GOG212: Taxane Maintenance

Transcription

1 GOG212: Taxane Maintenance Epithelial Ovarian or Primary Peritoneal Cancer Optimal or Suboptimal Cytoreduction Clinical C with normal CA125, no symptoms, normal CT Primary Carboplatin and Paclitaxel (or Docetaxel), 5-6 cycles Primary endpoints OS and Neurotoxicity I PG-Paclitaxel 175 mg/m 2 (15 min) Q28d x 12 cycles Primary x: Carboplatin and Taxane (5-6 Cy) II Paclitaxel 175 mg/m 2 (3 h) Q28d x 12 cycles III Observation Open: 21-MA-2005 Closed: 13-JAN-2014 (9 y) Target Accrual: Target 1100 pts (actual 1157) Copeland L, et al. SGO 2017

2 GOG212: Taxane Maintenance H (97.5% CI) CT-2103 vs OBS ( ) Paclitaxel vs OBS ( ) H (97.5% CI) CT-2103 vs OBS ( ) Paclitaxel vs OBS ( ) No established role for maintenance therapy using conventional cytotoxic agents, based on multiple phase III trials Copeland L, et al. SGO 2017

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4 NG-GY007: NACT +/- uxolitinib Epithelial ovarian, peritoneal, or fallopian carcinoma (EOPFC) Stage IIIC-IV and suitable for NACT with interval cytoreductive surgery Phase I to evaluate acute toxicity (C1) and cumulative tolerability Maintenance ruxolitinib permitted in patients tolerating concurrent therapy Primary Endpoints: PFS and molecular targeting (stem cells and IL6) CP (x3) ICS CP (x3) Observation Core Bx 1:2 CP (x3) + ux ICS CP (x3) + ux ux Maint (optional) CP = Carboplatin AUC 5 or 6 (D1), Paclitaxel 80 mg/m2 (D1,8,15) ux = uxolitinib mg PO BID (pending Phase 1) ICS = Interval Cytoreductive Surgery Open: 10-OCT-2016 Closed: (ongoing phase I) Accrual: Burger, for NG Oncology

5 GOG-3015: Chemo Bev ± Atezo YO39523/GOG-3015/ENGOT-ov39 Previously untreated high-grade cancer Stage III macroscopic or Stage IV (allows election of NACT), Bx cohort No history of serious autoimmune disorders Stratification PDL1 0 vs 1+, Stage, PS, NACT Co-Primary endpoints (PDL1+): OS H 0.72 (81%, 0.046), PFS H 0.7 I Carboplatin AUC=6 D1 Paclitaxel 175 mg/m 2 D1 Bevacizumab 15 mg/kg D1 Placebo IV D1 Bevacizumab 15 mg/kg Placebo (q3w x 16 cycles) II Carboplatin AUC=6 D1 Paclitaxel 175 mg/m 2 D1 Bevacizumab 15 mg/kg D1 Atezolizumab 800 mg D1 Bevacizumab 15 mg/kg D1 Atezolizumab 800 mg D1 (q3w x 16 cycles) Open: MA 2017 Closed: (ongoing) Target Accrual: 1300 Moore K and Pignata S, for NG-F and ENGOT

6 NG-GY009: PLD ± Atezo ± Bev ecurrent high-grade with PFI < 6 months (following most recent platinum) No more than 2 prior regimens (including primary therapy) ECIST measurable or evaluable disease with accessible tumor No prior anti-angiogenic therapy for platinum-resistant recurrence No history of serious autoimmune disorders Primary endpoints: Phase II PFS (selective) Phase III OS I II PLD 40 mg/m 2 IV q4w Atezolizumab 800 mg IV q2w PLD 40 mg/m 2 IV q4w Bevacizumab 10 mg/kg IV q2w Atezolizumab 800 mg IV q2w H PFS (88% power) H OS* (90% power) *one-tail α (multiple comparisons) III PLD 40 mg/m 2 IV q4w Bevacizumab 10 mg/kg IV q2w Open: 12 MAY 2017 Closed: (ongoing safety lead-in, Arm I, non-randomized) Target Accrual: 272 Phase II, Cumulative 488 Phase III O'Cearbhaill E, for NG

