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Burton Eisenberg, M.D., Chair
Initial discussion involved the RTOG 0330 study. Problems associated with Thalidomide use particularly in relation to reported DVT were reviewed. Decision to close the Cohort A-low grade sarcomas was approved.
Dr. Wang presented RTOG 0630 (IMRT extremity sarcoma study). A number of questions were addressed. It is likely this study will be sent for NCI review in June 2007. The meeting was concluded by a presentation of sarcoma translational research from the MD Anderson Sarcoma Program.
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Burton Eisenberg, M.D., Chair
Dr. Eisenberg discussed the upcoming RTOG grant submission and the site visit. This was followed by a review of the two open sarcoma studies (RTOG 0330 and RTOG 0132). It is anticipated RTOG 0132 will meet its accrual goals by the June 2006 meeting.
The remainder of the hour was spent by discussing the next planned RTOG study for an extremity sarcoma. This study will replace RTOG 0330. The concept is to design a phase II study based on Image Guided Radiation Therapy (IGRT) delivery for the purpose of smaller radiation fields and less toxicity with endpoints of QOL and local control. Additionally, there will be a comprehensive TRP associated with this study involving tissue procurement and addressing biological markers of radiosensitivity and toxicity. This concept was presented by Dr. Dian Wang of the University of Wisconsin and Dr. Tom Delaney of Massachusetts General Hospital. The plan presently is to work only with the QOL, TRP, and IGRT committees respectively to have a final draft for the June meeting.
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Burton L. Eisenberg, M.D., Chair
The meeting was called to order.
Dr. Eisenberg gave an overview of RTOG 0132 (Neo-Adjuvant Gleevec for Operable GIST). Accrual issues were discussed with presently 27 patients registered. A recent successful RO1 Grant was funded to support the correlative science associated with this study.
Dr. John Kane then presented RTOG 0330, the recently approved protocol for both low-grade and high-grade soft tissue sarcomas of the extremity and body wall. Because of its inclusive Phase 2 trial design, this study should provide for maximal participation in RTOG institutions.
Next, both Dr. Matt Ballo and Dr. Len Gunderson presented two developing protocols initiated by other cooperative groups utilizing radiation therapy for regional melanoma. It was the consensus melanoma studies should be discussed in the Sarcoma Committee since RTOG has no other venue for these proposals.
This was followed by a general discussion of a concept presented by Dr. Ballo with input from Dr. David Harmon concerning a draft proposal to evaluate efficacy and toxicity in a Phase 3 trial design comparing radiation field margins in the pre-operative management of soft tissue sarcomas of the extremity/body wall. This concept will be further developed into a formal proposal for research strategy discussion for the next RTOG meeting.
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Burton Eisenberg, M.D., Chair
Meeting began with Dr. Eisenberg presenting a short discussion of RTOG 0132 rational and scientific basis and the approved amendments. This included a discussion of accrual problems and goals.
Next Dr. Kane presented the proposal for RTOG 0330, the next RTOG extremity/body wall clinical research study. The study is entitled “A Pilot Phase II Study of Pre-operative Radiation Therapy and Thalidomide (IND 48832; NSC 66847) for Low Grade Primary Soft Tissue Sarcoma or Pre-operative MAID/Thalidomide/Radiation Therapy for High/Intermediate Grade Primary Soft Tissue Sarcoma of the Extremity or Body Wall” and was designed as a pilot study to evaluate the addition of Thalidomide to a combination pre-op neoadjuvant approach of RT/Chemo (high grade soft tissue sarcomas) and RT (low grade soft tissue sarcomas) with both clinical and correlative biological endpoints. A question and answer session followed this presentation. It is anticipated that this study will go active prior to the summer RTOG meeting.
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Burton Eisenberg, M.D., Chair
The meeting began with discussion concerning RTOG 0132, the Neoadjuvant Gleevec trial for bulky primary or recurrent GIST. The study has begun to accrue in a more rapid fashion with 18 patients now registered on the study. This represents a significant increase from that reported in the winter meeting. The study has now been opened in several other centers and has been amended to provide for easier patient registration. This includes the elimination of the requirement by ACRIN that the participating institution join ACRIN for the purpose of the PET portion of the clinical study. Additionally, ECOG will shortly join RTOG in registering patients eligible for this study.
