Study of Talazoparib, a PARP Inhibitor, in Patients With Advanced or Recurrent Solid Tumors

Study Overview
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Brief Summary
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This is a single-arm, open-label study to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of talazoparib in patients with advanced tumors with DNA-repair pathway deficiencies. There will be 2 parts to the study: a dose escalation phase in which the maximum tolerated dose will be defined, and a dose expansion phase.

Official Title
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A Phase 1, First In Human, Single-arm, Open-label Study Of Once A Day, Orally Administered Talazoparib (Bmn 673) In Patients With Advanced Or Recurrent Solid Tumors

Conditions
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Advanced or Recurrent Solid Tumors, Breast Neoplasms, Ovarian Cancer, Epithelial, Ewing Sarcoma, Small Cell Lung Carcinoma, Prostate Cancer, Pancreas Cancer

Intervention / Treatment
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* Drug: Talazoparib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically documented, unresectable, locally advanced or metastatic solid tumor Must have available archived tumor tissue (formalin-fixed paraffin-embedded) [FFPE]. 18 years of age or older. Have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST, v1.1) or increased CA-125 (ovarian cancer) or PSA (prostate cancer) and/or CA 19-9 (pancreatic cancer). Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1. Have adequate organ function Able to take oral medications. Willing and able to provide informed consent. Sexually active patients must be willing to use an acceptable method of contraception. Females of childbearing potential must have a negative serum pregnancy test at screening. Willing and able to comply with all study procedures. Part 2 Dose Expansion Tumor Types: Breast and ovarian cancer patients with deleterious or pathogenic BRCA mutations who have received no more than 4 prior regimens for metastatic disease. Prostate or pancreatic cancer patients with deleterious or pathogenic BRCA mutations who have received no more than 2 prior regimens for metastatic disease. Small cell lung cancer (SCLC) patients who have received no more than one prior regimen for SCLC. Ewing's sarcoma patients who have received no more than 3 prior regimens for metastatic disease. Exclusion Criteria: Part 2 Expansion: Prior treatment with a PARP inhibitor. Has history of central nervous system (CNS) metastasis. * Exception: In patients with SCLC, history of adequately treated brain metastasis who do not require corticosteroids for management of CNS symptoms. Has had major surgery within 28 days before Cycle 1, Day 1. Has active peptic ulcer disease. Active gastrointestinal tract disease with malabsorption syndrome. Pregnant or breastfeeding at screening or planning to become pregnant (in each case, either oneself or one's partner) at any time during the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Talazoparib<br> | Drug: Talazoparib<br>* Oral capsule with multiple dosage forms given once daily<br>* Other names: MDV3800;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Objective Response | Objective response in participants was defined as the number of participants with complete response (CR) or partial response (PR) after treatment with talazoparib and maintained for at least 4 weeks (28 days) as assessed by response evaluation criteria in solid tumors (RECIST) version 1.1. CR defined as disappearance of all non-nodal target lesions (where all target lesions were recorded with a length of 0 millimeter [mm] on the case report form [CRF]) and the reduction of the shortest diameter of all nodal lesions to less than [<] 10 mm. PR was defined by a 30% or more decrease in the sum of the longest diameters (SLD) + sum of shortest diameters (SSD) of target lesions, taking as reference the baseline SLD+SSD. | From Baseline until disease progression or death due to any cause (maximum duration: 1071 days for Part 1; 834 days for Part 2) | 
| Number of Participants With Best Overall Response | Best overall response: best response (in the order of confirmed CR, confirmed PR, stable disease [SD] and progressive disease [PD]) among all overall response as RECIST 1.1, recorded from date of first dose of talazoparib until participant withdrew from study/data cut-off date, whichever earlier. CR defined as disappearance of all non-nodal target lesions (where all target lesions recorded with a length of 0 mm on the CRF) and the reduction of the shortest diameter of all nodal lesions to < 10 mm. PR defined as at least a 30% decrease in sum of the diameters of target lesions, reference to baseline sum diameters. SD defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD defined as at least a 20% increase in sum of diameters of target lesions, reference to the smallest sum on study (this includes the baseline sum if that was the smallest on study). | From Baseline until disease progression or death due to any cause (maximum duration: 1071 days for Part 1; 834 days for Part 2) | 
| Progression-Free Survival (PFS) | PFS was defined as the time (in weeks) from the date of first dose of study drug to the earlier date of the documented PD or death due to any cause. PD as per RECIST 1.1 defined as at least a 20% increase in the sum of diameters of target lesions, reference to the smallest sum on study (this includes the baseline sum if that was the smallest on study). | Baseline, until PD or death due to any cause (maximum duration:1071 days for Part 1; 834 days for Part 2) | 
| Duration of Response | Duration of response was defined as the time (in weeks) from the date of the first documented objective response confirmed at least 28 days later to the date of the first documented PD or date of death, whichever occurred first. PD as per RECIST version 1.1 defined as at least a 20% increase in the sum of diameters of target lesions, reference to the smallest sum on study (this includes the baseline sum if that was the smallest on study). | Baseline until PD or death due to any cause (maximum duration: 1071 days for Part 1; 834 days for Part 2) | 
| Number of Participants With Stable Disease | SD defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD defined as at least a 20% increase in sum of diameters of target lesions, reference to the smallest sum on study (this includes the baseline sum if that was the smallest on study). | Baseline, until PD or death due to any cause (maximum duration: 1071 days for Part 1; 834 days for Part 2) | 
| Part 1: Maximum Tolerated Dose (MTD) | The MTD was defined as the highest dose at which no more than 1 of 6 participants experienced a Dose Limiting Toxicity (DLT). DLT defined as any of the following occurring during cycle 1 of part 1 of study, Hematologic toxicity: Any grade 4 or higher hematologic adverse event, Grade 3 thrombocytopenia associated with grade 2 or higher haemorrhage, Grade 3 thrombocytopenia or neutropenia that led to interruption of dosing for 5 or more days. Nonhematologic toxicity: grade 3 or higher laboratory AE which was asymptomatic and rapidly reversible adverse events (returned to baseline or to grade 1 or lower within 7 days), Grade 3 nausea, vomiting, or diarrhea that could be medically managed to grade 2 or lower with anti-emetics and/or anti-diarrheals within 24 hours, Grade 3 fatigue that improved to grade 2 or lower in 5 days or less, Alopecia. Grades based on National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. | Cycle 1 (Day 1 up to Day 42) | 
| Part 1: Recommended Part 2 Dose of Talazoparib | The Recommended dose of talazoparib for use in Part 2 was determined in Part 1 (dose escalation) on the basis of the totality of safety, pharmacokinetics (PK), pharmacodynamic and preliminary efficacy data observed in Cycles 1 and 2 and beyond. | Baseline up to Cycle 50 (each cycle 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BRCA1 Protein, BRCA2 Protein