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

• ClinicalTrials.gov Identifier: NCT01286987
• Recruitment Status: Completed
• First Posted: February 1, 2011
• Results First Posted: January 10, 2019
• Last Update Posted: January 10, 2019
• Sponsor: Pfizer
• Collaborator: Medivation, Inc.
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: January 26, 2011
• First Posted Date: February 1, 2011
• Results First Submitted Date: January 31, 2018
• Results First Posted Date: January 10, 2019
• Last Update Posted Date: January 10, 2019
• Actual Study Start Date: January 3, 2011
• Actual Primary Completion Date: March 31, 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 29, 2018)

• Number of Participants With Objective Response [ Time Frame: From Baseline until disease progression or death due to any cause (maximum duration: 1071 days for Part 1; 834 days for Part 2) ]
  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.
• Number of Participants With Best Overall Response [ Time Frame: From Baseline until disease progression or death due to any cause (maximum duration: 1071 days for Part 1; 834 days for Part 2) ]
  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).
• Progression-Free Survival (PFS) [ Time Frame: Baseline, until PD or death due to any cause (maximum duration:1071 days for Part 1; 834 days for Part 2) ]
  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).
• Duration of Response [ Time Frame: Baseline until PD or death due to any cause (maximum duration: 1071 days for Part 1; 834 days for Part 2) ]
  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).
• Number of Participants With Stable Disease [ Time Frame: Baseline, until PD or death due to any cause (maximum duration: 1071 days for Part 1; 834 days for Part 2) ]
  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).
• Part 1: Maximum Tolerated Dose (MTD) [ Time Frame: Cycle 1 (Day 1 up to Day 42) ]
  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.
• Part 1: Recommended Part 2 Dose of Talazoparib [ Time Frame: Baseline up to Cycle 50 (each cycle 28 days) ]
  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.

• Original Primary Outcome Measures (submitted: January 28, 2011): The primary outcome of this study is to determine the maximum tolerated dose (MTD) of daily oral BMN 673 [ Time Frame: Assessed after each visit until completion of Part 1 (Estimated duration is 12-18 months) ]
• Current Secondary Outcome Measures: Not Provided

Original Secondary Outcome Measures (submitted: January 28, 2011)

• Number of participants with adverse events [ Time Frame: Assessed after each visit until completion of the study (Estimated duration is 24-30 months) ]
• Determine the pharmacokinetic (PK) profile of BMN 673 [ Time Frame: Assessed at each visit in cycle 1 - 5 (Estimated duration is 24 months) ]
  Sample collection times vary per visit. PK parameters that will be evaluated include: maximum concentration (Cmax), minimum concentration (Cmin), time to maximum plasma concentration (Tmax), area under the curve from 0 to last quantifiable sampling point postdose (AUC0-inf), are under the curve extrapolated to infinity (AUC0-last), half life (t1/2), systemic clearance (CL/f) and volume of ditribution (VZ/f)
• Determine the Recommended Phase 2 Dose (RP2D) of oral daily BMN 673 [ Time Frame: Assessed after each visit until completion of the study (Estimated duration is 24-30 months) ]
• Assess preliminary efficacy of BMN 673 by Response Rate, based on RECIST (Response Evaluation Criteria In Solid Tumors) [ Time Frame: Assessed approximately every 8 weeks (Estimated duration is 24-30 months) ]

Current Other Pre-specified Outcome Measures (submitted: June 29, 2018)

• Part 1 and 2: Number of Participants With Treatment-Emergent Adverse Events and Serious Adverse Events [ Time Frame: Part 1: Baseline up to 1071 days; Part 2: Baseline up to 834 days ]
  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: Maximum Observed Plasma Concentration (Cmax) of Talazoparib [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 ]
  Area under the plasma concentration time-curve from zero to the time of last measured concentration (AUC0-last).
• 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 [ Time Frame: Cycle 1 and 2: Predose, 0.5, 1, 2, 3 and 4 hours postdose on Day 1 ]
  Area under the plasma concentration time-curve from zero to the time of last measured concentration (AUC0-last).
• Part 1: Minimum Observed Plasma Concentration (Cmin) of Talazoparib [ Time Frame: 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 [ Time Frame: 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 ]
  AUC (0-inf) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time.
• Part 1: Terminal Half-Life (t1/2) of Talazoparib [ Time Frame: 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 ]
  T1/2 is the time measured for the plasma concentration of talazoparib to decrease by one half.
• Part 1: Apparent Oral Clearance (CL/F) of Talazoparib [ Time Frame: 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 ]
  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.
• Part 1: Apparent Volume of Distribution (Vz/F) of Talazoparib [ Time Frame: 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 ]
  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.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Talazoparib, a PARP Inhibitor, in Patients With Advanced or Recurrent Solid Tumors
• 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
• Brief 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Masking: None (Open Label); Primary Purpose: Treatment

Condition

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

Intervention

Drug: Talazoparib

Oral capsule with multiple dosage forms given once daily

Other Names:

• BMN 673
• MDV3800

Study Arms

Experimental: Talazoparib

Intervention: Drug: Talazoparib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 28, 2017): 113
• Original Estimated Enrollment (submitted: January 28, 2011): 70
• Actual Study Completion Date: January 30, 2017
• Actual Primary Completion Date: March 31, 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United Kingdom, United States

Administrative Information

• NCT Number: NCT01286987
• Other Study ID Numbers: PRP-001; 2010-023062-40 ( EudraCT Number ); C3441007 ( Other Identifier: Alias Study Number )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Pfizer
• Original Responsible Party: Andres Gutierrez, Medical Director, BioMarin Pharmaceutical Inc.
• Current Study Sponsor: Pfizer
• Original Study Sponsor: BioMarin Pharmaceutical
• Collaborators: Medivation, Inc.

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer
• Study Director: Medical Director; Medivation, Inc.

• PRS Account: Pfizer
• Verification Date: June 2018