A Phase 3, Randomized, Double-blind, Placebo-controlled Study Of Talazoparib In Combination With Physician’s Choice Of Enzalutamide Or Abiraterone Acetate/Prednisone In Metastatic Castration-resistant Prostate Cancer With Dna Damage Repair Deficiencies

Condition: mCRPC

Intervention:

• Drug: Talazoparib with enzalutamide
• Drug: Placebo with enzalutamide

Purpose: This study compares rPFS in men with mCRPC treated with talazoparib plus enzalutamide vs. enzalutamide after confirmation of the starting dose of talazoparib in combination with enzalutamide.

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03395197

Sponsor: Pfizer

Primary Outcome Measures:

• Measure: Confirm the dose of Talazoparib (part 1)
• Time Frame: Day 1 up to 28 days
• Safety Issue:
• Measure: Radiographic PFS (part 2) in unselected patients and in patients harboring DDR deficiencies
• Time Frame: randomization up to 25 months
• Safety Issue:

Secondary Outcome Measures:

• Measure: Overall survival (part 2) in unselected patients and in patients harboring DDR deficiencies
• Time Frame: randomization up to 47 months
• Safety Issue:
• Measure: Objective response in measurable soft tissue disease (part 2) in unselected patients and in patients harboring DDR deficiencies
• Time Frame: baseline up to 6 months
• Safety Issue:
• Measure: Duration of soft tissue response (part 2) in unselected patients and in patients harboring DDR deficiencies
• Time Frame: baseline up to 25 months
• Safety Issue:
• Measure: PSA response (part 2) in unselected patients and in patients harboring DDR deficiencies
• Time Frame: baseline up to 25 months
• Safety Issue:
• Measure: Time to PSA progression (part 2) in unselected patients and in patients harboring DDR deficiencies
• Time Frame: baseline up to 25 months
• Safety Issue:
• Measure: Time to initiation of cytotoxic chemotherapy (part 2) in unselected patients and in patients harboring DDR deficiencies
• Time Frame: randomization up to 47 months
• Safety Issue:
• Measure: Time to initiation of antineoplastic therapy (part 2) in unselected patients and in patients harboring DDR deficiencies
• Time Frame: randomization up to 47 months
• Safety Issue:
• Measure: Time to first symptomatic skeletal event (part 2) in unselected patients and in patients harboring DDR deficiencies
• Time Frame: randomization up to 47 months
• Safety Issue:
• Measure: PFS on next line of therapy (PFS2) in unselected patients and in patients harboring DDR deficiencies
• Time Frame: randomization up to 47 months
• Safety Issue:
• Measure: Opiate use for cancer pain (part 2) in unselected patients and in patients harboring DDR deficiencies
• Time Frame: randomization up to 47 months
• Safety Issue:
• Measure: Incidence of adverse events (part 1 and 2)
• Time Frame: Day 1 up to 26 months
• Safety Issue:
• Measure: Pharmacokinetic assessment of talazoparib (part 1)
• Time Frame: Week 1, 5, 9, and 13
• Safety Issue:
• Measure: Pharmacokinetic assessment of talazoparib (part 2)
• Time Frame: week 3, 5, 9 13, and 17
• Safety Issue:
• Measure: Pharmacokinetic assessment of enzalutamide (part 1)
• Time Frame: week 1, 5, 9, and 13
• Safety Issue:
• Measure: Pharmacokinetic assessment of enzalutamide (part 2)
• Time Frame: week 3, 5, 9 13, and 17
• Safety Issue:
• Measure: Patient-reported outcome:pain symptoms (part 2) in unselected patients and in patients harboring DDR deficiencies
• Time Frame: baseline up to 47 months
• Safety Issue:
• Measure: Patient-reported outcome: pain symptoms (part 2) in unselected patients and in patients harboring DDR deficiencies
• Time Frame: baseline up to 47 months
• Safety Issue:
• Measure: Patient-reported outcome: cancer specific global health status/QoL, functioning, and symptoms (part 2) in unselected patients and in patients harboring DDR deficiencies
• Time Frame: baseline up to 47 months
• Safety Issue:
• Measure: Patient-reported outcome: cancer specific global health status/QoL, functioning, and symptoms (part 2) in unselected patients and in patients harboring DDR deficiencies
• Time Frame: baseline up to 47 months
• Safety Issue:
• Measure: Patient-reported outcome: general health status (part2) in unselected patients and patients harboring DDR deficiencies
• Time Frame: baseline up to 47 months
• Safety Issue:
• Measure: Patient-reported outcome: general health status (part 2) in unselected patients and patients harboring DDR deficiencies
• Time Frame: baseline up to 47 months
• Safety Issue:

Estimated Enrollment: 872

Study Start Date: December 18, 2017

Phase: Phase 3

Eligibility:

• Age: minimum 18 Years maximum N/A
• Gender: Male

Inclusion Criteria:

• Histologically or cytologically confirmed adenocarcinoma of the prostate withoutsmall cell or signet cell features Asymptomatic or mildly symptomatic metastatic castration resistant prostate cancer (mCRPC) (score on BPI-SF Question #3 must be < 4). For enrollment into Part 2 only (optional in Part 1): assessment of DDR mutation status Consent to a saliva sample collection for a germline comparator unless prohibited by local regulations or ethics committee decision (optional for patients in Part 1). Surgically or medically castrated, with serum testosterone ≤ 50 ng/dL (≤ 1.73 nmol/L) at screening. Metastatic disease in bone documented on bone scan or in soft tissue documented on CT/MRI scan. Progressive disease at study entry in the setting of medical or surgical castration as defined by 1 or more of the following 3 criteria:
• Prostate specific antigen (PSA) progression defined by a minimum of 2 rising PSA values from 3 consecutive assessments with an interval of at least 7 days between assessments..
• Soft tissue disease progression as defined by RECIST 1.1.
• Bone disease progression defined by Prostate Cancer Working Group 3 (PCWG3) with 2 or more new metastatic bone lesions on a whole body radionuclide bone scan. Bisphosphonate or denosumab dosage must have been stable for at least 4 weeks before Day 1 (Part 1) or randomization (Part 2) for patients receiving these therapies Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1. Life expectancy ≥ 12 months as assessed by the investigator. Able to swallow the study drug and have no known intolerance to study drugs or excipients. Must agree to use a condom when having sex with a partner from the time of the first dose of study drug through 4 months after last dose of study treatment. Must also agree for female partner of childbearing potential to use an additional highly effective form of contraception from the time of the first dose of study treatment through 4 months after last dose of study treatment when having sex with a non pregnant female partner of childbearing potential. Must agree not to donate sperm from the first dose of study drug to 4 months after the last dose of study drug. Evidence of a personally signed and dated informed consent document (and molecular prescreening consent if appropriate) indicating that the patient [or a legally acceptable representative/legal guardian] has been informed of all pertinent aspects of the study. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures

Exclusion Criteria:

• Any prior systemic cancer treatment initiated in in the non metastatic CRPC and mCRPC disease state. Patients whose only evidence of metastasis is adenopathy below the aortic bifurcation. Prior treatment with a PARP inhibitor, cyclophosphamide, or mitoxantrone for prostate cancer. Prior treatment with platinum-based chemotherapy within 6 months prior to Day 1 (Part 1) or randomization (Part 2), or any history of disease progression on platinum-based therapy at any time in the past. Treatment with cytotoxic chemotherapy, biologic therapy including sipuleucel T (other than approved bone targeting agents and GnRH agonist/antagonist therapy), or radionuclide therapy in the 28 days prior to Day 1 (Part 1) or randomization (Part 2). Treatment with any investigational agent within 4 weeks or 5 half-lives of the drug (whichever is longer) before Day 1 (Part 1) or randomization (Part 2). Prior treatment with opioids for pain related to either primary prostate cancer or metastasis within 28 days prior to Day 1 (Part 1) or randomization (Part 2) unless no pain related to prostate cancer has been reported in the 28 days prior to Day 1 (Part 1) or randomization (Part 2). Current use (within 7 days prior to Day 1 (Part 1) or randomization (Part 2) or anticipated use during the study of the following medications:
• Potential DDI with talazoparib: P gp inhibitors (amiodarone, carvedilol, clarithromycin, cobicistat, darunavir, dronedarone, erythromycin, indinavir, itraconazole, ketoconazole, lapatinib, lopinavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir, telaprevir, tipranavir, verapamil, and valspodar).
• Potential DDI with enzalutamide: strong cytochrome P450 2C8 (CYP2C8) inducers (eg, rifampin), strong CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin and rifapentine), moderate CYP3A4 inducers (eg, bosentan, efavirenz, etravirine, modafinil and nafcillin), and substrates of CYP3A4 (eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (eg, phenytoin), or CYP2C19 (eg, S mephenytoin) with a narrow therapeutic index. Major surgery (as defined by the investigator) within 2 weeks before Day 1 (Part 1) or randomization (Part 2). Clinically significant cardiovascular disease Significant renal dysfunction as defined by any of the following laboratory abnormalities: • Renal: eGFR < 30 mL/min/1.73 m2 by the MDRD equation (available via www.mdrd.com). Patients enrolled in Part 1 only: Moderate renal impairment (eGFR 30-59 mL/min/1.73 m2) at screening. Significant hepatic dysfunction as defined by any of the following laboratory abnormalities on screening labs:
• Total serum bilirubin >1.5 times the upper limit of normal (ULN) (>3 × ULN for patients with documented Gilbert syndrome or for whom indirect bilirubin concentrations suggest an extrahepatic source of elevation).
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 times ULN (>5 × ULN if liver function abnormalities are due to hepatic metastasis).
• Albumin <2.8 g/dL Absolute neutrophil count < 1500/µL, platelets < 100,000/µL, or hemoglobin < 9 g/dL (may not have received growth factors or blood transfusions within 14 days before obtaining the hematology values at screening). Known or suspected brain metastasis or active leptomeningeal disease. Symptomatic or impending spinal cord compression or cauda equina syndrome. History of another cancer including myelodysplastic syndrome or acute myeloid leukemia, with the exception of uncomplicated nonmelanoma skin cancers, or American Joint Committee on Cancer stage 0 or stage 1 cancer that has a remote probability of recurrence in the opinion of the investigator and the sponsor Gastrointestinal disorder affecting absorption. Fertile male subjects who are unwilling or unable to use highly effective methods of contraception for the duration of the study and for 4 months after the last dose of investigational product. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or patients who are Pfizer employees, including their family members, directly involved in the conduct of the study. Other acute or chronic medical (concurrent disease, infection, or comorbidity) or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that interferes with ability to participate in the study, may increase the risk associated with study participation or investigational product administration, or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study. History of seizure or any condition that may predispose to seizure (eg, prior cortical stroke, significant brain trauma). Also, history of loss of consciousness or transient ischemic attack within 12 months of randomization (Part 2).

Contact:

• Pfizer CT.gov Call Center
• 1-800-718-1021

Locations:

• Alaska Urological Institute dba Alaska Clinical Research Center
• Anchorage Alaska 99503 United States

• Urological Associates of Southern Arizona, PC
• Tucson Arizona 85715 United States

• Urological Associates of Southern Arizona, P.C.
• Tucson Arizona 85741 United States

• Marin Cancer Care, Inc.
• Greenbrae California 94904 United States

• Tower Urology
• Los Angeles California 90048 United States

• San Diego Clinical Trials
• San Diego California 92120 United States

• The Urology Center of Colorado
• Denver Colorado 80211 United States

• UroPartners LLC
• Melrose Park Illinois 60160 United States

• Regional Urology Oncology & Radiation Center
• Shreveport Louisiana 71106 United States

