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 | 20.0 |
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) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
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) |
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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 efficacy, as measured by best objective response rate (ORR) |
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E.2.2 | Secondary objectives of the trial |
• Time to objective response
• Duration of response
• Proportion of patients with prostate-specific antigen (PSA) response ≥ 50%
• Proportion of patients with conversion of circulating tumor cell (CTC) count
• Time to PSA progression
• Radiographic progression-free survival (PFS)
• Overall survival
• Pain as assessed by the Brief Pain Inventory Short Form (BPI-SF)
• Patient-reported outcome as assessed by the European Quality of Life 5-Domain 5-Level Scale (EQ-5D-5L)
• Safety
• Pharmacokinetics (PK) of talazoparib
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-At least 18 years of age and willing and able to provide informed consent.
- Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation, signet cell, or small cell features.
- Consent to a fresh tumor biopsy before enrollment unless adequate archival tissue is available for molecular analyses. Consent to blood sample collection for germline DNA and biomarker analysis is required.
•If the patient does not have a prior histologic diagnosis, a baseline fresh tumor biopsy may be used for both the purpose of confirming the histologic diagnosis and for biomarker analysis.
• Sponsor preapproval is required when a biopsy procedure is needed for the sole purpose of determining study eligibility. Biopsies of the 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.
- A genomic defect in a DNA repair gene that is likely to or that may sensitize to PARP inhibition as assessed by a gene mutation biomarker panel.
- 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.
- Metastatic disease with measurable soft tissue disease by CT or MRI per RECIST 1.1. Patients with disease spread limited to regional pelvic lymph nodes (below the aortic bifurcation) are not eligible. Patients may also have metastatic disease documented by bone lesions on whole body radionuclide bone scan.
- Previous treatment with 1 or 2 chemotherapy regimens including at least 1 taxane-based regimen for metastatic prostate cancer. Patients may have received radium-223 and/or cabazitaxel, or were deemed unsuitable, declined, or did not have access to these therapies.
- A history of disease progression during previous treatment for metastatic CRPC with at least 1 novel hormonal therapy (enzalutamide and/or abiraterone acetate/prednisone) in the opinion of the investigator.
-Bisphosphonate or denosumab dosage must have been stable for at least 4 weeks before day 1 for patients receiving these therapies.
- ECOG performance status of 0 to 2.
-Estimated life expectancy of ≥ 6 months.
-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 with a pregnant woman or with a woman of childbearing potential from the time of the first dose of study drug through 105 days after last dose of study drug. Contraception should be considered for a nonpregnant female partner of childbearing potential.
-Must agree not to donate sperm from the first dose of study drug to 105 days after the last dose of study drug. |
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E.4 | Principal exclusion criteria |
- Use of systemic 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, platinum, cyclophosphamide, or mitoxantrone chemotherapy.
- 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, 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).
• 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.
- Significant organ dysfunction as defined by the following laboratory abnormality:
• 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 times 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 < 3.0 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).
- Known or suspected brain metastasis or active leptomeningeal disease.
- Symptomatic or impending spinal cord compression or cauda equina syndrome.
- Diagnosis of MDS.
- 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 of a strong P-gp inhibitor (eg, dronedarone, quinidine, ranolazine, itraconazole, ketoconazole), strong P-gp inducer (eg, rifampin, tipranavir, ritonavir), or strong inhibitor of BCRP (eg, elacridar [GF120918]).
- Any other 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Best objective response rate (ORR) |
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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. |
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E.5.2 | Secondary end point(s) |
• Time to objective response
• Duration of response |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Time to objective response: 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 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. |
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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 prescreening (optional) or screening for whole exome sequencing, homologous recombination deficiency (HRD) analysis, and transcriptome studies. Blood samples for germline DNA sequencing will be collected at prescreening (optional) or screening. Blood samples for circulating tumor cells (CTC), circulating tumor DNA (ctDNA), and protein biomarker analyses will be collected throughout the study. |
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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 |
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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 | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 59 |
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 |
Austria |
Belgium |
Brazil |
Canada |
Denmark |
France |
Germany |
Hungary |
Italy |
Korea, Republic of |
Netherlands |
New Zealand |
Poland |
Spain |
United Kingdom |
United States |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 7 |