change as a possible surrogate for QOL; this will be discussed further in the outcomes committee.

4. Dr. Ali Choucair provided an update on neurocognitive testing in brain tumor patients on RTOG clinical trials.

5. Dr. Kevin Camphausen has initiated a surrogate predictive marker (using urinary and serum MMPs and VEGF levels) trial at the NCI and has requested access to RTOG GBM patients for this. The Brain Tumor Committee is fully supportive of this as an appendix protocol for all open GBM trials.

6. Dr. Arnab Chakravarti chaired the second meeting of the Brain Tumor Committee TRP, which will now be responsible for developing biological questions and endpoints for various trials, with a specific emphasis on RTOG 0525.

7. Dr. Mark Gilbert chaired a workshop on DNA methylation, with a plan to publish this as journal proceedings.

Manuscripts

1. The following is a list of primary manuscripts that need to be completed:

STUDY PI
RTOG 9006: Phase III GBM Trial Walter Curran
RTOG 9402: Phase III AO Trial (+/-PCV) Gregory Cairncross
RTOG 9710: Phase II GBM Trial (+ B-interferon) Alfred Yung
RTOG 9803: Phase I/II GBM 3-D dose-escalation Jeff Michalski
RTOG 9806: Phase II GBM Trial (+ Thalidomide) Alfred Yung
RTOG 0023: Phase II GBM Trial (+ FSRT boost) Robert Cardinale
RTOG 0113: Phase II GBM Trial (+ Bleomycin) Roy Patchell
RTOG 0118: Phase III Mets Trial (+ Thalidomide) Jonathan Knisley
RTOG 0119: Phase IIR Mets Trial (+ Melatonin) Larry Berk


2. The following is a list of secondary manuscripts that need to be completed:

STUDY PI
RTOG 8315/8806: EBV status in PCNSL Chris Schultz
RTOG 9404: 6 mo PFS as a surrogate for survival Ian Robins
RTOG 9802: Observation arm Ed Shaw
GBM: Impact of race on outcome Ed Shaw
GBM: Modified RPA Ed Shaw
GBM: RPA-matched analysis of MGd Judith Ford
Gliomas: her2neu expression Ian Robins
Predictive value of early radiographic failure R. Lustig


3. The following is a list of planned analysis for ASCO/ASTRO 2006 submission:

STUDY PI
RTOG 0420 GBM Temozolomide/CPT-11 toxicity F. Liebermann
RTOG 9802: LGG-Failure analysis by treatment arm Ed Shaw
RTOG 0211: GBM: Iressa plus XRT A. Chakravarti
RTOG 0131: AO: Pre-RT Temozolomide M. Vogelbaum
BRAIN TUMOR COMMITTEE (January 2005)
Minesh P. Mehta, M.D., Chair

Active Trials

1. RTOG 0227–This is a Phase I/II trial of pre-radiation Methotrexate, Rituximab, and Temozolomide and post-radiation Temozolomide for primary central nervous system lymphoma. The primary phase I goal is to assess the MTD of Temozolomide in combination with Methotrexate and Rituximab when administered prior to twice daily fractionated whole brain radiation therapy. The Arm 1 dose of Temozolomide is 100 mg/m2, and the first 6 patients have been enrolled at this dose level, and toxicity review has been completed. The next dose level will open in the next 2-4 weeks.

2. RTOG 0320–This is a Phase III protocol in patients with 1-3 brain metastases (from NSCLC) eligible for radiosurgery. The concept allows for randomization to radiosurgery with whole brain radiation therapy and either Temozolomide or Iressa. With the recent results from the Iressa ISEL trial, the Iressa arm has been dropped. At this point, 0320 stands as a 2-arm trial. There was discussion to consider changing the third arm to include Tarceva, instead of Iressa. We are awaiting the corporate response to this, and if it is positive, the Iressa arm will be edited to become the Tarceva arm; if corporate support is not forthcoming, we will proceed with a 2-arm trial. A final decision will be made in the next 2 weeks.

3. RTOG 0420- This is a phase II study of radiation therapy plus low dose Temozolomide followed by 1 year of Temozolomide plus Irinotecan for glioblastoma multiforme. The protocol has just been activated, and current enrollment is 5/99 patients. No undue toxicities have been reported.

4. RTOG 0424–This is a Phase II study for patients with high-risk low-grade glioma, receiving Temozolomide during and post-radiation. RTOG HQ has received CTEP approval and the study will be forwarded to institutions next week. The accrual goal is 72 patients.

5. RTOG 9813–This is a Phase III randomized study of radiation therapy and Temozolomide vs. radiation therapy and BCNU vs. radiation therapy and Temozolomide + BCNU for anaplastic astrocytoma. A total of 163/483 patients have now been enrolled. The Phase III arms are accruing well and no specific new or unique toxicities have been identified.

Developing Trials

1. RTOG 0217–This is a Phase II concept of radiation therapy plus Temozolomide plus R115777 (a farnesyl transferase inhibitor) for GBM. Dr. Ian Robins has worked with headquarters to submit an LOI, which has been approved by CTEP and a protocol has been developed. We are awaiting the DLT from the NABTC trial.

2. RTOG 0240- This was a Phase II proposal (presented by Dr. Paul Brown), using cox-II inhibitors for low-risk low-grade glioma, with the end-point being 2-year progression free survival. Because of the recent toxicity concerns surrounding these agents, this concept has been dropped.

3. RTOG 0242- This is a pilot feasibility study of new technologies in GBM. In one arm, near-totally or gross-totally resected patients with <4 cm cavity will be treated with the GliaSite device as a boost for newly diagnosed glioblastoma multiforme patients, with standard external beam radiotherapy and Temozolomide; in the second arm, patients with larger tumors, and those ineligible for GliaSite placement will be treated with IMRT, with concomitant boost. Because there is considerable interest in incorporating advanced imaging in future RTOG brain tumor trials, a recommendation was made to explore the possibility of permitting a subset of institutions to perform target delineation for the IMRT using 3-D multivoxel MR spectroscopy. Dr. Stieber represented the RTOG Brain Tumor Committee at the recent ACRIN meeting and Drs. Stieber and Tsien will continue the development of this proposal, with input from ACRIN.

4. RTOG 0425–This is a Phase II study for patients with anaplastic oligodendroglioma, receiving Temozolomide during and post-radiation. Dr. Vogelbaum is completing trial development. 1p19q status will be determined prospectively, but will not be used as a stratification variable.

5. RTOG 0426–This is a Phase II concept of radiation therapy plus Temozolomide plus Sarasar (a farnesyl transferase inhibitor) for GBM. Phase I data for combining this regimen do not exist, and a proposal was made to either conduct a Phase I trial outside the RTOG, or change the study design to include a Phase I component.

6. RTOG 0512- This was a Phase II proposal (presented by Dr. Lee Rogers), using cox-II inhibitors for patients with meningioma, with the end-point being 3-year progression free survival. Because of the recent toxicity concerns surrounding these agents, this concept has been dropped, and alternative stud-design options are being explored.

7. RTOG 0513-This is a Phase II trial of the radiosensitizer MGd with standard XRT and Temozolomide for GBM. The protocol was submitted to CTEP and a recommendation as been made to resubmit as a PhaseI/II design and the appropriate changes are being made by Brian Berkey and Dr. Dave Brachman.

8. RTOG 0513- This is a phase III randomized trial of low-dose Temozolomide plus radiotherapy followed by either standard monthly Temozolomide (x 12 months) or dose-intense Temozolomide (21 days on, 7 days off x 12 months) for GBM patients, including stratification by MGMT status (which will require submission of a tissue block as part of study eligibility). The study is estimated to require 667 patients. The protocol has been completely written, and the targeted submission date is within 1 month. We are currently discussing participation on this trial by the EORTC. This trial is the highest priority developing GBM trial within the committee.