The second portion of the meeting centered around discussion of two developing protocols involving the use of Thalidomide and radiation therapy for soft tissue sarcomas of the extremity and body wall. These studies were presented to CTEP as LOI's and have been approved in principle. It was further decided that the two studies would actually be written as one study that would stratify patients for tumor grade. The high-grade patients entered into the study will be treated with the addition of Thalidomide to the schema taken from RTOG 9514 and the low-grade sarcomas would be treated with combination of Thalidomide and radiation therapy. These studies will be developed into protocol form over the next several months with coordination and advice from both CTEP and IDB regarding the study design. Additionally, Celgene will have to approve these studies since they supply the thalidomide for the trials.
Dr. Bill Kraybill presented an overview of the results from RTOG 9514 and will be involved in writing the manuscript that will be submitted to the Journal of Clinical Oncology.
The meeting was concluded with Jodi Cummings, the representative and patient advocate from the Sarcoma Alliance, discussing his organization's role in promoting sarcoma research and supporting correlative basic science studies.
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Burton Eisenberg, M.D., Chair
The agenda for the meeting was outlined and discussions began around study RTOG 0132. This study involves the neoadjuvant use of Gleevec for patients with locally advanced, recurrent, or metastatic gastrointestinal stromal tumors. This study is also being supported by ACRIN with financial arrangements to perform the PET scans required by the study. The presentation centered around the study criteria for eligibility, the necessity of the PET scans, and the difficulty in patient accrual. The difficulty is multifaceted since this is a rather complex study. However, it does appear that the separate application of necessity to join ACRIN and to qualify the PET scanner for digital transmission has been an accrual problem. Individual institutions were encouraged to place patients on this trial.
The next area of discussion was for the replacement studies for RTOG 0120 and 0121 sarcoma extremity trials. These trials were prematurely halted because of the unavailability of the antiangiogenic molecule SU5416. The proposal is to initiate two new studies using Thalidomide as an oral antiangiogenic agent. Dr. Eisenberg discussed a replacement for RTOG 0120 which includes all patients with low and intermediate grade soft tissue sarcomas of the extremity 5 cm or greater with the treatment scheme of combined modality therapy of radiation and Thalidomide followed by postoperative Thalidomide given as an adjuvant for one year. It was also decided based on discussions that high grade patients should be included in this study, if they are not otherwise a candidate for chemotherapy and that size criteria could be adjusted to include those patients with tumors less than 5 cm who would be subject to radiation as a standard therapy.
Next, Dr. William Kraybill discussed replacement for RTOG 0121, the high grade, high risk extremity sarcoma study. This would include the use of Thalidomide, a modified MAID regimen and radiation therapy for these patients. This also led to a presentation discussion by Dr. Kraybill of the preliminary results from RTOG 9514. Emphasis was placed on the potential toxicity of the MAID/radiation therapy protocol that was utilized in this study. It was decided that the MAID chemotherapy would be modified for this study to include the possibility of three courses preoperatively and simply give Thalidomide postoperatively. It was also felt that we should have a 2 to 1 randomization scheme with some patients receiving RT and chemotherapy alone without Thalidomide so that we may be able to obtain baseline biologic studies.
Dr. Chris Watson then presented the biological correlates for these studies which would include serum levels of angiogenic growth factors and serum levels of circulating endothelial cells including the potential for phenotyping these cells. These biological correlates would be built into these pilot studies. Two LOI's will be submitted to NCI CTEP for their consideration in the use of thalidomide for these studies.
The next discussion was the retroperitoneal sarcoma protocol RTOG 0124 by Dr. Ivy Petersen. There was an emphasis on the necessity for patient accrual since this study has also had some problems with patient accrual. It was suggested that perhaps IMRT could be included so that some patients would not need to get intraoperative radiation therapy. This perhaps would open the study to more centers. Additionally, it was felt that the study should try to be as inclusive as possible. And, with this in mind, Dr. Petersen will contact all those institutions that took part in RTOG 9514 for potential enhancement of accrual for this study.
