Melanoma in 2009: therapeutic p rogress on two fronts tumor and - PowerPoint PPT Presentation

Melanoma in 2009: therapeutic p rogress on two fronts — tumor and host John M. Kirkwood, MD Director, Melanoma and Skin Cancer Program University of Pittsburgh Cancer Institute Professor and Vice Chairman for Clinical Research Departments of Medicine and Dermatology University of Pittsburgh School of Medicine Chair, Melanoma Committee Eastern Cooperative Oncology Group kirkwood@pitt.edu

Systemic therapies for melanoma are needed • One FDA-approved cytotoxic agent in use – Dacarbazine (Temozolomide): 6.8-15% response rate in modern trials, rarely durable • Never compared to observation or supportive care • Temozolomide no better than dacarbazine (Patel 2008) • One therapy approved in modern times – High-dose IL-2: 16% response rate and ~6% durable as tested in collected phase II trials • No phase III trial previously conducted • Phase III trial building on IL-2 first reported by Schwartzentruber et al., ASCO 2009 Atkins et al., JCO 1999 Luikart, Kirkwood, JCO 1984; Hill et al Cancer 1984 (n=580); Middleton et al., JCO 2001;Avril et al., JCO 2004; Patel et al ESMO 2008

What have we learned in the past 35 years of phase II clinical trials? • Meta-analysis of 42 Phase II trials of SWOG, ECOG, CALGB, NCCTG, and NCIC-CTG between 1975 and 2005 • Benchmarks for overall survival (OS) , and progression-free survival (PFS) endpoints sought for future phase II trials – 1-year OS rate – 6-month PFS rate

New benchmarks for Phase II trials Survival at 1 year; Progression-free Survival at 6 mos Progression Free Survival at 1 year = 25% Survival at 1 year = 15% Six month PFS  15% One year OS  25% Numbers of patients  Numbers of patients  Meta-analysis of 70 Phase II Trials in 2100 Patients over past 35 Years Korn…Kirkwood, J. Clin. Onc, 2008

Current Therapy of Metastatic Melanoma • Systemic therapy does not alter natural history of advanced melanoma – Dacarbazine (Temozolomide) palliative in a minority of patients – High-dose IL-2 cures a small ~6% fraction of patients • No established mechanistic basis or predictive factors established • VEGF a suggested potential biomarker of resistance (Sabatini, JCO 2009) • Gp100 vaccine adds to IL-2 (Schwartzentruber, Proc. ASCO 2009) – Phase III trials negative to date • Chemotherapy (dacarbazine) plus antisense Bcl-2 (Genasense) 2006 • Chemobiotherapy (Cisplatin, Vinblastine, DTIC, IL-2, IFN 2008 • Chemotherapy (Paclitaxel) plus elesclomol 2009 Chemotherapy (Paclitaxel and Carboplatin) +/- Sorafenib E2603 – Pending Phase III results Sabatini et al., J Clin Onc 2009 • Ab-Paclitaxel Kirkwood and Tarhini, JCO 2009 • CTLA4 blocking antibodies Bedekian et al JCO 2007 • Allovectin B7

A Randomized, Double-blind, Phase 3 Trial of STA-4783 (elesclomol) in Combination with Paclitaxel versus Paclitaxel Alone for Treatment of Patients with Stage IV Metastatic Melanoma (SYMMETRY) Review of Preliminary Data A. Hauschild, A.M. Eggermont, E. Jacobson, S. O ’ Day. University of Kiel, Kiel, Germany; Erasmus University Medical Center, Rotterdam, The Netherlands; Synta Pharmaceuticals, Lexington, MA; The Angeles Clinic and Research Institute, Santa Monica, CA On behalf of the SYMMETRY Trial Investigators

Elesclomol: Mechanism of Action • Elesclomol is an investigational drug candidate that induces oxidative stress (reactive oxygen species, ROS) 1 • Oxidative stress induction represents a potential novel way of selectively targeting and killing cancer cells • Cancer cells produce higher levels of reactive oxygen species (ROS) than normal cells, making them potentially more susceptible to further oxidative stress and ROS mediated apoptosis 2 • Elevation of ROS may facilitate the ability of taxanes to induce apoptosis through the intrinsic mitochondrial pathway 3 • Preclinical in vivo studies demonstrated synergistic efficacy of paclitaxel and elesclomol in a variety of solid tumor models, including melanoma 1. Kirshner et al . (2008) Molecular Cancer Therapy 7:2319-2327 2. Kong et al . (2000) Medical Hypothesis 55:29-35; Pelicano et al. (2004) Drug Resistance Updates 7:97-110 3. Ramanathan et al . (2005) Cancer Research 65:8455-8460

Elesclomol-ROS- apoptosis pathway Elesclomol ROS Increase  Pro-apoptotic factors (Bax) H 2 O 2 , OH, O -  Anti-apoptotic factors (Bcl-2; XIAP) Cyt C Opening of (1) Direct mitochondrial apoptosis membrane pores induction Apoptosis Caspase Cyt C cascade

Elesclomol-ROS- apoptosis pathway Chemotherapy agents Elesclomol acting through intrinsic mitochondria apoptosis pathway (taxanes) ROS Increase  Pro-apoptotic factors (Bax) H 2 O 2 , OH, O -  Anti-apoptotic factors (2) Enhancement (Bcl-2; XIAP) of chemo-driven Cyt C apoptosis Opening of (1) Direct mitochondrial apoptosis membrane pores induction Apoptosis Caspase Cyt C cascade

