Advanced Solid Tumors, Breast Cancer, Colorectal Cancer, NSCLC, Ovarian Cancer, Pancreatic Cancer, Prostate Cancer, Solid Tumors
Conditions
Keywords
PARP inhibitor, Talazoparib, Talzenna, BRCA mutation, ATM mutation, Pharmacokinetics, Bioequivalence, Bioavailability, Food effect
Brief summary
This will be a Phase 1, open label, 2-sequence, crossover study to establish the BE of the current commercial formulation (Generation 3.1 talazoparib capsules) to the proposed talazoparib liquid-filled soft gelatin capsule (soft gel capsule) formulation after multiple dosing under fasting conditions in participants with advanced solid tumors. In addition, the effect of food on the PK of the proposed talazoparib soft gel capsule formulation will be evaluated in fixed sequence after the 2 BE assessment periods.
Interventions
DRUGTALZENNA capsule
Current commercial talazoparib formulation 1 mg once daily given under fasting condition
DRUGTalazoparib soft gel capsule
Proposed talazoparib soft gel capsule formulation 1 mg once daily under fasting condition
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Participants will be randomly assigned to 1 of 2 sequences to receive Treatment A, B and C in different order as shown below. The first 2 periods will be for BE assessment, with the first period being 28 days and the following periods being 21 days. Period 3 will be a 21 day period to evaluate the food effect on the PK of the proposed talazoparib soft gel capsule formulation that will be included in the fixed sequence after the 2 BE assessment periods (for participants who can tolerate one high-fat/high-calorie meal). Participants must have received 21 consecutive days of continuous 1mg QD drug administration to be considered as completers of a treatment period, before moving on to the next scheduled treatment.
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Histological diagnosis of recurrent, locally advanced or metastatic solid tumor that is not amenable for treatment with curative intent. * Solid tumors with known or likely pathogenic germline or somatic tumor gene defect (eg, one or more BRCA1 or BRCA2 gene defect except for ovarian cancer) that would benefit from PARPi therapy per current approvals for the tumor indication or supported by strong scientific evidence. * Received at least 1 prior SOC regimen, if it exists, as appropriate for the respective tumor type unless deemed unsuitable or declined these therapies; ovarian cancer participants must have at least 1 prior cytotoxic chemotherapy regimen, including at least 1 course of platinum-based therapy. Participants must not have had disease progression within 6 months of initiation of platinum containing regimen. 2. ECOG performance score of 0-1. 3. Adequate bone marrow function: * ANC ≥1500 cells/mm3 * Platelets ≥100,000 cells/mm3 * Hemoglobin ≥10.0 g/dL 4. Adequate organ functions: * CLCR ≥60 mL/min and no documented CLCR \<60 mL/min and no change in CLCR \>25% in the past 4 weeks * AST and ALT ≤2.5 × ULN; if liver function abnormalities are due to hepatic metastasis, then AST and ALT ≤5 × ULN; * Total bilirubin ≤1.5 × ULN (≤3 × ULN for Gilbert's syndrome);
Exclusion criteria
1. For ovarian participants: Non-epithelial tumors or ovarian tumors with low malignant potential (ie, borderline tumors) or mucinous tumors. 2. Toxicities from previous anti-cancer therapies must be resolved to NCI CTCAE \<Grade 2, except for alopecia, sensory neuropathies ≤Grade 2, or other Grade ≤2 AEs not constituting a safety risk, based on investigator's judgment, are acceptable. 3. Diagnosed with MDS or AML. 4. Active infection requiring systemic therapy within 2 weeks of enrollment. 5. Any condition in which active bleeding or pathological conditions may carry a high risk of bleeding (eg, known bleeding disorder, coagulopathy or tumor involvement with major vessels). 6. Known or suspected brain metastasis or active leptomeningeal disease undergoing or requiring treatment. Asymptomatic brain metastases currently not undergoing treatment are allowed. 7. Known history of testing positive for HIV, AIDS, positive HBV surface antigen, positive HCV RNA, or positive COVID-19 viral test. Asymptomatic patients with no active infection detected but positive antibody tests, indicating past infection, are allowed. 8. Current or anticipated use of P-gp inhibitors, BCRP inhibitors, and P-gp inducers within 2 weeks or 5 half-lives prior to randomization (whichever is longer) .