The committee discussion ended with Mr. Jody Cummings from the Sarcoma Foundation discussing this foundation as a patient advocacy support group as well as the potential for providing additional funds for pilot studies in soft tissue sarcomas. Mr. Cummings will make an attempt to attend future Sarcoma Committee meetings for RTOG.
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Burton L. Eisenberg, M.D., Chair
The meeting began with Dr. Eisenberg announcing that S-0120 and S-0121 would be closed. The reason for the suspension of these studies was the CTEP withdrawal of the study drug SU5416. SUGEN Pharmaceuticals has decided not to clinically develop this anti-angiogenic specific drug and has requested that the NCI discontinue the present clinical studies sponsored through CTEP.
Discussion among the participants concerned possible replacement studies. CTEP had recommended three potential replacement drugs for the two extremity studies including Thalidomide, Bevacizamab, and Avistatin. These will all be considered for their potential into incorporation for these multimodality protocols for soft tissue sarcoma. It was further decided to continue the development of a Phase II proof of principle concept evaluating molecular specific targets as the previous studies were designed to do.
Next, Dr. Eisenberg presented RTOG 01-32 the neoadjuvant gastrointestinal tumor study. At the present time, there are 5 patients registered to this study and the study was beginning to open up in other centers including recent request from the Mayo Clinic, Roswell Park, MD Anderson, and the University of Washington. There were some difficulties in activating this study within RTOG because of the strict ACRIN requirement for PET certification and qualification. However, RTOG is actively working with ACRIN to simplify this process and develop the critical mass of institutions necessary to meet accrual goals. These points were emphasized and the protocol was again reviewed.
The last study presentation was by Dr. Peter Pisters of the MD Anderson Cancer Center with a discussion of S-1024 the neoadjuvant chemotherapy, radiation therapy high grade retroperitoneal sarcoma study. Again it was emphasized for the necessity of patient accrual and for the larger centers that have a track record of seeing these patients to participate in this very valuable multimodality RTOG study.
Dr. Chris Watson then provided a discussion on an update of the clinical use of a variety of different angiogenic biomarkers of response. This included a presentation of a research project utilizing circulating endothelial cells to evaluate the clinical response to anti-angiogenic drugs.
This concluded the Sarcoma Committee session. Plans for next meeting in the Fall include replacement studies for S-0120 and S-0121 to be presented at that time.
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Burton L. Eisenberg, M.D., Chair
The meeting began with a brief overview of goals and prior accomplishments of the Sarcoma Committee. It was highlighted that the committee received an excellent score from the site visit consensus and was approved for funding. Subsequent to the site visit, the previous Sarcoma Working Group was designated as the Sarcoma Committee. After introductions, Dr. Eisenberg discussed the present status of three recently initiated sarcoma clinical trials. They are RTOG 01-20, RTOG 01-21, and RTOG 01-32. The first two studies involve soft tissue sarcomas of the extremity and body wall with the intent of utilizing an antiangiogenic agent to address biological and clinical questions in combination therapy. The third study involves the use of a novel agent of a specific molecularly targeted small molecule treatment of patients with gastrointestinal stromal tumor. This study is designed as a neoadjuvant/adjuvant trial using Gleevec (a RTK inhibitor of c-kit) combined with surgical resection/debulking for primary and recurrent gastrointestinal stromal tumors. The purpose of this study will be to define specific molecular events involved in response to this targeted therapy agent and to evaluate the predictability of PET scans in quantifying response to this new class of drugs. This study will be done in conjunction with ACRIN to provide for quality control and funding of the PET studies.
The next portion of the committee meeting involved discussions of retroperitoneal sarcomas. This was led by Drs. Peter Pisters and Brian O'Sullivan. RTOG 01-24 criteria of eligibility were described. This is a recently initiated study to evaluate multimodality preoperative treatment of high-grade primary and recurrent retroperitoneal sarcomas. Discussion then took place with an introduction of a developmental protocol which was initiated at the request of the NCI Sarcoma Intergroup Committee. This concept will consider the question of efficacy of radiation therapy given preoperatively to patients with low grade retroperitoneal sarcomas. It was decided to further develop this study by conference calls to refine the design and feasibility of the RTOG lead Phase III trial in retroperitoneal sarcoma. This study would require intergroup support as well as possible participation through the Canadian Cancer Network and the EORTC.
