| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| 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) |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10036909 |
| E.1.2 | Term | Prostate cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10076506 |
| E.1.2 | Term | Castration-resistant prostate cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of single agent talazoparib in DNA damage repair (DDR) + metastatic CRPC, as measured by best objective response rate (ORR). |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate efficacy with respect to the following parameters:
-Time to objective response;
-Duration of response;
-Proportion of patients with prostate-specific antigen (PSA) decrease ≥50%;
-Proportion of patients with conversion of circulating tumor cell (CTC) count;
-Time to PSA progression;
-Radiographic progression-free survival (PFS);
-Overall survival.
To evaluate the safety of talazoparib in this patient population.
To evaluate the following patient-reported outcomes:
-Time to deterioration in pain as assessed by the Brief Pain Inventory Short Form (BPI-SF);
-Change from baseline in pain per BPI-SF;
-Change from baseline in general health status as assessed by the European Quality of Life 5-Domain 5-Level Scale (EQ-5D-5L).
To evaluate the pharmacokinetics (PK) of talazoparib |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.For patients who are at least 18 years of age, there must be evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study.
2.Histologically or cytologically confirmed adenocarcinoma of the prostate without signet cell, or small cell features. Histologic confirmation may be based on a de novo tumor biopsy obtained for purposes of screening. Biopsies of the brain, lung/mediastinum, pancreas, or endoscopic procedures extending beyond the esophagus, stomach, or bowel may not be performed for the sole purpose of determining study eligibility.
3.Patients must have measurable soft tissue disease per RECIST1.1.
4.DNA damage repair gene alterations likely to sensitize to PARP inhibition (DDR positive) as determined by:
•Prospective testing of de novo or archival tumor tissue (via central laboratory) or prior historical (with Sponsor preapproval) testing of tumor tissue using the Foundation Medicine, FoundationOne® NGS gene panel test;
Archival or de novo tumor tissue also should be submitted prior to Day 1 if possible to support concordance analyses and additional molecular profiling.
5.Unless prohibited by local regulations or ethics committee (EC) decision, consent to a saliva sample collection for retrospective sequencing of DDR genes used to assess patient eligibility based on tumor tissue, and to serve as a germline control in identifying tumor mutations.
6.Serum testosterone ≤ 1.73 nmol/L (50 ng/dL) at screening.
7.Bilateral orchiectomy or ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) agonist/antagonist (surgical or medical castration).
8.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.
9.Metastatic disease. Patients whose only evidence of metastasis is measurable soft tissue disease below the aortic bifurcation will be acceptable. Neither bone metastases on bone scan nor non- measurable soft tissue disease alone will qualify a patient.
10.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.
11.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.
12.Bisphosphonate or denosumab dosage must have been stable for at least 4 weeks before day 1 for patients receiving these therapies.
13.ECOG performance status of 0 to 2.
14.Estimated life expectancy of ≥ 6 months as assessed by the investigator.
15.Able to swallow the study drug, have no known intolerance to study drugs or excipients, and comply with study requirements.
16.Must use a condom when having sex with a pregnant woman from the time of the first dose of study drug through 105 days after last dose of study drug. An additional highly effective form of contraception (Section 4.3.1) must be used from the time of the first dose of study drug through 105 days after last dose of study drug when having sex with a non
pregnant female partner of childbearing potential.
17.Must agree not to donate sperm from the first dose of study drug to 105 days after the last dose of study drug.
18.Patients must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures. |
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| E.4 | Principal exclusion criteria |
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.
2.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.
3.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.
4.Radiation therapy within 3 weeks (within 2 weeks, if single fraction of radiotherapy) before day 1.
5.Major surgery within 2 weeks before day 1.
6.Clinically significant cardiovascular disease, including any of the following:
•Myocardial infarction or symptomatic cardiac ischemia within 6 months before screening.
•Congestive heart failure New York Heart Association class III or IV.
•History of clinically significant ventricular arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsade de pointes) within 1 year before screening.
•History of Mobitz II second degree or third degree heart block unless a permanent pacemaker is in place.
•Hypotension as indicated by systolic blood pressure < 86 mm Hg at screening.
•Bradycardia as indicated by a heart rate of < 45 beats per minute on the screening electrocardiogram.
•Uncontrolled hypertension as indicated by systolic blood pressure >170 mm Hg or diastolic blood pressure > 105 mm Hg at screening.
7.Significant organ dysfunction as defined by any one of the following laboratory abnormalities:
•Renal: eGFR < 30 mL/min /1.73 m2 by the MDRD equation (Modification of Diet in Renal Disease [available via www.mdrd.com]).
•Hepatic:
•Total serum bilirubin > 1.5 times the upper limit of normal (ULN) (> 3 × ULN for patients with 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 (if liver test abnormalities are due to hepatic metastasis, then AST or ALT ≥ 5 × ULN);
•Albumin < 2.8 g/dL.
•Bone marrow reserve: absolute neutrophil count < 1500/μL, platelets < 100,000/μL, or hemoglobin < 9 g/dL (NOTE: may not have received growth factors or blood transfusions within 14 days before obtaining the hematology values at screening).
8.Known or suspected brain metastasis or active leptomeningeal disease.
9.Symptomatic or impending spinal cord compression or cauda equina syndrome.
10.Diagnosis of myelodysplastic syndrome.
11.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.
12.Gastrointestinal disorder affecting absorption.
13.Current or anticipated use 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), P gp inducers (avasimibe, carbamazepine, phenytoin, rifampin, and St. John's wort), or BCRP inhibitors (curcumin, cyclosporine, elacridar [GF120918] and eltrombopag).
14.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 medical monitor, 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.
15.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.
16.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 105 days after the last dose of investigational product. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Best objective response rate (ORR). The proportion of patients with a
best overall
soft tissue response of CR or PR per RECIST 1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary endpoint analysis will be performed when the last enrolled patient completes at least 6 months of study drug treatment, withdraws consent, discontinues from the study, or dies, whichever occurs first. |
|
| E.5.2 | Secondary end point(s) |
• Time to objective response
• Duration of response
- Proportion of patients with conversion of CTC count
- Time to PSA progression |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Time to objective response: time from first dose of talazoparib 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 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 to the first subsequent objective evidence of radiographic progression or death due to any cause, whichever occurs first.
-CTC assessment at weeks 1,9,17,25, safety follow up
-PSA assessment at weeks 1,9,13,17,21,25, safety follow up |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Exploratory biomarker assessments: Sufficient fresh or archival tumor tissue must be submitted at prescreen (optional) or screening for whole exome sequencing, (HRD) analysis, and transcriptome studies. Blood samples for germline DNA sequence collected at prescreen (optional) or screening. Blood samples for (CTC), (ctDNA), and prot BM analyses will be collected through the study. Saliva samples collected as a germline DNA sequencing comparator to assist in identifying tumor tissue mutations. |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 61 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Brazil |
| Canada |
| Korea, Republic of |
| United States |
| Austria |
| France |
| Poland |
| Netherlands |
| Spain |
| Germany |
| Italy |
| Belgium |
| Denmark |
| Hungary |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | 30 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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