Advanced Solid Tumors
Conditions
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..
Interventions
DRUGTalazoparib
1 mg of talazoparib containing100 μCi of 14C-radiolabeled talazoparib
Sponsors
Medivation, Inc.
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. At least 18 years of age and willing and able to provide informed consent. 2. 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. 3. Eastern Co-Operative Oncology Group (ECOG) performance status ≤ 2 at screening and Day -1. 4. Expected life expectancy of ≥ 3 months. 5. Able to swallow the study drug and comply with study requirements. 6. 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. 7. 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. 8. Female patients must not be breastfeeding at screening and during the study participation until 45 days after the last dose of the study drug. 9. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.
Exclusion criteria
1. 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. 2. Major surgery within 8 weeks before screening. 3. Serious accompanying disorder or impaired organ function. 4. Symptomatic or impending spinal cord compression or cauda equina syndrome. 5. Non-healing wound, ulcer, or bone fracture, not including a pathological bone fracture caused by a pre-existent pathological bone lesion. 6. Known myelodysplastic syndrome. 7. Patients with the following serologies should be excluded: HBsAg+ or anti-HBc+; HCV+; HIV+. 8. Serious or unstable medical condition that interferes with ability to tolerate treatment or assessments associated with the protocol. 9. Gastrointestinal disorder affecting absorption. 10. Known hypersensitivity to any of the talazoparib solution components. 11. 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. 12. 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 \[e.g. opiates for pain relief\]).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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. |
| 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. |
| 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. |
| 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. |
| 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). |
| 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 | — |
| 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 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). |
| 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. |
| 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 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. |
| 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 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. |
| 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. |
| 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 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 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 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 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 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. |
| 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. |
Countries
Hungary
Participant flow
Pre-assignment details
This is a mass balance study with 14C-radiolabeled talazoparib in at least 6 participants with advanced solid tumors who qualified for treatment with talazoparib. Participants who completed the mass-balance part in this study had the option to continue treatment on an open-label extension protocol.
Participants by arm
| Arm | Count |
|---|---|
| Talazoparib Participants with advanced solid tumors received a single dose of talazoparib 1 mg oral solution (containing approximately 100 micro Curie of 14C-talazoparib) on Day 1. Participants were followed-up within 14 days after the last day of mass balance phase and at least 30 days after Day 1 or the first day of extension protocol, whichever occurred first (up to maximum duration of 8 weeks from screening to follow-up for each participant). | 6 |
| Total | 6 |
Baseline characteristics
| Characteristic | Talazoparib |
|---|---|
| Age, Continuous | 50.2 years STANDARD_DEVIATION 17.61 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 6 |
| other Total, other adverse events | 4 / 6 |
| serious Total, serious adverse events | 0 / 6 |
Outcome results
Primary
Amount of Talazoparib Excreted in Urine During Each Collection Interval (Ae t1-t2)
Ae t1-t2 was defined as the amount of talazoparib excreted into urine during each collection interval (t1-t2).
Time frame: 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
Population: PK population included all participants who received talazoparib and had at least 1 sample with sufficient concentration data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Talazoparib | Amount of Talazoparib Excreted in Urine During Each Collection Interval (Ae t1-t2) | 366.07 micrograms | Standard Deviation 45.56 |
Primary
Apparent Total Plasma Clearance (CL/F) of 14C- Radioactivity
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.
Time frame: 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
Population: PK population included all participants who received talazoparib and had at least 1 sample with sufficient concentration data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Talazoparib | Apparent Total Plasma Clearance (CL/F) of 14C- Radioactivity | 5.35 liter/hour | Standard Deviation 2.35 |
Primary
Apparent Total Plasma Clearance (CL/F) of Talazoparib
Clearance of a drug was measure of the rate at which a drug was metabolized or eliminated by normal biological processes.
Time frame: 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
Population: PK population included all participants who received talazoparib and had at least 1 sample with sufficient concentration data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Talazoparib | Apparent Total Plasma Clearance (CL/F) of Talazoparib | 8.39 liter/hour | Standard Deviation 3.7 |
Primary
Apparent Total Whole Blood Clearance (CL/F) of 14C- Radioactivity
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.
Time frame: 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
Population: PK population included all participants who received talazoparib and had at least 1 sample with sufficient concentration data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Talazoparib | Apparent Total Whole Blood Clearance (CL/F) of 14C- Radioactivity | 5.21 liter/hour | Standard Deviation 2.51 |
Primary
Apparent Volume of Distribution (Vd/F) of 14C- Radioactivity in Plasma
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 frame: 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
Population: PK population included all participants who received talazoparib and had at least 1 sample with sufficient concentration data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Talazoparib | Apparent Volume of Distribution (Vd/F) of 14C- Radioactivity in Plasma | 655.8 liter | Standard Deviation 338.1 |
Primary
Apparent Volume of Distribution (Vd/F) of 14C- Radioactivity in Whole Blood
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.