Concepts

1. A neuroprotection pharmacologic trial in patients who have previously received cranial irradiation and have clinical manifestations of neurocognitive deficits was discussed. Dr. Paul Brown will further develop this concept.

2. Dr. Kevin Camphausen has initiated a surrogate predictive marker (using urinary and serum MMPs and VEGF levels) trial at the NCI and has requested access to RTOG GBM patients for this; he will be requested to develop a companion protocol for 0525 for this purpose.

3. Dr. Arnab Chakravarti chaired the first meeting of the Brain Tumor Committee TRP, which will now be responsible for developing biological questions and endpoints for various trials. The first trial to be focused on will be RTOG 0525. Additional ideas will be forthcoming.

Manuscripts

1. The following is a list of primary manuscripts that need to be completed:

STUDY PI
RTOG 9006: Phase III GBM Trial Walter Curran
RTOG 9402: Phase III AO Trial (+/-PCV) Gregory Cairncross
RTOG 9710: Phase II GBM Trial (+ B-interferon) Alfred Yung
RTOG 9803: Phase I/II GBM 3-D dose-escalation Jeff Michalski
RTOG 9806: Phase II GBM Trial (+ Thalidomide) Alfred Yung
RTOG 0021: Phase II GBM Trial (+ Tamoxifen) Ian Robins
RTOG 0023: Phase II GBM Trial (+ FSRT boost) Robert Cardinale
RTOG 0113: Phase II GBM Trial (+ Bleomycin) Roy Patchell
RTOG 0118: Phase III Mets Trial (+ Thalidomide) Jonathan Knisley
RTOG 0119: Phase IIR Mets Trial (+ Melatonin) Larry Berk

2. The following is a list of secondary manuscripts that need to be completed:

STUDY PI
RTOG 8315/8806: EBV status in PCNSL Chris Schultz
RTOG 9404: 6 months PFS as a surrogate for survival Ian Robins
RTOG 9802: Observation arm Ed Shaw
GBM: Impact of race on outcome Ed Shaw
GBM: Modified RPA Ed Shaw
BRAIN TUMOR COMMITTEE (June, 2004)
Minesh Mehta, M.D., Chair

CLOSED TRIALS

RTOG 0013: This Phase II study of intra-ommaya Bleomycin was opened in June 2001. After accruing 17 patients the trial was closed. The projected accrual of 72 patients was not met. The 17 patient cohort will be evaluated from a feasibility perspective.

RTOG 0211: This Phase I/II study of ZD1839 in GBM accrued 158 patients. The trial has met accrual objectives and is currently closed.

RTOG 0131: This Phase II trial of pre-radiation Temozolomide in anaplastic oligodendroglioma accrued 38 patients and has closed, having reached accrual.

ACTIVE TRIALS

RTOG 9813: This Phase III study randomizes patients with anaplastic astrocytoma to radiation therapy with BCNU vs. Temozolomide. The trial is open for patients with anaplastic astrocytoma or mixed predominantly astrocytic tumors with a minor oligodendroglial component (less than 25%). Accrual is proceeding well. Total accrual is 117 patients. We have enrolled 93 patients on the Phase III arm.

RTOG 0118: This Phase III randomized trial of Thalidomide and whole brain radiation therapy for patients with brain metastases is proceeding as expected. A total of 176 of an expected 332 patients have been enrolled.

RTOG 0227: This Phase II trial in primary CNS lymphoma of multi-agent chemotherapy followed by radiation and maintenance chemotherapy is proceeding well. The first 6 patients have been accrued. As per trial design, the study is currently closed to analyze toxicities in these first 6 patients and will be reopened. Dr. Jon Glass will review the possibility of decreasing the number of lumbar punctures necessary.

DEVELOPING PROTOCOLS

RTOG 0320: This is a Phase III trial of radiosurgery alone or radiosurgery with either Temozolomide or Iressa in patients with 1-3 brain metastases from non-small cell lung cancer. The trial has been approved by CTEP and comments have been received from the central IRB, which are being addressed.

RTOG 0311: This is a Phase II trial of CPT11 and Temozolomide in patients with newly diagnosed glioblastoma multiforme. The trial has been forwarded to CTEP.

RTOG 0424 : This is a Phase II randomized trial of 2 different scheduled of Temozolomide and radiation therapy in patients with low-grade glioma. The trial has been forwarded to CTEP.

RTOG 0216: This is a Phase II trial in patients with meningioma. Presently 3 separate cohorts will be evaluated with a target enrollment of 150 patients. The first 2 cohorts with grade I or II meningioma would be treated with Vioxx alone whereas the third cohort of grade III meningioma would be treated with Vioxx plus radiation therapy.

RTOG 0328: This is a Phase II proposal evaluating motexafin gadolinium for patients with glioblastoma multiforme. The trial will be redesigned to include Temozolomide. Research strategy approved this change and recommended that we proceed straight to a Phase II trial rather than a Phase I/II trial. Dr. David Brachman will develop the Phase II study.

RTOG DEV: This will be the Phase II replacement trial for RTOG 0131 in patients with anaplastic oligodendroglioma. This trial will utilize the Stupp regimen for patients with anaplastic oligodendroglioma. Dr. Vogelbaum will develop this trial.

RTOG 0131: This was initially a Phase I/II trial of the farnesyl transference inhibitor Sarasar with radiation therapy in patients with GBM. This study will be redesigned as a Phase I/II study. Drs. Ian Robins and Mark Gilbert will assist Dr. Norman Laperriere in developing this protocol. Drug supply issues have been worked out.

RTOG 0240: This is a Phase III trial of a Cox 2 inhibitor in low risk low-grade glioma patients. Dr. Paul Brown is developing the trial.

RTOG 0242: This was a Phase II concept evaluating Gliasite. This particular trial needs to incorporate Temozolomide. Dr. Mehta will coordinate a conference call between Dr. Christina Tsien and Dr. Volker Stieber to discuss the development of this trial as well as the 3D dose escalation trial with Temozolomide.

RTOG 0217: This was a Phase II proposal to evaluate the farnesyl transference inhibitor R115777. This needs to be rewritten to incorporate Temozolomide. It is unclear whether NCI is still interested in supporting this study. Dr. Robins will discuss this on a conference call with Drs. Janet Dempsey and John Wright at the NCI. If the NCI is still willing to support such a trial the suggestion is to combine RTOG 0217 with 0135 in a Phase II randomized setting.

BRAIN TUMOR COMMITTEE (January, 2004)
Minesh Mehta, M.D., Chair

Active Trials
RTOG 9813: This Phase III study randomizes patients with anaplastic astrocytoma to radiation therapy with BCNU vs. Temozolomide. The trial is open for patients with anaplastic astrocytoma or mixed predominately astrocytic tumors with a minor oligodendroglio component (< 25%). Central pathology review is proceeding well. Accrual is proceeding well. Current accrual is 89 out of an expected 483.

RTOG 0013: This Phase II study of intratumoral bleomycin following external beam radiotherapy for glioblastoma multiform (GBM) has accrued 17 of an expected 72 patients. The trial is beginning to be opened up by Canadian centers. This trial will be monitored carefully for accrual.

RTOG 0118: This is a Phase III randomized trial of Thalidomide and whole brain radiation therapy for patients with brain metastases. Current enrollment is 139 out of 332. No major toxicities have been reported.

