A Study of Talazoparib in Patients With Advanced Solid Tumors

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).

AUC(0-last) was defined as the area under the plasma concentration-time curve from zero to the time of the last measurable concentration.

Terminal elimination half-life was defined as time measured for the plasma concentration of talazoparib to decrease by one half.

Clearance of a drug was measure of the rate at which a drug was metabolized or eliminated by normal biological processes.

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.

100 micro-curie of 14C-radiolabeled talazoparib was present in 1 mg of talazoparib.

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.

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 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.

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 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.

100 micro-curie of 14C-radiolabeled talazoparib was present in 1 mg of talazoparib.

100 micro-curie of 14C-radiolabeled talazoparib was present in 1 mg of talazoparib.

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.

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.

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 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.

Ae t1-t2 was defined as the amount of talazoparib excreted into urine during each collection interval (t1-t2).

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 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).

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).

100 micro-curie of 14C radiolabeled talazoparib was present in 1 mg of talazoparib.

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.

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.

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).

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.

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.

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.

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.

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.