7 PAP Inhibition Who? What? Where? When? Why? CSI: Chemo Scene Investigation

8 GOG3005: PAPi Primary Therapy High-grade extrauterine serous tumors, Stage I-C, II, III, IV Election for NACT-ICS and scheduling of paclitaxel (no IP therapy) Primary endpoint PFS: (1) Entire Population, (2) BCA1/2 Population Stratifications: Stage, esidual Disease, NACT-ICS, egion, gbca status 1:1:1 I II Paclitaxel (standard or dose-dense) Carboplatin AUC 6 (IV)* Placebo PO BID Paclitaxel (standard or dose-dense) Carboplatin AUC 6 (IV)* Veliparib 150 mg PO BID x 6 x 6 Placebo PO BID Placebo PO BID II Paclitaxel (standard or dose-dense) Carboplatin AUC 6 (IV)* Veliparib 150 mg PO BID x 6 Veliparib 400 mg PO BID Collaborative development with AbbVie (M13-694) including international participation, seeking EMA and FDA regulatory approval Open: JUL 2015 Closed: MAY 2017 Target Accrual: ~1100 pts (264 BCA1/2 +) Coleman, for GOG Foundation

9 NG-GY004: PAPi +/- Cediranib ecurrent HGSC with PFI > 6 months (following most recent platinum) No more than 3 prior regimens (including primary therapy) ECIST measurable or evaluable disease with accessible tumor No prior PAPi therapy, prior bevacizumab permitted Stratify for BCA status, number of prior treatment regimens Primary endpoint: PFS 85% Power with H Olaparib 300 mg BID Cediranib 30 mg QD Olaparib 200 mg BID Projected interim analysis JUL 2018 Platinum-based combo* (IV) *Carboplatin + gemcitabine or paclitaxel or PLD Open: FEB 2016 Closed: (ongoing) Target Accrual: 550 pts (135 BCA1/2 +) Liu J, for NG

10 NG-GY005: PAPi +/- Cediranib ecurrent HGSC with PFI < 6 months (following most recent platinum) No more than 2 prior regimens (including primary therapy) ECIST measurable or evaluable disease, biopsy accessible No prior PAPi therapy, prior bevacizumab permitted Stratify for BCA status, number of prior treatment regimens Primary endpoint: OS 90% Power with H Phase II (n = 180) Cediranib (PO) Phase III (n = 280) Olaparib (PO) Cediranib + Olaparib (PO) 1:1 Selected egimen (PO) Non-Platinum Chemo* (IV) Non-Platinum Chemo* (IV) * Weekly paclitaxel or PLD Open: FEB 2106 Closed: (ongoing) Target Accrual: 460 pts (135 BCA1/2 +) Lee J-M, for NG

11 PAPi: Maintenance vs Treatment What are the endpoints?

12 PAPi: Maintenance vs Treatment Emerging data with maintenance and treatment is compelling, with an immediate impact on regulatory approvals and PAPi utilization Should control of small-volume asymptomatic disease be our goal? Timing and sequence has not been addressed in any prospective clinical trial It is difficult to monitor ongoing response in a maintenance setting with normal CA125 and imaging (+/- secondary cytoreduction), and many patients could receive long-term ineffective therapy Consider the importance of balancing treatment-related toxicity, risk of symptomatic recurrence, and time off-therapy (in a non-curative setting) Current long-term PAPi treatment is associated with emergence of resistance, potentially limiting subsequent therapeutic benefit

13 Generally Well-Tolerated 78 year-old, recurrent HGSC, Stage III-C, originally diagnosed 2001 gbcawt, multiple lines of therapy, new pulmonary nodules in 2015 Living independently, asymptomatic Enrolled on a Phase II trial with PAPi Pre-x NOV2015 Near-complete response, all lesions Dose-limiting toxicity requiring multiple dose reductions and treatment interruptions, including anemia (Hgb 7.6), Plts, weakness, fatigue, nausea, appetite, weight Treatment self-discontinued after one year Post-x DEC2016 PAPi symptoms resolved to baseline within 4 weeks Minor progression on CT imaging at 5 months No additional therapy... Bookman MA 2017

14 ecurrence Therapance: PAPi Therapy vs Maintenance Enroll patients at completion of primary therapy (C or P) Flexible allowance for chemotherapy, PAPi, and utilization of bevacizumab, (reflecting local standards and regulatory approvals) Minimized data collection to limit study cost Primary Endpoint: OS at 3 Years (from diagnosis) Secondary Endpoints: Cumulative time on/off therapy, etc. Chemo +/- Bev 2L Treatment Primary Therapy +/- Bevacizumab C, P PAPi Maintenance OBS +/- Bev Maintenance PAPi 2L Treatment PAPi Maint Chemo +/- Bev 2L Treatment OBS?? Bookman MA (for anyone interested)