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1 Albumin-Bound Paclitaxel for the Treatment of Melanoma Clinical data 2 Chemotherapy in Metastatic Melanoma: Survival Outcomes Phase II/III Trials Author No. Patients Evaluable di Pietro1 Median PFS or TTP Median OS Agents Dose 36 DTIC BEV 800 mg/m2 q 4 weeks 10 mg/kg q 2 weeks 6 mo (TTP) 16.5 mo von Moos2 SAKK 50/07 trial 62 TMZ BEV 150 mg/m2 days 1-7 (q 2 w) 10 mg/kg q 2 weeks 4.2 mo 9.3 mo Perez3 NCCTG –NO47A trial 53 Paclitaxel Carboplatin BEV 80 mg/m2 d. 1,8,15 (q 4 w) AUC 6 (q 4 w) 10 mg/kg q 2 weeks 6 mo 12 mo O’Day4 214 Paclitaxel Carboplatin BEV 175 mg/m2 q 3 weeks AUC 5 q 3 weeks 15 mg/kg q 3 weeks 5.6 mo 12.3 mo Hauschild5 270 Paclitaxel Carboplatin Sorafenib 225 mg/m2 q 3 weeks AUC 6 q 3 weeks 400 mg BID d2-19 (q 3 w) 17.4 weeks 42 weeks AUC, area under the curve; BEV, bevacizumab; BID, twice daily; DTIC, dacarbazine; TMZ, temozolomide; TTP, time to progression. 1.Di Pietro A, et al. J Clin Oncol 2010;28:15s [abstr. 8536]. 2. von Moos R, et al. Ann Oncol 2011:epub. 3. Perez D.G, et al. Cancer 2009 Jan 1;115(1):119-27. 4. O’Day K, et al. Eur J Cancer 2009; Supplement 7:13. 5. Hauschild A, et al. J Clin Oncol. 2009 ;27:2823-30. 2 3 Rationale for NAB-Paclitaxel in Melanoma • Dacarbazine is frequently used in the care of malignant melanoma1 • As a single agent, paclitaxel has been reported to have limited activity in patients with malignant melanoma2-5 • In a phase I study of AB-paclitaxel in patients with advanced solid tumors, 3 of 14 patients with malignant melanoma experienced disease stabilization for > 4 months6 • In a phase 2 study of AB-paclitaxel in patients with metastatic melanoma, activity was seen in both previously treated (PT) and chemotherapy-naïve (CN) populations7 – PT: Median PFS 3.5 months, median OS 12.1 months – CN: Median PFS 4.5 months, median OS 9.6 months – Results compare favorably with previous reports of standard dacarbazine or temozolomide8,9 • Median PFS ≈1.6 months • Median OS < 8 months AB, albumin-bound; OS, overall survival; PFS, progression-free survival. 1. NCCN Clinical Practice Guidelines in Oncology: Melanoma, v4.2011. 2. Bedikian AY, et al. Melanoma Res. 2004;14:63-66. 3. Einzig AI, et al. Invest New Drugs. 1991;9:59-64. 4. Legha SS, et al. Cancer. 1990;65:2478-2481. 5. Walker L, et al. Melanoma Res. 2005;15:453-459. 6. Nyman DW, et al. J Clin Oncol. 2005;23:7785-7793. 7. Hersh EM, et al. Cancer. 2010;116:3.155-163. 8. Bedikian AY, et al. J Clin Oncol. 2006;24:3738-4745. 9. Middleton MR, et al. J Clin Oncol. 2000;18:158-166. 4 nab-paclitaxel in Metastatic Melanoma Trial Description N Dose ORR • Chemonaive: ABX 100 and 10 (25.6%) carboplatin AUC 2 administered on • Previously days 1, 8, and 15 treated: 3 every 28 days (8.8%) mg/m2 Phase II ABX + Carboplatin in Unresectable Advanced Melanoma A Randomized Phase II Trial of Emosolomide (TMZ) and Avastin or ABI-007/Carboplatin (CBDCA) and Avastin in Patients with Unresectable Stage IV Malignant Melanoma (N0775) A Pilot Study of nab-paclitaxel® (Albumin-bound Paclitaxel) and Temodar® (Temozolomide) plus Genasense® (Oblimersen Sodium) in Subjects with Advanced Melanoma (“The ATG Study”) Phase II Study of nab-paclitaxel® and Avastin as Therapy for Patients with Metastatic Melanoma 76 94 Carboplatin (AUC 6; day 1), ABX (100mg/m2 days 1, 8 and 15), and • 17 (33%) Avastin (10mg/kg on days 1 and 15) every 28 days 32 ABX 175 mg/m2 or 260 mg/m2 d8 +d29 Temo 75 mg/m2 Obl 7 mg/kg/day CIV or 900 mg IV over 1 hour 50 ABX 150mg/m2 d 1, 8, 15 and Avastin10mg/kg d 1 and 15, 28d cycle • 12 (31%) • 18 (36%) PFS • Chemonaive: 4.5 mo OS • Chemonaive: 11.1 mo • Previously • Previously treated: 10.9 treated: 4.1 mo mo • 6.6 mo • PFS at 6 mo: 54.9% • NR • 7.6 mo Abstract/ Publication • Published Cancer 2011; 117:1704-10. • 13.9 mo • ASCO 2011 [abstract #8532 Kottschade] • Manuscript in development • 14.7 mo • ASCO 2009 • ASCO 2010 [abstract #8561] • ASCO 2011 [abstract 8545 Chang] • Manuscript in development • 16.8 mo • ASCO 2011 [abstract #8543 Boasberg] • Manuscript in development 4 5 Melanoma: new chemotherapeutical approaches A PHASE 2 CLINICAL TRIAL OF NAB-PACLITAXEL IN PREVIOUSLY TREATED AND CHEMOTHERAPY-NAIVE PTS WITH MM HERSH ET AL, CANCER 2010 A PHASE II TRIAL OF NAB-PACLITAXEL (ABI-007) AND CARBOPLATIN IN PTS WITH MM: A NORTH CENTRAL CANCER TREATMENT GROUP STUDY, N057E1 KOTTSCHADE ET AL, CANCER 2011 AN OPEN-LABEL MULTICENTRE, PHASE III TRIAL OF ABI-007 (nab-paclitaxel) VS DACARBAZINE IN PREVIOUSLY UNTREATED MM PTS ON GOING 6 A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naive pts with Metastatic Melanoma Hersh et al. Cancer 2010, 116 (1): 155-63 7 nab-paclitaxel in previously treated and chemotherapynaive pts with Metastatic Melanoma Objectives Primary objectives – to evaluate the antitumor activity and safety/tolerability of nab-paclitaxel® on a schedule of qw for 3 wks out of 4 (one cycle) in each cohort • 100 mg/m2 previously treated • 150 mg/m2 chemotherapy naïve Secondary objectives – to evaluate PFS in each cohort – to evaluate OS in each cohort Hersh et al. Cancer 2010, 116 (1): 155-63 8 A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naive pts with MM METHODS: nab-Paclitaxel iv weekly for 3 of 4 weeks at a dose of 100/150 mg/m2 (in previously treated/naive pts) RESULTS: 37 treated (PT) pts - OR: - OR+SD: - PFS: - OS: 2.7% 37.8% 3.5 months 12.1 months 37 chemonaive (CN) pts 21.6% 48.6% 4.5 months 9.6 months 22% chemotherapy-naive patients discontinued therapy because of toxicities (grade 3 to 4 neuropathy, alopecia, neutropenia, and fatigue) CONCLUSIONS: nab-Paclitaxel was found to be well tolerated and demonstrated activity in both previously treated and chemotherapy-naive patients with MM. Hersh et al. Cancer 2010, 116 (1): 155-63 9 Study Design and Objectives • Study design: a multi-center phase II trial of albumin-bound paclitaxel in patients with metastatic melanoma – N = 74 – Patients with ECOG PS 0-1, adequate organ function and histologically confirmed malignant melanoma either previously treated with chemotherapy or chemotherapy-naïve – Cycles of 28 days until disease progression or dose-limiting toxicity PT Cohort Albumin-bound paclitaxel 100 mg/m2 Days 1, 8, and 15 CN Cohort Albumin-bound paclitaxel 150 mg/m2 Days 1,8 and 15 • Objective: to investigate safety and efficacy of this regimen in patients with metastatic melanoma • Primary endpoint: safety • Secondary endpoints: PFS, OS ECOG PS, Eastern Cooperative Oncology Group performance status; ORR, overall response rate; OS, overall survival; PFS, progression-free survival. Hersh et al. Cancer 2010, 116 (1): 155-63 10 Efficacy and tolerability of nab-paclitaxel in PT and CN metastatic melanoma patients Hersh et al. Cancer 2010, 116 (1): 155-63 11 Median PFS and OS Hersh et al. Cancer 2010, 116 (1): 155-63 12 Safety nab-paclitaxel’s patients Main most common treatment-related adverse eventsa, ≥ grade 3, % PT CN Neutropenia 14 40 Febrile neutropenia 0 3 Sensory neuropathy 5 19 Adverse events reported to be probably, possibly, or definitely related to study treatment; only grade 3 or higher adverse events shown. • 22% of chemo-naïve pts discontinued treatment due to toxicity Hersh et al. Cancer 2010, 116 (1): 155-63 13 Phase 2 Trial of nab-paclitaxel in previously treated