An Open-Label Pharmacokinetics and Safety Study of Talazoparib (MDV3800)

A PHASE I OPEN-LABEL PHARMACOKINETICS AND SAFETY STUDY OF TALAZOPARIB (MDV3800) IN PATIENTS WITH ADVANCED SOLID TUMORS AND NORMAL OR VARYING DEGREES OF HEPATIC IMPAIRMENT

This is a trial to investigate the pharmacokinetics (PK) and the safety of talazoparib in patients with advanced solid tumors and impaired hepatic function.

Study Overview

• Status: Completed
• Conditions: Advanced Solid Tumors
• Intervention / Treatment: Drug: Talazoparib

Detailed Description

At the end of the study, patients with no clinically significant toxicities, no contraindications to continue treatment with talazoparib, and no disease progression (underlying cancer progression) may be eligible to continue talazoparib treatment in a separate open-label extension study. The decision to allow the patient to continue dosing with talazoparib in an open-label extension (OLE) study will be based on potential overall benefit-risk and patient meeting eligibility criteria for OLE.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Alhambra, California, United States, 91801
      • UCLA Hematology/Oncology - Alhambra
    • Bakersfield, California, United States, 93309
      • CBCC Global Research, Inc. at Comprehensive Blood and Cancer Center
    • Fullerton, California, United States, 92835
      • St. Joseph Heritage Healthcare
    • Fullerton, California, United States, 92835
      • St. Jude Hospital Yorba Linda dba St. Joseph Heritage Healthcare
    • Los Angeles, California, United States, 90095
      • UCLA Hematology/Oncology
    • Porter Ranch, California, United States, 91326
      • UCLA Hematology/Oncology - Porter Ranch
    • Santa Monica, California, United States, 90404
      • UCLA Hematology/Oncology - Santa Monica
    • Torrance, California, United States, 90505
      • UCLA Torrance Oncology
    • Valencia, California, United States, 91355
      • UCLA Hematology/Oncology - Santa Clarita
  • Florida
    • Orlando, Florida, United States, 32806
      • Orlando Health, Inc.
  • Texas
    • Houston, Texas, United States, 77030
      • 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:

1. Signed and dated Informed Consent Form (by the patient or a legally acceptable representative as per the local regulations).
2. Female or male at least 18 years of age.
3. Histologically or cytologically confirmed advanced solid tumor with no available standard treatment options in the opinion of the Investigator
4. Eastern Cooperative Oncology Group (ECOG) Performance status ≤ 2.
5. Expected life expectancy of ≥ 3 months.
6. Able to swallow the study drug (no contraindication to oral agents).
7. Hepatic function at screening and enrollment as defined by the NCI organ dysfunction working group (NCI-ODWG) criteria.
8. Adequate other organ function at screening and enrollment.
9. Female patients of childbearing potential must have a negative serum pregnancy test at screening and must agree to use a highly effective form of contraception from the time of the first dose of study drug through 7 months after the last dose of study drug.
10. Male patients must agree to use a condom when having sex with a pregnant woman or with a non-pregnant female partner of childbearing potential, from 21 days before the first dose of study drug through 4 months after last dose of study drug.
11. Female patients must not be breastfeeding at screening nor during the study participation until 7 months after the last dose of the study drug.
12. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.

Exclusion Criteria:

