Clinical Trials /

Talazoparib + Enzalutamide vs. Enzalutamide Monotherapy in mCRPC

NCT03395197

Description:

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.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Talazoparib + Enzalutamide vs. Enzalutamide Monotherapy in mCRPC
  • Official Title: A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF TALAZOPARIB WITH ENZALUTAMIDE IN METASTATIC CASTRATION-RESISTANT PROSTATE CANCER

Clinical Trial IDs

  • ORG STUDY ID: C3441021
  • SECONDARY ID: 2017-003295-31
  • SECONDARY ID: TALAPRO-2
  • NCT ID: NCT03395197

Conditions

  • mCRPC

Interventions

DrugSynonymsArms
Talazoparib with enzalutamideCombination arm
Placebo with enzalutamideMonotherapy arm

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.

Detailed Description

      Part 1 is an open-label, non-randomized, safety and PK run-in study designed to confirm the
      starting dose of talazoparib in combination with enzalutamide through assessment of target
      safety events and PK at select sites. Part 2 is a randomized, double-blind,
      placebo-controlled, multinational study comparing talazoparib plus enzalutamide vs. placebo
      plus enzalutamide in patients with mCRPC.
    

Trial Arms

NameTypeDescriptionInterventions
Combination armExperimentalTalazoparib plus enzalutamide
  • Talazoparib with enzalutamide
Monotherapy armActive ComparatorEzalutamide plus placebo
  • Placebo with enzalutamide

Eligibility Criteria

        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).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Confirm the dose of Talazoparib (part 1)
Time Frame:Day 1 up to 28 days
Safety Issue:
Description:determined based on the safety profile

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:
Description:time from randomization to death from any cause
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:
Description:proportion of patients with measurable soft tissue disease at baseline with objective response per RECIST 1.1
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:
Description:duration of responses in patients with measurable soft tissue disease at baseline per RECIST 1.1
Measure:PSA response (part 2) in unselected patients and in patients harboring DDR deficiencies
Time Frame:baseline up to 25 months
Safety Issue:
Description:proportion of patients with PSA response grater than or equal to 50%
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:
Description:time from baseline to PSA progression
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:
Description:time from randomization to initiation of cytotoxic chemotherapy
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:
Description:time from randomization to initiation of antineoplastic treatment
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:
Description:time from randomization to first symptomatic skeletal event (symptomatic fractures, spinal cord compression, surgery or radiation to the bone whichever is first)
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:
Description:PFS2 based on investigator assessment
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:
Description:time from randomization to opiate use for prostate cancer pain
Measure:Incidence of adverse events (part 1 and 2)
Time Frame:Day 1 up to 26 months
Safety Issue:
Description:AEs and SAEs incidence by type and severity (graded by NCI CTCAE version 4.03)
Measure:Pharmacokinetic assessment of talazoparib (part 1)
Time Frame:Week 1, 5, 9, and 13
Safety Issue:
Description:plasma concentration of talazoparib
Measure:Pharmacokinetic assessment of talazoparib (part 2)
Time Frame:week 3, 5, 9 13, and 17
Safety Issue:
Description:plasma concentration of talazoparib
Measure:Pharmacokinetic assessment of enzalutamide (part 1)
Time Frame:week 1, 5, 9, and 13
Safety Issue:
Description:plasma concentration of enzalutamide
Measure:Pharmacokinetic assessment of enzalutamide (part 2)
Time Frame:week 3, 5, 9 13, and 17
Safety Issue:
Description:plasma concentration of enzalutamide
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:
Description:change from baseline in patient-reported pain symptoms per Brief Pain Inventory Short Form (BPI-SF)
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:
Description:time to deterioration in patient-reported pain symptoms per Brief Pain Inventory Short Form (BPI-SF)
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:
Description:change from baseline in patient-reported Global health status/QoL per EORTC QLQ-C30
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:
Description:time to definitive deterioration in patient-reported global health status/QoL per EORTC QLQ-C30
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:
Description:change from baseline in patient-reported general health status per EQ-5D-5L
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:
Description:time to definitive deterioration in patient-reported disease-specific urinary symptoms per EORTC QLQ-PR25

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Pfizer

Trial Keywords

  • mCRPC (metastatic castration-resistant prostate cancer)

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