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-Time Profile From Time 0 to 24 Hours (AUC24) of Talazoparib After Multiple Dosing Under Fasted Conditions | Serial blood sample (4 mL) each was collected at predose on Day 27 of Period 1 and Day 20 of Periods 2 and predose and 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, and 24 hours postdose on Day 28 of Period 1 and Day 21 of Period 2 to 3, respectively. | AUC24 was defined as area under the plasma concentration-time profile from time zero to 24 hours post dose. The geometric coefficient of variation is expressed in percentage. The ratio (Test/Reference) of adjusted means and 90% CI were expressed as percentages. |
| Maximum Observed Plasma Concentration (Cmax) of Talazoparib After Multiple Dosing Under Fasted Conditions | Serial blood sample (4 mL) each was collected at predose on Day 27 of Period 1 and Day 20 of Periods 2 and predose and 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, and 24 hours postdose on Day 28 of Period 1 and Day 21 of Period 2 to 3, respectively. | Cmax was the maximum observed plasma concentration and was directly observed from data. The geometric coefficient of variation was expressed in percentage. The ratio (Test/Reference) of adjusted means and 90% CI were expressed as percentages. |
| Area Under the Plasma Concentration-Time Profile From Time 0 to 24 Hours (AUC24) of Talazoparib After Multiple Dosing Under Fed Conditions | Serial blood sample (4 mL) each was collected at predose on Day 27 of Period 1 and Day 20 of Periods 2 and predose and 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, and 24 hours postdose on Day 28 of Period 1 and Day 21 of Period 2 to 3, respectively. | AUC24 was defined as area under the plasma concentration-time profile from time zero to 24 hours post dose. The geometric coefficient of variation is expressed in percentage. The ratio (Test/Reference) of adjusted means and 90% CI were expressed as percentages. |
| Maximum Observed Plasma Concentration (Cmax) of Talazoparib After Multiple Dosing Under Fed Conditions | Serial blood sample (4 mL) each was collected at predose on Day 27 of Period 1 and Day 20 of Periods 2 and predose and 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, and 24 hours postdose on Day 28 of Period 1 and Day 21 of Period 2 to 3, respectively. | Cmax was the maximum observed plasma concentration and was directly observed from data. The geometric coefficient of variation was expressed in percentage. The ratio (Test/Reference) of adjusted means and 90% CI were expressed as percentages. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causalities) | Day 1 up to 28 days after last dose of study drug (maximum up to 388 days) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. Treatment-emergent adverse event (TEAE) means event between first dose of study treatment and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. An SAE was an AE resulting in any of death; inpatient hospitalization; life-threatening experience; disability; congenital anomaly or deemed significant for any other reason. |
| Apparent Clearance After Oral Dose (CL/F) of Talazoparib After Multiple Dosing | Serial blood sample (4 mL) each was collected at predose on Day 27 of Period 1 and Day 20 of Periods 2 and predose and 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, and 24 hours postdose on Day 28 of Period 1 and Day 21 of Period 2 to 3, respectively. | Apparent Clearance After Oral Dose (CL/F) was defined as apparent clearance after oral dose on the last day of treatment period. The geometric coefficient of variation is expressed in percentage. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Treatment Related) | Day 1 up to 28 days after last dose of study drug (maximum up to 388 days) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. Treatment-emergent adverse event (TEAE) means event between first dose of study treatment and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. An SAE was an AE resulting in any of death; inpatient hospitalization; life-threatening experience; disability; congenital anomaly or deemed significant for any other reason. |
| Time of Observed Maximum Plasma Concentration (Tmax) of Talazoparib After Multiple Dosing | Serial blood sample (4 mL) each was collected at predose on Day 27 of Period 1 and Day 20 of Periods 2 and predose and 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, and 24 hours postdose on Day 28 of Period 1 and Day 21 of Period 2 to 3, respectively. | Tmax was defined as time to reach maximum observed plasma concentration. |
| Area Under the Plasma Concentration-Time Profile From Time 0 to Time of the Last Quantifiable Concentration (AUClast) of Talazoparib After Multiple Dosing | Serial blood sample (4 mL) each was collected at predose on Day 27 of Period 1 and Day 20 of Periods 2 and predose and 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, and 24 hours postdose on Day 28 of Period 1 and Day 21 of Period 2 to 3, respectively. | AUClast was area under the plasma concentration time-curve from zero (pre-dose) to the last measured concentration. The geometric coefficient of variation was expressed in percentage. |
| Predose Concentration During Multiple Dosing (Ctrough) of Talazoparib After Multiple Dosing | Serial blood sample (4 mL) each was collected at predose on Day 27 of Period 1 and Day 20 of Periods 2, predose and 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, and 24 hours postdose on Day 28 of Period 1 and Day 21 of Period 2 to 3, respectively. | Ctrough was the pre-dose concentration during multiple dosing and was directly observed from data. The geometric coefficient of variation is expressed in percentage. |
Countries
Australia, United States
Participant flow
Pre-assignment details
A total of 73 participants were assigned to study treatment, and all of them were permanently discontinued from study treatment. Fifty-two participants entered the safety follow-up phase and 46 of them completed the safety follow-up.