1. Treatment within 14 days or five half lives prior to enrollment whichever is longer with any type of systemic anticancer-therapy or any investigational drug
2. Have not recovered (recovery is defined as CTCAE grade ≤ 1) from the acute toxicities of previous anticancer standard or investigational therapy, except treatment-related alopecia or laboratory abnormalities otherwise meeting eligibility requirements.
3. Major surgery within 28 days prior to enrollment.
4. Serious accompanying cardiac disorder
5. Active known or suspected brain metastasis or active leptomeningeal disease needing treatment
6. Symptomatic or impending spinal cord compression or cauda equine syndrome
7. Has undergone a liver transplant, kidney transplant or nephrectomy.
8. Prior allergic reaction or severe intolerance (meeting the criteria for a serious adverse event, a grade 3 or 4 AE, or permanent treatment discontinuation) to a poly ADP ribose polymerase (PARP) inhibitor.
9. Known myelodysplastic syndrome
10. Seropositive for human immunodeficiency virus (HIV).
11. Any serious or unstable medical condition that interferes with ability to tolerate treatment or assessments associated with the protocol.
12. Gastrointestinal disorder affecting absorption.
13. Known or suspected hypersensitivity to any of the talazoparib capsule components.
14. Any condition or reason that interferes with ability to participate in the study, tolerate treatment or assessments associated with the protocol, causes undue risk, or complicates the interpretation of safety data, in the opinion of the Investigator or Medical Monitor

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A (control, normal hepatic function)	Drug: Talazoparib; Daily oral doses of talazoparib 0.5 mg; Other Names: MDV3800; BMN673
Experimental: Group B (mild hepatic dysfunction)	Drug: Talazoparib; Daily oral doses of talazoparib 0.5 mg; Other Names: MDV3800; BMN673
Experimental: Group C (moderate hepatic dysfunction)	Drug: Talazoparib; Daily oral doses of talazoparib 0.5 mg; Other Names: MDV3800; BMN673
Experimental: Group D (severe hepatic dysfunction)	Drug: Talazoparib; Daily oral doses of talazoparib 0.5 mg; Other Names: MDV3800; BMN673

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Free Plasma Concentration Time Curve From Zero to 24 Hours (AUC0-24) of Talazoparib on Day 22	AUC0-24 of talazoparib was defined as the area under the free plasma concentration time curve from time 0 to 24 hours post-dose.	Pre-dose (24 hours +/- 60 minutes from the previous dose on Day 21 but within 60 minutes prior to next dose), 0.5, 1, 2, 4, 6, anytime from 8 to 12 and 24 hours post-dose on Day 22
Maximum Observed Plasma Concentration (Cmax) of Talazoparib on Day 22	Cmax was defined as the maximum observed plasma concentration of talazoparib.	Pre-dose (24 hours +/- 60 minutes from the previous dose on Day 21 but within 60 minutes prior to next dose), 0.5, 1, 2, 4, 6, anytime from 8 to 12 and 24 hours post-dose on Day 22
Unbound Area Under the Free Plasma Concentration Time Curve From Zero to 24 Hours (AUC0-24u) of Talazoparib on Day 22	AUC0-24u for unbound talazoparib was defined as the area under the free plasma concentration time curve from time 0 to 24 hours post-dose. AUC0-24u = fu*AUC0-24. fu= Fraction of Unbound (fu) Plasma.	Pre-dose (24 hours +/- 60 minutes from the previous dose on Day 21 but within 60 minutes prior to next dose), 0.5, 1, 2, 4, 6, anytime from 8 to 12 and 24 hours post-dose on Day 22
Unbound Maximum Observed Plasma Concentration (Cmaxu) of Talazoparib on Day 22	Cmaxu was defined as the maximum observed plasma concentration for unbound talazoparib. Cmaxu = fu*Cmax.	Pre-dose (24 hours +/- 60 minutes from the previous dose on Day 21 but within 60 minutes prior to next dose), 0.5, 1, 2, 4, 6, anytime from 8 to 12 and 24 hours post-dose on Day 22