or chemotherapy naïve metastatic melanoma (CA014) Summary Design • Phase 2, metastatic melanoma, PS 0-1 • N=74 • ABX 100 mg/m2 (3 wk on/1 wk off) in previously treated pts (N=37) • Mean age 56 yrs, 70% visceral mets, 62% elevated LDH • ABX 150 mg/m2 (3 wk on/ 1 wk off) in chemonaïve pts (N=37) • Mean age 61 yrs, 81% visceral mets, 51% elevated LDH Response Safety Response in previously treated and chemo-naïve pts: • ORR = 2.7% and 22% • Median PFS: 3.5 and 4.5 mo • Median OS: 12.1 and 9.6 mo • 1 yr survival: 49% and 41% • Response duration: 13 and 25 mo • Stable disease for ≥16 wk: 35% and 27% • 11% of chemo-naïve pts were stable for ≥12 mo Safety in previously treated and chemo-naïve pts: • Gr 3/4 Neutropenia: 14% and 40% • Gr 3 Febrile Neutropenia: 0 and 3% • Gr 3/4 Sensory Neuropathy: 5% and 19% • 22% of chemonaïve pts discontinued treatment due to toxicity ABX, nab-paclitaxel; DLT, dose limiting toxicity; MTD, maximum tolerated dose; ORR, overall response rate; OS, overall survival; PC, pancreatic cancer; PS, performance status; pts, patients; SPARC, secreted protein acidic and rich in cysteine. Key Points • Both ORR and PFS compare favorably with dacarbazine, single-agent paclitaxel, and combination regimens • Slow progression or long disease stabilization observed in substantial number of pts Hersh E.M, et al. Cancer 2010;116:155-63. 13 14 A phase II trial of nab-paclitaxel and carboplatin in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group Study, N057E(1): ABX054 Kottschade L.A, et al. Cancer 2011;117:1704-10. 15 Study Design and Objectives • Study design: a multi-center phase II trial of albumin-bound paclitaxel plus carboplatin in patients with unresectable stage IV melanoma – N = 76 – Patients with ECOG PS 0-2, adequate organ function and histologically confirmed stage IV melanoma either previously treated with chemotherapy (Cohort 1, PT) or chemotherapy-naïve (Cohort 2, CN) – Cycles of 28 days until disease progression or dose-limiting toxicity (maximum 8 cycles) Albumin-bound paclitaxel 100 mg/m2 Days 1, 8, and 15 Carboplatin AUC2 Days 1,8 and 15 • Objective: to investigate safety and efficacy of this combination regimen in patients with unresectable melanoma • Primary endpoint: ORR • Secondary endpoints: PFS, OS, and safety ECOG PS, Eastern Cooperative Oncology Group performance status; ORR, overall response rate; OS, overall survival; PFS, progression-free survival. Kottschade L.A, et al. Cancer 2011;117:1704-10. 16 Efficacy and tolerability nab-paclitaxel’s patients PT (n=35) CN (n=41) ORR 8.8 25.5 ORR+SD 37.8 48.6 PSF 4.1 4.5 OS 10.9 11.1 • Adverse events included neutropenia, thrombocytopenia, neurosensory problems, fatigue, nausea, and vomiting Kottschade L.A, et al. Cancer 2011;117:1704-10. 17 A phase II trial of nab-paclitaxel and carboplatin in patients with unresectable stage IV melanoma a North Central Cancer Treatment Group Study, N057E(1): ABX054 METHODS: MM pre-treated and naive pts nab-Paclitaxel iv weekly for 3 weeks at a dose of 100 mg/m2; Carbo AUC 2 RESULTS: 35 treated (PT) pts - ORR: - ORR+SD: - PFS: - OS: 8.8% 37.8% 4.1 months 10.9 months 41 chemonaive (CN) pts 25.6% 48.6% 4.5 months 11.1 months CONCLUSIONS: nab-Paclitaxel + Carbo was moderately be well tolerated and demonstrated activity in both previously treated and chemotherapy-naive patients with MM. Kottschade L.A, et al. Cancer 2011;117:1704-10. 