Time frame: 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
Population: PK population included all participants who received talazoparib and had at least 1 sample with sufficient concentration data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Talazoparib | Apparent Volume of Distribution (Vd/F) of 14C- Radioactivity in Whole Blood | 484.4 liter | Standard Deviation 237.5 |
Primary
Apparent Volume of Distribution (Vd/F) 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.
Time frame: 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
Population: PK population included all participants who received talazoparib and had at least 1 sample with sufficient concentration data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Talazoparib | Apparent Volume of Distribution (Vd/F) of Talazoparib | 922.6 liter | Standard Deviation 445.8 |
Primary
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of 14C- Radioactivity
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.
Time frame: 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
Population: PK population included all participants who received talazoparib and had at least 1 sample with sufficient concentration data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Talazoparib | Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of 14C- Radioactivity | 222.9 hour*nanogram equivalent/mililiter | Standard Deviation 108.8 |
Primary
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) 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).
Time frame: 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
Population: PK population included all participants who received talazoparib and had at least 1 sample with sufficient concentration data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Talazoparib | Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Talazoparib | 129.9 hour*nanogram per milliliter (hr*ng/mL) | Standard Deviation 70.4 |
Primary
Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-last) of 14C- Radioactivity
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.
Time frame: 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
Population: PK population included all participants who received talazoparib and had at least 1 sample with sufficient concentration data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Talazoparib | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-last) of 14C- Radioactivity | 199.3 hour*nanogram equivalent/mililiter | Standard Deviation 101.9 |
Primary
Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-last) 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.
Time frame: 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
Population: PK population included all participants who received talazoparib and had at least 1 sample with sufficient concentration data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Talazoparib | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-last) of Talazoparib | 118.9 hr*ng/mL | Standard Deviation 65.4 |
Primary
Area Under the Whole Blood Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of 14C- Radioactivity
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.
Time frame: 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
Population: PK population included all participants who received talazoparib and had at least 1 sample with sufficient concentration data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Talazoparib | Area Under the Whole Blood Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of 14C- Radioactivity | 234.1 hour*nanogram equivalent/mililiter | Standard Deviation 114.1 |
Primary
Area Under the Whole Blood Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-last) of 14C- Radioactivity
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.
Time frame: 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
Population: PK population included all participants who received talazoparib and had at least 1 sample with sufficient concentration data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Talazoparib | Area Under the Whole Blood Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-last) of 14C- Radioactivity | 205.8 hour*nanogram equivalent/mililiter | Standard Deviation 101 |
Primary
Maximum Observed Plasma Concentration (Cmax) of 14C- Radioactivity
100 micro-curie of 14C-radiolabeled talazoparib was present in 1 mg of talazoparib.
Time frame: 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
Population: PK population included all participants who received talazoparib and had at least 1 sample with sufficient concentration data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Talazoparib | Maximum Observed Plasma Concentration (Cmax) of 14C- Radioactivity | 12.1 nanogram equivalent/mililiter | Standard Deviation 5.8 |
Primary
Maximum Observed Plasma Concentration (Cmax) of Talazoparib
Time frame: 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
Population: Pharmacokinetic (PK) population included all participants who received talazoparib and had at least 1 sample with sufficient concentration data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Talazoparib | Maximum Observed Plasma Concentration (Cmax) of Talazoparib | 8.4 nanogram per milliliter (ng/mL) | Standard Deviation 3.8 |
Primary
Maximum Observed Whole Blood Concentration (Cmax) of 14C- Radioactivity
100 micro-curie of 14C-radiolabeled talazoparib was present in 1 mg of talazoparib.
Time frame: 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
Population: PK population included all participants who received talazoparib and had at least 1 sample with sufficient concentration data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Talazoparib | Maximum Observed Whole Blood Concentration (Cmax) of 14C- Radioactivity | 12.5 nanogram equivalent/mililiter | Standard Deviation 5.7 |
Primary
Percentage of Dose of Talazoparib Excreted During Each Collection Interval (Aet1-t2%) of Talazoparib
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).
Time frame: 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
Population: PK population included all participants who received talazoparib and had at least 1 sample with sufficient concentration data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Talazoparib | Percentage of Dose of Talazoparib Excreted During Each Collection Interval (Aet1-t2%) of Talazoparib | 40.92 percentage of dose | Standard Deviation 4.324 |
Primary
Renal Clearance (CLr) of Talazoparib
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).
Time frame: 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
Population: PK population included all participants who received talazoparib and had at least 1 sample with sufficient concentration data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Talazoparib | Renal Clearance (CLr) of Talazoparib | 3.808 liter/hour | Standard Deviation 1.979 |
Primary
Terminal Elimination Half-Life (t1/2) of 14C- Radioactivity in Plasma
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.
Time frame: 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
Population: PK population included all participants who received talazoparib and had at least 1 sample with sufficient concentration data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Talazoparib | Terminal Elimination Half-Life (t1/2) of 14C- Radioactivity in Plasma | 96.2 hours | Standard Deviation 55.1 |
Primary
Terminal Elimination Half-Life (t1/2) of Talazoparib
Terminal elimination half-life was defined as time measured for the plasma concentration of talazoparib to decrease by one half.