Participants by arm
| Arm | Count |
|---|---|
| All Participants Participants were randomly assigned to 1 of 2 sequences to receive treatments A, B and C in different order with 3 periods. The first 2 periods were for BE assessment with treatment A and B (Period 1 was 28 days and Period 2 was 21 days); Period 3 was a 21-day period to evaluate the food effect with treatment C. Sequence 1 (Period 1: Treatment B; Period 2: Treatment A; Period 3: Treatment C); Sequence 2 (Period 1: Treatment A; Period 2: Treatment B; Period 3: Treatment C); Treatment A: current commercial talazoparib formulation 1 mg once daily given under fasting condition (reference for BE evaluation); Treatment B: the proposed talazoparib soft gel capsule formulation 1 mg once daily given under fasting condition (test for BE evaluation, reference for food effect evaluation); Treatment C: the proposed talazoparib soft gelatin capsule formulation 1 mg once daily given with food (on the PK sampling day, high-fat/high-calorie meal was administered in the clinical sites prior to the administration of the proposed talazoparib soft gelatin capsule formulation; test for food-effect evaluation). | 73 |
| Total | 73 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Bioequivalence Phase: Period 1 (28 Days) | Adverse Event | 3 | 0 |
| Bioequivalence Phase: Period 1 (28 Days) | Death | 1 | 2 |
| Bioequivalence Phase: Period 1 (28 Days) | Global deterioration of health status | 0 | 1 |
| Bioequivalence Phase: Period 1 (28 Days) | Other | 1 | 0 |
| Bioequivalence Phase: Period 1 (28 Days) | Progressive disease | 2 | 4 |
| Bioequivalence Phase: Period 1 (28 Days) | Withdrawal by Subject | 0 | 3 |
| Bioequivalence Phase: Period 2 (21 Days) | Progressive disease | 1 | 5 |
| Bioequivalence Phase: Period 2 (21 Days) | Withdrawal by Subject | 1 | 0 |
| Food Effect Phase: Period 3 (21 Days) | Adverse Event | 1 | 0 |
| Food Effect Phase: Period 3 (21 Days) | Other | 1 | 0 |
| Food Effect Phase: Period 3 (21 Days) | Progressive disease | 3 | 1 |
| Food Effect Phase: Period 3 (21 Days) | Refused further treatment | 0 | 1 |
| Food Effect Phase: Period 3 (21 Days) | Withdrawal by Subject | 0 | 1 |
| Maintenance Phase: Period 4 (28 Days) | Adverse Event | 1 | 0 |
| Maintenance Phase: Period 4 (28 Days) | Other | 9 | 8 |
| Maintenance Phase: Period 4 (28 Days) | Progressive disease | 10 | 12 |
| Maintenance Phase: Period 4 (28 Days) | Refused further treatment | 1 | 0 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 56.8 Years STANDARD_DEVIATION 9.18 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 63 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 11 Participants |
| Race/Ethnicity, Customized Not reported | 4 Participants |
| Race/Ethnicity, Customized White | 57 Participants |
| Sex: Female, Male Female | 43 Participants |
| Sex: Female, Male Male | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 65 | 5 / 60 | 0 / 30 | 1 / 41 |
| other Total, other adverse events | 25 / 65 | 25 / 60 | 12 / 30 | 20 / 41 |
| serious Total, serious adverse events | 9 / 65 | 7 / 60 | 1 / 30 | 7 / 41 |
Outcome results
Primary
Area Under the Plasma Concentration-Time Profile From Time 0 to 24 Hours (AUC24) of Talazoparib After Multiple Dosing Under Fasted Conditions
AUC24 was defined as area under the plasma concentration-time profile from time zero to 24 hours post dose. The geometric coefficient of variation is expressed in percentage. The ratio (Test/Reference) of adjusted means and 90% CI were expressed as percentages.
