Baker, Laurence H., D.O. ABSTRACT

Transcription

1 ABSTRACT Since the last renewal submission (1/2002-9/2008), 993 patients have been enrolled onto 14 Melanoma Committee trials, including 466 onto SWOG-coordinated Intergroup trials and 375 onto other Intergroup trials. During this time, approximately 28% of all adult patients entered onto cooperative group melanoma trials were enrolled onto SWOG-led studies. Specific achievements include: Continued to evaluate new treatment strategies for unresectable stage IV cutaneous melanoma. SWOG enrolled 195 melanoma patients onto the Intergroup phase III trial E2603, evaluating carboplatin-paclitaxel with sorafenib or placebo, in just under 3 years. Another 64 patients were entered onto S0508, a phase II trial evaluating the combination of temozolomide and thalidomide in advanced melanoma with no or one prior treatment for systemic disease, in 18 months. Although this is a widely used combination, the low activity level observed did not appear superior to that of single agent temozolomide or DTIC. Our current trial S0438, is a highly innovative trial evaluating two strategies of combination receptor tyrosine kinase (RTK) inhibitor therapy in a randomized phase II trial: vertical inhibition of two targets along the same pathway or horizontal inhibition of two targets in parallel pathways. In one arm, sorafenib (BAY ), which inhibits BRAF in the MAPK pathway, is combined with tipifarnib (R115777), which inhibits RAS activity in the same pathway. In the other arm, sorafenib is combined with temsirolimus (CCI-779), which inhibits mtor in the parallel PTEN/AKT/PI3K pathway. The accrual goal is 55 patients per arm. Accrual to this study commenced April , with 47 patients entered as of December 5, Continued to explore adjuvant therapy for intermediate- and high-risk melanoma patients. SWOG-coordinated Intergroup trial S0008 compares standard high-dose interferon for one year to 9 weeks of biochemotherapy (cisplatin, vinblastine, DTIC, interleukin-2 and interferon) in patients with high-risk melanoma (stage IIIB/C). This study enrolled a total of 432 patients. ECOG, CALGB and COG all contributed patients to this trial, marking the first time children have been eligible for and enrolled onto a SWOG melanoma trial. SWOG also supported E4697 and E1697, contributing 114 and 104 patients (as of December 5, 2008) respectively. Conducted the first successful cooperative group trials in metastatic Merkel cell carcinoma and ocular melanoma. S0331 enrolled 25 patients with CD117 (KIT) positive metastatic Merkel cell carcinoma in just over 3 years to a phase II trial of imatinib mesylate. S0512 enrolled 25 patients with stage IV ocular melanoma in less than 2 years to a single-arm phase II trial evaluating carboplatin-paclitaxel plus sorafenib (the investigational arm of E2603, which excluded patients with ocular primaries). In the next funding period, the SWOG Melanoma Committee will continue to explore new approaches to the treatment of metastatic melanoma, will seek to better understand the role of autoimmunity in adjuvant therapy, and will conduct trials of chemoprevention in patients with curatively treated early-stage melanoma at high risk of developing a second primary melanoma. Recognizing the inherent genetic diversity encompassed in the group of tumors we call melanoma, we continue to coordinate our efforts with those of our Translational Medicine Subcommittee, to evaluate tumor and host factors influencing response to therapy. MELANOMA COMMITTEE MC- 1

2 MEMBERSHIP COMMITTEE LEADERSHIP Chair: Vice-Chair: Executive Officer: Statistician: SCIENTIFIC LEADERSHIP Translational Medicine Translational science: Early Therapeutics: Radiation Oncologist: Surgical Oncologist: Medical Oncologist: Pathologist: Non melanoma Skin Cancer Vernon K. Sondak. M.D. Lawrence L. Flaherty, M.D. Bruce Redman, D.O. Mike LeBlanc, PhD. Jeffrey A. Sosman, M.D. John Fruehauf, M.D., Ph.D. Robert Whitehead, M.D. James G. Douglas, M.D. Robert Andtbacka, M.D. Lawrence L. Flaherty, M.D. Ralph J. Tuthill, M.D. Wolfram Samlowski, M.D. DESIGNATES Clinical Research Associate: Mary McGreevy, CCRA Sandy Allten, R.N. Control/Prevention Liaison: Marie-France Demierre, M.D. Data Coordinator: Brian Zeller Nurse: Karen L. Mack, R.N.P. Patient Advocate: Valerie Guild Pharmacist: Siu-Fun Wong, Pharm D. Protocol Coordinator: David Bernal Statistician: James Moon, M.S. The Melanoma Committee leadership remains largely unchanged over the current funding cycle. Sondak remains as Chair of the Committee, with Flaherty as Vice-Chair, positions both have held since Sondak also serves as a member of the SWOG Scientific Advisory Board. Biostatistical leadership is provided by Dr. Michael Leblanc, who replaced P-Y Liu in 2008, and James Moon. Jeffrey Sosman is Chair of the Translational Medicine Subcommittee, and in 2008 John Fruehauf assumed the role of Vice-Chair of that Subcommittee. Marie-France Demierre is the Committee s liaison to the Cancer Control and Prevention Committee. Wolfram Samlowski heads the Nonmelanoma Skin Cancer Subcommittee and Ralph Tuthill leads the Pathology effort. In addition to convening in person at the twice-yearly Group meetings, the leaders of the Melanoma Committee and Translational Medicine Subcommittee, along with all the Study Coordinators of active and recently completed trials, participate in a monthly teleconference led by the Committee Chair. New concepts are discussed during this conference call and developed prior to the Group meeting, during protocol-specific teleconferences when necessary, so that well-developed concepts can be presented to the entire Committee membership at the Group meetings. Ideas for protocol development are integrated from the outset with the Translational Medicine Subcommittee, to ensure that appropriate correlative science is incorporated into new trial design, and that the results of ongoing translational efforts inform and influence the MELANOMA COMMITTEE MC- 2