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Free Plasma Concentration Time Curve From Zero to 24 Hours (AUC0-24) of Talazoparib on Day 1	AUC0-24 of talazoparib was defined as the area under the free plasma concentration time curve from time 0 to 24 hours post-dose.	Pre-dose (within 60 minutes prior to dose), 0.5, 1, 2, 4, 6, anytime between 8 to 12 and 24 hours post-dose on Day 1
Maximum Observed Plasma Concentration (Cmax) of Talazoparib on Day 1	Cmax was defined as the maximum observed plasma concentration of talazoparib.	Pre-dose (within 60 minutes prior to dose), 0.5, 1, 2, 4, 6, anytime between 8 to 12 and 24 hours post-dose on Day 1
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Talazoparib on Day 1	Tmax was defined as the time to reach maximum observed plasma concentration of talazoparib.	Pre-dose (within 60 minutes prior to dose), 0.5, 1, 2, 4, 6, anytime between 8 to 12 and 24 hours post-dose on Day 1
Fraction of Unbound (fu) Plasma Talazoparib on Day 1	Fraction of unbound drug (fu) was defined as the ratio of unbound drug concentration to the total drug concentration and reported as percentage (%).	Pre-dose (within 60 minutes prior to dose), 0.5, 1, 2, 4, 6, anytime between 8 to 12 and 24 hours post-dose on Day 1
Unbound Area Under the Free Plasma Concentration Time Curve From Zero to 24 Hours (AUC0-24u) of Talazoparib on Day 1	AUC0-24u for unbound talazoparib was defined as the area under the free plasma concentration time curve from time 0 to 24 hours post-dose. AUC0-24u = fu*AUC0-24.	Pre-dose (within 60 minutes prior to dose), 0.5, 1, 2, 4, 6, anytime between 8 to 12 and 24 hours post-dose on Day 1
Unbound Maximum Observed Plasma Concentration (Cmaxu) of Talazoparib on Day 1	Cmaxu was defined as the maximum observed plasma concentration for unbound talazoparib. Cmaxu = fu*Cmax	Pre-dose (within 60 minutes prior to dose), 0.5, 1, 2, 4, 6, anytime between 8 to 12 and 24 hours post-dose on Day 1
Plasma Trough Concentration (Ctrough) of Talazoparib on Day 8, 15 and 22	Ctrough was defined as plasma trough (pre-dose) concentration of talazoparib. Acceptance criteria for Ctrough on Day 15 and Day 22: received 10 consecutive days of dosing immediately before PK sampling day; Sample drawn within 24 +/-2 hours of the previous dose, and not more than +10 minute after the drug administration on the PK collection day. Ctrough on Day 8: received 7 consecutive days of dosing immediately before PK sampling day; sample drawn within 24 +/- 2 hours of the previous dose, and not more than +10 minute after the drug administration on the PK collection day.	Pre-dose on Day 8, 15 and 22
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Talazoparib on Day 22	Tmax was defined as the time to reach maximum observed plasma concentration of talazoparib.	Pre-dose (24 hours +/- 60 minutes from the previous dose on Day 21 but within 60 minutes prior to next dose), 0.5, 1, 2, 4, 6, anytime from 8 to 12 and 24 hours post-dose on Day 22
Fraction of Unbound (fu) Plasma Talazoparib on Day 22	Fraction of unbound drug (fu) was defined as the ratio of unbound drug concentration to the total drug concentration and reported as percentage (%).	Pre-dose (24 hours +/- 60 minutes from the previous dose on Day 21 but within 60 minutes prior to next dose), 0.5, 1, 2, 4, 6, anytime from 8 to 12 and 24 hours post-dose on Day 22
Accumulation Ratio (Rac) of Plasma Talazoparib	Accumulation ratio for AUC0-24 was calculated as area under the curve from time zero to 24 hours on Day 22 divided by area under the curve from time zero to 24 hours on Day 1.	Pre-dose (within 60 minutes prior to dose) on Day 1, pre-dose(24 hours +/- 60 minutes from the previous dose on Day 21 but within 60 minutes prior to next dose) on Day 22 and 0.5, 1, 2, 4, 6, anytime between 8 to 12 and 24 hours post-dose on Days 1 and 22
