A Study of Talazoparib in Patients With Advanced Solid Tumors

Phase 1

Completed

Conditions: Advanced Solid Tumors

Interventions: Drug: Talazoparib

Registration Number: NCT03070548

Lead Sponsor: Pfizer

Brief Summary: This study will evaluate the mass balance of talazoparib after a single dose of talazoparib.

Detailed Description: Patients participating in this study with no clinically significant toxicities may be eligible to continue treatment on a separate extension protocol after discussion with the Principal Investigator and obtaining Sponsor permission..

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 6

Inclusion Criteria

At least 18 years of age and willing and able to provide informed consent.
Histologically confirmed advanced solid tumor (limited to platinum-resistant ovarian carcinoma, cervical adenocarcinoma, small cell lung carcinoma or triple-negative breast cancer) judged by the Investigator to not be appropriate for standard therapy.
Eastern Co-Operative Oncology Group (ECOG) performance status ≤ 2 at screening and Day -1.
Expected life expectancy of ≥ 3 months.
Able to swallow the study drug and comply with study requirements.
Female subjects may be enrolled if they are considered not of childbearing potential, or who are post-menopausal, or of childbearing potential using a highly effective form of contraception, and female subjects should not donate eggs from the time point of IMP administration until at least 45 days thereafter.
Males with partners of childbearing potential may be enrolled if they use a condom when having sex with a pregnant woman or with a woman of childbearing potential from 21 days before the first dose of study drug through 105 days after the last dose of study drug, and males should not donate sperm from the time point of study drug administration until at least 105 days thereafter.
Female patients must not be breastfeeding at screening and during the study participation until 45 days after the last dose of the study drug.
Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.

Exclusion Criteria

Treatment within 14 weeks or five half-live prior to dosing with any type of systemic anticancer therapy or any investigational agent, whichever is longer.
Major surgery within 8 weeks before screening.
Serious accompanying disorder or impaired organ function.
Symptomatic or impending spinal cord compression or cauda equina syndrome.
Non-healing wound, ulcer, or bone fracture, not including a pathological bone fracture caused by a pre-existent pathological bone lesion.
Known myelodysplastic syndrome.
Patients with the following serologies should be excluded: HBsAg+ or anti-HBc+; HCV+; HIV+.
Serious or unstable medical condition that interferes with ability to tolerate treatment or assessments associated with the protocol.
Gastrointestinal disorder affecting absorption.
Known hypersensitivity to any of the talazoparib solution components.
Use of a strong P-gp inhibitor, strong P-gp inducer, or strong inhibitor of BRCP within 7 days or 5 half-lives, whichever is longer, before Day 1.
Any condition or reason that interferes with ability to participate in the study, causes undue risk, or complicates the interpretation of safety data, in the opinion of the Investigator or Sponsor (e.g. non-compliance, excessive alcohol consumption, intake of drugs of abuse unless these drugs are medically indicated [e.g. opiates for pain relief]).

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
ADME	Talazoparib	1 mg talazoparib containing100 μCi of 14C-radiolabeled talazoparib

