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

Prostate Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01286987
• Other study ID #: PRP-001
• Secondary ID: 2010-023062-40C3
• Status: Completed
• Phase: Phase 1
• Start date: January 3, 2011
• Est. completion date: January 30, 2017

Study information

• Verified date: June 2018
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 113
• Est. completion date: January 30, 2017
• Est. primary completion date: March 31, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Advanced or Recurrent Solid Tumors
• Breast Neoplasms
• Ewing Sarcoma
• Lung Neoplasms
• Neoplasms, Glandular and Epithelial
• Ovarian Cancer, Epithelial
• Ovarian Neoplasms
• Pancreas Cancer
• Pancreatic Neoplasms
• Prostate Cancer
• Sarcoma, Ewing
• Small Cell Lung Carcinoma

Intervention

Drug:
• Talazoparib
Oral capsule with multiple dosage forms given once daily

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
Pfizer	Medivation, Inc.

Countries where clinical trial is conducted

United States,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)