3 design of new trials. Accrual to ongoing trials is also monitored during these monthly conference calls, and any safety or toxicity issues discussed. Because not all the adult cooperative groups have Melanoma Committees, SWOG has offered Special Member status to individuals from non-swog institutions who have an interest in melanoma but no venue within their own group. These Special Members can participate fully in the SWOG Melanoma Committee s activities and have been supported by SWOG to attend the Group meetings. Special Members from Ohio State University (Kari Kendra and William Carson) and the University of California at San Francisco (Adil Daud) have recently brought concepts for phase II clinical trials to the Committee for consideration (the Ohio State proposal is already in active development), and new translational collaborations are being forged with Special Members from the University of Chicago (Thomas Gajewski) and Yale University (Mario Sznol), which holds a melanoma/skin cancer SPORE grant. Specialty Participants Clinical Research Associates 1 Medical Oncology 39 Pathology 3 Registered Nurse 2 Radiation Therapy 2 Surgery 14 Translational Medicine 2 Other 8 Sum 71 PROTOCOLS ACTIVE DURING REPORTING PERIOD SWOG or SWOG-coordinated Intergroup: S9430 Intergroup, S9431 Biologic Intergroup, S0008 Intergroup, S0026, S0116, S0331 Intergroup, S0438 Intergroup, S0508, S0512 Intergroup trials coordinated by other Groups: E3695 Intergroup, E1697 Intergroup, E2697 Biologic Intergroup, E4697 Intergroup, E2603 Intergroup MELANOMA COMMITTEE MC- 3

4 Admin Phase/Coordinating Group StudyID Accrual 2004 Accrual 2005 Accrual 2006 Accrual 2007 Accrual 2008 Total Total in Followup MELAN Biological S /15/2005 MELAN Phase II S /01/2007 MELAN Phase II S MELAN Phase II S /01/2007 MELAN Phase II S /01/2009 MELAN Phase II S /15/2005 Phase III,Intergroup (SWOG MELAN coordinated) S /15/2007 MELAN Phase III,Intergroup (non-swog coordinated) E /31/2006 MELAN Endorsed E MELAN Endorsed E /22/2008 Accr Prev Period Total Accrua l for Study Closed * Registrations are through 12/31/2008 **Other Includes non-tx Intervention (symptom control)","pilot","quality of Life","Treatment (Prevention)" and "Treatment (Symptom)". MELANOMA COMMITTEE MC- 4

5 RELVANT PAST, PRESENT AND FUTURE STUDIES ADJUVANT THERAPY STUDIES S0008 Intergroup (Coordinating Group - SWOG): Phase III Trial of High Dose Interferon Alpha-2b vs Cisplatin, Vinblastine, DTIC plus IL-2 and Interferon in Patients with High Risk Melanoma (Activated: 08/01/2000; Permanently Closed: 11/15/2007) Schema Rationale Malignant melanoma has been well recognized to affect a young patient population. In three recent ECOG or Intergroup adjuvant interferon trials (E1684, E1690 and E1694), the median age of diagnosis was approximately 50 years of age. All three trials demonstrated a statistically significant relapse-free survival advantage for patients receiving high-dose interferon (IFN) compared with either observation or a ganglioside vaccine. The effect of IFN on overall survival, however, is less clear, and the long treatment duration (one year) and side effect profile has often made it a difficult standard for physicians and patients to embrace. Clearly, additional strategies to build on or replace this treatment approach are warranted in this relatively young, high-risk patient population. Interleukin-2 (IL-2) has single agent activity in stage IV melanoma patients, with a durable complete response rate of 6%. Many investigators have combined IL-2 with chemotherapy and IFN in multi-agent regimens referred to as biochemotherapy. Over 1,000 patients have been treated on phase II institutional trials demonstrating response rates in the 30-60% range with durable complete remissions in approximately 10%. A meta-analysis involving over 7,000 patients concluded that the highest response rates (average 47%) were found when IL-2 was combined with IFN, cisplatin and dacarbazine (DTIC). Response duration for IL-2, IFN and chemotherapy was also statistically superior (10.0 months, p<0.05) to either IL-2 alone or chemotherapy alone. Legha et al piloted several biochemotherapy trials with IL-2, IFN, DTIC and cisplatin and found the greatest benefit when the chemotherapy was either given first or concurrently with IL-2. Atkins et al demonstrated equivalent effectiveness with a modified 5-day regimen administered every 21 days. Modifications included prophylactic antibiotics, replacement of central lines, aggressive hydration and antiemetic use, use of growth factor support and strict dose adjustments for toxicity, and made this regimen acceptable for cooperative group use. Of note, equivalent response rates were seen in stage IV patients who had or had not received prior adjuvant IFN, suggesting a possible independent mechanism of action. This important observation, combined with the young median age of patients with highrisk melanoma and the toxicity and long duration of IFN adjuvant therapy, made this short-duration (9 weeks) biochemotherapy regimen a compelling regimen to compare with IFN in a group of very high risk (Stage IIIB/C) patients. Patients with Stage IIIA melanoma (sentinel node positive without ulceration of the primary) were excluded. MELANOMA COMMITTEE MC- 5