A multi-center, randomized Phase 2 trial of elesclomol in combination with paclitaxel for the treatment of patients with metastatic melanoma • Double-blind, randomized, controlled; 21 centers in U.S. • Cross-over for paclitaxel alone arm after PD Study Population paclitaxel 80 mg/m 2 • Stage IV + metastatic elesclomol 213 mg/m 2 melanoma Randomization (N=53) • 0-1 prior Primary 2:1 chemo for endpoint: qw for 3 weeks; 1 week off metastatic (N=81) disease Progression- • ECOG PS 0-2 free survival • No brain mets paclitaxel 80 mg/m 2 (N=28) Principal Investigator: Steven O’Day, M.D., The Angeles Clinic and Research Institute (Los Angeles, CA) Ref: O’Day, et al. JCO in press

Kaplan-Meier Plot of Progression-Free Survival ITT population ELPAC PAC (N=53) (N=28) Median (months) 3.7 1.8 (2.5 – 5.5) (1.6 – 3.4) 95% CI 6 Month PFS Rate 35% 15% HR (ELPAC vs. PAC) 0.58 (0.35 – 0.97) 95% CI p-value 0.035 *Chemo-Naïve subgroup had a significantly higher median Ref: O’Day, et al. JCO in press PFS which led to the chemo-naïve patient population for the SYMMETRY study

A Randomized, Double-blind, Phase 3 Trial of STA-4783 (elesclomol) in Combination with Paclitaxel versus Paclitaxel Alone for Treatment of Patients with Stage IV Metastatic Melanoma (SYMMETRY) Review of Preliminary Data

SYMMETRY Study design • 160 centers in 15 countries • Tumor Assessment: at baseline and every 8 weeks from time of randomization (RECIST) • No patient cross-over Study Population paclitaxel 80mg/m 2 + Randomization • Stage IV elesclomol 213 mg/m 2 1:1 metastatic (N=315) (N=630) Primary melanoma endpoint: • Chemo-naïve qw for 3 weeks; 1 week off Stratification Factors • LDH ≤ 2x ULN • LDH status Progression- • M1 subclass • ECOG PS 0-2 free survival • Prior permitted • Absence of paclitaxel 80mg/m 2 (non-chemo) therapy* CNS mets (N=315) * Kinase inhibitor, immunotherapy, biologic therapy, vaccine, or investigational non-chemo Study Steering Committee: Steven O’Day, Axel Hauschild, Alexander Eggermont

Subject Accrual, Randomization, and Treatment *Data cut April 2009 • Accrual period: Sep 2007- Feb Enrolled 2009 (N = 651) ITT- all randomized • Peak accrual: June 08-Jan09 * N=621 Safety- received at least 1 dose 1:1 Randomization ELPAC PAC alone ITT (n = 309) (n = 312) ELPAC PAC alone Safety (n = 304) (n = 311) PD PD Symptomatic Symptomatic (n = 157) Deterioration Deterioration (n = 186) (n=10) (n=6) Died Died Adverse Adverse (n=5) (n = 1) Event (n = 15) Event (n = 13) Other Other Withdrew Withdrew (n=8) (n=4) consent consent (n = 9) (n = 5) Sponsor Sponsor Decision Decision (n=105) (n=97)

Progression-Free Survival - ITT Population ELPAC PAC Events/Number at risk 170/309 192/312 Median (months) 3.4 1.9 95% CI (2.6 - 3.6) (1.9 - 2.9) 6 Month PFS Rate 23% 17% HR (ELPAC vs. PAC) 0.84 (0.68 – 1.04) 95% CI p-value (Stratified Log-Rank) 0.1107 Subjects at Risk PAC 312 200 87 42 20 8 2 2 1 0 0 ELPAC 309 187 107 53 21 10 6 3 2 2 0

Overall Survival: Not Yet Mature Currently Favors PAC Arm ITT Population (N=651) Data Cut % censored HR p-value (CI) 80% 1.62* 0.0068 Feb 2009 (1.14 - 2.31) 72% 1.31 0.0719 April 2009 (0.98 - 1.76) Pts enrolled as of Sep 1, 2008 (N=300) Data Cut % censored HR p-value (CI) Feb 2009 63% 1.28 0.1930 (0.88 - 1.87) April 2009 54% 1.22 0.2552 (0.87 - 1.71) * There were 80 OS events in the ELPAC arm vs. 53 OS events in the PAC arm

Conclusions • Despite a trend in improvement of PFS, elesclomol in combination with paclitaxel (ELPAC) failed to demonstrate a statistically significant improvement when compared with paclitaxel alone in chemo-naive patients with metastatic melanoma • There was a statistically significant increase in PFS with ELPAC in the subgroup of patients with normal LDH (68% of the ITT, pre-specified exploratory analysis) • An imbalance in deaths favoring the paclitaxel arm was observed, leading to early study termination • No organ-specific toxicities have been identified that explain the observed imbalance in deaths at this time; safety data is continuing to be evaluated • At this point OS data is not mature; mature data will be presented at a future scientific meeting

Prediction of response to alkylator-based chemotherapy in metastatic melanoma (MM) using gene expression and promoter methylation signatures (ASCO #9009) Hussein Tawbi MD, MS H. Tawbi, S. Buch, P. Pancoska, Y. Lin, M. Saul, M. Romkes, R. Sobol, J. Kirkwood University of Pittsburgh Melanoma and Skin Cancer Program Tawbi et al., Proc ASCO 2009 #9009