RTOG 0131: This is a Phase II trial of pre-radiation Temozolomide for patients with pure or mixed anaplastic oligodendroglioma, confirmed by central pathology review. Current enrollment is 30 out of 37. It was proposed that the trial should be expanded to include an adequate cohort of patients with 1p and/or 19q deletions in order to have the primary endpoint of six-month progression free survival sufficiently analyzed in this cohort of patients. This will expand the cohort to approximately 100.

RTOG 0211: This is a Phase I/II trial of ZD1839 with radiation therapy in patients with GBM. The trial has accrued a total of 105 out of 158 patients. The Phase II arm of the trial in patients with non-enzyme inducing anti-convulsants is proceeding well. For patients with enzyme producing anti-convulsants the amendment for dose escalation to 1,000 mg is being submitted to the NCI. It is expected that the trial will close once accrual on the Phase II component has been achieved and the Phase I MTD for the enzyme-inducing cohort has been defined.

RTOG 0227: This is the trial of multi-agent chemotherapy followed by radiation and maintenance chemotherapy in patients with primary CNS lymphoma. The trial was recently activated and has accrued 2 out of an expected 64 patients.

Recently Closed Protocols
RTOG 9803: This is a Phase I trial of radiation dose escalation using 3-D conformal radiation therapy. A total of 209 patients were enrolled. The trial was open from September 1998 to September 2003. The highest dose reached was 84 Gy. Dr. Michalski is currently reviewing the necrosis rates by arm and dose level with the expectation to have this ready for submission at ASTRO 2004.

Developing Protocols
RTOG 0135: This is a Phase I/II trial of the farnesyl transferase inhibitor, Sarasar, with radiation therapy. Dr. Laperriere developed the trial. Schering Plough has now committed drug for this in 2004 and the study has therefore been moved up in the priority list for activation.

RTOG 0216: This is Phase II proposal for a clinical trial in patients with meningioma. Three separate cohorts are proposed for enrollment with a total enrollment target of 150 patients. The first two cohorts with grade 1 or 2 meningioma would be treated with Vioxx alone whereas the 3rd cohort of grade 3 meningioma would be treated with Vioxx plus radiation therapy.

RTOG 0217: This is a Phase II trial evaluating the farnesyl transferase inhibitor R115777 with radiation therapy in patients with GBM. The trial has been written up by Dr. Robins, and we are awaiting the Phase I dose from NABTC. It was suggested that the trial should be forwarded to CTEP, and once the Phase I dose is available this could be introduced into the protocol.

RTOG 0240: This is a proposal by Dr. Paul Brown to test a Cox 2 inhibitor in low risk, low grade glioma. This awaits concept and protocol completion.

RTOG 0242: This is a feasibility trial of the gliasite device for GBM patients. Dr. Steiber has completed writing up the trial with a plan for evaluating 40 patients.

RTOG 0311: This was a proposal developed to test b-interferon plus Temozolomide with radiation therapy in patients with GBM. Because of availability issues with b-interferon, recent data from NABTC were reviewed and it is proposed that instead of b-interferon, CPT11 be considered. Dr. Frank Lieberman, from the University of Pittsburgh, has submitted an LOI and as soon as drug supply issues have been clarified the proposal is to change RTOG 0311 to a combination of CPT11 plus Temozolomide instead of b-interferon plus Temozolomide.

RTOG 0320: This is the Phase III trial of radiosurgery alone or radiosurgery with either Temozolomide or Iressa in patients with 1-3 brain metastases from non-small cell lung cancer. Comments were received from CTEP and responses have been submitted.

RTOG 0328: This is a Phase II proposal of motexafin gadolinium and radiation therapy in patients with GBM. Dr. Brachman, the PI, has written the full protocol and the trial awaits activation.

RTOG 0332: This is a Phase II proposal to test two different schedules of Temozolomide plus radiation in patients with low-grade glioma. Dr. Fisher, the PI, has written the trial, which awaits activation.

Concepts
1. Dr. Steiber has a concept in place to evaluate the role of IMRT in patients with resected brain metastases. He is continuing to develop this.

2. Dr. Tsien has presented the concept of dose perfection escalation as a replacement study for RTOG 9803 and continues to develop this protocol.

3. Extensive discussion took place about a proposed Phase III trial in case the EORTC Temozolomide trial is positive. It was planned that Drs. Mehta and Robins will begin developing this trial in the event that the EORTC trial is positive.

4. Dr. Chakravarti is continuing to work with Dr. Paul Mischel to develop a proposal for a combined radiation rapamycin analog.
BRAIN TUMOR COMMITTEE (June, 2003)
Luis Souhami, M.D., for
Minesh Mehta, M.D., Chair

Active Trials

RTOG 9803 – This is a Phase I/II radiation dose escalation study using 3D conformal RT in patients with supratentorial glioblastoma multiforme. Dose level 4 (84 Gy) is nearing accrual completion and the trial will be closing in a few weeks. Dr. Christina Tsien proposed a follow-up study using a dose-per-fraction escalation approach and the new concept is discussed below.

RTOG 9813 – This Phase I/III study has completed its Phase I component and the Phase III is now open. The study randomizes patients to BCNU vs Temozolamide with both arms receiving radiation therapy. The trial is open for patients with anaplastic astrocytomas or mixed oligodendroglial/astrocytic tumors if the oligo component is less than 25%. Pathology is centrally reviewed. Accrual has picked up and to date 49 patients have been entered onto the trial. Schering is providing an extra $3,000 per patient accrued. Temozolamide is provided free of charge.

RTOG 0013 – This Phase II study of intratumoral bleomycin following EBRT for GBM patients. This trial is accruing poorly and to date only 13 patients have been entered on this trial. The study has only recently been submitted to the Canadian regulatory agency and has not yet received approval for patient entry in Canada. Enrollment needs to improve or the trial may have to be closed prematurely. Possible strategies to improve accrual were discussed by Dr. Patchell.

RTOG 0118 – Phase III randomized trail of Thalidomide and WBRT for patients with metastatic brain disease. Enrollment is satisfactory and to date 77/332 patients have been accrued. No major toxicities to report.

RTOG 0131 – Phase II trial of pre-radiation Temozolomide for patients with pure or mixed anaplastic oligodendrogliomas confirmed by central pathology review. Enrollment is satisfactory and to date 7 patients have been accrued.

RTOG 0211 – Phase I/II of ZD1839 (Iressa), an EGFR tyrosine kinase inhibitor for patients with GBM. Thirty patients have been accrued on the Phase I component and the trial is temporarily closed for toxicity assessment. Discussions were centered on whether to escalate the ZD1839 dose beyond 500 mg for patients in-group 2 given results from the NABTC trial. Total sample size of this trial is 160 patients.

Recently Closed Protocols

RTOG 0119 – Randomized Phase II study of AM vs PM melatonin plus whole brain RT for metastatic brain disease. Trial closed on June 30th after reaching accrual target.

RTOG 0023 – This is a Phase II trial of fractionated stereo tactic radiotherapy for selected GBM patients. The trial has reached accrual target and was closed June 30th.

Developing Protocols

RTOG 1081 – Phase II trial of the radiosensitizer MGd and RT for GBM patients. The trial builds on the UCLA data, which showed a 17.6 months median survival for RPA classes III and IV. Patients will receive MGd during brain RT followed by BCNU.

RTOG 1089 – Phase II concept of a COX-2 inhibitor for GBM patients. Dr. Dicker, who originally proposed the concept, is less enthusiastic about the idea and given the lack of priority for this trial at the present time, it was agreed that the study would be dropped from the list of developing studies.

RTOG 1094 – This is a Phase IIR study for patients with low-grade gliomas. The randomization is to Temozolomide during/post-radiation or after RT only. Neurocognitive studies will be incorporated into the trial. Tissue to be collected for translational studies.