Primary Outcome Measures

Name	Time	Method
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Talazoparib	Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264, 336, 384, 432 and 504 hours post-dose	AUC(0-inf) was defined as the area under the plasma concentration-time curve from time zero (pre-dose) to extrapolated infinite time (0-inf).
Terminal Elimination Half-Life (t1/2) of Talazoparib	Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264, 336, 384, 432 and 504 hours post-dose	Terminal elimination half-life was defined as time measured for the plasma concentration of talazoparib to decrease by one half.
Apparent Volume of Distribution (Vd/F) of Talazoparib	Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264, 336, 384, 432 and 504 hours post-dose	Apparent 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 the drug.
Maximum Observed Plasma Concentration (Cmax) of 14C- Radioactivity	Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264, 336, 384, 432 and 504 hours post-dose	100 micro-curie of 14C-radiolabeled talazoparib was present in 1 mg of talazoparib.
Time to Attain Maximum Observed Plasma Concentration (Tmax) of Talazoparib	Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264, 336, 384, 432 and 504 hours post-dose
Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-last) of Talazoparib	Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264, 336, 384, 432 and 504 hours post-dose	AUC(0-last) was defined as the area under the plasma concentration-time curve from zero to the time of the last measurable concentration.
Maximum Observed Plasma Concentration (Cmax) of Talazoparib	Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264, 336, 384, 432 and 504 hours post-dose
Apparent Total Plasma Clearance (CL/F) of Talazoparib	Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264, 336, 384, 432 and 504 hours post-dose	Clearance of a drug was measure of the rate at which a drug was metabolized or eliminated by normal biological processes.
Time to Attain Maximum Observed Plasma Concentration (Tmax) of 14C- Radioactivity	Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264, 336, 384, 432 and 504 hours post-dose	100 micro-curie of 14C-radiolabeled talazoparib was present in 1 mg of talazoparib.
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of 14C- Radioactivity	Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264, 336, 384, 432 and 504 hours post-dose	AUC(0-inf) was defined as the area under the plasma concentration-time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). 100 micro-curie of 14C-radiolabeled talazoparib was present in 1 mg of talazoparib.
Maximum Observed Whole Blood Concentration (Cmax) of 14C- Radioactivity	Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264, 336, 384, 432 and 504 hours post-dose	100 micro-curie of 14C-radiolabeled talazoparib was present in 1 mg of talazoparib.
Area Under the Whole Blood Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-last) of 14C- Radioactivity	Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264, 336, 384, 432 and 504 hours post-dose	AUC(0-last) was defined as the area under the plasma concentration-time curve from zero to the time of the last measurable concentration. 100 micro-curie of 14C-radiolabeled talazoparib was present in 1 mg of talazoparib.
Terminal Elimination Half-Life (t1/2) of 14C- Radioactivity in Plasma	Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264, 336, 384, 432 and 504 hours post-dose	Terminal elimination half-life was defined as the time measured for the plasma radioactivity concentration to decrease by one half. 100 micro-curie of 14C-radiolabeled talazoparib was present in 1 mg of talazoparib.
Apparent Total Whole Blood Clearance (CL/F) of 14C- Radioactivity	Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264, 336, 384, 432 and 504 hours post-dose	Clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. 100 micro-curie of 14C-radiolabeled talazoparib was present in 1 mg of talazoparib.
The Recovery of 14C-Radioactivity as a Percentage of the Administered Dose	From 0 to 8 hrs, 8 to 24 hrs, 24 to 48 hrs and then after every 24 hrs until up to 504 hrs post-dose	Recovery of 14C-radioactivity in urine and feces was calculated in terms of percentage of administered dose after administration of a single 1 mg dose of oral solution (containing 100 micro-curie 14C-labeled talazoparib).
Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-last) of 14C- Radioactivity	Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264, 336, 384, 432 and 504 hours post-dose	AUC(0-last) was defined as the area under the plasma concentration-time curve from zero to the time of the last measurable concentration. 100 micro-curie of 14C-radiolabeled talazoparib was present in 1 mg of talazoparib.
Apparent Total Plasma Clearance (CL/F) of 14C- Radioactivity	Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264, 336, 384, 432 and 504 hours post-dose	Clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. 100 micro-curie of 14C-radiolabeled talazoparib was present in 1 mg of talazoparib.
Apparent Volume of Distribution (Vd/F) of 14C- Radioactivity in Plasma	Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264, 336, 384, 432 and 504 hours post-dose	Apparent 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. 100 micro-curie of 14C-radiolabeled talazoparib was present in 1 mg of talazoparib.
Time to Attain Maximum Observed Whole Blood Concentration (Tmax) of 14C- Radioactivity	Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264, 336, 384, 432 and 504 hours post-dose	100 micro-curie of 14C-radiolabeled talazoparib was present in 1 mg of talazoparib.
Area Under the Whole Blood Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of 14C- Radioactivity	Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264, 336, 384, 432 and 504 hours post-dose	AUC(0-inf) was defined as the area under the plasma concentration-time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). 100 micro-curie of 14C-radiolabeled talazoparib was present in 1 mg of talazoparib.
Apparent Volume of Distribution (Vd/F) of 14C- Radioactivity in Whole Blood	Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264, 336, 384, 432 and 504 hours post-dose	Apparent 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 the drug. 100 micro-curie of 14C-radiolabeled talazoparib was present in 1 mg of talazoparib.
Amount of Talazoparib Excreted in Urine During Each Collection Interval (Ae t1-t2)	Pre-dose, 0 to 8 hours (hrs), 8 to 24 hrs, 24 to 48 hrs, 48 to 72 hrs, 72 to 96 hrs and then after every 24 hrs until up to 504 hrs post-dose	Ae t1-t2 was defined as the amount of talazoparib excreted into urine during each collection interval (t1-t2).
Percentage of Dose of Talazoparib Excreted During Each Collection Interval (Aet1-t2%) of Talazoparib	Pre-dose, 0 to 8 hrs, 8 to 24 hrs, 24 to 48 hrs, 48 to 72 hrs, 72 to 96 hrs and then after every 24 hrs until up to 504 hrs post-dose	Aet1-t2% was the percentage of Aet1-t2, where Aet1-t2 was defined as the amount of talazoparib excreted into urine during each collection interval (t1-t2).
Renal Clearance (CLr) of Talazoparib	Pre-dose, 0 to 8 hrs, 8 to 24 hrs, 24 to 48 hrs, 48 to 72 hrs, 72 to 96 hrs and then after every 24 hrs until up to 504 hrs post-dose	Renal clearance was calculated as cumulative amount of drug excreted in urine divided by AUC(0-last) (area under the plasma concentration-time curve from zero to the time of the last measurable concentration).