Time frame: Serial blood sample (4 mL) each was collected at predose on Day 27 of Period 1 and Day 20 of Periods 2 and predose and 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, and 24 hours postdose on Day 28 of Period 1 and Day 21 of Period 2 to 3, respectively.
Population: The analysis population was defined as all participants randomized and treated who had primary PK parameter of AUC24 or Cmax in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Commercial Capsule Fast | Area Under the Plasma Concentration-Time Profile From Time 0 to 24 Hours (AUC24) of Talazoparib After Multiple Dosing Under Fasted Conditions | 178.7 nanograms*hour/millilitre (ng*hr/mL) | Geometric Coefficient of Variation 40 |
| Treatment B: Soft Gel Capsule Fast | Area Under the Plasma Concentration-Time Profile From Time 0 to 24 Hours (AUC24) of Talazoparib After Multiple Dosing Under Fasted Conditions | 173.0 nanograms*hour/millilitre (ng*hr/mL) | Geometric Coefficient of Variation 32 |
Comparison: Treatment A were reference; treatment B were test.90% CI: [99, 111.7]Mixed Models Analysis
Primary
Area Under the Plasma Concentration-Time Profile From Time 0 to 24 Hours (AUC24) of Talazoparib After Multiple Dosing Under Fed Conditions
AUC24 was defined as area under the plasma concentration-time profile from time zero to 24 hours post dose. The geometric coefficient of variation is expressed in percentage. The ratio (Test/Reference) of adjusted means and 90% CI were expressed as percentages.
Time frame: Serial blood sample (4 mL) each was collected at predose on Day 27 of Period 1 and Day 20 of Periods 2 and predose and 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, and 24 hours postdose on Day 28 of Period 1 and Day 21 of Period 2 to 3, respectively.
Population: The analysis population was defined as all participants randomized and treated who had primary PK parameter of AUC24 or Cmax in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Commercial Capsule Fast | Area Under the Plasma Concentration-Time Profile From Time 0 to 24 Hours (AUC24) of Talazoparib After Multiple Dosing Under Fed Conditions | 173.0 ng*hr/mL | Geometric Coefficient of Variation 32 |
| Treatment B: Soft Gel Capsule Fast | Area Under the Plasma Concentration-Time Profile From Time 0 to 24 Hours (AUC24) of Talazoparib After Multiple Dosing Under Fed Conditions | 151.3 ng*hr/mL | Geometric Coefficient of Variation 38 |
Comparison: Treatment B were reference; treatment C were test.90% CI: [81.82, 94.58]Mixed Models Analysis
Primary
Maximum Observed Plasma Concentration (Cmax) of Talazoparib After Multiple Dosing Under Fasted Conditions
Cmax was the maximum observed plasma concentration and was directly observed from data. The geometric coefficient of variation was expressed in percentage. The ratio (Test/Reference) of adjusted means and 90% CI were expressed as percentages.
Time frame: Serial blood sample (4 mL) each was collected at predose on Day 27 of Period 1 and Day 20 of Periods 2 and predose and 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, and 24 hours postdose on Day 28 of Period 1 and Day 21 of Period 2 to 3, respectively.
Population: The analysis population was defined as all participants randomized and treated who had primary PK parameter of AUC24 or Cmax in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Commercial Capsule Fast | Maximum Observed Plasma Concentration (Cmax) of Talazoparib After Multiple Dosing Under Fasted Conditions | 14.95 nanograms/millilitre (ng/mL) | Geometric Coefficient of Variation 40 |
| Treatment B: Soft Gel Capsule Fast | Maximum Observed Plasma Concentration (Cmax) of Talazoparib After Multiple Dosing Under Fasted Conditions | 19.19 nanograms/millilitre (ng/mL) | Geometric Coefficient of Variation 32 |
Comparison: Treatment A were reference; treatment B were test.90% CI: [125.05, 149.27]Mixed Models Analysis
Primary
Maximum Observed Plasma Concentration (Cmax) of Talazoparib After Multiple Dosing Under Fed Conditions
Cmax was the maximum observed plasma concentration and was directly observed from data. The geometric coefficient of variation was expressed in percentage. The ratio (Test/Reference) of adjusted means and 90% CI were expressed as percentages.