RTOG 0216 – This Phase II study will look at progression free survival of patients with moderate-risk meningiomas treated with a COX-2 inhibitor. Central Pathology and imaging studies to be performed. Translational studies built in.

RTOG 0217 – This developing Phase II trial will study the concept of R115777 an FTI agent plus radiation therapy for GBM patients. The protocol is written and we are awaiting the MTD from the NABTC trial. CTEP would not allow 2 groups, thus patients on enzyme inducing anticonvulsants will be allowed to switch to Keppra. TRP studies to be incorporate into the study.

RTOG 0227 – This Phase II trial is ready for activation and should be open soon. Fifty-seven patients will be enrolled in this study of Rituxan, Methotrexate and Temozolomide followed by whole brain RT BID and Temolozamide given as maintenance for PCNSL.

RTOG 0242 – Dr. Stieber reviewed this concept. This would be a feasibility study of Gliasite for GBM patients. There are forty patients who are candidates for maximal resection, to be studied. Gliasite dose to be determined by NABTC trial 2115. The success of this trial will require full cooperation from the neurosurgeons.

RTOG 0311 – Phase II study of ß-interferon and Temozolomide for GBM.72 patients to be accrued. This trial is to be open soon.

RTOG 0320 – This is a Phase III study for patients with 1-3 brain metastases from non-small cell lung cancer. Patients are randomized to whole brain RT plus radio surgery and either Iressa or Temozolamide. Sample size of 381 patients. Cost-utility analysis to be done. Patients on EIACT will have to be switched to non-EIACT if randomized to Iressa. Post-RT systemic therapy is incorporated into the trial.

Concepts

RTOG dev. – Dr. Tsien presented the concept of dose-per-fraction escalation for GBM patients. This concept was developed as a possible replacement study for RTOG 9803. However, given the differences in biologic strategy, RT technique and possible patient selection, it was decided that this proposal should be considered a new study. Research strategy has approved the concept. Dr. Tsien is to develop the protocol.

RTOG dev. – Drs. Robins and Gilbert represented the proposal to replace enzyme-inducing anticonvulsants therapy to Keppra, which is non-enzyme-inducing. This concept was originally presented as an independent Phase III study where patients are randomized to either Dilantin or Keppra and seizure activity is monitored for 3 months. There is enough enthusiasm among the members of the committee for the trial. However, given the actual protocol prioritization, it is unlikely that this proposal, as proposed, would be open in the near future. Thus the PIs have suggested tagging the randomization to the next 2 or 3 GBM trials to be open. The research committee approved the idea, although further details will have to be worked out.
BRAIN TUMOR COMMITTEE (January, 2003)
Minesh P. Mehta, M.D., Chair

Active Trials

1. RTOG 9803–This is a Phase I/II radiation dose escalation study applying conformal radiation therapy in supratentorial glioblastoma multiforme. The 78 Gy arm has completed accrual and the 84 Gy arm is now open. A total of 167 patients have been accrued. No DLTs have been reported so far. There was discussion about possibly changing the dose-escalation strategy to a dose-per-fraction escalation approach and this concept will be further discussed by the GBM Working Group. Dr. Michalski has asked for another Radiation Oncologist to help run the trial and Dr. Christina Tsien from the University of Michigan will do so. Dr. Mark Gilbert will be the Medical Oncology Investigator on the trial.

2. RTOG 9813–This is a Phase I/III randomized study of radiation therapy and temozolomide vs. radiation therapy and BCNU vs. radiation therapy and temozolomide + BCNU for anaplastic astrocytoma. The revised Phase I arm has completed its 15-patient accrual. A total of 29 patients have now been enrolled on two Phase I arms. Toxicity analysis reveals that at least 7/11 patients needed to be dose reduced by cycle 1 and at least 2 pulmonary toxicities have been observed. The Phase III study has now opened as a 2-arm trial without the combination BCNU/Temozolomide arm.

3. RTOG 0013–This is a Phase II trial of intratumor bleomycin following external beam radiation therapy. A total of two patients have been enrolled. The study requires 72 patients. 17 institutions have the protocol through their IRBs. Enrollment is picking up (12 patients enrolled to date).

4. RTOG 0023–This is a Phase II trial of fractionated stereotactic radiotherapy boost. A total of 43 out of 76 patients have been enrolled. There are no major toxicities to report.

5. RTOG 0118–This is a randomized Phase III trial of thalidomide and whole brain radiotherapy in patients with brain metastases. The trial opened in 2/02 and has accrued 32/332 patients; accrual is proceeding well.

6. RTOG 0119–This is a Phase II randomized trial of am vs pm melatonin with whole brain radiation in patients with brain metastases. The trial opened in 5/02 and has accrued 32/128 patients; accrual is proceeding well.

7. RTOG 0131–This is a Phase II trial of pre-radiation temozolomide for patients with anaplastic oligodendroglioma which has replaced RTOG 94-02. The trial opened in 7/02 and has accrued 2/37 patients.

8. RTOG 0211–This is a Phase I/II trial of ZD1839, an epidermal growth factor receptor, and tyrosine kinase inhibitor with radiation therapy in glioblastoma multiforme. 18 patients have been enrolled on the Phase I arm and the trial is currently open for further accrual in the Phase I arms.

Recently Closed Protocols

1. RTOG 9402–This was a Phase III inter-group randomized comparison of radiation alone vs. pre-radiation chemotherapy for pure and fixed anaplastic oligodendroglioma. 299/292 patients have been enrolled and the study closed on 3/29/02. Dr. Jenkins, at the Mayo Clinic, has completed the molecular analysis for 1p119q LOH on these patients. Wendy Seiferheld has initiated the response analysis on the combined chemoradiotherapy arm by 1p19q status.. The replacement study (0131) is discussed above.

2. RTOG 9802–This was a Phase II study of observation in favorable low-grade glioma and Phase 3 study of radiation with or without PCV chemotherapy in unfavorable low-grade glioma. 252 of the required 252 patients have been enrolled. An additional 110 patients are on the Phase 2 arm. The study was closed in June 2002. Two replacement studies are being developed and are summarized below.

Protocols On Hold

1. RTOG 0115–This is a Phase II trial of radiation and Squalamine in patients with glioblastoma multiforme. Because of drug supply issues, Squalamine as an agent was abandoned in 06/02; instead, the possibility of using the antiangiogenesis agent Neovastat was explored and this too did not yield a substantial opportunity and this concept is now abandoned.

Developing Trials

1. RTOG 0311–Given the somewhat positive results from the b-interferon trial, Dr. Yung has developed this as a single arm Phase II trial of b-interferon and temozolomide; this has been approved by Research Strategy and a final version will be submitted to CTEP.

2. RTOG 0217–This is a developing Phase II concept of radiation therapy plus R115777 an FTI agent. Dr. Ian Robins has worked with headquarters to submit an LOI, which has been approved by CTEP and a protocol is being developed. We are awaiting the DLT from the NABTC trial; the TRP form needs to be completed. Research Strategy has approved the protocol.

3. RTOG 1081- This is a Phase II trial of the radiosensitizer MGd with standard XRT. Research Strategy had the opportunity to review the UCLA vs. RTOG database comparison and approved the concept. Dr. Brachman is developing the protocol.

4. RTOG 0135–This is a Phase II concept of the Schering farnesyl transferase inhibitor SCH 66336 (Sarasar). The concept and protocol are at headquarters. We are awaiting confirmation from Schering regarding availability. Research Strategy has approved the protocol.

5. RTOG 1089–This is a Phase II concept of a Cox 2 inhibitor (Celebrex) previously presented by Dr. Adam Dicker; he is continuing to develop this. Research Strategy has approved.

