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Pfizer C3441021 (TALAPRO-2): A phase 3, randomized, double-blind, placebo-controlled study Of talazoparib with enzalutamide in metastatic castration-resistant prostate cancer

Description

This study compares radiographic progression free survival (rPFS) in men with metastatic castration-resistant prostate cancer (mCRPC) treated with talazoparib plus enzalutamide versus enzalutamide after confirmation of the starting dose of talazoparib in combination with enzalutamide. 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.

Status

Accepting new patients

Primary Study Objective(s)

The primary objectives of this study are to determine:

  • The starting dose of talazoparib when given in combination with enzalutamide during Part 2 (double-blind treatment period).
  • Radiographic PFS (part 2) in unselected patients and in patients harboring DDR deficiencies.

Core eligibility

Note: This is only a partial list of eligibility criteria.

Including patients who:

  • Have histologically or cytologically confirmed adenocarcinoma of the prostate without small cell or signet cell features
  • Are 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)
  • Have been surgically or medically castrated, with serum testosterone ≤ 50 ng/dL (≤ 1.73 nmol/L) at screening
  • Have metastatic disease in bone documented on bone scan or in soft tissue documented on CT/MRI scan
  • Have 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 two rising PSA values from three consecutive assessments with an interval of at least seven days between assessments
    • Soft tissue disease progression as defined by RECIST 1.1
    • Have bone disease progression defined by Prostate Cancer Working Group 3 (PCWG3) with two or more new metastatic bone lesions on a whole body radionuclide bone scan
  • Have bisphosphonate or denosumab dosage that has been stable for at least four weeks before day 1 (part 1) or randomization (part 2) for patients receiving these therapies
  • Have Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
  • Have a life expectancy at least 12 months as assessed by the investigator
  • Are able to swallow the study drug and have no known intolerance to study drugs or excipients
  • Agree to use a condom when having sex with a partner from the time of the first dose of study drug through four months after last dose of study treatment (Note: 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 four months after last dose of study treatment when having sex with a non-pregnant female partner of childbearing potential.)
  • Agree not to donate sperm from the first dose of study drug to four months after the last dose of study drug
  • Have 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

Excluding patients who:

  • Had any prior systemic cancer treatment initiated in in the non-metastatic CRPC and mCRPC disease state
  • Are patients whose only evidence of metastasis is adenopathy below the aortic bifurcation
  • Had treatment with a PARP inhibitor, cyclophosphamide, or mitoxantrone for prostate cancer
  • Had treatment with platinum-based chemotherapy within six 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
  • Had 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).
  • Had treatment with any investigational agent within four weeks or five half-lives of the drug (whichever is longer) before day 1 (part 1) or randomization (part 2)
  • Had 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.
  • Had major surgery (as defined by the investigator) within 2 weeks before day 1 (part 1) or randomization (part 2).
  • Have clinically significant cardiovascular disease
  • Have 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
  • Have 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
  • Have 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)
  • Have known or suspected brain metastasis or active leptomeningeal disease
  • Have symptomatic or impending spinal cord compression or cauda equina syndrome
  • Have a 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
  • Have gastrointestinal disorder affecting absorption.
  • Fertile men unwilling or unable to use highly effective methods of contraception for the duration of the study and for four 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.
  • Have 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
  • Have a 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)

 

     

Accepting new patients

 

Learn more at

clinicaltrials.gov

 

Principal Investigator(s)

Evan Pisick

David L. Topolsky

Mahdi Taha