• Regional Urology, LLC
• Shreveport Louisiana 71106 United States

• Michigan Institute of Urology, PC
• Troy Michigan 48084 United States

• Michigan Institute of Urology
• Troy Michigan 48084 United States

• Oncology Hematology West, PC dba Nebraska Cancer Specialists
• Omaha Nebraska 68114 United States

• Oncology Hematology West, PC dba Nebraska Cancer Specialists
• Omaha Nebraska 68124 United States

• GU Research Network/Urology Cancer Center
• Omaha Nebraska 68130 United States

• Oncology Hematology West, PC dba Nebraska Cancer Specialists
• Omaha Nebraska 68130 United States

• New Jersey Urology, LLC
• Voorhees New Jersey 08043 United States

• Premier Medical Group of the Hudson Valley PC
• Poughkeepsie New York 12601 United States

• Associated Medical Professionals of New York, PLLC
• Syracuse New York 13210 United States

• TriState urologic Services PSC Inc., dba The Urology Group
• Cincinnati Ohio 45212 United States

• Clinical Research Solutions
• Middleburg Heights Ohio 44130 United States

• Cascade View Medical Building
• Corvallis Oregon 97330 United States

• Good Samaritan Hospital – Corvallis
• Corvallis Oregon 97330 United States

• Lancaster Urology
• Lancaster Pennsylvania 17604 United States

• Carolina Urologic Research Center
• Myrtle Beach South Carolina 29572 United States

• Urology Associates P.C.
• Nashville Tennessee 37209 United States

• Houston Metro Urology
• Houston Texas 77027 United States

• University of Utah, Huntsman Cancer Hospital
• Salt Lake City Utah 84112 United States

• University of Utah, Huntsman Cancer Institute
• Salt Lake City Utah 84112 United States

• University of Wisconsin Clinical Science Center
• Madison Wisconsin 53792 United States

• University of Wisconsin Hospital & Clinics
• Madison Wisconsin 53792 United States

• Port Macquarie Base Hospital
• Port Macquarie New South Wales 2444 Australia

• ICON Cancer Centre Wesley
• Auchenflower Queensland 4066 Australia

• River City Pharmacy
• Auchenflower Queensland 4066 Australia

• Princess Alexandra Hospital
• Brisbane Queensland 4102 Australia

• ICON Cancer Centre Chermside
• Chermside Queensland 4032 Australia

• ICON Cancer Centre South Brisbane
• South Brisbane Queensland 4101 Australia

• Integrated Clinical Oncology Network Pty Ltd (ICON)
• South Brisbane Queensland 4101 Australia

• ICON Cancer Centre Southport
• Southport Queensland 4215 Australia

• HUS Helsinki University Hospital
• Helsinki 00029 Finland

• Docrates Cancer Center
• Helsinki 00180 Finland

• HUS Pharmacy, Clinical Trials
• Helsinki 00290 Finland

• Kuopio University Hospital
• Kuopio 70029 Finland

• Kuopio University Hospital
• Kuopio 70210 Finland

• Pirkanmaan sairaanhoitopiiri/Sairaala-apteekki/Tutkimusfarmaseutti
• Tampere 33520 Finland

• Tampere University Hospital
• Tampere 33520 Finland

• Turku University Hospital
• Turku 20520 Finland

• Orszagos Onkologiai Intezet
• Budapest 1122 Hungary

• Országos Onkológiai Intézet
• Budapest 1122 Hungary

• Uzoki Utcai Korhaz
• Budapest 1145 Hungary

• Uzsoki Utcai Kórház
• Budapest 1145 Hungary

• Debreceni Egyetem Klinikai Kozpont Klinikai Gyogyszertar
• Debrecen 4032 Hungary