The meeting was then adjourned with plans to enhance accrual to these recently opened studies in sarcoma. Of important note, there were two new members who attended this Sarcoma Committee session: Dr. Tom Sullivan, an orthopedic oncologist from the University of Miami, and Dr. Parker Gibbs, an orthopedic oncologist from the University of Colorado. We welcome their participation in clinical sarcoma research addressing multimodality questions.
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Burton L. Eisenberg, M.D., Chair
The meeting began with a review of the data from the completed sarcoma study RTOG 95-14. Dr. Bill Kraybill reviewed the present data previously given as an oral presentation at this year's ASCO meeting. At this time, the plan is to allow this data to mature and to complete information collection for other areas of the data base for submission as an abstract to the Connective Tissue Oncology Society Meeting as well as next year's Society of Surgical Oncology Meeting.
The next discussion included three new sarcoma studies. Dr. Burton Eisenberg reviewed the rationale and the clinical study design for a neoadjuvant gastrointestinal stromal tumor study. This study has unique features including the clinical endpoints of recurrence free and overall survival as well as biological endpoints looking at mutational analysis as well as protein phosphorylation and microarray global gene expression for these tumors both pre- and post-Gleevec treatment.
The other two studies that were discussed constitute the new extremity sarcoma studies. RTOG 0120 and 0121 include the antiangiogenic agent (SU5416) in combination therapy schemes for both low/intermediate grade and high grade extremity and truncal sarcomas. It is expected that these studies will begin accrual during the summer of 2001.
After this discussion was completed, Dr. Peter Pisters gave a presentation of the new RTOG retroperitoneal sarcoma study, (RTOG #0124). This is a multimodality neoadjuvant study for retroperitoneal sarcomas and it will also begin accrual during the summer of 2001.
The meeting was then completed with a discussion as to how these studies might be successfully presented and accomplished within the stated objectives.
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Burton Eisenberg, M.D., Chair
The session was opened and chaired by Burton L. Eisenberg. He reported that RTOG 95-14 had met its accrual goals. There were a total of 66 patients entered and the data was being analyzed. A planned presentation at the Connective Tissue Oncology Society Meeting in Amsterdam in November would follow the initial analysis of the early data.
Next, a discussion took place on RTOG Developmental Protocol 1060. This is a study of combined modality therapy for high-grade primary and recurrent retroperitoneal sarcoma. This study was developed and co-chaired by Dr. Ivy Petersen of the Mayo Clinic and Dr. Peter Pisters of the M.D. Anderson Hospital. The various details of the study were reviewed by Dr. Ivy Petersen including the radiation therapy boost dose scheme and subsequent anticipated quality control issues. This was followed by a general discussion of the protocol and the goals as stated within the objectives. This portion of the discussion was chaired by Dr. Peter Pisters. Following this, the scheme for the preoperative chemotherapy with adriamycin and ifosfamide were reviewed along with potential toxicity problems. This was discussed by Dr. Shreyas Patel of the M.D. Anderson Hospital and was based on their clinical experience with a similar pilot study. After a question and answer discussion regarding this protocol, it was decided that this study was ready for CTEP review and pending any issues relating to the CTEP review would be ready for individual institutional IRB's for approval.
A general discussion chaired by Dr. Burton Eisenberg then took place on the use of anti-angiogenesis combined therapy in the treatment of soft tissue sarcomas. The rationale for the planned studies for extremity sarcoma was reviewed and a presentation was given as to the nature of these planned studies. Two letters of intent have been approved by the NCI and are awaiting approval from a pharmaceutical company for the use of SU5416, which is a small molecule tyrosine kinase inhibitor of the VEGF receptor. The plan for this anti-angiogenesis compound is for combination therapy with radiation with the objective of evaluating toxicity and potential synergism in patients with low and intermediate grade large deep sarcomas of the extremity. Additionally, a second study is planned for the continuation of the schema presented in 95-14 with the addition of an anti-angiogenesis compound. Patients eligible for this study have high-grade large deep sarcomas of the extremity and trunk. Pending pharmaceutical approval of the use of the drug, these protocols will be developed and have been approved in principle by the RTOG Research Review Committee.
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