Time frame: Serial blood sample (4 mL) each was collected at predose on Day 27 of Period 1 and Day 20 of Periods 2 and predose and 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, and 24 hours postdose on Day 28 of Period 1 and Day 21 of Period 2 to 3, respectively.
Population: The analysis population was defined as all participants randomized and treated who had primary PK parameter of AUC24 or Cmax in at least 1 treatment period. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Commercial Capsule Fast | Maximum Observed Plasma Concentration (Cmax) of Talazoparib After Multiple Dosing Under Fed Conditions | 19.19 ng/mL | Geometric Coefficient of Variation 32 |
| Treatment B: Soft Gel Capsule Fast | Maximum Observed Plasma Concentration (Cmax) of Talazoparib After Multiple Dosing Under Fed Conditions | 11.36 ng/mL | Geometric Coefficient of Variation 38 |
Comparison: Treatment B were reference; treatment C were test.90% CI: [51.55, 65.84]Mixed Models Analysis
Secondary
Apparent Clearance After Oral Dose (CL/F) of Talazoparib After Multiple Dosing
Apparent Clearance After Oral Dose (CL/F) was defined as apparent clearance after oral dose on the last day of treatment period. The geometric coefficient of variation is expressed in percentage.
Time frame: Serial blood sample (4 mL) each was collected at predose on Day 27 of Period 1 and Day 20 of Periods 2 and predose and 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, and 24 hours postdose on Day 28 of Period 1 and Day 21 of Period 2 to 3, respectively.
Population: The analysis population was defined as all participants randomized and treated who had primary PK parameter of AUC24 or Cmax in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Commercial Capsule Fast | Apparent Clearance After Oral Dose (CL/F) of Talazoparib After Multiple Dosing | 5.631 liter per hour (L/hr) | Geometric Coefficient of Variation 40 |
| Treatment B: Soft Gel Capsule Fast | Apparent Clearance After Oral Dose (CL/F) of Talazoparib After Multiple Dosing | 5.808 liter per hour (L/hr) | Geometric Coefficient of Variation 32 |
| Treatment C: Soft Gel Capsule Fed | Apparent Clearance After Oral Dose (CL/F) of Talazoparib After Multiple Dosing | 6.648 liter per hour (L/hr) | Geometric Coefficient of Variation 38 |
Secondary
Area Under the Plasma Concentration-Time Profile From Time 0 to Time of the Last Quantifiable Concentration (AUClast) of Talazoparib After Multiple Dosing
AUClast was area under the plasma concentration time-curve from zero (pre-dose) to the last measured concentration. The geometric coefficient of variation was expressed in percentage.
Time frame: Serial blood sample (4 mL) each was collected at predose on Day 27 of Period 1 and Day 20 of Periods 2 and predose and 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, and 24 hours postdose on Day 28 of Period 1 and Day 21 of Period 2 to 3, respectively.
Population: The analysis population was defined as all participants randomized and treated who had primary PK parameter of AUC24 or Cmax in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Commercial Capsule Fast | Area Under the Plasma Concentration-Time Profile From Time 0 to Time of the Last Quantifiable Concentration (AUClast) of Talazoparib After Multiple Dosing | 178.5 ng*hr/mL | Geometric Coefficient of Variation 41 |
| Treatment B: Soft Gel Capsule Fast | Area Under the Plasma Concentration-Time Profile From Time 0 to Time of the Last Quantifiable Concentration (AUClast) of Talazoparib After Multiple Dosing | 173.4 ng*hr/mL | Geometric Coefficient of Variation 33 |
| Treatment C: Soft Gel Capsule Fed | Area Under the Plasma Concentration-Time Profile From Time 0 to Time of the Last Quantifiable Concentration (AUClast) of Talazoparib After Multiple Dosing | 152.1 ng*hr/mL | Geometric Coefficient of Variation 38 |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causalities)
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. Treatment-emergent adverse event (TEAE) means event between first dose of study treatment and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. An SAE was an AE resulting in any of death; inpatient hospitalization; life-threatening experience; disability; congenital anomaly or deemed significant for any other reason.