18 A phase II trial of nab-paclitaxel and carboplatin in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group Study, N057E(1): ABX054 Summary Design • Phase 2, unresectable stage IV melanoma, chemotherapy naive (CN) or previously treated (PT). • N=76 • ABX 100 mg/m2 and carboplatin area under the curve (AUC2) administered on days 1, 8, and 15 every 28 days. • Primary endpoint: ORR • Secondary endpoint: PFS, OS Response • CN: • 10 (25.6%) responses (1 complete response [CR] and 9 partial responses [PRs]) in the CN cohort (90% CI, 16.7%-42.3%) • Median PFS=4.5 mos • Median OS= 11.1 mos • PT: • 3 (8.8%) responses (3 PRs) in the PT cohort (90% CI, 2.5%-21.3%). • Median PFS =4.1 mos • Median OS = 10.9 mos ABX, nab-paclitaxel; DLT; ORR, overall response rate; OS, overall survival; PFS, progression free survival. Safety • Adverse events included neutropenia, thrombocytopenia, neurosensory problems, fatigue, nausea, and vomiting Key Points • The weekly combination of ABX and carboplatin appears to be moderately well tolerated, with promising clinical activity Kottschade L.A, et al. Cancer 2011;117:1704-10. 18 19 An Open-Label, Multicenter, Phase 3 Trial of ABPaclitaxel vs Dacarbazine in Previously Untreated Patients With Metastatic Malignant Melanoma (CA033) Kottschade L.A, et al. Ongoing study 22 Phase III study of Nab Paclitaxel vs dacarbazine in previously untreated metastatic malignant melanoma 23 Melanoma: Other combinations with nab-paclitaxel ASCO 2011 update 24 Abstract #8532 A randomized phase II trial of temozolomide and bevacizumab or albumin-bound paclitaxel/carboplatin and bevacizumab in patients with unresectable stage IV metastatic melanoma: A North Central Cancer Treatment Group Study (N0775) L. A. Kottschade, V. Suman, D. G. Perez, R. R. McWilliams, J. S. Kaur, T. Amatruda, F. J. Geoffroy, H. M. Gross, P. A. Cohen, A. J. Jaslowski, M. L. Kosel, S. Markovic Kottschade LA et al. ASCO. 2011 [Abstract 8532]. 25 Study Design and Objectives • Study design: a randomized phase II trial of two different treatments for stage IV melanoma patients – N = 94 – Twenty-eight day cycles Arm A Arm Ba Temozolomide 200 mg/m2 Days 1 – 5 Albumin-bound paclitaxel 80 – 100 mg/m2 Days 1, 8, and 15 Bevacizumab 10 mg/kg Days 1 and 15 Carboplatin AUC = 5 – 6 Day 1 Bevacizumab 10 mg/kg Days 1 and 15 a Doses of albumin-bound paclitaxel and carboplatin were reduced to 80 mg/m2 and AUC = 5, respectively, due to toxicity • Objective: to independently investigate the progression-free survival at 6 months AUC, area under the curve. Kottschade LA et al. ASCO. 2011 [Abstract 8532]. 26 Baseline Characteristics Baseline characteristic TMZ + Bev (n = 42) AB-Paclitaxel + Carbo + Bev (n = 51) Age in years, median (range) 57 (25 – 82) 57 (22 – 83) 57.1 56.9 23.8 17.6 61.9 35.7 2.4 58.8 39.2 2.0 - ECOG PS, % 0 1 73.8 26.2 64.7 35.3 M1 sub-stage, % M1a M1b M1c 23.8 31.0 45.2 23.5 25.5 51.0 Elevated LDHa, % 38.1 47.1 Male, % Prior treatment, % Radiation therapy Systemic therapies None Immunotherapy Vaccine therapy Combination immuno/vaccine therapy AB, albumin-bound; Bev, bevacizumab; Carbo, carboplatin; ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrgonase; TMZ, temozolomide. a Elevated LDH values exclude the 21.4% of TMZ+Bev patients and 7.8% of AB-Paclitaxel+Carbo+Bev patients of unknown baseline LDH. Kottschade LA et al. ASCO. 2011 [Abstract 8532]. 27 Results: Efficacy and VEGF Correlatives TMZ + Bev (n = 43) AB-Paclitaxel + Carbo + Bev (n = 51) PFS at 6 months, % (95% CI) 32.0 (20.5 – 50.1) 54.9 (42.8 – 70.4) PFS at 1 year, % (95% CI) 10.0 (3.9 – 25.0) 27.5 (17.6 – 42.9) 3.8 6.6 53.8 (40.5 – 71.4) 58.1 (45.9 – 73.6) 12.3 13.9 10 (23.3) 1 (2.3) 9 (20.9) 17 (33.3) 0 17 (33.3) Clinical outcome PFS in months, median OS at 1 year, % (95% CI) OS in months, median ORR, n (%) CR PR AB, albumin-bound; Bev, bevacizumab; Carbo, carboplatin; CI, confidence interval; CR, complete response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; TMZ, temozolomide. TMZ + Bev (n = 29) AB-Paclitaxel + Carbo + Bev (n = 44) VEGF-A 58 52 VEGF-D 16 5 Reduction in VEGF staining from baselinea, % AB, albumin-bound; Bev, bevacizumab; Carbo, carboplatin; TMZ, temozolomide; VEGF, vascular endothelial growth factor. a After 1 cycle of treatment. Kottschade LA et al. ASCO. 2011 [Abstract 8532]. 