6 Objectives To compare overall survival and disease-free survival between patients with high risk melanoma who receive high dose interferon alpha-2b versus cisplatin, vinblastine, DTIC plus IL-2 and interferon. To evaluate the toxicities of these two regimens in this patient population. To investigate the predictive value for disease outcome (OS and DFS) and explore the relationship with patient clinical characteristics (# of involved nodes, ulcerated primary, extracapsular extension) of minimal residual disease (MRD) by RT-PCR in the peripheral blood at baseline. To investigate the effects of treatment (high dose IFN vs. biochemotherapy) on the status of MRD in peripheral blood at 12 and 52 weeks. To explore the relationship between minimal residual disease (MRD) status at 12 weeks and 52 weeks with subsequent overall survival. Statistical Endpoints Based on previous data, the 5-year survival rate for the control arm is estimated to be approximately 40%. Four-hundred and ten eligible patients are targeted over three years. With three additional years follow-up, the power to detect a survival increase is approximately 0.91 and 0.80 if the true death hazard ratio is 1.53 and 1.42 respectively. With exponential survival distributions, these hazard ratios correspond to 5-year survival rates of 55% and 52.5%, respectively in the biochemotherapy arm. The power calculations also assume uniform patient entry and a one-sided logrank test at 0.05 significance level. Interim analyses will be performed when 80% of patients have been accrued and when 2/3 of the anticipated deaths on the control arm have been observed. Results The final accrual was 432 patients, with a target of 410 eligible patients. Although there was concern that the negative results of E3695, which did not demonstrate a significant benefit for biochemotherapy over chemotherapy alone in stage IV melanoma, might adversely impact accrual to S0008, this fear never materialized and accrual remained strong and consistent over the course of the study. Twenty-five patients are currently ineligible, mostly for a non-ulcerated primary with only one micrometastatic node (8), inadequate lymph node dissection (4) or distant metastases (4). Therefore, this study successfully met its target accrual with 407 total eligible patients. On the biochemotherapy arm, 168 eligible patients have been evaluated for adverse events. One death, which occurred within one day after receiving the third cycle treatment, was judged to be treatment-related. An additional 68 patients (40%) have experienced Grade 4 adverse events, primarily hematologic. On the interferon alone arm, 186 eligible patients have been evaluated for adverse events. There was one death attributed to treatment, due in part to apnea although the exact cause of death was indeterminate. An additional 13 patients (7%) have experienced Grade 4 adverse events. On the companion correlative science study of minimal residual disease, 578 peripheral blood samples have been collected from 302 patients. These are being analyzed for the presence of multiple markers of circulating melanoma cells as assessed by RT-PCR. At baseline, the presence or absence of RT-PCR evidence of minimal residual disease will be correlated with outcome, and for patients with initially negative markers, the significance of conversion to marker-positive status will be assessed. The 2 nd interim analysis is expected sometime in spring or summer Based on the event rate observed to date, final analysis is anticipated in MELANOMA COMMITTEE MC- 6

7 E1697, Intergroup: A Randomized Study of Four Weeks of High Dose Interferon Alfa-2b in Stage T2b N0, T3a-b, T4a-b N0, and T1-4 N1a-2a-3 (Microscopic) Melanoma (Activated: 10/15/2002) Schema R A N D O M I Z A T I O N Observation 4 week high dose IFN Alfa-2b Rationale High-dose IFN alfa given for 1 year, consisting of an initial 4 week intravenous induction phase followed by an 11 month subcutaneous maintenance phase, is the standard adjuvant therapy in use in the USA today for patients with thick node-negative or nodepositive melanoma. As previously discussed, significant questions remain as to whether the duration and toxicity of this year-long therapy are justified. A consistent observation from cooperative group trials of high-dose IFN has been an early separation of the relapse-free survival curves, suggesting the possibility that the intravenous induction phase of therapy may be necessary and sufficient to see a benefit of therapy. This shorter-duration therapy would also be far more acceptable to patients, especially those with relatively favorable prognosis E1697 represents another effort to balance the toxicity and duration of therapy with the risk of relapse, in this case by targeting a group of patients with an intermediate risk of death from melanoma within 5 years of diagnosis. Because of their overall somewhat more favorable risk profile, these patients were excluded from S0008. Objectives To compare the effect of treatment with four weeks of high dose IFN alfa-2b on the relapse-free and overall survival of patients with resected melanoma in the following categories: (1) T2b N0, (2) T3a-b N0, (3) T4a-b N0, (4) T1-4 N1a,2a,3 (microscopic). To assess the toxicity of high dose IFN alfa-2b. To compare the two treatment arms (observation versus high dose IFN alfa-2b) with respect to quality-adjusted survival. Statistical Endpoints The accrual goal for this study is 1,278 eligible patients. Results ECOG reports that as of June 30, 2008, a total of 850 patients have been registered, including 104 by the Southwest Oncology Group as of December 5, MELANOMA COMMITTEE MC- 7

8 E4697, Intergroup: A Randomized, Placebo-Controlled Phase III Trial of Yeast- Derived GM-CSF Versus Peptide Vaccination Versus GM-CSF Plus Peptide Vaccination Versus Placebo in Patients with "No Evidence of Disease" after Complete Surgical Resection of "Locally Advanced" and/or Stage IV Melanoma (Activated: 03/1/2002; Permanently Closed: 10/31/2006) Schema Rationale As previously discussed, the efficacy of high-dose IFN adjuvant therapy has been questioned and alternative approaches are clearly needed. Increasingly, melanoma patients with regionally recurrent or oligometastatic disease are being treated aggressively by resection of all known disease. As shown in S9430, overall survival for patients with resectable stage IV melanoma (21 months median) was superior to what has been seen for systemic therapy of unresectable disease (6 months median in the cooperative group phase II trial meta-analysis), but S9430 also demonstrated a relatively short median relapse-free survival of 6 months. Since many patients with resected stage IV melanoma have already received high-dose IFN, this population represents an important group to test innovative approaches to adjuvant therapy. A single-arm, open label multicenter adjuvant trial of recombinant yeast-derived granulocyte-macrophage colony stimulating factor (GM-CSF, also referred to as sargramostim) suggested a long overall survival for resected stage IV melanoma patients treated postoperatively with GM-CSF compared to historical controls. This study led to the widespread use of adjuvant GM-CSF, which is commercially available as a hematopoietic growth factor, outside of the protocol setting. Even recognizing the limitations of historical controls in this setting, the lack of available options and the increasing off-protocol use of GM-CSF provided a strong rationale for conducting a phase III trial. Because GM-CSF was available outside the protocol setting, randomization MELANOMA COMMITTEE MC- 8

