NRG Oncology: Ovarian Cancer

Closed: • GOG0212 Front-Line Maintenance, Letter to Investigators (26-SEP-2016) • GOG0252 Front-Line IP vs IV Chemotherapy Ongoing: • GOG3005 Front-Line Chemotherapy +/- Veliparib (Treatment and Maintenance) • GOG0213 Platinum-Sensitive Recurrence, Secondary Cytoreductive Surgery • NRG GY004 Platinum-Sensitive Recurrence, Cediranib-Olaparib Phase III • NRG GY005 Platinum-Resistant Recurrence, Cediranib-Olaparib Phase III New Studies • NRG GY007 Front-Line NACT +/- Ruxolitinib JAK2i (open to accrual) • OVM 1509 Front-Line NACT +/- Pembrolizumab (pending GCSC review) • OVM 1629 Front-Line NACT +/- Metformin (U Chicago SPORE project)

• 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 Neutotoxicity

GOG212: Ovarian Maintenance

x 12 I PG-Paclitaxel 175 mg/m2 (15 m), q28d

x 12 II Paclitaxel 175 mg/m2 (3 h), q28d

III Observation

Open: 21-MAR-2005 Closed: 13-JAN-2014 (9 y) Target Accrual: Target 1100 pts (actual 1157)

Copeland L, for NRG (pending)

Primary Rx: Carboplatin and Taxane (5-6 Cy)

GOG212: Ovarian Maintenance

Letter to Investigators 26-SEP-2016: “…The NRG Oncology Data Monitoring Committee recently reviewed the results from a scheduled interim analysis and voted to release the study results early due to futility. In other words, the study results indicate it is unlikely that either of the taxane regimens significantly reduces the hazard of death when compared to no further anti-cancer treatment until disease progression…”

• Epithelial Ovarian, Fallopian, or Primary Peritoneal Cancer • Optimal and Suboptimal Disease (through April 2011) • Primary Endpoint: PFS (Analysis JAN 2016)

GOG0252: IP Therapy

Open: 27-Jun-2009 Closed: 29-Oct-2011 Accrual: 1560 pts (max 250 suboptimal)

Walker J. for GOG, SGO 2016

Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 IV (d1,8,15) Bevacizumab (C2-6)

Cisplatin 75 mg/m2 (IP) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2-6)

I

III

II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1,8,15) Bevacizumab (C2-6)

Bevacizumab q21d x 16

Bevacizumab q21d x 16

Bevacizumab q21d x 16

IV Carbo IP Carbo IP Cisplatin

0.0

0.2

0.4

0.6

0.8

1.0

0 12 24 36 48 60 72

Pro

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sion

-Fre

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urvi

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Months on Study

GOG0252: IP vs IV (PFS)

Walker J. et al, SGO LBA 2016

Regimen Events Median Carboplatin (IV) + Paclitaxel (IV) 303/461 26.8 Carboplatin (IP) + Paclitaxel (IV) 300/464 28.7 Cisplatin (IP) + Paclitaxel (IV+IP) 307/456 27.8

Optimal Cytoreduction (Stage II-III)

Regimen HR (95% CI) Logrank (2T) Carboplatin (IP) 0.947 (0.808 - 1.11) 0.416 Cisplatin (IP) 1.01 (0.858 - 1.18) 0.727

GOG0252: IP vs IV (PFS)

Walker J. for GOG, 2016

ITT (All Eligible Patients)

GOG3005: PARPi Primary Therapy & Maint • 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

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

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

Coleman R, et al. for GOG

Open: JUL 2015 Closed: (ongoing) Target Accrual: ~1100 pts (264 BRCA1/2 +)

x 6 II Placebo PO BID

Paclitaxel (standard or dose-dense) Carboplatin AUC 6 (IV)* Veliparib 150 mg PO BID

1:1:1

GOG3005: PARPi Primary Therapy & Maint

Coleman R, et al. for GOG

0

250

500

750

1000

1250

Jul-1

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Sep-

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Jan-

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Projected SubjectsCumulative (Balanced)Actual SubjectsCumulative (Balanced)Projected SubjectsCumulative (Aggressive) 645

Currently accruing several months ahead of original projection

GOG3005: PARPi Primary Therapy & Maint

Coleman R, et al. for GOG

Recent Updates:

• Change in global study chair from Kathy Bell-McGuinn to Robert Coleman

• Clarification of dose and schedule modification for management of hematologic toxicity

• Adjustment of starting dose for maintenance veliparib/placebo from 400 mg BID to 300 mg BID for 2 weeks, with option for escalation as tolerated

• Following IDMC review, gBRCA status has been incorporated as a stratification factor (pre-randomization) and other stratifications have been simplified (to avoid over-stratification)

Maximal Secondary

Cytoreduction

No Secondary Surgery

• Epithelial Ovarian, Fallopian, or Peritoneal Cancer • One prior therapy, Platinum-free interval > 6 months • Primary Endpoint: OS • Surgical accrual expanded to 485 patients to accertate analysis (2019)

Open: 06-Dec-07 Closed: Ongoing (surgical) Target Accrual: 785 pts (485 surgical)

I

II

GOG 0213: Recurrent Disease

Coleman RL, et al. SGO 2015

Carboplatin AUC=5 Paclitaxel 175 mg/m2

(No further therapy)

Carboplatin AUC=5 Paclitaxel 175 mg/m2

Bevacizumab 15 mg/kg

Bevacizumab 15 mg/kg (Until progression)

A

B

R1

Not Surgical Candidate III

x 6-8

x 6-8

R2

NRG-GY004: Platinum-Sensitive • Recurrent HGSC with PFI >6 months (following most recent platinum) • No more than 3 prior treatment 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 2106 Closed: (ongoing) n=130 as of 14OCT2016 Target Accrual: 450 pts (135 BRCA1/2 +) Liu J, for GOG

NRG-GY005: Platinum-Resistant • Recurrent HGSC with PFI <6 months (following most recent platinum) • No more than 2 prior treatment 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) n=53 as of 14OCT2016 Target Accrual: 460 pts (135 BRCA1/2 +) Lee J-M, for GOG

Cediranib (PO)

Olaparib (PO)

Cediranib + Olaparib (PO) R

Randomized Phase II (n = 180)

Selected Regimen (PO)

Non-Platinum Chemo* (IV) R

Randomized Phase III (n = 280)

* Weekly paclitaxel or PLD

1:1

Non-Platinum Chemo* (IV)

• 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:

OVM1509: NACT +/- Pembrolizumab

Gaillard S, for NRG (pending GCSC review)

OVM1629: NACT +/- Metformin

Serum

Yamada D, for NRG and U Chicago Ovarian SPORE (pending CTEP review)