28 Safety AB-Paclitaxel + Carbo + Bev TMZ + Bev (n = 42) Before dose reductions (n = 28) After dose reductions (n = 23) Anemia 5 21 17 Leukopenia 10 29 26 Neutropenia 10 54 43 Thrombocytopenia 5 21 17 Dyspnea 2 14 0 Fatigue 10 21 9 Hypertension 2 7 0 Nausea 7 0 4 Thrombosis 5 14 9 Vomiting 12 4 0 Sensory neuropathy 0 0 0 Most common treatment-related adverse eventsa, ≥ grade 3, % AB, albumin-bound; Bev, bevacizumab; Carbo, carboplatin; TMZ, temozolomide. a Adverse events reported to be probably, possibly, or definitely related to study treatment; only grade 3 or higher adverse events shown. Kottschade LA et al. ASCO. 2011 [Abstract 8532]. 29 Authors’ Conclusions • Both treatment arms showed tolerable toxicities • There may be a suggestion of clinical benefit for both arms over the expected outcomes for chemotherapy alone • The albumin-bound paclitaxel plus carboplatin plus bevacizumab arm is under consideration for further clinical testing Kottschade LA et al. ASCO. 2011 [Abstract 8532]. 30 Phase II trial of temozolomide and bevacizumab or nab-paclitaxel/carboplatin (CBDCA) and bevacizumab in patients with unresectable stage IV metastatic melanoma: Study N0775 (ABX220) Summary Design • Phase 2 trial , chemotherapy naïve patients with unresectable stage IV mM • TMZ (200 mg/m2 on days 1-5) and BEV (10mg/kg IV days 1 and 15 ) every 28 days (arm A) or CBDCA (AUC 6; day 1), ABX (100mg/m2 days 1, 8 and 15), and BEV (10mg/kg on days 1 and 15) every 28 days (arm B) • N=94 • The majority of patients had M1c disease (46.5%-Arm A & 51%-Arm B) • Primary objective: PFS at 6 months Response Safety Key Points Arm A: • PFS at 6 mo =31.2% (95% CI: 19.9-49.0%) • median PFS = 3.8 months • OS =12.2 months Arm B: • PFS at 6 mo =54.9% (95% CI: 42.8-70.4%) • median PFS = 6.6 months • OS of 15.4 months • CBDCA and ABX starting dose was reduced to AUC 5 and 80mg/m2 respectively, due to unexpected AE’s • The most common severe (≥ grade 3) toxicities in both groups (Arm A and B) were: neutropenia (9% & 49%); leukopenia (9% & 27%); fatigue (9% & 16%); vomiting (12% & 2%) and thrombosis (5% & 12%) • Both treatment arms exhibited tolerable toxicities with a suggestion of clinical benefit vs expected outcomes for chemotherapy alone • The regimen in Arm B is being considered for phase III clinical testing ABX, nab-paclitaxel; AE, adverse event; BEV, bevacizumab; mM, metastatic melanoma; PFS, progression free survival; OS, overall survival; TMZ, temozolomide. Kottschade L.A, et al. J Clin Oncol 2011 ;29 [ abstr. 8532]. 30 31 Abstract #8543 Phase II trial of albumin-bound paclitaxel and bevacizumab as first-line therapy in patients with unresectable melanoma P. D. Boasberg, R. W. Weber, S. Cruickshank, O. Hamid, S. O'Day, L. E. Spitler Boasberg PD et al. ASCO. 2011 [Abstract 8543]. 32 Study Design and Objectives • Study design: a multi-center phase II trial of albumin-bound paclitaxel plus bevacizumab in treatment-naïve patients with unresectable stage III and IV melanoma – N = 50 – Patients with ECOG PS 0-1, adequate organ function, LDH ≤ 2 Χ upper limit of normal, and no signs of central nervous system metastases – Cycles of 28 days until disease progression or dose-limiting toxicity Albumin-bound paclitaxel 150 mg/m2 Days 1, 8, and 15 Bevacizumab 10 mg/m2 Days 1 and 15 • Objective: to investigate safety and efficacy of this combination regimen in patients with unresectable melanoma • Primary endpoint: PFS at 4 months • Secondary endpoints: PFS, OS, ORR, and safety ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; ORR, overall response rate; OS, overall survival; PFS, progression-free survival. Boasberg PD et al. ASCO. 2011 [Abstract 8543]. 