6. RTOG 0242- This is a pilot feasibility study of the Proxima device as a boost for newly diagnosed glioblastoma multiforme patients, with standard external beam radiotherapy. This was approved by Research Strategy and protocol development is proceeding (Dr. Volker Stieber).

7. RTOG dev- There has been considerable discussion about the difficulty in conducting new molecularly targeted therapeutic studies with XRT in malignant glioma patients because of the enzyme-inducing anti-epileptic agents. One option would be consider a switch to Keppra which is not enzyme-inducing, but this has not been approved for seizures as a monotherapy; Dr. Robins and Gilbert are developing a trial where a randomized allocation is made to Dilantin or Keppra and seizure activity is tracked for 3 months, while undergoing definitive therapy for GBM. Patients would also receive Temozolomide as per the Stupp regime for this protocol. Research Strategy has approved the protocol.

8. RTOG 0227–This is a Phase II protocol for primary CNS lymphoma. The protocol is finalized and ready to go to CTEP with responses to a previous review. There was discussion about the observation that the bid arm which initially showed less neurotoxicity may not appear to be the case with longer follow-up. A recommendation was made to revert to the qd arm, using 1.5 Gy fraction sizes for the WBRT component. Dr. Glass will discuss this with Dr. Schultz, and make the necessary changes. Research Strategy has approved this protocol.

9. RTOG 1094–This is a Phase IIR replacement study for RTOG 9802. The concept is a Phase II design in patients with low grade gliomas randomized to radiation and temozolomide. The randomization is to temozolomide during and post-radiation vs post-radiation only. Dr. Barbara Fisher has developed the study. She will discuss molecular biology questions and TRP analysis issues with Drs. Aldape and Perry. Research Strategy has approved this.

10. Dr. Shaw represented a concept initially presented by Dr. Brown for low-risk low grade glioma. These patients would be treated with Cox-II inhibitors and the end-point would be 2-year progression free survival. Since the last meeting, some data have emerged suggesting that these tumors variably express Cox-II. Research Strategy approved a Phase II concept evaluating this question, with a plan to do molecular analysis and to use the historic control from RTOG 9802.

11. RTOG 0320–This is a Phase III protocol in patients with 1-3 brain metastases (from NSCLC) eligible for radiosurgery. The concept allows for randomization to radiosurgery with whole brain radiation therapy and either Temozolomide or Iressa. Drs. Sperduto/Robins have developed the protocol, based on the positive results from RTOG 9508. This has been approved by Research Strategy and is ready to go to CTEP. The ACOSOG trial was also discussed. The final decision was to seek input relative to accrual from ACOSOG later in the year and use this information for decision-making.

12. RTOG dev- Dr. Siebert has started developing a focal radiotherapy (IMRT) trial for resected brain metastases and will continue this effort; approval from Research Strategy was not sought as there are several remaining issues that need to be codified:
    a. Endpoints: Primary endpoint will be lack-of failure within the tumor bed, using the University of Kentucky data for historic comparison. Secondary endpoints will be failure rates in the rest of the brain, and a neurological endpoint, using the tests piloted by Dr. Regine. The proportion of patients avoiding whole-brain XRT will also is considered a secondary end-point.
    b. IMRT issues: This would be developed as an IMRT concept and therefore feasibility questions regarding this would also need to be studied.
13. RTOG 0216–This was originally proposed as a Phase III concept for patients with newly diagnosed meningioma. After further discussion, it was redesigned as a Phase II concept in “moderate-risk” meningioma, to be treated with a Cox-II inhibitor for one year. The end-point will be progression-free survival at 3 years. Molecular end-points would be built in. This was approved by research strategy.

Concepts

1. Dr. Chang presented an analysis of failure patterns in GBM and superimposed these first failures onto either RTOG-designed or MD Anderson designed fields, showing that the vast majority of failures still occur within 2 cm of the original enhancing tumor volume and targeting the T2 abnormality does not alter failure patterns. The GBM working group will continue to deliberate on this issue.

2. On behalf of Drs. Tim Cloughsey and Paul Mischel, Dr. Mehta presented a Phase II concept of the motor inhibitor Rapamycin with XRT for GBM. Research Strategy approved the concept.

3. Dr. Lisa Rogers presented ideas in early developmental phases for necrosis; these included:
    a. Serum and tissue marker analysis on patients with frank, histologically confirmed necrosis. Dr. Rogers is currently sending these to outside experts.
    b. Prospective serum collection on a large group of patients undergoing radiotherapy; this would be an attempt to predict who is destined to develop necrosis. Funding has not yet been identified.
    c. Developing a treatment protocol for necrosis.
These ideas will be further discussed within the GBM Working Group.

4. The Brain Tumor Steering Committee has now been reorganized as follows:
    a. A formal Executive Committee is formed, consisting of the Site Chair (Mehta), and co-Chairs representing Neurosurgery (Bullard), Medical-Neuro-Oncology (Yung), Biostatistics (Seiferheld) and Translational Research (Guha).
    b. The Steering Committee has been formalized and in addition to the above 4 individuals, will include PIs of all ongoing Brain Tumor protocols (and also protocols closed within the preceding 12 months), as well as Group Leaders representing the 6 Working Groups (GBM [Gilbert], Anaplastic Gliomas [MacDonald], Low Grade Glioma [Shaw], Metastases [Sperduto], Benign Tumors [Rogers] and PCNSL [Glass], and Group Leaders of the Special Expertise Groups (Physics [Gillin], Imaging [TBD], Outcomes [Choucair], Pathology [Arie Perry], Molecular Targeting [Dicker] and Advocacy [G. Segal].
    c. The Steering Committee will plan to have approximately 4 teleconferences a year (one every 3 months), lasting 1 hour and these shall be scheduled on a routine basis. These will be facilitated by HQ.
    d. Each working group will select members; the current roster is:
      i. GBM: Gilbert, Siebert, Suh, Cloughsey, Johnston, Robins, Mischel, Chakravarti, Seiferheld.
      ii. AA/AO: MacDonald, Chang, Souhami, Vogelbaum, Aldape, Seiferheld.
      iii. LGG: Shaw, Fisher, Brown, Barger, Macdonald, Tatter, Perry, Lesser, Seiferheld.
      iv. Brain Mets: Sperduto, Werner-Wasik, Regine, Patchell, Bullard, Sawaya, Langer, Seiferheld.
      v. Benign Tumors: Rogers, Shaw, Simpson, Patchell, Vogelbaum, Perry, Gutmann, Dicker, Seiferheld.
Some of these roster member nominations are in the process of being confirmed.
BRAIN TUMOR COMMITTEE (June, 2002)
Minesh P. Mehta, M.D., Chair

Active Trials

1. RTOG 98-02–This is a Phase II study of observation in favorable low-grade glioma and Phase 3 study of radiation with or without PCV chemotherapy in unfavorable low-grade glioma. 252 of the required 252 patients have been enrolled. An additional 110 patients are on the Phase 2 arm. Study closure has been scheduled for June 2002. A replacement study (1094) is being developed.

2. RTOG 98-03–This is a Phase I/II radiation dose escalation study applying conformal radiation therapy in supratentorial glioblastoma multiforme. The 78 Gy arm has completed. A total of 146 patients have been accrued. No DLTs so far.

3. RTOG 98-13–This is a Phase I/III randomized study of radiation therapy and temozolomide vs. radiation therapy and BCNU vs. radiation therapy and temozolomide + BCNU for anaplastic astrocytoma. The revised Phase I arm has completed its 15-patient accrual. A total of 30 patients have now been enrolled on two Phase I arms. Toxicity analysis reveals that at least 7/11 patients needed to be dose reduced by cycle 1 and at least 2 pulmonary toxicities have been observed. The Phase III study will open as a 2-arm trial without the combination BCNU/Temozolomide arm. Dr. Chang will work with HQ to make the appropriate protocol modifications.

