NRGGU 007 NADIR Trial Randomized Phase II Trial

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NRG-GU 007 NADIR Trial: Randomized Phase II Trial of Niraparib With Standard Combination Androgen

NRG-GU 007 NADIR Trial: Randomized Phase II Trial of Niraparib With Standard Combination Androgen Deprivation Therapy (ADT) and Radiotherapy In High Risk Prostate Cancer (With Initial Phase I) PI: Dror Michaelson Rad Onc Co-Chair: Zachary Zumsteg Translational Co-Chair: Phuoc Tran Physics Co-Chair: Rajat Kudchadker Statistics: Theodore Karrison NRG Oncology Semi-Annual Meeting July 2020 @NRGOnc NRG Oncology

Schema – Phase I Register GS ≥ 9, PSA ≤ 150 12 months 12

Schema – Phase I Register GS ≥ 9, PSA ≤ 150 12 months 12 Months ADT + PARPi ADT PSA Testing After 2 months ADT+PARPi: DE-EBRT Dose Escalation Levels: • Level 1: Niraparib 100 mg PO daily for 12 months, including during RT • Level 2: Niraparib 200 mg PO daily for 12 months, except 100 mg PO daily during RT • Level 3: Niraparib 200 mg PO daily for 12 months, including during RT • Level 0: Niraparib 100 mg PO daily for 12 months, except during RT NRG-GU 007

Schema – Phase II NRG-GU 007

Schema – Phase II NRG-GU 007

Current Progress • • • Cohort #1 Complete: 3/5/2020 Re-activation for Cohort #2: 5/4/2020

Current Progress • • • Cohort #1 Complete: 3/5/2020 Re-activation for Cohort #2: 5/4/2020 Sites Active: 63 Sites Pending: 114 Current Accrual: 4 – No DLT’s to date • Target Accrual – Phase I: 27 – 36 patients – Phase II: 180 patients (90 patients per arm) • Study Duration – Both phase I and II 3. 5 years NRG-GU 007

Dose Limiting Toxicity • DLT Definition – Any ≥ grade 3 GU/GI toxicity lasting

Dose Limiting Toxicity • DLT Definition – Any ≥ grade 3 GU/GI toxicity lasting > 1 week OR – Any grade 4 toxicity (any type) lasting > 1 week • DLT Window: 6 months – Part 1 = ADT+PARPi (8 weeks) – Part 2 = ADT+PARPi+RT (6 -8 weeks) – Part 3 = ADT+PARPi after RT (remainder of 6 month window) NRG-GU 007

Radiation Therapy • IMRT Credentialing is required for this trial See section 8. 3

Radiation Therapy • IMRT Credentialing is required for this trial See section 8. 3 of the protocol for credentialing details • All patients are required to be treated with intensity modulated radiotherapy (IMRT) techniques, including volume modulated arc therapy (VMAT) and tomotherapy • Physicians may elect to treat the prostate with either standard fractionation or hypofractionation See section 5. 2 of the protocol for radiation therapy treatment details. NRG-GU 007

Radiation Details • General Details – – – • Strict dose constraints/planning criteria Brachytherapy

Radiation Details • General Details – – – • Strict dose constraints/planning criteria Brachytherapy not allowed Daily image guidance required (CBCT, 2 D-k. V/MV with fiducials, MRI) Full bladder strongly recommended Space. OAR allowed (not required) Standard Fractionation – Whole pelvis: 45. 00 Gy/25 fractions – Boost: 34. 20 Gy/19 fractions – Total Dose 79. 20 Gy/44 fractions • Hypofractionation – Whole pelvis: 45. 00 Gy/25 fractions – Boost: 70. 00 Gy/28 fractions NRG-GU 007

Eligibility Criteria • • • Histologically confirmed (within 180 days prior to registration) adenocarcinoma

Eligibility Criteria • • • Histologically confirmed (within 180 days prior to registration) adenocarcinoma of the prostate at high risk for recurrence as determined by the following criteria, according to AJCC 8 th edition: – Phase I enrollment • Gleason ≥ 9, PSA ≤ 150 ng/m. L, any T-stage • Prior androgen suppression for prostate cancer is not allowed prior to registration – Phase II enrollment • Gleason ≥ 9, PSA ≤ 150 ng/m. L, any T-stage • Gleason 8, PSA < 20 ng/m. L, and ≥ T 2 • Gleason 8, PSA ≥ 20 -150 ng/m. L, any T-stage • Gleason 7, PSA ≥ 20 -150 ng/m. L, any T-stage No distant metastases History/physical examination within 90 days prior to registration ECOG performance status of 0 or 1 within 180 days prior to registration Pretreatment serum PSA, obtained prior to any androgen suppression therapy and within 180 days of registration. Adequate hematologic, renal, and hepatic function within 90 days prior to registration NRG-GU 007

Primary Objective • Phase I: To establish the preferred dose of niraparib in combination

Primary Objective • Phase I: To establish the preferred dose of niraparib in combination with radiation and ADT • Phase IIR: To compare the disease-free state, defined as PSA remaining < 0. 1 ng/ml at the end of ADT therapy in men with high risk prostate cancer treated with standard therapy with or without the addition of niraparib NRG-GU 007

Exploratory Objectives • To identify genomic biomarkers of response to combination therapy with radiation,

Exploratory Objectives • To identify genomic biomarkers of response to combination therapy with radiation, ADT and PARP inhibition • Targeted exome sequencing of genes most commonly altered in prostate cancer, including DNA repair genes (BRCA 2, BRCA 1, ATM, PALB 2, RAD 51 B, and RAD 51 C) – Transcriptome-wide gene expression using analysis using Affymetrix oligonucleotide array. – Whole blood samples will be analyzed for single nucleotide polymorphisms previously associated with prostate cancer risk. – Plasma samples will be assessed for: • Baseline and post-therapy alterations in a targeted gene panel • Reversion mutations in DNA repair genes as early biomarkers of treatment resistance. NRG-GU 007

Survey Question • When phase I completes and identifies recommended phase 2 dose, will

Survey Question • When phase I completes and identifies recommended phase 2 dose, will your site be willing to participate in randomized phase 2 portion of trial: • • Arm 1: RT + ADT (2 years) + PARPi Arm 2: RT + ADT (2 years) A) YES B) NO C) UNSURE NRG-GU 007

NRG-GU 007 Study Chairs/Leadership/Champion Dror Michaelson, MD, Ph. D; Massachusetts General Hospital PI/ Med.

NRG-GU 007 Study Chairs/Leadership/Champion Dror Michaelson, MD, Ph. D; Massachusetts General Hospital PI/ Med. Oncology Zachary Zumsteg, MD; Samuel Oschin Comprehensive Cancer Center Rad. Oncology Phuoc T. Tran, MD, Ph. D; The Sidney Kimmel Comprehensive Cancer Center Translational Rajat Kudchadker, Ph. D; University of Texas MD Anderson Cancer Center Physics Theodore Karrison, Ph. D; University of Chicago and NRG Oncology Statistics NRG-GU 007

NRG-GU 007 NRG Operations and SDMC Study Team For Contact Information (see protocol cover

NRG-GU 007 NRG Operations and SDMC Study Team For Contact Information (see protocol cover page) Clinical Trials Administration/ Clinical Project Specialist Erin J. Moye Data Management Elaine Moytka-Welsh Margaret Kennish Core Services for Radiation Therapy/Dosimetrists Joanne Hunter Protocol Development Carol Lam Statistics Theodore Karrison Joseph Rodgers NRG-GU 007