33 Baseline Characteristics Baseline characteristic (N = 50) n (%) Sex Male Female 32 (64) 18 (36) Tumor stage IIIC IV: M1a IV: M1b IV: M1c 2 (4) 4 (8) 11 (22) 34 (66) LDH Normal Elevated 30 (60) 20 (40) LDH, lactate dehydrogenase. Boasberg PD et al. ASCO. 2011 [Abstract 8543]. 34 Results Survival outcome (N = 50) Overall survival in months, median (95% CI) 16.8 (11.3 – 20.7)a Survival at 1 year, % 62 Survival at 2 years, % 30 Progression-free survival in months, median (95% CI) Progression-free survival at 4 months, % 7.6 (5.6 – 9.9) 73 CI, confidence interval. a Ten patients alive at the time of this analysis. Response outcomea (N = 50) n (%) Complete response 2 (4) Partial response 16 (32) Stable disease 22 (44) Clinical benefit (CR+PR+SD) 40 (80) Progressive disease 10 (20) CR, complete response; PR, partial response; SD, stable disease. a By Response Evaluation Criteria in Solid Tumors (RECIST). Boasberg PD et al. ASCO. 2011 [Abstract 8543]. 35 Safety Treatment-related grade 3 adverse events (N = 50) n (%) Neutropenia 10 (20) Neuropathy 7 (14) Mucositis 4 (8) Fatigue 3 (6) Proteinuria 1 (2) Hand/foot syndrome 1 (2) • Overall, 673 grade 1 – 3 adverse events occurred • No grade 4 adverse events occurred Boasberg PD et al. ASCO. 2011 [Abstract 8543]. 36 Authors’ Conclusions • The primary endpoint of PFS at 4 months of 73% exceeded the predicted 15% based on historical reports • Overall survival (median 16.8 months), 1-year survival (62%), and clinical benefit (80%) also exceeded values from previous reports of approved therapies • Administration of albumin-bound paclitaxel plus bevacizumab in this trial of patients with unresectable melanoma was well-tolerated • Follow-up trials are warranted Boasberg PD et al. ASCO. 2011 [Abstract 8543]. 37 Phase II trial of nab-paclitaxel and bevacizumab as firstline therapy in patients with unresectable melanoma Summary Design • Phase 2, chemotherapynaive patients with unresectable melanoma, no central nervous system metastases, ECOG performance status of 0-1, and adequate organ function • N=50 • 66% with stage IV M1c disease, 40% with elevated LDH • The treatment was given in a 28 day cycle in which ABX 150mg/m2 was administered on days 1, 8, 15 and bevacizumab 10mg/kg on days 1 and 15 Response Safety Key Points • Median OS= 15.6 mos (95% CI: 11.5, 20.7) • 1-year survival = 63% (95% CI: 50%, 77%) • 2-year survival =31% (95% CI: 17%, 44%) • Dose modifying toxicities consisted of proteinuria, neutropenia, neuropathy, and mucositis • ABX and bevacizumab has activity in patients with metastatic melanoma, is well tolerated, and offers efficacy comparable or superior to alternative treatment options • A randomized Phase II or a Phase III trial with this doublet would be required to compare efficacy with alternative approaches ABX, nab-paclitaxel; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; OS, overall survival. Boasberg P.D. et al. J Clin Oncol 2011;29: [abstr. 8543]. 37 38 Abstract #8545 Albumin-bound paclitaxel, temozolomide, and oblimersen (The ATG Trial): A final report of toxicity and clinical efficacy in metastatic melanoma patients with normal lactate dehydrogenase J. L. Chang, P. A. Ott, C. Sorlie, C. Escano, E. Yepes, S. Mendoza, A. Gandhi, L. Liebes, A. C. Pavlick Chang JL et al. ASCO. 2011 [Abstract 8545]. 