4. RTOG 00-13–This is a Phase II trial of intratumor bleomycin following external beam radiation therapy. A total of two patients have been enrolled. The study requires 72 patients. 17 institutions have the protocol through their IRBs. Enrollment is slow (3 patients enrolled to date) and participating institutions are encouraged to help improve this.

5. RTOG 00-23–This is a Phase II trial of fractionated stereotactic radiotherapy boost. A total of 22 out of 76 patients have been enrolled.

6. RTOG 02-11–This is a Phase I/II trial of ZD1839, an epidermal growth factor receptor, tyrosine kinase inhibitor with radiation therapy in glioblastoma multiforme. 9 patients have been enrolled on the Phase I arm and the trial is currently suspended for analysis of the Phase I data prior to opening it up for further accrual.

7. RTOG 01-31–This is a Phase II trial of pre-radiation temozolomide for patients with anaplastic oligodendroglioma which has replaced RTOG 94-02. Activation is expected shortly. Dr. Vogelbaum is finalizing the study radiologist and as soon as this is completed, the trial shall be activated.

8. RTOG 00-19–This is a Phase II randomized trial of am vs pm melatonin with whole brain radiation in patients with brain metastases. The trial has just received CTEP approval and is being activated at various institutions.

9. RTOG 01-18–This is a randomized Phase III trial of thalidomide and whole brain radiotherapy in patients with brain metastases. The trial has just received CTEP approval for thalidomide dose-modification, and is being opened group-wide.

Recently Closed Protocols

1. RTOG 94-02–This is a Phase III inter-group randomized comparison of radiation alone vs. pre-radiation chemotherapy for pure and fixed anaplastic oligodendroglioma. 299/292 patients have been enrolled and the study closed on 3/29/02. Dr. Jenkins, at the Mayo Clinic, is continuing the molecular analysis of these patients. It is not expected that data will be available for survival analysis for at least 6+ months. The replacement study ( RTOG 01-31) is discussed above.

Protocols On Hold

1. RTOG 1021–This is a pilot study evaluating the value of MR spectroscopy treatment planning for GBM patients. Because of technical reasons, this study has run into some difficulties and we are attempting to work with neuro-radiologists to resolve these issues.

2. RTOG 01-15–This is a Phase II trial of radiation and squalamine in patients with glioblastoma multiforme. Because of drug supply issues, this trial will now be abandoned and instead, Dr. Dicker will explore the possibility of using the antiangiogenesis agent Neovastat. Research Strategy has approved the proposal to discontinue further development of RTOG 01-15 and instead explore the possibility of a Neovastat trial.

Developing Trials

1. RTOG 1041–This was originally proposed as a randomized Phase II concept involving doublets with radiation therapy. After significant discussion in 2/02, it was felt that temozolomide thalidomide doublet has been tested at UCSF without substantially significant difference in survival, and the UCSF group is currently also testing the temozolomide and cisretinoic acid combination. Given the modestly positive results from the b-interferon trial, Dr. Yung will modify this study to become a single arm Phase II trial of ß-interferon and temozolomide, and will forward the revised concept and protocol to headquarters. This has previously been approved by Research Strategy.

2. RTOG 02-17–This is a developing Phase II concept of radiation therapy plus R115777 an FTI agent. Dr. Ian Robins has worked with headquarters to submit an LOI, which has been approved by CTEP and a protocol is being developed. Research Strategy has approved.

3. RTOG 01-35–This is a Phase II concept of the Schering farnesyl transferase inhibitor SCH 66336 (Sarasar). The concept and protocol are at headquarters. There was some concern about possible drug supply issues. We have checked with Schering Plough and were informed the agent should be available in the first quarter of 2003. Study development is therefore proceeding. Research Strategy has approved.

4. RTOG 1089–This is a Phase II concept of a Cox 2 inhibitor (Celebrex) previously presented by Dr. Adam Dicker; he is continuing to develop this. Research Strategy has approved.

5. RTOG 1081- This is a Phase I/II trial of the radiosensitizer MGd with radiosurgery followed by standard XRT for radiosurgery-eligible GBM. Given the negative results from the recent GBM Phase III radiosurgery trial, there were significant reservations about just adding a radiosensitizer to one radiation fraction as a worthwhile strategy; Dr. Brachman will therefore redesign this as a standard Phase II XRT plus MGd trial. Research Strategy voted to permit the Brain Tumor Committee to contact Dr. Ford at UCLA (who has a Phase I MGd GBM trial with encouraging results) to inquire whether she would allow an RPA type analysis of her patients, and if positive, to consider a Phase II trial.

6. RTOG Developing- This is a pilot feasibility study of the Proxima device as a boost for newly diagnosed glioblastoma multiforme patients, with standard external beam radiotherapy. This was approved by Research Strategy and protocol development is proceeding (Dr. Volker Seibert).

7. RTOG 1094–This is a Phase IIR replacement study for RTOG 98-02. The concept is a Phase II design in patients with low grade gliomas randomized to radiation and temozolomide. The randomization is to temozolomide during and post-radiation vs post-radiation only. Dr. Barbara Fisher is developing the study. Research Strategy has approved this concept.

8. RTOG 02-27–This is a Phase II concept for primary CNS lymphoma. The LOI has been submitted by Dr. Glass and will be forwarded to CTEP. There was considerable discussion about reducing the dose of Temozolomide or eliminating the Temozolomide altogether during the initial phase; Dr. Glass will make this minor modification and then the LOI will be submitted to CTEP. Research Strategy has approved this.

9. RTOG 02-16–This is a Phase III concept for patients with newly diagnosed meningioma. The Brain Tumor Committee had significant interest in pursuing this trial. Research Strategy felt that we should proceed with a Phase II trial first prior to embarking on a Phase III trial. The meningioma subgroup is re-evaluating this possibility. There was further discussion on this and the recommendation was to consider developing two trials; the first would be a Phase II study in anaplastic and malignant meningioma treated with surgery, XRT and a Cox-II inhibitor during and post XRT (for 6-12 months) and to evaluate 1 and 2-year progression-free survival. This trial would go first and would be an attempt at demonstrating our ability to accrue meningioma patients within RTOG. In parallel, development could begin on a Phase III trial in benign meningioma (XRT vs observation); the activation of this trial would be contingent on progress on the first trial and also neurosurgical buy-in.

10. RTOG 02-28–This is a Phase III concept in patients with 1-3 brain metastases (from NSCLC) eligible for radiosurgery. The concept allows for randomization to radiosurgery with whole brain radiation therapy and either Temozolomide or Iressa. Drs. Sperduto/Robins are developing the protocol, based on the positive results from RTOG 95-08. This has been approved by Research Strategy.

11. RTOG Developing- Dr. Steiber has started developing a focal radiotherapy (radiosurgery) trial for resected brain metastases and will continue this effort; approval from Research Strategy was not sought as there are several remaining issues that need to be codified:

a. What should be the precise endpoint? Perhaps a neurologic endpoint; if so, MMSE is probably inadequate in this context. A more refined analysis such as the one developed and piloted by Dr. Regine could be used; Dr. Steiber will discuss and further develop this with Dr. Regine.

b. Should the proportion of patients avoiding whole-brain XRT be considered a secondary end-point?

c. If the endpoint is neurocognitive in nature, what do we compare to as there is no database? Should this then be a Phase IIR study, randomizing patients to WBRT vs surgery? If so, would this be too hard to accrue? Dr. Steiber will consider this issue as well.