9 against a placebo was considered an important safeguard to minimize the likelihood that patients randomized to the control arm would receive GM-CSF outside the protocol context. Vaccine therapy also been an area of considerable interest for melanoma patients, and makes most sense for adjuvant applications. S9035 demonstrated that melanoma patients expressing HLA-A2 and/or HLA-C3 derived relapse-free and overall survival benefit from a polyvalent melanoma cell lysate vaccine. These results remain statistically significant in a follow-up analysis done this year. Many melanoma-associated antigens are known to have epitopes (peptide fragments) recognized by T cells in the context of HLA-A2. The decision was made to include HLA typing in E4697, and for HLA-A2 positive patients include a second randomization to an HLA-A2 specific multipeptide vaccine or placebo, in addition to the GM-CSF versus placebo randomization. Patients are stratified by HLA-A2 status: positive vs negative; site of metastases; and number of metastatic lesions. Objectives To compare overall survival, two-year survival, and time to progression of patients with completely resected Stage IV melanoma or Stage III melanoma with gross extranodal extension, satellites and/or in-transit lesions, or with other high risk factors when treated with GM-CSF versus no GM-CSF. To compare overall survival, two-year survival, and time to progression of HLA-A2 positive patients treated with peptide vaccination versus no peptide vaccination. To perform descriptive evaluations of overall survival and time to progression of HLA- A2 positive patients treated with GM-CSF plus peptide vaccination versus peptide vaccination alone, GM-CSF plus peptide vaccination versus GM-CSF alone, and GM- CSF plus peptide vaccination versus placebo. In addition, for descriptive purposes, survival and time to progression of HLA-A2 positive patients not receiving peptide vaccination will be compared to that of HLA-A2 negative patients. To investigate the influence of GM-CSF on circulating dendritic cell numbers in peripheral blood of patients receiving and not receiving GM-CSF. Statistical Endpoints The accrual goal is 800 patients, with 110 patients in each of the four treatment arms for the HLA-A2 positive group and 180 patients in each of the two treatment arms for the HLA-A2 negative group. Results ECOG reported that this study met its accrual goal and was permanently closed on October 31, Final accrual was 816 patients, including 114 by the Southwest Oncology Group. Final analysis is planned for April Accrual was steady over the course of the trial, and indicated that the use of a placebo control was feasible in this patient population. The final distribution of patients by stage and site of metastatic disease was somewhat different than originally anticipated, with only a minority of patients actually having resected stage IV disease. Nonetheless, this trial demonstrated the ability to conduct complex, placebo-controlled trials in patients with resected stage IV melanoma, as well as the ability to conduct vaccine trials in HLA-restricted subsets of patients. MELANOMA COMMITTEE MC- 9

10 S0808: Phase II Study of Biologic Correlates in Resected High Risk Patients with Melanoma (T4 and Stage III) Receiving Adjuvant High-Dose Interferon Alpha-2b (Proposed) Rationale High-dose IFN is the only FDA approved adjuvant treatment for patients with Stage IIB, IIC and III melanoma after surgical resection. A consistent prolongation of relapse free survival (RFS) has been associated with its use, which in a recent meta-analysis represented a relative RFS benefit of 26% (p = ) and a relative overall survival benefit of 15% (p = 0.06). New adjuvant treatments with improved efficacy compared to IFN would be most welcome. Phase III trial designs directly comparing a treatment of interest to IFN in this setting, however, would require over 1200 patients for an agent that had a 10% absolute benefit over IFN. Presently, while we await the results of S0008 and E4697, there are no candidate agents with sufficiently strong scientific rationale to justify conducting a phase III adjuvant trial of that size in the stage IIB/C and III patient population. Recently, Gogas et al reported that approximately 25% of stage IIB/C and III patients treated in Greece with adjuvant IFN developed clinical or serologic evidence of autoimmunity, and this development was strongly correlated with a favorable outcome: these patients had an 80% relapse free survival at 5 years. In contrast, the 75% who did not manifest autoimmunity had a 5-year relapse free survival of only 20%. Overall survival was also significantly better for those developing manifestations of autoimmunity during or after IFN. Important in their observations was the fact that approximately twothirds of the group developing autoimmunity did so by 3 months into IFN therapy. While these findings are striking, two serologic studies of IFN-treated patients by ECOG and the EORTC did not show associations of such magnitude, and the potential to exploit this observation regarding autoimmunity such as to identify patients who might benefit from switching from IFN to more intense therapies aimed at further stimulating autoimmunity remains unrealized. S0808 is designed to prospectively test the incidence and time course of autoimmunity associated with IFN, as well as assess whether developing autoimmunity correlates with outcome in North American patients. Patients will be treated with IFN for 12 months, based on standard indications for adjuvant therapy currently in use. Assessment of serologic autoimmunity (anti-thyroglobulin, anticardiolipin and antinuclear antibodies) at baseline and at 1, 3, 6, 9 and 12 months after beginning therapy will be performed. Clinical evidence of autoimmunity (e.g., hypothyroidism, depigmentation/vitiligo) will also be noted. The primary endpoint will be to evaluate patients for the development of autoimmunity at 3 months after beginning IFN. If it could be confirmed that a significant fraction of patients who are going to manifest autoimmunity do so by month 3, and that those who fail to manifest autoimmunity have a markedly worse outcome, a randomized clinical trial targeting the subset of autoimmunity negative patients for intensified therapy (e.g., anti-ctla4 antibody therapy, which is known to induce autoimmunity in melanoma patients). Such a trial design would require many fewer patients to be randomized by targeting a subset least likely to benefit from continued IFN treatment. In addition to the primary translational endpoints relating to autoimmunity, other correlative studies aimed at increasing our understanding of the mechanism of action of IFN and its relationship to autoimmunity will be incorporated into S0808. To ensure standardization and maximize the ability to validate the Gogas findings, autoantibodies will be measured in a centralized, CLIA-certified laboratory using the identical kits employed in Gogas study. In additional exploratory analyses, peripheral blood will be MELANOMA COMMITTEE MC- 10