39 Study Design and Objectives • Study design: a phase I trial of metastatic melanoma patients with normal LDH receiving different dosing regimens of albumin-bound paclitaxel plus temozolomide plus the bcl-2 inhibitor oblimersen – Fifty-six day cycle Cohort 1 Cohort 2 Cohort 3 Albumin-bound paclitaxel 175 mg/m2 IV Days 8 and 29 Albumin-bound paclitaxel 260 mg/m2 IV Days 8 and 29 Albumin-bound paclitaxel 175 mg/m2 IV Days 4 and 25 (after oblimersen) Temozolomide 75 mg/m2 PO Days 1 – 42 Temozolomide 75 mg/m2 PO Days 1 – 42 Temozolomide 75 mg/m2 PO Days 1 – 42 Oblimersen 7 mg/kg/day CIV Days 1 – 7 and 22 – 28 Oblimersen 7 mg/kg/day CIV Days 1 – 7 and 22 – 28 Oblimersen 900 mg IV over 1 hour Days 1, 4, 8, 11, 22, 25, 29, 32 • Objective: to evaluate safety and clinical efficacy of this combination treatment bcl-2, B cell lymphoma gene 2; CIV, continuous intravenous; IV, intravenous; LDH, lactate dehydrogenase; PO, orally. Chang JL et al. ASCO. 2011 [Abstract 8545]. 40 Baseline Characteristics Baseline characteristic Age in years, median (range) N = 32a 61 (34 – 78) Sex, n (%) Male Female 17 (53) 15 (47) Stage IV sub-stage, n (%) M1a M1b M1c 8 (25) 8 (25) 16 (50) Race, n (%) Caucasian African American Indian 30 (94) 1 (3) 1 (3) ECOG PS, n (%) 0 1 29 (91) 3 (9) ECOG PS, Eastern Cooperative Oncology Group performance status. a Combined data for all 3 cohort; Individual n per cohort: 1 – 14; 2 – 4; 3 –14. Chang JL et al. ASCO. 2011 [Abstract 8545]. 41 Results: Efficacy Response outcome (N = 32)a n (%) Duration in months, median Complete response 2 (6) 12.6, 50.2b Partial response 11 (34) 3.9 Stable disease 11 (34) 5.6 Disease control rate (CR+PR+SD) 24 (75) NA Progressive disease 8 (25) NA CR, complete response; NA, not applicable; PR, partial response; SD, stable disease. a Cohort 1: n = 14; cohort 2: n = 4; cohort 3: n = 14. b For complete response, the actual durations were given for both patients, rather than a median; the patient with a complete response at 50.2 months continues to exhibit a complete response. Survival outcome (N = 32) n (%) Survival 12 months 15 monthsa 18 monthsb 16 (50) 12 (38) 9 (28) Subsequent brain metastases 12 (38) a b One patient with ongoing response under 15 months. Three patients with ongoing responses under 18 months. Chang JL et al. ASCO. 2011 [Abstract 8545]. 42 Safety Grade 3, n (%) Grade 4, n (%) Neutropenia 3 (9) 3 (9) Sensory neuropathy 4 (13) 0 Pleural effusion 3 (9) 0 0 1 (3) Port infection 1 (3) 0 OBL hypersensitivity 1 (3) 0 Fatigue 1 (3) 0 Supraventricular tachycardia 1 (3) 0 Dyspnea 1 (3) 0 Adverse event (N = 32) Thrombocytopenia OBL, oblimersen. Chang JL et al. ASCO. 2011 [Abstract 8545]. 43 Authors’ Conclusions • The combination treatment of albumin-bound paclitaxel plus oblimersen plus temozolomide is well-tolerated in metastatic melanoma patients with normal LDH • The disease control rate of 75% and the survival data from this study are encouraging • The twice-weekly fixed-dose oblimersen schedule appears to be similar to the 7-day CIV regimen in terms of safety and efficacy CIV, continuous intravenous; LDH, lactate dehydrogenase. Chang JL et al. ASCO. 2011 [Abstract 8545]. 