A Study of Talazoparib in Men With DNA Repair Defects and Metastatic Castration-Resistant Prostate Cancer
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The purpose of this international, phase 2, open-label, response rate study of talazoparib is to assess the efficacy and safety of talazoparib in men with DNA repair defects metastatic castration-resistant prostate cancer (CRPC) who previously received taxane-based chemotherapy and progressed on at least 1 novel hormonal agent (enzalutamide and/or abiraterone acetate/prednisone).
TALAPRO-1: A PHASE 2, OPEN-LABEL, RESPONSE RATE STUDY OF TALAZOPARIB IN MEN WITH DNA REPAIR DEFECTS AND METASTATIC CASTRATION-RESISTANT PROSTATE CANCER WHO PREVIOUSLY RECEIVED TAXANE-BASED CHEMOTHERAPY AND PROGRESSED ON AT LEAST 1 NOVEL HORMONAL AGENT (ENZALUTAMIDE AND/OR ABIRATERONE ACETATE/PREDNISONE)
Actual Study Start Date :
July 4, 2017
Estimated Primary Completion Date :
April 3, 2020
Estimated Study Completion Date :
March 3, 2022
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Objective Response Rate (ORR) [ Time Frame: Anticipated in about 34 months following first patient enrolled ]
The best ORR is defined as the proportion of patients with a best overall soft tissue response of CR (complete response) or PR (partial response) per RECIST 1.1 by independent central review.
Secondary Outcome Measures :
Time to objective response [ Time Frame: Anticipated in about 34 months following first patient enrolled ]
The time from enrollment to the first objective evidence of soft tissue response with no evidence of confirmed bone disease progression on bone scan per PCWG3.
Duration of response [ Time Frame: Anticipated in about 34 months following first patient enrolled ]
The duration of response is defined as the time from the first objective evidence of soft tissue response (subsequently confirmed) per RECIST 1.1 by independent central review and no evidence of confirmed bone disease progression per PCWG3 (the Prostate Cancer Clinical Trials Working Group 3) to the first subsequent objective evidence of radiographic progression or death due to any cause, whichever occurs first.
Proportion of patients with prostate-specific antigen (PSA) response ≥ 50% [ Time Frame: Anticipated in about 34 months following first patient enrolled ]
PSA response will be calculated as a decline from baseline PSA (ng/mL) to the maximal PSA response with a threshold of 50%.
Proportion of patients with conversion of circulating tumor cell (CTC) count [ Time Frame: Anticipated in about 34 months following first patient enrolled ]
The CTC count conversion rate will be defined as the proportion of patients with a CTC count ≥ 5 CTC per 7.5 mL of blood at study entry that decreases to < 5 CTC per 7.5 mL of blood anytime on study. In addition, proportion of patients with a CTC count of 1 or more (detectable) per 7.5 mL of blood at study entry that decreases to CTC=0 (undetectable) per 7.5 mL of blood any time on study
Time to PSA progression [ Time Frame: Anticipated in about 34 months following first patient enrolled ]
The time to PSA progression is defined as the time from enrollment to the date that a ≥ 25% increase in PSA with an absolute increase of ≥ 2 μg/L (2 ng/mL) above the nadir (or baseline for patients with no PSA decline) is documented, confirmed by a second consecutive PSA value obtained ≥ 3 weeks (21 days) later.
Radiographic progression-free survival (PFS) [ Time Frame: Anticipated in about 34 months following first patient enrolled ]
Radiographic PFS is defined as the time from enrollment to radiographic progression in soft tissue per RECIST 1.1 by independent central review, in bone per PCWG3 by independent central review, or death on study (defined as death within 168 days of study drug discontinuation without evidence of radiographic progression), whichever occurs first.
Overall survival [ Time Frame: Anticipated in about 34 months following first patient enrolled ]
Overall survival is defined as the time from enrollment to death due to any cause.
Patient-reported pain as assessed by the Brief Pain Inventory Short Form (BPI-SF) [ Time Frame: Anticipated in about 34 months following first patient enrolled ]
Patient-reported pain assessed by the BPI-SF will be summarized descriptively by study visit.
Patient-reported health-related quality of life as assessed by the European Quality of Life 5-Domain 5-Level Scale (EQ-5D-5L) [ Time Frame: Anticipated in about 34 months following first patient enrolled ]
Patient-reported health-related quality of life assessed by the EQ-5D-5L will be summarized descriptively.