Secondary Outcome Measures

Name	Time	Method
Ratio of Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity to Area Under the Whole Blood Concentration-Time Curve From Time Zero to Infinity for 14C- Radioactivity	Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264, 336, 384, 432 and 504 hours post-dose	AUC(0-inf) was defined as the area under the plasma concentration-time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). 100 micro-curie of 14C-radiolabeled talazoparib was present in 1 mg of talazoparib.
Ratio of Maximum Observed Plasma Concentration to Maximum Observed Whole Blood Concentration for 14C- Radioactivity	Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264, 336, 384, 432 and 504 hours post-dose	100 micro-curie of 14C radiolabeled talazoparib was present in 1 mg of talazoparib.
Ratio of Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration to Area Under the Whole Blood Concentration-Time Curve From Time Zero to Last Quantifiable for 14C- Radioactivity	Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264, 336, 384, 432 and 504 hours post-dose	AUC(0-last) was defined as the area under the plasma concentration-time curve from zero to the time of the last measurable concentration. 100 micro-curie of 14C-radiolabeled talazoparib was present in 1 mg of talazoparib.
Number of Participants With Clinically Significant Vital Signs Parameters	Baseline up to Day 22	Vital Signs included heart rate, respiratory rate, body temperature, systolic blood pressure and diastolic blood pressure. clinical significance of vital signs was determined at the investigator's discretion.
Number of Participants With Treatment Emergent Adverse Events (AEs)	Day 1 to 14 days after last day of mass balance phase and at least 30 days after Day1/before initiation of new cytotoxic chemotherapy, new investigational treatment/first day of extension protocol, whichever occurs first(up to maximum duration of 8 weeks)	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent were events between first dose of study drug through 14 days after the last day of mass balance phase and at least 30 days after Day 1 or before initiation of new cytotoxic chemotherapy, new investigational treatment, or the first day of extension protocol, whichever occurs first (up to maximum duration of 8 weeks from screening to follow-up for each participant) or before initiation of new cytotoxic chemotherapy, new investigational treatment, or the first day of extension protocol, whichever occurs first, that were absent before treatment or that worsened relative to pre-treatment state. AEs included both non-serious (AEs) and serious adverse events (SAEs).
Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities	Baseline up to Day 22	Criteria for clinically significant ECG abnormalities : Heart Rate; increase from baseline greater than (\>)25 %and to a value \>100, decrease from baseline \>25% and to a value \< 50; PR Interval: increase from baseline \>25% and to a value \>200; QRS Duration: increase from baseline \>25% and to a value \>100; QT interval using Fridericia's correction (QTcF): ranges \>450 msec, \>480 msec, \>500 msec, Increase from baseline \>30 msec and \>60 msec; QT Interval: ranges \>450 msec, \>480 msec, \>500 msec, Increase from baseline \>30 msec and \>60 msec.
Number of Participants With Clinically Significant Laboratory Abnormalities	Baseline up to Day 22	Haematological, biochemistry and urinalysis parameters. Biochemistry parameters:alkaline phosphatase 30-120units per liter(U/L), creatinine 53-110micromole/L(micromol/L), gamma glutamyl transferase 7-50U/L, glucose 3.3-5.5millimoles/L(mmol/L), lactate dehydrogenase 200-460U/L, triglycerides 0.4-1.7mmol/L, cholesterol 2.6-5.2mmol/L, phosphate 0.8-1.45mmol/L, sodium 135-146mmol/L, urea 2.8-7.2mmol/L, chloride 95-109mmol/L, creatine kinase 24-170U/L, aspartate aminotransferase 4-46U/L, potassium 3.5-5.5mmol/L. Haematology parameters:haemoglobin 120-155 gram/L(g/L), erythrocytes 4-5.2 10\^12/L, haematocrit 0.35-0.45, prothrombin time 13.7-15.6 second(sec), lymphocytes 1-3.7 10\^9/L, platelets 150-400 10\^9/L, prothrombin intl. normalized ratio 0.89-1.1, activated partial thromboplastin time 25-43 sec, basophils 0-0.09 10\^9/L, neutrophils 1.5-7 10\^9/L, and leukocytes 4-10 10\^9/L. Urinalysis parameters:urinalysis specific gravity 1.012-1.03, urinalysis pH 4.8-7.8.
Number of Participants With Change From Baseline in Physical Examination Findings	Baseline up to Day 22	Physical examination included examination of abdomen, cardiovascular, eyes, ears, nose, throat, general appearance, head, neck, thyroid, lymph nodes, musculoskeletal, neurological, skin/subcutaneous tissue and thorax/lungs.
Amount of Any Significant Metabolites of Talazoparib in Urine and Feces	From 0 to 8 hrs, 8 to 24 hrs, 24 to 48 hrs and then after every 24 hrs until up to 504 hrs post-dose	M4 (M481/1, cysteine conjugate of mono-desfluoro-talazoparib) metabolite was found in urine. MDV10595 (M1, dehydrogenated talazoparib (PF-07052386), M556/1 (glucuronide conjugate of talazoparib), and M2 (M396/1, mono-oxidative talazoparib) metabolites were calculated together and were also found in urine. Three metabolites named as: MDV10595 (M1)/M556/1 and M2 (M396/1) which were calculated together were detected in feces. Amount of metabolite in this outcome measure was measured in terms of percentage of dose of talazoparib.