44 nab-paclitaxel, temozolomide, and oblimersen (The ATG Trial): A final report of toxicity and clinical efficacy in metastatic melanoma patients with normal lactate dehydrogenase (LDH) Summary Design Response Safety Key Points • Phase 1, Chemo-naïve metastatic melanoma • OBL, TMZ and ABX 175 mg/m2 or 260 mg/m2 • N=32 • Median age= 58 years (range: 34-78). Stage M1a-4; M1b-2; M1c-26. • Correlative biomarker analysis were performed in pre- and post-therapy tumor samples • ABX and OBL PK • Responses • 2-CR (48+ and 14 mos) • 10 pts PR • 13 pts SD • 7-pts PD • DCR (CR+PR+SD) 78.1% • OS =14.7 mos • 50% survived > 1y • Correlates: No impact of combo on ABX PK • • • • • • • • • • ABX, nab-paclitaxel; DCR, disease control rate; mM, metastatic melanoma; OBL, oblimersen; OS, overall survival; PD, progressive disease; PK, pharmacokinetics; PR, partial response; pts, patients; SD, stable disease; TMZ, temozolomide Grade 3: leukopenia (n=1) neutropenia(n=2) thrombocytopenia (n=1) sensory neuropathy (n=2) OBL hypersensitivity (n=2) Grade 4 neutropenia (n=1) thrombocytopenia (n=1) sensory neuropathy (n=4). • The combo of OBL, TMZ, and ABX in mM pts is safe resulted in a DCR of 78.1% and prolonged survival • Bcl-2 antisense therapy effectively targets apoptotic signaling pathways in MM cells • The twice-weekly, fixed-dose OBL schedule appears to be similar in safety and efficacy as the 7-day CIV regimen Chang J.L, et al. J Clin Oncol 2011;29: [ abstr. 8545]. 44 45 Back up 46 Melanoma Disease Background • In 2011, it is estimated that – 70,230 people will be diagnosed with melanoma of the skin1 – 8790 deaths will occur1 • 2008 prevalence of approximately 822,770 people in the United States with melanoma2 • Least common form of skin cancer, but leading cause of skin cancer– related deaths3 – Mortality rate: 3 per 100,000 people3 – 5-year survival rate: 91% for all stages of melanoma1 • For patients with metastatic melanoma, long-term survival rates are less than 10%4 1. American Cancer Society. Cancer Facts & Figures 2011. Atlanta, GA: American Cancer Society; 2011. 2. http://www.seer.cancer.gov/statfacts/html/melan.html. 3. Jemal A, et al. CA Cancer J Clin. 2010;60:277-300. 4. NCCN Clinical Practice Guidelines in Oncology: Melanoma, v4.2011. 47 Albumin-Bound Paclitaxel • Albumin is an endogenous carrier of hydrophobic molecules1 – – Most abundant protein in plasma with substantial ligand-binding capacity2 Important factor in the pharmacokinetic behavior of many drugs, affecting efficacy and rate of delivery2 nab-paclitaxel particle3 (mean particle size 130 nm) • Albumin-bound paclitaxel, produced by a proprietary nab platform, is solvent-free3 – Provides greater tumor uptake of active paclitaxel4 and allows for dosing 49% more of active paclitaxel compared with solvent-based paclitaxel3,5 • Indication: treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy; prior therapy should have included anthracycline unless clinically contraindicated 1. Moorthi C, et al. J Pharm Pharmaceut Sci. 2011;14:67-77. 2. Fasano M, et al. IUBMB Life. 2005; 57:787-796. 3. nab-paclitaxel (paclitaxel protein-bound particles) [package insert]. Bridgewater, NJ: Abraxis BioScience, LLC, a wholly owned subsidiary of Celgene Corporation; 2010. 4. Desai N, et al. Clin Cancer Res. 2006; 15:1317-1324. 5. Taxol (paclitaxel) [package insert]. Princeton, NJ: Bristol-Myers Squibb Co; 2010. 48 Accumulation of Albumin-Bound Paclitaxel in Tumors Accumulation of active paclitaxel in tumors was 33% higher for albumin-bound paclitaxel compared with Cremophor® EL paclitaxel (P < .0001)1 AB, albumin-bound; ANOVA, analysis of variance; AUC, area under the curve; CrEL, Cremophor EL; Ka, absorption rate. 1. Desai N, et al. Clin Cancer Res. 2006;15:1317-1324. 49 Comparison to cooperative group meta-analysis Progression-Free Survival (months) Overall Survival, (months) nab-paclitaxel® Previously treated 3.5 12.1 * nab-paclitaxel® Chemo naive 4.6 9.6 * Cooperative Group Meta-analysis 1.7 6.2 Group Korn, EL et al. J Clin Oncol 26:527-534 (2008) (42 trials)