Safety as assessed by percentage of patients with any Adverse Event (AE), AE leading to Study Drug Discontinuation, AE leading to death, Serious Adverse Event (SAE), AE related to study drug, SAE related to study drug [ Time Frame: Anticipated in about 34 months following first patient enrolled ]
All safety analyses will be performed using the safety population, defined as all patients in the ITT population who receive any amount of any study drug.
Pharmacokinetics (PK) of talazoparib as assessed by trough plasma concentrations [ Time Frame: Anticipated in about 34 months following first patient enrolled ]
PK data analyses will include descriptive summary statistics of the predose Cmin and postdose concentrations of talazoparib by study visit for each treatment group.
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Ages Eligible for Study:
18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:
Gender Based Eligibility:
Accepts Healthy Volunteers:
At least 18 years of age.
Histologically or cytologically confirmed adenocarcinoma of the prostate without signet cell, or small cell features.
Patients must have measurable soft tissue disease per RECIST 1.1
DNA damage repair deficiency as assessed centrally by a gene mutation biomarker panel (testing of de novo or archival tumor tissue (via central laboratory) or prior historical testing (with Sponsor approval) using the Foundation Medicine, FoundationOne CDx™ NGS gene panel test.
Consent to a saliva sample collection for a germline comparator, unless prohibited by local regulations or ethics committee (EC) decision.
Serum testosterone ≤ 1.73 nmol/L (50 ng/dL) at screening.
Bilateral orchiectomy or ongoing androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) agonist/antagonist (surgical or medical castration).
Progressive disease at study entry defined as 1 or more of the following 3 criteria:
A minimum of 3 rising PSA values with an interval of at least 1 week between determinations. The screening central laboratory PSA value must be ≥ 2 μg/L (2 ng/mL) if qualifying solely by PSA progression.
Soft tissue disease progression as defined by RECIST 1.1.
Bone disease progression defined by PCWG3 with 2 or more new metastatic lesions on bone scan.
Previous treatment with 1 or 2 chemotherapy regimens including at least 1 taxane-based regimen for metastatic (non castrate or castrate) prostate cancer. Patients may have received radium-223 and/or cabazitaxel, or were deemed unsuitable, declined, or did not have access to these therapies.
Documented disease progression (either radiographic or biochemical) on at least 1 novel hormonal therapy (enzalutamide and/or abiraterone acetate/prednisone) for the treatment of metastatic CRPC, irrespective of prior NHT treatment for non castrate prostate cancer or nonmetastatic (M0) CRPC.
Bisphosphonate or denosumab dosage must have been stable for at least 4 weeks before day 1 for patients receiving these therapies.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
Estimated life expectancy of ≥ 6 months as assessed by the investigator.
Able to swallow the study drug, have no known intolerance to study drugs or excipients, and comply with study requirements.
Must use a condom when having sex from the time of the first dose of study drug through 4 months after last dose of study drug. A highly effective form of contraception must be used from the time of the first dose of study drug through 4 months after last dose of study drug 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.
Patients must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
1. Use of systemic chemotherapeutic (including but not limited to taxanes), hormonal, biologic, or radionuclide therapy for treatment of metastatic prostate cancer (other than approved bone targeting agents and GnRH agonist/antagonist) or any other investigational agent within 4 weeks before day 1.
Prior treatment with a PARP inhibitor, cyclophosphamide, or mitoxantrone chemotherapy. Patients who discontinued prior platinum based chemotherapy <=6 months prior to screening or whose disease previously progressed on platinum based therapy at any time in the past are also excluded.
Treatment with any concurrent cytotoxic chemotherapy or investigational drug(s) within 4 weeks or 5 half lives of the drug (whichever is longer) before Day 1 and/or during study participation
Radiation therapy within 3 weeks (within 2 weeks, if single fraction of radiotherapy) before day 1.
Major surgery within 2 weeks before day 1.
Clinically significant cardiovascular disease.
Significant renal, hepatic, or bone marrow organ dysfunction.
Known or suspected brain metastasis or active leptomeningeal disease.
Symptomatic or impending spinal cord compression or cauda equina syndrome.
Prior diagnosis of myelodysplastic syndrome or acute myeloid leukemia
History of another cancer within 3 years before enrollment with the exception of 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.
Current or anticipated use within 7 days prior to first dose of study drug or anticipated use during the study of the following 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).
Any other acute or chronic medical or psychiatric condition (concurrent disease, infection, or comorbidity) that interferes with ability to participate in the study, causes undue risk, or complicates the interpretation of data, in the opinion of the investigator or sponsor, including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that 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.
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.
Fertile male subjects who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 4 months after the last dose of investigational product.
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:
Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.