GOG212: Taxane Maintenance Epithelial Ovarian or Primary Peritoneal - - PowerPoint PPT Presentation

• Epithelial Ovarian or Primary Peritoneal Cancer
• Optimal or Suboptimal Cytoreduction
• Clinical CR with normal CA125, no symptoms, normal CT
• Primary Carboplatin and Paclitaxel (or Docetaxel), 5-6 cycles
• Primary endpoints OS and Neurotoxicity

GOG212: Taxane Maintenance

I PG-Paclitaxel 175 mg/m2 (15 min) Q28d x 12 cycles II Paclitaxel 175 mg/m2 (3 h) Q28d x 12 cycles III Observation Open: 21-MAR-2005 Closed: 13-JAN-2014 (9 y) Target Accrual: Target 1100 pts (actual 1157) Copeland L, et al. SGO 2017 Primary Rx: Carboplatin and Taxane (5-6 Cy)

GOG212: Taxane Maintenance

Copeland L, et al. SGO 2017

HR (97.5% CI) CT-2103 vs OBS 0.979 (0.781 - 1.23) Paclitaxel vs OBS 1.104 (0.884 - 1.38) HR (97.5% CI) CT-2103 vs OBS 0.847 (0.721 - 0.995) Paclitaxel vs OBS 0.783 (0.783 - 0.921)

No established role for maintenance therapy using conventional cytotoxic agents, based on multiple phase III trials

• 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 CP (x3) + Rux CP (x3) + Rux Rux Maint (optional) ICS Core Bx

R

CP = Carboplatin AUC 5 or 6 (D1), Paclitaxel 80 mg/m2 (D1,8,15) Rux = Ruxolitinib 10-15 mg PO BID (pending Phase 1) ICS = Interval Cytoreductive Surgery

1:2

Burger R, for NRG Oncology

NRG-GY007: NACT +/- Ruxolitinib

Open: 10-OCT-2016 Closed: (ongoing phase I) Accrual:

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 HR 0.72 (81%, 0.046), PFS HR 0.7

Open: MAR 2017 Closed: (ongoing) Target Accrual: 1300 Moore K and Pignata S, for NRG-F and ENGOT Carboplatin AUC=6 D1 Paclitaxel 175 mg/m2 D1 Bevacizumab 15 mg/kg D1 Atezolizumab 800 mg D1 R Carboplatin AUC=6 D1 Paclitaxel 175 mg/m2 D1 Bevacizumab 15 mg/kg D1 Placebo IV D1

I II

Bevacizumab 15 mg/kg Placebo (q3w x 16 cycles) Bevacizumab 15 mg/kg D1 Atezolizumab 800 mg D1 (q3w x 16 cycles)

NRG-GY009: PLD ± Atezo ± Bev

• Recurrent high-grade with PFI < 6 months (following most recent platinum)
• No more than 2 prior regimens (including primary therapy)
• RECIST 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

Open: 12 MAY 2017 Closed: (ongoing safety lead-in, Arm I, non-randomized) Target Accrual: 272 Phase II, Cumulative 488 Phase III O'Cearbhaill RE, for NRG PLD 40 mg/m2 IV q4w Bevacizumab 10 mg/kg IV q2w Atezolizumab 800 mg IV q2w PLD 40 mg/m2 IV q4w Bevacizumab 10 mg/kg IV q2w R PLD 40 mg/m2 IV q4w Atezolizumab 800 mg IV q2w

I II III

HR PFS ≤ 0.783 (88% power) HR OS* ≤ 0.625 (90% power) *one-tail α 0.0115 (multiple comparisons)

PARP Inhibition…

Who? What? Where? When? Why?

CSI: Chemo Scene Investigation

GOG3005: PARPi 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) BRCA1/2 Population
• Stratifications: Stage, Residual Disease, NACT-ICS, Region, gBRCA status

Collaborative development with AbbVie (M13-694) including international participation, seeking EMA and FDA regulatory approval

Coleman R, for GOG Foundation Open: JUL 2015 Closed: MAY 2017 Target Accrual: ~1100 pts (264 BRCA1/2 +)

x 6 II Veliparib 400 mg PO BID Paclitaxel (standard or dose-dense) Carboplatin AUC 6 (IV)* Veliparib 150 mg PO BID x 6 I Paclitaxel (standard or dose-dense) Carboplatin AUC 6 (IV)* Placebo PO BID Placebo PO BID x 6 II Placebo PO BID Paclitaxel (standard or dose-dense) Carboplatin AUC 6 (IV)* Veliparib 150 mg PO BID

1:1:1

NRG-GY004: PARPi +/- Cediranib

• Recurrent HGSC with PFI > 6 months (following most recent platinum)
• No more than 3 prior regimens (including primary therapy)
• RECIST measurable or evaluable disease with accessible tumor
• No prior PARPi therapy, prior bevacizumab permitted
• Stratify for BRCA status, number of prior treatment regimens
• Primary endpoint: PFS 85% Power with HR 0.625

Cediranib 30 mg QD Olaparib 200 mg BID Platinum-based combo* (IV) R *Carboplatin + gemcitabine or paclitaxel or PLD Olaparib 300 mg BID Open: FEB 2016 Closed: (ongoing) Target Accrual: 550 pts (135 BRCA1/2 +) Liu J, for NRG

Projected interim analysis JUL 2018

NRG-GY005: PARPi +/- Cediranib

• Recurrent HGSC with PFI < 6 months (following most recent platinum)
• No more than 2 prior regimens (including primary therapy)
• RECIST measurable or evaluable disease, biopsy accessible
• No prior PARPi therapy, prior bevacizumab permitted
• Stratify for BRCA status, number of prior treatment regimens
• Primary endpoint: OS 90% Power with HR 0.625

Open: FEB 2106 Closed: (ongoing) Target Accrual: 460 pts (135 BRCA1/2 +) Lee J-M, for NRG Selected Regimen (PO) Non-Platinum Chemo* (IV) R Phase III (n = 280) * Weekly paclitaxel or PLD 1:1 Cediranib (PO) Olaparib (PO) Cediranib + Olaparib (PO) R Phase II (n = 180) Non-Platinum Chemo* (IV)

PARPi: Maintenance vs Treatment What are the endpoints?

PARPi: Maintenance vs Treatment

• Emerging data with maintenance and treatment is compelling, with an

immediate impact on regulatory approvals and PARPi 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 PARPi treatment is associated with emergence of

resistance, potentially limiting subsequent therapeutic benefit

“Generally Well-Tolerated”

Bookman MA 2017

• 78 year-old, recurrent HGSC, Stage III-C, originally diagnosed 2001
• gBRCAwt, multiple lines of therapy, new pulmonary nodules in 2015
• Living independently, asymptomatic
• Enrolled on a Phase II trial with PARPi

Pre-Rx NOV2015 Post-Rx DEC2016

• 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
• PARPi symptoms resolved to baseline within 4 weeks
• Minor progression on CT imaging at 5 months
• No additional therapy...

Chemo +/- Bev 2L Treatment R PARPi 2L Treatment

Therapance: PARPi Therapy vs Maintenance

Bookman MA (for anyone interested)

Primary Therapy +/- Bevacizumab OBS +/- Bev Maintenance R PARPi Maintenance CR, PR Chemo +/- Bev 2L Treatment Recurrence OBS R PARPi Maint

??

• Enroll patients at completion of primary therapy (CR or PR)
• Flexible allowance for chemotherapy, PARPi, 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.