Time frame: Day 1 up to 28 days after last dose of study drug (maximum up to 388 days)
Population: Population analysis set included all participants randomly assigned to investigational product (IP) and who took at least 1 dose of IP.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment A: Commercial Capsule Fast | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causalities) | Participants discontinued study drug due to adverse events | 3 Participants |
| Treatment A: Commercial Capsule Fast | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causalities) | Participants with Maximum Grade 3 or 4 adverse events | 13 Participants |
| Treatment A: Commercial Capsule Fast | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causalities) | Participants with Maximum Grade 5 adverse events | 3 Participants |
| Treatment A: Commercial Capsule Fast | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causalities) | Participants with adverse events | 42 Participants |
| Treatment A: Commercial Capsule Fast | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causalities) | Participants with dose reduced or temporary discontinuation due to adverse events | 13 Participants |
| Treatment A: Commercial Capsule Fast | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causalities) | Participants with serious adverse events | 9 Participants |
| Treatment B: Soft Gel Capsule Fast | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causalities) | Participants with Maximum Grade 5 adverse events | 4 Participants |
| Treatment B: Soft Gel Capsule Fast | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causalities) | Participants with adverse events | 36 Participants |
| Treatment B: Soft Gel Capsule Fast | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causalities) | Participants with Maximum Grade 3 or 4 adverse events | 10 Participants |
| Treatment B: Soft Gel Capsule Fast | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causalities) | Participants discontinued study drug due to adverse events | 4 Participants |
| Treatment B: Soft Gel Capsule Fast | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causalities) | Participants with dose reduced or temporary discontinuation due to adverse events | 9 Participants |
| Treatment B: Soft Gel Capsule Fast | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causalities) | Participants with serious adverse events | 7 Participants |
| Treatment C: Soft Gel Capsule Fed | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causalities) | Participants with Maximum Grade 5 adverse events | 0 Participants |
| Treatment C: Soft Gel Capsule Fed | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causalities) | Participants with dose reduced or temporary discontinuation due to adverse events | 6 Participants |
| Treatment C: Soft Gel Capsule Fed | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causalities) | Participants with adverse events | 15 Participants |
| Treatment C: Soft Gel Capsule Fed | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causalities) | Participants with serious adverse events | 1 Participants |
| Treatment C: Soft Gel Capsule Fed | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causalities) | Participants with Maximum Grade 3 or 4 adverse events | 5 Participants |
| Treatment C: Soft Gel Capsule Fed | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causalities) | Participants discontinued study drug due to adverse events | 1 Participants |
| Maintenance | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causalities) | Participants with dose reduced or temporary discontinuation due to adverse events | 13 Participants |
| Maintenance | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causalities) | Participants with adverse events | 31 Participants |
| Maintenance | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causalities) | Participants with serious adverse events | 7 Participants |
| Maintenance | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causalities) | Participants with Maximum Grade 5 adverse events | 1 Participants |
| Maintenance | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causalities) | Participants discontinued study drug due to adverse events | 2 Participants |
| Maintenance | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causalities) | Participants with Maximum Grade 3 or 4 adverse events | 12 Participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Treatment Related)
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. Treatment-emergent adverse event (TEAE) means event between first dose of study treatment and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. An SAE was an AE resulting in any of death; inpatient hospitalization; life-threatening experience; disability; congenital anomaly or deemed significant for any other reason.