Concepts

1. Dr. Ali Choucair presented a strategy for incorporating QOL end-points in CNS trials.

2. A proposal incorporating Tamoxifen and Thalidomide with XRT, with preclinical data exploring the possible mechanisms for synergy was presented by Dr. Stephen DiBase from University of Maryland.

3. Dr. Brown presented a concept in low-risk low grade glioma, treating these patients with Cox-II inhibitors and measuring 2-year progression free survival; after considerable discussion at the Steering and Research Committee, the following points were raised:

a. The scientific rationale for using Cox-II inhibitors in these patients is not sufficiently compelling.

b. The long-term toxicity profile of Cox-II inhibitors is unknown, and there is increasing concern about GI toxicity; in addition, the possibility of other toxicities (perhaps intracranial hemorrhage) cannot be discounted.

c. The suggestion was to utilize tissue from RTOG 98-02 to apply for an NIH grant for molecular analysis and based on the findings, select appropriate molecularly targeted therapies for this patient group. Drs. Brown and Perry will discuss this with Dr. Shaw.

4. There was considerable discussion about the difficulty in conducting new molecularly targeted therapeutic studies with XRT in malignant glioma patients because of the enzyme-inducing anti-epileptic agents. One option recommended was to consider a switch to Depakote which is not enzyme-inducing and is approved as monotherapy for seizures. It would be more attractive to use an agent such as Keppra, but this has not been approved for seizures as a monotherapy; Dr. Robins and Gilbert were charged with coming up with an interim Depakote-based strategy for the next 1-2 trials and in the meantime to also consider developing a trial where a randomized allocation is made to Dilantin or Keppra and seizure activity is tracked for 3 months, while undergoing definitive therapy for GBM.

5. Starting this month, the following structural changes will be made to the operation of the Brain Tumor Committee:

a. A formal Executive Committee is formed, consisting of the Site Chair (Mehta), and co-Chairs representing Neurosurgery (Bullard), Medical-Neuro-Oncology (Yung), Biostatistics ( Seiferheld) and Translational Research (Guha).

b. The Steering Committee has been formalized and in addition to the above 4 individuals, will include PIs of all ongoing Brain Tumor protocols (and also protocols closed within the preceding 12 months), as well as Group Leaders representing the 6 Working Groups (GBM [Gilbert], Anaplastic Gliomas [MacDonald], Low Grade Glioma [Shaw], Metastases [Sperduto], Benign Tumors [Rogers] and PCNSL [Glass], and Group Leaders of the Special Expertise Groups (Physics [Gillin], Imaging [TBD], Outcomes [Choucair], Pathology [Arie Perry; pending acceptance] and Molecular Targeting [Dicker; pending acceptance].

c. The Steering Committee will plan to have approximately 6 teleconferences a year (one every 2 months), lasting 1 hour and these shall be scheduled from 4 to 5 pm of the first Tuesday of every other month, in order to allow both East and West coast participation. These will be facilitated by HQ.

d. All new concepts shall be processed through the appropriate Group.

e. The RTOG semi-annual Saturday meeting shall be expanded to 3 hours (11 to 2pm) and will be a closed meeting to include the Steering Committee members plus PIs of developing protocols and listed co-PIs on ongoing protocols. Members of Working Groups may also attend. All new concepts shall be presented at the Saturday meeting for discussion regarding feasibility within the group.

f. The semi-annual Sunday meeting shall remain open to all members and run from 8-10 am.
BRAIN TUMOR COMMITTEE (January, 2002)
Minesh P. Mehta, M.D., Chair

Active Trials

1. RTOG 94-02–This is a Phase III inter-group randomized comparison of radiation alone vs. pre-radiation chemotherapy for pure and fixed anaplastic oligodendroglioma. 294 patients have been enrolled. The required enrollment is 292 patients. The protocol will be closing between February and March 2002. Dr. Jenkins, at the Mayo Clinic, is continuing the molecular analysis of these patients. It is not expected that data will be available for survival analysis for at least 12+ months. This requires a replacement study which has been developed and is discussed below.

2. RTOG 98-02–This is a Phase II study of observation in favorable low-grade glioma and Phase 3 study of radiation with or without PCV chemotherapy in unfavorable low-grade glioma. 224 of the required 252 patients have been enrolled. An additional 99 patients are on the Phase 2 arm. The anticipated closure is May 2002. A replacement study is being developed.

3. RTOG 98-03–This is a Phase I/II radiation dose escalation study applying conformal radiation therapy in supratentorial glioblastoma multiforme. The 79 Gy arm is currently accruing. A total of 119 patients have been accrued.

4. RTOG 98-13–This is a Phase I/III randomized study of radiation therapy and temozolomide vs. radiation therapy and BCNU vs. radiation therapy and temozolomide + BCNU for anaplastic astrocytoma. The revised Phase I arm has completed its 15-patient accrual. A total of 30 patients have now been enrolled on two Phase I arms. Toxicity analysis is ongoing. Depending on the results of this Phase I arm, a decision will be made regarding activation of the Phase III arm. Dr. Chang will consider the data for a possible ASTRO abstract.

5. RTOG 00-13–This is a Phase II trial of intratumor bleomycin following external beam radiation therapy. A total of two patients have been enrolled. The study requires 72 patients. 17 institutions have the protocol through their IRBs.

6. RTOG 00-23–This is a Phase II trial of fractionated stereotactic radiotherapy boost. A total of 8 out of 76 patients have been enrolled.

7. RTOG 10-80/01-31–This is a Phase II trial of pre-radiation temozolomide for patients with anaplastic oligodendroglioma which will replace RTOG 94-02. The study has received CTEP approval and is just being opened through the RTOG.

8. RTOG 10-13–This is a Phase II randomized trial of melatonin with whole brain radiation in patients with brain metastases. The trial has just received CTEP approval and will be activated shortly.

9. RTOG 01-18–This is a randomized Phase III trial of thalidomide and whole brain radiotherapy in patients with brain metastases. The trial has just received CTEP approval and will be opened through the RTOG.

Recently Closed Protocols

1. RTOG 00-18–This was a pilot study testing a neurocognitive battery in brain metastases patients. Fifty (50) patients were required, and the trial met its accrual objectives and has closed. This neurocognitive battery will be expanded to other trials. Dr. Regine will consider presenting an abstract at ASTRO.

2. RTOG 00-21–This was a Phase II trial of radiation + tamoxifen in newly diagnosed glioblastoma multiforme. The trial required 72 patients; 74 patients were enrolled, and the trial closed in December 2001. Dr. Robins is currently analyzing the trial for early incidence of DVT and may consider submitting this as a possible ASTRO abstract.

3. RTOG 93-05–This was a Phase III randomized study comparing stereotactic external beam radiosurgery boost after standard radiosurgery for glioblastoma multiforme. The trial has been closed to accrual for some time. The data are now available for presentation at ASTRO, and Dr. Louis Souhami will consider generating an abstract.

4. RTOG 95-08–This was a Phase III trial comparing whole brain radiation with or without stereotactic radiosurgery boost in patients with 1-3 unresected brain metastases. The 2 and 3 brain metastases cohort had previously been closed, and the 1 brain metastases cohort has also reached accrual and has closed. The data are currently being analyzed, and Dr. Sperduto will consider presenting this to ASTRO.

Protocols On Hold

1. RTOG 99-08–This is a trial of RSR13 + radiosurgery with external beam radiosurgery for patients with brain metastases. The trial is currently on hold while corporate issues are being resolved.

2. RTOG 10-21–This is a pilot study evaluating the value of MR spectroscopy treatment planning for GBM patients. Because of technical reasons, this study has run into some difficulties and we are attempting to work with neuro-radiologists to resolve these issues.