• Debreceni Egyetem Klinikai Kozpont
• Debrecen 4032 Hungary

• ASST di Cremona
• Cremona CR 26100 Italy

• Nagoya University Hospital
• Nagoya Aichi 466-8560 Japan

• National Cancer Center Hospital East
• Kashiwa Chiba 277-8577 Japan

• National Hospital Organization Hokkaido Cancer Center
• Sapporo Hokkaido 003-0804 Japan

• Hokkaido University Hospital
• Sapporo Hokkaido 060-8648 Japan

• Yokohama City University Medical Center
• Yokohama Kanagawa 232-0024 Japan

• Yokosuka Kyosai Hospital
• Yokosuka Kanagawa 238-8558 Japan

• Kindai University Hospital
• Osakasayama Osaka 589-8511 Japan

• Hamamatsu University School of Medicine, University Hospital
• Hamamatsu Shizuoka 431-3192 Japan

• National Hospital Organization Tokyo Medical Center
• Meguro-ku Tokyo 152-8902 Japan

• Keio University Hospital
• Shinjuku-ku Tokyo 160-8582 Japan

• Chiba Cancer Center
• Chiba 260-8717 Japan

• National Hospital Organization Kyushu Cancer Center
• Fukuoka 811-1395 Japan

• National Hospital Organization Kumamoto Medical Center
• Kumamoto 860-0008 Japan

• Tokushima University Hospital
• Tokushima 770-8503 Japan

• Yamagata Prefectural Central Hospital
• Yamagata 990-2292 Japan

• Clinical Trial Pharmacy, National Cancer Center
• Goyang-si Gyeonggi-do 10408 Korea, Republic of

• National Cancer Center
• Goyang-si Gyeonggi-do 10408 Korea, Republic of

• Pusan National University Hospital
• Busan 49241 Korea, Republic of

• Kyungpook National University Chilgok Hospital
• Daegu 41404 Korea, Republic of

• Department of Urology, Seoul National University Hospital
• Seoul 03080 Korea, Republic of

• Clinical Trial Center, Serverance Hospital, yonsei University Health System
• Seoul 03722 Korea, Republic of

• Severance Hospital, Yonsei University Health System
• Seoul 03722 Korea, Republic of

• Asan Medical Center
• Seoul 05505 Korea, Republic of

• Cancer Center Clinical Trial, Asan Medical Center
• Seoul 05505 Korea, Republic of

• Clinical Trials Center Pharmacy
• Seoul 06351 Korea, Republic of

• Samsung Medical Center
• Seoul 06351 Korea, Republic of

• Clinical Trial Pharmacy, The Catholic University of Korea
• Seoul 06591 Korea, Republic of

• The Catholic University of Korea
• Seoul 06591 Korea, Republic of

• Tauranga Urology Research Limited
• Tauranga BAY OF Plenty 3112 New Zealand

• Auckland City Hospital
• Auckland 1023 New Zealand

• Szpital Specjalistczny W Brzozowie Podkarpack I Osrodek Onkologiczny im. Ks. B Markiewicza
• Brzozow 36-200 Poland

• Szpitale Pomorskie Sp. z o.o. Oddzial Onkologii i Radioterapii
• Gdynia 81-519 Poland

• Europejskie Centrum Zdrowia Otwock Szpital im. Fryderyka Chopina
• Otwock 05-400 Poland

• NZOZ Szpital Mazovia; Oddzial urologiczny
• Warszawa 02-797 Poland

• Hospital Clinico Universitario de Santiago de Compostela
• Santiago de Compostela A Coruna 15706 Spain

• Royal Cornwall Hospitals NHS Trust
• Cornwall TR1 3LJ United Kingdom

• NHS Greater Glasgow and Clyde (Radiology/Scans Address)
• Glasgow G12 0YN United Kingdom

• NHS Greater Glasgow and Clyde, The Beatson West of Scotland Cancer Centre
• Glasgow G12 0YN United Kingdom

View trial on ClinicalTrials.gov