Time frame: 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
Population: PK population included all participants who received talazoparib and had at least 1 sample with sufficient concentration data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Talazoparib | Terminal Elimination Half-Life (t1/2) of Talazoparib | 89.8 hours | Standard Deviation 57.6 |
Primary
The Recovery of 14C-Radioactivity as a Percentage of the Administered 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).
Time frame: 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
Population: PK population included all participants who received talazoparib and had at least 1 sample with sufficient concentration data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Talazoparib | The Recovery of 14C-Radioactivity as a Percentage of the Administered Dose | Urine | 68.647 Percentage of dose | Standard Deviation 8.592 |
| Talazoparib | The Recovery of 14C-Radioactivity as a Percentage of the Administered Dose | Feces | 19.669 Percentage of dose | Standard Deviation 5.493 |
Primary
Time to Attain Maximum Observed Plasma Concentration (Tmax) of 14C- Radioactivity
100 micro-curie of 14C-radiolabeled talazoparib was present in 1 mg of talazoparib.
Time frame: 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
Population: PK population included all participants who received talazoparib and had at least 1 sample with sufficient concentration data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Talazoparib | Time to Attain Maximum Observed Plasma Concentration (Tmax) of 14C- Radioactivity | 0.5 hours |
Primary
Time to Attain Maximum Observed Plasma Concentration (Tmax) of Talazoparib
Time frame: 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
Population: PK population included all participants who received talazoparib and had at least 1 sample with sufficient concentration data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Talazoparib | Time to Attain Maximum Observed Plasma Concentration (Tmax) of Talazoparib | 0.5 hours |
Primary
Time to Attain Maximum Observed Whole Blood Concentration (Tmax) of 14C- Radioactivity
100 micro-curie of 14C-radiolabeled talazoparib was present in 1 mg of talazoparib.
Time frame: 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
Population: PK population included all participants who received talazoparib and had at least 1 sample with sufficient concentration data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Talazoparib | Time to Attain Maximum Observed Whole Blood Concentration (Tmax) of 14C- Radioactivity | 0.5 hours |
Secondary
Amount of Any Significant Metabolites of Talazoparib in Urine and Feces
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.
Time frame: 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
Population: PK population included all participants who received talazoparib and had at least 1 sample with sufficient concentration data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Talazoparib | Amount of Any Significant Metabolites of Talazoparib in Urine and Feces | M481/1: Urine | 4.2 percentage of dose |
| Talazoparib | Amount of Any Significant Metabolites of Talazoparib in Urine and Feces | MDV10595+M556/1+M396/1: Urine | 0.8 percentage of dose |
| Talazoparib | Amount of Any Significant Metabolites of Talazoparib in Urine and Feces | MDV10595+M556/1+M396/1: Feces | 1.5 percentage of dose |
Secondary
Number of Participants With Change From Baseline in Physical Examination Findings
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.
Time frame: Baseline up to Day 22
Population: Safety population set included all participants who received at least 1 dose of talazoparib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Talazoparib | Number of Participants With Change From Baseline in Physical Examination Findings | 0 participants |
Secondary
Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities
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.
Time frame: Baseline up to Day 22
Population: Safety population set included all participants who received at least 1 dose of talazoparib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Talazoparib | Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities | 0 participants |
Secondary
Number of Participants With Clinically Significant Laboratory Abnormalities
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.
Time frame: Baseline up to Day 22
Population: Safety population set included all participants who received at least 1 dose of talazoparib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Talazoparib | Number of Participants With Clinically Significant Laboratory Abnormalities | 0 participants |
Secondary
Number of Participants With Clinically Significant Vital Signs Parameters
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.
Time frame: Baseline up to Day 22
Population: Safety analysis set included all participants who received at least 1 dose of talazoparib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Talazoparib | Number of Participants With Clinically Significant Vital Signs Parameters | 0 participants |
Secondary
Number of Participants With Treatment Emergent Adverse Events (AEs)
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).
Time frame: 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)
Population: Safety analysis set included all participants who received at least 1 dose of talazoparib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Talazoparib | Number of Participants With Treatment Emergent Adverse Events (AEs) | 4 participants |
Secondary
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
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.
Time frame: 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
Population: PK population included all participants who received talazoparib and had at least 1 sample with sufficient concentration data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Talazoparib | 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 | 1.047 ratio | Standard Deviation 0.1155 |
Secondary
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
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.
Time frame: 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
Population: PK population included all participants who received talazoparib and had at least 1 sample with sufficient concentration data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 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 | 1.037 ratio | Standard Deviation 0.1243 |
Secondary
Ratio of Maximum Observed Plasma Concentration to Maximum Observed Whole Blood Concentration for 14C- Radioactivity
100 micro-curie of 14C radiolabeled talazoparib was present in 1 mg of talazoparib.
Time frame: 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
Population: PK population included all participants who received talazoparib and had at least 1 sample with sufficient concentration data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Talazoparib | Ratio of Maximum Observed Plasma Concentration to Maximum Observed Whole Blood Concentration for 14C- Radioactivity | 1.050 ratio | Standard Deviation 0.0625 |