3. RTOG 10-36–This is a Phase II trial of radiation and squalamine in patients with glioblastoma multiforme. The trial is currently on hold while corporate issues are being resolved.

Developing Trials

1. RTOG 10-07–This is a Phase I/II trial of ZD1839, an epidermal growth factor receptor, tyrozin kinase inhibitor with radiation therapy in glioblastoma multiforme. The protocol is currently at CTEP with what is probably the final set of revisions, and will likely be activated shortly.

2. RTOG 10-41–This is a randomized Phase II concept involving doublet with radiation therapy. After significant discussion, it was felt that temozolomide thalidomide doublet has been tested at UCSF without substantially significant difference in survival, and the UCSF group is currently also testing the temozolomide cisretinoic acid combination. Given the modestly positive results from the b-interferon trial, Dr. Yung will modify this study to become a single arm Phase II trial of b-interferon and temozolomide, and will forward the revised concept and protocol to headquarters.

3. RTOG 02-17–This is a developing Phase II concept of radiation therapy plus R115 777 an FTI agent. Dr. Ian Robins has worked with headquarters to submit an LOI, and we are awaiting the CTEP response.

4. RTOG 10-20–This is a Phase II concept of the Schering farnesyl transferase inhibitor. The concept and protocol are at headquarters. There was some concern about possible drug supply issues. We have checked with Schering and were informed the agent should be available in the Fall 2002. Development will therefore proceed with this study.

5. RTOG 10-94–This is a replacement study for RTOG 98-02. The concept is a Phase II design in patients with low grade gliomas randomized to radiation and temozolomide. The randomization is to temozolomide during radiation or post-radiation. Dr. Barbara Fisher is developing the study.

6. RTOG 10-89–This is a Phase II concept of a Cox 2 inhibitor previously presented by Dr. Adam Dicker; he is continuing to develop this.

7. RTOG 10-62–This is a Phase II concept for primary CNS lymphoma. The LOI has been submitted by Dr. Glass.

8. RTOG 02-16–This is a Phase III concept for patients with newly diagnosed meningioma. The Brain Tumor Committee had significant interest in pursuing this trial. Research Strategy felt that we should proceed with a Phase II trial first prior to embarking on a Phase III trial. The meningioma subgroup will be asked to re-evaluate this possibility.

9. RTOG 10-02–This is a Phase III concept in patients with 1-3 brain metastases eligible for radiosurgery. The concept allows for randomization to radiosurgery with or without whole brain radiation therapy. ACOSOG has activated a protocol with exactly the same study design. This, therefore, now becomes a CTEP issue. The plan is to set up a conference call with Rick Kaplan at NCI regarding the possibility of protocol modifications and an intergroup study.

Concepts

1. Dr. Volker Seibert presented a concept in brain metastases patients (1-3) following resection. The Research Strategy Committee felt that rather than embarking on a Phase III study, we should probably come up with a Phase II concept first to demonstrate that local therapy for this is acceptable, and achievable within RTOG.

2. Dr. Volker Seibert presented a concept for the Proxima device as a feasibility study for newly diagnosed glioblastoma multiforme patients. This was approved by Research Strategy and concept and protocol development will proceed.
BRAIN TUMOR COMMITTEE (November, 2001)
Minesh P. Mehta, M.D., Chair

Active Trials

1. RTOG 94-02: This is a Phase III intergroup randomized comparison of radiation alone vs. pre-radiation chemotherapy for pure and mixed anaplastic oligodendroglioma. The study has accrued 281 of the 292 required patients. Dr. Jenkins at the Mayo Clinic has commenced evaluation of the 1p19q status of patients on this protocol, which will be correlated with outcomes.

2. RTOG 98-02: This is a Phase II study of observation in favorable low grade glioma and Phase III study of radiation with or without PCV chemotherapy in unfavorable low grade glioma. The total accrual on this study is 279. The randomized arm requires 252 patients of which over 180 have now been accrued. The anticipated closure date is early 2002. A replacement protocol is being developed by Dr. Barbara Fisher, with Dr. Shaw.

3. RTOG 98-03: This is a Phase I/II radiation dose escalation study applying conformal radiation therapy in supratentorial glioblastoma multiforme. The 66 and 72 Gy dose arms have been closed. A total of 104 patients have been accrued. The 78 Gy arm will open in the next four months.

4. RTOG 98-13: This is a Phase I/III randomized study of radiation therapy and temozolomide vs. radiation therapy and BCNU vs. radiation therapy and temozolomide and BCNU for anaplastic astrocytoma. Fifteen patients have been accrued on the Phase I arm. Because of the higher than acceptable rate of cytopenia requiring dose reduction, the following modifications have been made: 1) the BCNU dose has been reduced to 150 mg/m2, 2) BCNU will now be given on day 5 after five days of temozolomide in order to exploit AGT depletion induced by BCNU, 3) The minimum entry DLCO criterion has been raised to 70%.

An additional change is that patients with minimal anaplastic oligodendroglial component (< 25%) mixed with anaplastic astrocytoma will be eligible for this study.

5. RTOG BR00-13: This is a Phase II study of intraommaya bleomycin for patients with glioblastoma multiform following radiotherapy. The trial has just been activated.

6. RTOG BR00-18: This is a feasibility study of neurocognitive evaluation in patients treated for brain metastases. Forty of 50 patients have been accrued, and the protocol is expected to close within the next two months.

7. RTOG BR00-21: This is a Phase II trial of high dose tamoxifen for the treatment of newly diagnosed supratentorial glioblastoma multiform. Thirty-one of 72 patients have been accrued.

8. RTOG 00-23: This is a Phase II trial of fractionated stereotactic radiosurgery boost concomitant with external beam radiotherapy. The trial has just been activated. This trial requires institutions to be certified. The institutions and the membership are urged to contact Dr. Gillin for details regarding physics certification.

Protocols Recently Closed

1. RTOG 95-08: This Phase III trial comparing whole brain radiation with vs. without stereotactic radiosurgery boost for patients with 1-3 unresected brain metastases has reached its accrual goal and has now been closed.

Protocols to be Activated Shortly

1. RTOG 99-08: This is a trial of RSR-13 plus radiosurgery and external beam radiotherapy for patients with brain metastases. The corporate contractual negotiations are being completed after which the study will be activated.

2. RTOG 10-06: This is a Phase III proposal to test thalidomide with whole brain radiotherapy in patients with brain metastases. The changes requested in the consent form by the NCI have been made, and this has been sent back to the NCI for approval. In further discussion, it was felt that one of the eligibility criteria, specifically pertaining to the use of chemotherapy following brain radiotherapy needed to be modified. This modification will be completed by Dr. Knisely and will require NCI approval prior to activating the study.

3. RTOG 10-36: This is a Phase II trial of squalamine as an angiogenesis inhibitor for glioblastoma multiform. The protocol has been completed and activation will occur in the next several weeks.

Developing Trials

1. RTOG 10-07: This is a Phase I/II trial evaluating ZD1839 with radiotherapy in newly diagnosed glioblastoma multiform. The protocol is being written up.

2. RTOG 10-02: This is a replacement trial for radiosurgery eligible brain metastases patients that Dr. Sperduto is developing. The proposed trial will be a randomized study of radiosurgery vs. whole brain radiotherapy plus radiosurgery with neurocognitive outcomes as the primary measurement. The hypothesis underlying this study is that the omission of whole brain radiotherapy will result in equivalent survival, but improved neurocognitive outcome in patients with brain metastases treated by upfront radiosurgery alone.

3. RTOG 10-13: This is