Apparent Clearance (CL/F) of Plasma Talazoparib on Day 22	Talazoparib clearance is a measure of the rate at which talazoparib is metabolized or eliminated by normal biological processes.	Pre-dose (24 hours +/- 60 minutes from the previous dose on Day 21 but within 60 minutes prior to next dose), 0.5, 1, 2, 4, 6, anytime from 8 to 12 and 24 hours post-dose on Day 22
Unbound Apparent Clearance (CLu/F) of PlasmaTalazoparib on Day 22	Clearance of unbound talazoparib is a measure of the rate at which unbound talazoparib is metabolized or eliminated by normal biological processes.	Pre-dose (24 hours +/- 60 minutes from the previous dose on Day 21 but within 60 minutes prior to next dose), 0.5, 1, 2, 4, 6, anytime from 8 to 12 and 24 hours post-dose on Day 22
Amount of Talazoparib Excreted Unchanged in Urine From Time Zero to 24 Hours (Ae 0-24) on Day 1	Ae 0-24 is the amount of talazoparib excreted unchanged in urine from time 0 to 24 hours post dose.	A single void at pre-dose, post-dose at any time between 0 to 12 and any time between 12 to 24 hours on Day 1
Percentage of Talazoparib Excreted in Urine From Time Zero to 24 Hours (Ae 0-24%) on Day 1	Ae0-24% was defined as the amount of talazoparib excreted in urine from time 0 to 24 hours expressed as percentage of administered dose.	A single void at pre-dose, post-dose at any time between 0 to 12 and any time between 12 to 24 hours on Day 1
Amount of Talazoparib Excreted Unchanged in Urine From Time Zero to 24 Hours (Ae 0-24) on Day 22	Ae 0-24 is the amount of talazoparib excreted unchanged in urine from time 0 to 24 hours post dose.	Urine voided post-dose at any time between 0 to 12 and any time between 12 to 24 hours on Day 22
Percentage of Talazoparib Excreted in Urine From Time 0 to 24 Hours (Ae 0-24%) on Day 22	Ae 0-24% was defined as the amount of talazoparib excreted in urine from time 0 to 24 hours expressed as percentage of administered dose.	Urine voided post-dose at any time between 0 to 12 and any time between 12 to 24 hours (hrs) on Day 22
Renal Clearance (CLr) of Talazoparib on Day 22	Renal clearance was calculated as cumulative amount of drug excreted in urine during the 24 hours dosing interval (Ae) divided by area under the plasma concentration time-curve from time zero to 24 hours post dose (AUC0-24).	Ae: Post-dose at any time between 0 to 12, 12 to 24 hrs on Day 22; AUC0-24: Pre-dose (24 hrs +/- 60 minutes from previous dose on Day 21 but within 60 minutes prior to next dose), 0.5, 1, 2, 4, 6, any time between 8 to12, 24 hrs post-dose on Day 22
Number of Participants With Clinically Significant Laboratory Abnormalities	Clinically significant laboratory abnormalities included aspartate transaminase (AST) or alanine aminotransferase (ALT) >=3 times ULN (>5 *ULN if baseline ALT/AST is >3 *ULN) and total bilirubin (TBL) >2 times ULN or INR >1.5, AST or ALT >=3 times ULN with signs and symptoms consistent with hepatitis and/or eosinophilia (>=500 eosinophils/microliter).	Baseline up to 30 days after last dose of study drug (up to 52 days)
Change From Baseline in Vital Sign -Blood Pressure at Day 2, 8, 15, 22 and End of Study	Systolic blood pressure and diastolic blood pressure were evaluated for examination of vital signs.	Baseline, Day 2, 8, 15, 22 and End of Study (Day 52)
Change From Baseline in Vital Sign- Heart Rate at Day 2, 8, 15, 22 and End of Study	Heart rate was measured in beats per minute.	Baseline, Day 2, 8, 15, 22 and End of Study (Day 52)
Change From Baseline in Vital Sign- Respiratory Rate at Day 8, 15, 22 and End of Study	Respiratory rate was measured in terms of breaths per minute.	Baseline, Day 8, 15, 22 and End of Study (Day 52)
Change From Baseline in Vital Sign- Weight at Day 8, 15, 22 and End of Study		Baseline, Day 8, 15, 22 and End of Study (Day 52)
Number of Participants Who Met the Pre-specified 12-Lead Electrocardiogram (ECG) Criteria	Pre-specified 12-Lead electrocardiogram (ECG) Criteria: QTCF (Fridericia's correction formula) : >=450 to <480 milliseconds, >=480 to <500 milliseconds, >=500 milliseconds, increase from baseline >=30 - <60, increase from baseline >=60, PR interval: >=300 milliseconds, increase from baseline >=25%; QRS duration: >=140 milliseconds, increase from baseline >=50%; QT interval: >=500 milliseconds; QT Interval: >= 500 milliseconds.	Baseline up to 30 days after last dose of study drug (up to 52 days)
