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

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

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.

Study Overview

• Status: Completed
• Conditions: Breast Neoplasms; Small Cell Lung Carcinoma; Prostate Cancer; Ewing Sarcoma; Pancreas Cancer; Ovarian Cancer, Epithelial; Advanced or Recurrent Solid Tumors
• Intervention / Treatment: Drug: Talazoparib

• Study Type: Interventional
• Enrollment (Actual): 113
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Surrey
    • Sutton, Surrey, United Kingdom, SM2 5PT
      • Royal Marsden Hospital NHS Foundation Trust
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • Scottsdale Healthcare
    • Scottsdale, Arizona, United States, 85258
      • Virginia G. Piper Cancer Center Research Pharmacy
  • California
    • Los Angeles, California, United States, 90095
      • Ronald Reagan UCLA Medical Center
    • Los Angeles, California, United States, 90095
      • UCLA Hematology/Oncology
    • Los Angeles, California, United States, 90095
      • Westwood Bowyer Clinic, Peter Morton Medical Building
    • Los Angeles, California, United States, 90095
      • (IRB# 12-000131) Ronald Reagan UCLA Medical Center, Drug Information Center
    • Santa Monica, California, United States, 90404
      • UCLA Hematology/Oncology - Santa Monica
    • Santa Monica, California, United States, 90404
      • Santa Monica - UCLA Medical Center & Orthopaedic Hospital
  • Indiana
    • Bloomington, Indiana, United States, 47403
      • IU health Bloomington Hospital
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Health Melvin and Bren Simon Cancer Center
    • Indianapolis, Indiana, United States, 46202
      • IU Health University Hospital
    • Indianapolis, Indiana, United States, 46202
      • Investigational Drug Services
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System
  • Texas
    • Houston, Texas, United States, 77030-4009
      • The University of Texas MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Talazoparib	Drug: Talazoparib; Oral capsule with multiple dosage forms given once daily; Other Names: BMN 673; MDV3800

What is the study measuring?

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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1 and 2: Number of Participants With Treatment-Emergent Adverse Events and Serious Adverse Events	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to end of study (up to 1071 days for Part 1 and up to 834 days for Part 2) that were absent before treatment or that worsened relative to pre-treatment state.	Part 1: Baseline up to 1071 days; Part 2: Baseline up to 834 days
Part 1: Maximum Observed Plasma Concentration (Cmax) of Talazoparib		Cycle 1: 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 10, 24, 48, 72 and 96 hours postdose on Day 1 and Day 35
Part 2: Maximum Observed Plasma Concentration (Cmax) of Talazoparib		Cycle 1 and 2: Predose, 0.5, 1, 2, 3 and 4 hours postdose on Day 1
Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Talazoparib		Cycle 1: 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 10, 24, 48, 72 and 96 hours postdose on Day 1 and Day 35
Part 2: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Talazoparib		Cycle 1 and 2: Predose, 0.5, 1, 2, 3 and 4 hours postdose on Day 1
Part 1: Area Under the Plasma Concentration-Time Curve (AUC) From Time 0 to the Time of the Last Measurable Concentration (AUC0-last) of Talazoparib	Area under the plasma concentration time-curve from zero to the time of last measured concentration (AUC0-last).	Cycle 1: 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 10, 24, 48, 72 and 96 hours postdose on Day 1
Part 2: Area Under the Plasma Concentration-Time Curve (AUC) From Time 0 to the Time of the Last Measurable Concentration (AUC0-last) of Talazoparib	Area under the plasma concentration time-curve from zero to the time of last measured concentration (AUC0-last).	Cycle 1 and 2: Predose, 0.5, 1, 2, 3 and 4 hours postdose on Day 1
Part 1: Minimum Observed Plasma Concentration (Cmin) of Talazoparib		Cycle 1: 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 10, 24, 48, 72 and 96 hours postdose on Day 35
Part 1: Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0-inf)] of Talazoparib	AUC (0-inf) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time.	Cycle 1: 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 10, 24, 48, 72 and 96 hours postdose on Day 1
Part 1: Terminal Half-Life (t1/2) of Talazoparib	T1/2 is the time measured for the plasma concentration of talazoparib to decrease by one half.	Cycle 1: 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 10, 24, 48, 72 and 96 hours postdose on Day 1 and Day 35
Part 1: Apparent Oral Clearance (CL/F) of Talazoparib	Clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) was influenced by the fraction of the dose absorbed.	Cycle 1: 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 10, 24, 48, 72 and 96 hours postdose on Day 1
Part 1: Apparent Volume of Distribution (Vz/F) of Talazoparib	Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz/F was influenced by the fraction absorbed.	Cycle 1: 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 10, 24, 48, 72 and 96 hours postdose on Day 1 and Day 35

Collaborators and Investigators

• Sponsor: Pfizer
• Collaborators: Medivation, Inc.
• Investigators: Study Director: Medical Director, Medivation, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): January 3, 2011
• Primary Completion (Actual): March 31, 2015
• Study Completion (Actual): January 30, 2017

Study Registration Dates

• First Submitted: January 26, 2011
• First Submitted That Met QC Criteria: January 28, 2011
• First Posted (Estimate): February 1, 2011

Study Record Updates

• Last Update Posted (Actual): January 10, 2019
• Last Update Submitted That Met QC Criteria: June 29, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: BRCA1 Protein; BRCA2 Protein
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Skin Diseases; Respiratory Tract Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Disease Attributes; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Digestive System Neoplasms; Endocrine Gland Neoplasms; Breast Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Pancreatic Diseases; Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Sarcoma; Ovarian Neoplasms; Breast Neoplasms; Recurrence; Small Cell Lung Carcinoma; Pancreatic Neoplasms; Sarcoma, Ewing; Carcinoma, Ovarian Epithelial; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Talazoparib
• Other Study ID Numbers: PRP-001; 2010-023062-40 (EudraCT Number); C3441007 (Other Identifier: Alias Study Number)