11 obtained for HLA Class I and II and KIR polymorphisms, as well as other relevant polymorphisms for susceptibility to autoimmunity (e.g., CTLA4, PTNP22, NALP1, STAT3/4, FoxP3, TRAFR1-C5). Peripheral blood mononuclear cells for suppressor cells CD25+, FoxP3, CD45RO, GITR+ T cells will also be obtained. A requirement of this study will be the submission of tissue (formalin-fixed paraffin-embedded tumor blocks from the primary and/or lymph nodes), which will be used for studies of B-RAF and N- RAS mutations, PTEN loss and FISH/microarray CGH (already piloted in S9431) in hopes of developing new predictors of risk of relapse after surgery and/or profiles predictive of resistance or sensitivity to systemic treatment. If the S0808 trial confirms the role and timing of autoimmunity to IFN adjuvant therapy, it would lead to a paradigm shift in future adjuvant trial designs. On the one hand, it would identify patients whose benefit from IFN was more clear-cut and who should remain on standard therapy with good anticipated long term outcomes. Equally importantly, it would allow us to evaluate newer therapeutic treatments at an early time point (perhaps as early as 3 months after starting IFN) on the group of patients who are unlikely to benefit from IFN. This group s higher risk would allow us to conduct focused studies involving smaller patient numbers, with more rapid results. Objectives To assess the percentage of patients who develop autoimmunity during adjuvant highdose IFN as well as the time to development, the duration of autoimmunity and the type of autoimmunity that develops. To compare the relapse-free survival and overall survival in patients who develop autoimmunity during high-dose adjuvant IFN at 3 months to those patients who do not develop autoimmunity. Statistical Endpoints 250 evaluable patients are targeted for enrollment. The primary landmark analyses will be performed among patients who are alive, relapse-free and still on protocol at 3 months (the group planned to be targeted for a subsequent randomized trial). Based on data acquired in S0008, we assume that approximately 20% of the 250 eligible patients initially enrolled will either have had disease relapse by 3 months or will have dropped out due to toxicity or other reasons. Therefore, 200 patients will be available for the 3-month landmark analysis. To evaluate the validity of the reported findings of Gogas et al, both unadjusted and adjusted Cox model landmark analyses will be conducted to compare the autoimmune and non-autoimmune patients for relapse-free and overall survival. Status Report A letter of intent to conduct this trial has been submitted to CTEP and the protocol is currently in final development. Pilot funding to support the conduct of the proposed correlative studies has been obtained through a grant from the Hope Foundation, and additional funding is being sought. MELANOMA COMMITTEE MC- 11

12 ADVANCED DISEASE STUDIES S9430, Intergroup: A Phase II Trial of Complete Surgical Resection for Stage IV Melanoma: Surgical Resection with Biological Evaluation and Clinical Follow-Up (Activated: 11/15/1996; Permanently Closed: 11/15/2005) Rationale Increasingly, complete surgical resection is being advocated for patients with oligometastatic stage IV melanoma, but this approach has never been prospectively evaluated. Adjuvant trials that include patients with resected stage IV melanoma have provided evidence that survival is prolonged for these patients compared to those with unresected stage IV disease, but significant biases exist in these adjuvant trials: patients must have undergone successful surgery, survived and recovered from the aftereffects of surgery sufficiently to meet study entry criteria, and in almost all cases undergone repeat imaging to determine that they are in fact still disease-free after surgery. Thus, these studies do not allow us to estimate how many patients are actually resectable to a disease-free state, nor to estimate the relapse-free and overall survival for the entire cohort of patients subjected to surgery. Objectives To assess the overall survival and progression-free survival of patients with metastatic melanoma (beyond the draining lymph nodes) following complete surgical resection of all known disease. To determine the ability of the Southwest Oncology Group Melanoma Committee to enroll patients with metastatic melanoma who can be resected to a "disease-free" state, in order to assess the feasibility of future trials of specific interventions in this patient population. Results The final accrual was 77 patients. Three patients are ineligible, one due to unresectable brain metastases and two due to no evidence of Stage IV disease prior to surgery. After central review, 12 eligible patients were found to be not analyzable: nine who did not have disease completely resected and three whose specimen indicated no Stage IV disease. Surgical adverse events have been assessed for 61 evaluable patients. Five have experienced surgical adverse events including one Grade 4 pulmonary embolism. The estimated median progression-free survival is six months (95% confidence interval: 3-8 months), and the estimated median overall survival is 21 months (95% confidence interval: months). These results are far superior to what was observed in the cooperative group meta-analysis of systemic therapy of unresectable disease (median progression-free survival 1.7 months, median survival 6 months). Nonetheless, the relatively short duration of progression-free survival after surgery (6 months) justifies ongoing efforts to develop effective adjuvant therapies for this patient population, many of whom have already received IFN, such as the recently completed E4697 trial. MELANOMA COMMITTEE MC- 12