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status	As per ECOG, participant's performance status was measured as: 0=fully active/able to carry on all pre-disease activities without restriction; 1= restricted in physically strenuous activity but ambulatory and able to carry out work of a light and sedentary nature, e.g., light housework, office work; 2= ambulatory and capable of all self-care, but unable to carry out any work activities, up and about more than 50% of waking hours; 3=capable of only limited self-care, confined to bed/chair >50% of waking hours; 4=completely disabled, cannot carry on any self-care, totally confined to bed/chair.	Screening (2 to 28 days prior to Day 1), Day -1 (1 day prior to Day 1), safety follow up (Visit up to Day 52)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. 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; medically important events. TEAEs were events between first dose of Talazoparib and up to 30 days after the last dose of Talazoparib (up to 52 days) that were absent before treatment or that worsened relative to pretreatment state. AEs included both SAEs and all non-SAEs.	Baseline up to 30 days after last dose of study drug (up to 52 days)
Number of Participants With TEAEs Leading to Study Drug Discontinuation	An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. 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; medically important events. Treatment-emergent were events between first dose of Talazoparib and up to 30 days after the last dose of Talazoparib (up to 52 days) that were absent before treatment or that worsened relative to pretreatment state. AEs included both SAEs and non-SAEs. Number of participants with TEAEs leading to study drug discontinuation are reported.	Baseline up to 30 days after last dose of study drug (up to 52 days)
Number of Participants With TEAEs Resulting in Death	An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. 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; medically important events. Treatment-emergent were events between first dose of Talazoparib and up to 30 days after the last dose of Talazoparib (up to 52 days) that were absent before treatment or that worsened relative to pretreatment state. AEs included both SAEs and non-SAEs. Number of participants with TEAEs resulting in death are reported.	Baseline up to 30 days after last dose of study drug (up to 52 days)
Number of Participants With Treatment Emergent Treatment Related Adverse Events and SAEs	A treatment-related adverse event was any untoward medical occurrence attributed to talazoparib in a participant who received talazoparib. A treatment-related serious adverse event was a treatment-related adverse event resulting in any of the following outcomes or deemed significant for any other reason: death; life-threatening experience (immediate risk of dying); initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; Congenital anomaly. Relatedness to talazoparib was assessed by the investigator.	Baseline up to 30 days after last dose of study drug (up to 52 days)

Collaborators and Investigators

• Sponsor: Pfizer
• Collaborators: Medivation, Inc.

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2016
• Primary Completion (Actual): February 12, 2020
• Study Completion (Actual): February 12, 2020

Study Registration Dates

• First Submitted: December 15, 2016
• First Submitted That Met QC Criteria: December 15, 2016
• First Posted (Estimate): December 19, 2016

Study Record Updates

• Last Update Posted (Actual): February 25, 2021
• Last Update Submitted That Met QC Criteria: February 5, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Talazoparib
• Other Study ID Numbers: MDV3800-02; C3441002 (Other Identifier: Alias Study Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.