Time frame: Day 1 up to 28 days after last dose of study drug (maximum up to 388 days)
Population: Population analysis set included all participants randomly assigned to IP and who took at least 1 dose of IP.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment A: Commercial Capsule Fast | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Treatment Related) | Participants with Maximum Grade 3 or 4 adverse events | 9 Participants |
| Treatment A: Commercial Capsule Fast | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Treatment Related) | Participants with dose reduced or temporary discontinuation due to adverse events | 9 Participants |
| Treatment A: Commercial Capsule Fast | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Treatment Related) | Participants with adverse events | 22 Participants |
| Treatment A: Commercial Capsule Fast | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Treatment Related) | Participants discontinued study drug due to adverse events | 1 Participants |
| Treatment A: Commercial Capsule Fast | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Treatment Related) | Participants with serious adverse events | 2 Participants |
| Treatment B: Soft Gel Capsule Fast | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Treatment Related) | Participants with Maximum Grade 3 or 4 adverse events | 8 Participants |
| Treatment B: Soft Gel Capsule Fast | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Treatment Related) | Participants with serious adverse events | 0 Participants |
| Treatment B: Soft Gel Capsule Fast | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Treatment Related) | Participants with adverse events | 26 Participants |
| Treatment B: Soft Gel Capsule Fast | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Treatment Related) | Participants with dose reduced or temporary discontinuation due to adverse events | 7 Participants |
| Treatment B: Soft Gel Capsule Fast | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Treatment Related) | Participants discontinued study drug due to adverse events | 1 Participants |
| Treatment C: Soft Gel Capsule Fed | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Treatment Related) | Participants with serious adverse events | 0 Participants |
| Treatment C: Soft Gel Capsule Fed | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Treatment Related) | Participants with dose reduced or temporary discontinuation due to adverse events | 6 Participants |
| Treatment C: Soft Gel Capsule Fed | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Treatment Related) | Participants with adverse events | 11 Participants |
| Treatment C: Soft Gel Capsule Fed | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Treatment Related) | Participants discontinued study drug due to adverse events | 0 Participants |
| Treatment C: Soft Gel Capsule Fed | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Treatment Related) | Participants with Maximum Grade 3 or 4 adverse events | 4 Participants |
| Maintenance | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Treatment Related) | Participants with dose reduced or temporary discontinuation due to adverse events | 12 Participants |
| Maintenance | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Treatment Related) | Participants with serious adverse events | 3 Participants |
| Maintenance | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Treatment Related) | Participants with Maximum Grade 3 or 4 adverse events | 10 Participants |
| Maintenance | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Treatment Related) | Participants discontinued study drug due to adverse events | 1 Participants |
| Maintenance | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Treatment Related) | Participants with adverse events | 16 Participants |
Secondary
Predose Concentration During Multiple Dosing (Ctrough) of Talazoparib After Multiple Dosing
Ctrough was the pre-dose concentration during multiple dosing and was directly observed from data. The geometric coefficient of variation is expressed in percentage.
Time frame: Serial blood sample (4 mL) each was collected at predose on Day 27 of Period 1 and Day 20 of Periods 2, predose and 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, and 24 hours postdose on Day 28 of Period 1 and Day 21 of Period 2 to 3, respectively.
Population: The analysis population was defined as all participants randomized and treated who had primary PK parameter of AUC24 or Cmax in at least 1 treatment period. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Commercial Capsule Fast | Predose Concentration During Multiple Dosing (Ctrough) of Talazoparib After Multiple Dosing | 4.269 ng/mL | Geometric Coefficient of Variation 48 |
| Treatment B: Soft Gel Capsule Fast | Predose Concentration During Multiple Dosing (Ctrough) of Talazoparib After Multiple Dosing | 3.645 ng/mL | Geometric Coefficient of Variation 44 |
| Treatment C: Soft Gel Capsule Fed | Predose Concentration During Multiple Dosing (Ctrough) of Talazoparib After Multiple Dosing | 3.633 ng/mL | Geometric Coefficient of Variation 60 |
Secondary
Time of Observed Maximum Plasma Concentration (Tmax) of Talazoparib After Multiple Dosing
Tmax was defined as time to reach maximum observed plasma concentration.
Time frame: Serial blood sample (4 mL) each was collected at predose on Day 27 of Period 1 and Day 20 of Periods 2 and predose and 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, and 24 hours postdose on Day 28 of Period 1 and Day 21 of Period 2 to 3, respectively.
Population: The analysis population was defined as all participants randomized and treated who had primary PK parameter of AUC24 or Cmax in at least 1 treatment period. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment A: Commercial Capsule Fast | Time of Observed Maximum Plasma Concentration (Tmax) of Talazoparib After Multiple Dosing | 2.00 hour |
| Treatment B: Soft Gel Capsule Fast | Time of Observed Maximum Plasma Concentration (Tmax) of Talazoparib After Multiple Dosing | 0.975 hour |
| Treatment C: Soft Gel Capsule Fed | Time of Observed Maximum Plasma Concentration (Tmax) of Talazoparib After Multiple Dosing | 4.00 hour |