13 S9431, Intergroup: Cytogenetic, Molecular and Cellular Biology Studies in Metastatic Melanoma Patients, Ancillary (Activated: 11/15/1996; Permanently Closed: 12/15/2005) Schema S9035 FISH Analysis Submit: 1) Tumor block (collected as part of S9035) Project/ Parent Treatment Trial S9430 Other SWOG-coordinated melanoma treatment trial Submit: 1) Tumor block 2) Peripheral Blood (fresh tumor & snap frozen specimens optional) Submit: 1) Tumor block 2) Peripheral Blood 3) Fresh tumor specimen for cytogenetics 4) Snap frozen specimen Rationale The results of conventional therapies for treatment of metastatic melanoma have been largely disappointing. As previously described (S9430 above), patients with oligometastatic melanoma are increasingly being subjected to complete surgical resection as the primary treatment modality, with an apparent improved outcome compared to systemic therapy. But it is likely that patients with oligometastatic disease represent an inherently more favorable group, and if so there may be biologic factors that underlie this more favorable prognosis. Moreover, patients undergoing resection of metastatic disease present the opportunity to obtain tumor, serum and peripheral blood specimens for biologic characterization. S9431 was designed as a biologic companion to S9430, but was expanded to incorporate patients enrolled onto other SWOG stage IV melanoma trials and also patients enrolled on the S9035 adjuvant vaccine trial. Objectives To obtain paraffin-embedded tumor blocks, peripheral blood, and sera from patients with metastatic melanoma to form a tissue, cell and serum bank for future studies. To characterize the frequency of non-random cytogenetic abnormalities in regional and distant melanoma metastases and explore their association with clinical outcome of melanoma patients enrolled onto Southwest Oncology Group trials. To characterize the frequency of specific genetic alterations at either the DNA, mrna, or protein level and explore the association of these abnormalities with clinical outcome in patients with regional and distant metastases who are enrolled on Southwest Oncology Group melanoma trials. Attempt to correlate the most prevalent gene copy alterations observed in metastatic disease with the risk of progression in paraffin embedded tissue samples collected in S9035 in patients with primary melanoma ( mm). To characterize the host immunologic response to metastatic melanoma by determining whether the in-vivo pattern of cytokine expression is consistent with specific subsets of T helper cells (TH1 or TH2) within melanoma deposits. MELANOMA COMMITTEE MC- 13

14 To explore whether host immunologic response varies based on the site of metastatic disease and/or correlates with clinical outcome in patients enrolled on Southwest Oncology Group trials. Results This study was permanently closed on December 15, 2005, due to the closure of the associated treatment protocols. The final accrual was 91 patients. Five patients are ineligible: one who did not register to any Southwest Oncology Group coordinated melanoma treatment trial and four who were registered but never submitted specimens. Two eligible patients changed their minds after submitting samples for S9431, refusing registration to trial S0008 and are not analyzable. The collection of tumor specimens from surgery allowed the investigation of fluorescence in situ hybridization (FISH) and array comparative genomic hybridization to identify potentially relevant amplified or deleted genes. The results, published in Clinical Cancer Research, examined 16 selected gene loci on 8 chromosomes in a total of 19 specimens from individual patients enrolled onto S9341. Target genes were selected based on their known association with melanoma and/or melanocyte biology. Major alterations in copy number included gains in NEDD9, EGFR. MET and MYC and losses in CDKN2a, CCND3, WISP3, MLANA and APAF-1. CGH confirmed the results obtained with FISH. The ultimate goal is to predict DFS and OS outcomes for subsets of stage IV patients based on both clinical and biologic characteristics S0438, Intergroup: A Randomized Phase II Trial of BAY (Sorafenib; NSC ) with CCI-779 (Temsirolimus; NSC ) or R (Tipifarnib; NSC ) in Metastatic Melanoma (Activated: 08/01/2007) Schema Rationale Cytotoxic agents and immunotherapy strategies have not provided promising results in advanced melanoma. Recent improvements in the understanding of melanoma biology have provided a rationale for the design of therapies based on inhibition of essential molecular pathways that melanoma cells but not somatic cells depend on for survival, invasion and avoidance of apoptosis. In solid tumors, mutations that activate a single pathway are rarely sufficient to achieve and maintain tumorigenesis, so therapeutic interruption of a single pathway rarely results in major tumor regression or prolonged growth suppression, because other pathways can be altered to compensate and maintain tumor viability. While evidence of melanoma subsets that may be driven by a single pathway mutation has recently emerged, the separation of patients into therapeutic groups based on molecular analysis has not yet become clinically practical, so the heterogeneity of molecular subsets is another justification for attempting population coverage with combinations of agents. Optimal targeting of two or more pathways can be vertical by inhibiting two members of the same pathway, or horizontal by inhibiting parallel pathways. Specific genetic alterations found in melanoma include MELANOMA COMMITTEE MC- 14

15 1) Constitutive BRAF (a member of the MAPK pathway) activation by mutation at V600E 2) Genetic alterations in the PTEN gene leading to overactivation of downstream AKT and of the multifunctional mtor kinase 3) Mutations conferring constitutive activation of the N-Ras GTPase, which is upstream of MAPK and is activated by many growth factor and other cellular signals The concept for S0438 derived from data regarding the role played by these pathways in melanoma and the availability of agents (investigational at that time, now approved for renal cancer and other malignancies) that target the above pathways. Phase II trials were underway for each of the single agents in melanoma that later showed minimal activity in unselected groups of patients. For combinations, it was originally suggested by investigators at CTEP that full or near-full phase II doses could be combined for each of the agents in two-drug combinations. However, unexpectedly severe and overlapping (additive) toxicities became apparent in Phase I trials that had to be addressed before S0438, which was approved in concept in 2004 and written in 2005, could be activated. The 2 regimens chosen for evaluation in S0438 contain sorafenib, an inhibitor of BRAF that also inhibits several other cellular kinases, including c-kit, which may prove to be important in a subset of melanoma patients. The addition of tipifarnib, an inhibitor of Ras, is used to provide vertical inhibition through the MAPK pathway, while the addition of temsirolimus, an mtor inhibitor, represents horizontal inhibition of two separate pathways. This study provides for collection of blood and paraffin-embedded tissue as part of an ongoing CTEP initiative for molecularly targeted combinations. Objectives To assess the response rate (confirmed and unconfirmed, complete and partial response) and four-month progression-free survival rate of metastatic melanoma to BAY (sorafenib) plus CCI-779 (temsirolimus) or BAY (sorafenib) plus R (tipifarnib) and select the more promising regimen. To assess the safety and tolerability of therapy with these combinations, with an emphasis on long-term side-effects and toxicities. To investigate the relationship between tumor and blood biomarkers and clinical outcomes of patients treated with each combination of targeted agents. Statistical Endpoints Initially 30 eligible patients will be enrolled to each arm. If at least three responses are observed or at least nine patients are alive and progression-free at four months, 25 additional patients will be enrolled to that arm. Therefore, if both arms reach their second stage of accrual, a total of 110 eligible patients will be enrolled. Status Report Early in the development of S0438, at the request of NCI/CTEP, the American College of Radiology Imaging Network (ACRIN) approached the group with an offer to fund a series of correlative PET scans to assess tumor response to therapy by functional radiology. PET scanning has proven highly valuable in melanoma due to the high FDG avidity of melanoma tumor deposits and the widespread metastatic pattern that can result in deposits outside the confines of a traditional chest, abdomen and pelvis CT scan. PET could also be used for investigation of early changes in tumor viability in this study, analogous to the approach that has proven useful in GIST and lymphoma. After extensive discussions to complete the radiologic portion of the protocol, ACRIN concluded that the burden of assuring institutional certification was insurmountable and withdrew funding for PET scans on S0438. The study has since opened and has accrued MELANOMA COMMITTEE MC- 15

16 briskly, with 47 patients enrolled as of December 5, Importantly, this trial has been successful in obtaining biospecimens from participating patients for translational studies. As of November 19, 2008, the NCI-designated biospecimen repository for this study reports they have received 37 patient submissions including the following biospecimens: 18 paraffin embedded blocks, 81 stained slides, 199 unstained slides, 37 blood samples, 101 plasma aliquots and 91 serum aliquots. S0508: A Phase II Trial of Combination Thalidomide Plus Temozolomide in Patients with Metastatic Malignant Melanoma (Activated: 06/01/2005; Permanently Closed: 01/01/2007) Rationale Temozolomide, an oral congener of DTIC that can penetrate the blood-brain barrier and achieve significant levels of active metabolites inside the central nervous system, has activity against non-cns metastatic melanoma that is comparable to DTIC in prospective randomized trials. Single-institution nonrandomized trials suggested that the combination of temozolomide with another oral agent, thalidomide, was associated with superior response rates and time to progression. Despite a lack of prospective confirmation, this oral combination regimen rapidly became a community standard for patients with unresectable metastatic melanoma. The SWOG Melanoma Committee felt that prospective evaluation of this regimen was warranted, but that the available evidence did not support the conduct of a phase III trial. Rather, we elected to proceed with an adequately powered phase II trial to determine if the six-month progression-free survival of patients treated with this combination was sufficiently promising to justify a phase III trial. This approach is similar to the manner in which we chose to evaluate another community standard combination regimen the Dartmouth regimen in the prior grant funding cycle. S9348, with 79 eligible patients, demonstrated that this four-drug chemohormonal therapy regimen was not sufficiently promising to justify a phase III trial. That conclusion was subsequently validated when an ECOG/Hoosier Oncology Group randomized phase III trial involving 240 patients concluded that the Dartmouth regimen was not superior to DTIC alone in either response rate or overall survival but was more toxic. Objectives To assess the six-month progression-free survival in patients with metastatic malignant melanoma treated with the combination of oral thalidomide and temozolomide. To evaluate response probability (confirmed and unconfirmed, complete and partial responses) in the subset of patients with measurable disease. To assess the overall survival. To assess the qualitative and quantitative toxicities. To investigate in a preliminary manner: a) peripheral blood content as a percentage and as an absolute count of CD4+/CD25+/CD69+ and CD16+/CD56+ cells at baseline and at five, nine, and thirteen weeks; b) ELISPOT reactivity to a recall pool of antigens defined by the CEF pool consisting of 32 cytomegalovirus, EBV and influenza virus peptides at baseline and at five, nine, and thirteen weeks; c) the relationship between the biomarkers mentioned previously and clinical outcomes. Statistical Endpoints The accrual goal is 55 eligible patients. MELANOMA COMMITTEE MC- 16

17 Results This study was permanently closed on January 1, 2007, having reached its accrual goal. Final accrual was 64 patients. Two patients are currently ineligible due to insufficient documentation of baseline disease. In addition, two eligible patients who withdrew their consent never received any protocol treatment and are not evaluable for any of the study endpoints. Sixty patients have been assessed for adverse events. There has been one treatment-related death, due to cardiac ischemia/infarction along with Grade 4 thrombosis/embolism. An additional two patients have experienced Grade 4 adverse events, including one case each of neutropenia and CNS ischemia. Fifty-two patients had measurable disease at baseline and are included in the response analysis. Six of these patients could not have their exact response determined due to inadequate disease assessments and are counted as non-responders. There were seven partial responses for an estimated response rate of 13% (95% confidence interval: 6% - 26%). The estimated 6-month progression-free survival is 15% (95% confidence interval: 6% - 24%) and the estimated one-year overall survival is 35% (95% confidence interval: 23% - 48%). Based on these results, use of this combination regimen is not recommended nor is further evaluation in a phase III trial appropriate. Peripheral blood samples were obtained for approximately 1/3 of the 60 patients before and following therapy (at week 5, 9 and 13). The phenotyping of circulating mononuclear cells revealed a statistically significant association (p=0.048) of response (PR, CR) with declines levels of CD4/CD25+ (T regulatory) cells Other studies evaluating a panel of circulating cytokines including IL-2, IL-4, IL-5, IL-6, IL-10, TNF-α and IFN-γ showed an association with response only for IL-10. At week 5, this was statistically significant. These results, while highly exploratory in nature, illustrate the potential that profiling the cellular and cytokine response to immunologic and cytotoxic therapies could have in predicting response in melanoma patients. E3695, Intergroup: A Randomized Phase III Trial of Concurrent Biochemotherapy with Cisplatin, Vinblastine, Dacarbazine, IL-2 and Interferon Alpha-2b versus Cisplatin, Vinblastine, Dacarbazine Alone in Patients with Metastatic Malignant Melanoma (Activated: 10/15/1997; Permanently Closed: 04/17/2002) Rationale Combination chemotherapy, although commonly employed for patients with metastatic melanoma, has never been shown to convey a significant advantage over single agent therapy such as DTIC or interleukin-2. IL-2 has single agent activity in stage IV melanoma patients, with a durable complete response rate of 6%. Many investigators world-wide have combined IL-2 with chemotherapy and IFN in multi-agent regimens referred to as biochemotherapy. Over 1,000 patients have been treated on phase II institutional trials demonstrating response rates in the 30-60% range with durable complete remissions of approximately 10%. A meta-analysis by Allen at al involving over 7,000 patients in 154 different studies identified that the highest response rates (47%) were found when IL-2 was combined with IFN, cisplatin and DTIC. Response duration for IL-2, IFN and chemotherapy (10.0) months were statistically superior (p<0.05) to either IL- 2 alone or chemotherapy alone. The best way to sequence biologic and chemotherapeutic agents has been an area of interest. Legha et al piloted several institutional IL-2 biochemotherapy trials with IFN, DTIC and cisplatin and found the greatest benefit with regimens in which the chemotherapy was either given first or concurrently with IL-2. Atkins et al were able to demonstrate equivalent effectiveness with a 5-day regimen which could be administered every 21 days. Modifications which MELANOMA COMMITTEE MC- 17

18 included prophylactic antibiotics, replacement of central lines, aggressive hydration and antiemetic use, along with the use of growth factor support and strict dose modifications made these regimens acceptable for cooperative group use. This provided the opportunity and a strong rationale to evaluate the addition of IL-2 and IFN to chemotherapy in a prospective, randomized phase III trial. Although combination chemotherapy has never been shown to be superior to DTIC alone, the combination of cisplatin, vinblastine and DTIC (CVD) was chosen for the control arm to rigorously test the value of adding immunotherapeutic agents to cytotoxic chemotherapy. Objectives To determine whether an inpatient biochemotherapy of CVD + IL-2/interferon alpha- 2b/G-CSF is superior to CVD alone based on survival in patients with metastatic malignant melanoma. To determine whether this inpatient biochemotherapy is superior to CVD alone based on response rate, response duration, time to treatment failure, percent CR and percent durable CR. To determine the feasibility of administering this inpatient biochemotherapy regimen to patients with metastatic malignant melanoma in an intergroup multicenter setting. To determine the toxicity of this inpatient biochemotherapy regimen relative to CVD alone. Statistical Endpoints Four hundred sixty-eight eligible patients will be accrued to this study over a 40-month period. Interim analyses will be performed approximately 12, 19, and 26 months after the trial opens. Results This study was permanently closed April 17, 2002 based on the recommendation of the ECOG Data Monitoring Committee. A total of 415 patients had registered to this study (172 from the Southwest Oncology Group) prior to the early closure. On April 3, 2002, the ECOG Data Monitoring Committee reviewed interim results from E3695. Based on this analysis, the ECOG Data Monitoring Committee recommended that the study be closed to further accrual, and that continued treatment on the biochemotherapy arm should be left to the discretion of the patient and the treating physician. The rationale for this decision was explained in a letter from ECOG addressed to physician participants: "E3695 was designed to have an 85% power to detect a 33% improvement in median survival (from 9 months on the standard chemotherapy arm to 12 months on the biochemotherapy arm). The study employed a sequential monitoring scheme utilizing Pampallona-Tsiatis methodology to allow early stopping if interim results established either that biochemotherapy was superior to standard chemotherapy (the upper boundary) or that biochemotherapy was unlikely to prove superior to standard chemotherapy treatment (the lower boundary). In the current [April 3, 2002] interim results, at 63% of the total planned information, the test statistic for the overall survival endpoint crossed the lower Pampallona-Tsiatis boundary. Also, the overall difference between the two treatments corresponded to a 2% improvement in median survival for the biochemotherapy arm, rather than the desired [hypothesized] 33% improvement. These findings suggest that it is unlikely that the biochemotherapy arm will result in the desired improvement in overall survival. The analysis, however, did not suggest that the biochemotherapy arm was inferior to the chemotherapy arm for overall survival." MELANOMA COMMITTEE MC- 18