This is a Phase 1 study which consists of 2 parts; Dose Escalation part and Expansion part. The dose escalation part is open-label, and evaluates safety, preliminary efficacy and PK of single-agent talazoparib in sequential cohorts of adult patients with advanced solid tumors who are resistant to standard therapy or for whom no standard therapy is available. In the dose escalation part, up to 18 (minimum 3) patients are expected to be enrolled depending on the observed DLTs. The expansion part is designed to assess the efficacy, safety and PK of single-agent talazoparib at RP2D determined in the dose escalation part in adult patients with locally advanced or metastatic breast cancer who have deleterious or suspected deleterious germline BRCA1 or BRCA2 mutations. In the expansion part, a minimum of 17 patients will be enrolled evaluable for the primary endpoint.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
28
Talazoparib will be administered orally on a continuous basis. Talazoparib may be taken with or without food. Each cycle will consist of 28 days.
Aichi Cancer Center Hospital
Nagoya, Aichi-ken, Japan
National Cancer Center Hospital East
Kashiwa, Chiba, Japan
National Hospital Organization Hokkaido Cancer Center
Sapporo, Hokkaido, Japan
Kanagawa Cancer Center
Yokohama, Kanagawa, Japan
Saitama Cancer Center
Kitaadachi-gun, Saitama, Japan
National Cancer Center Hospital
Chuo-Ku, Tokyo, Japan
Hakuaikai Medical Corporation Sagara Hospital
Kagoshima, Japan
National Hospital Organization Osaka National Hospital
Osaka, Japan
Dose Escalation: Number of Participants With Dose-Limiting Toxicities (DLT)
DLT was defined as any of the following adverse events occurred in 1st treatment cycle and attributable to talazoparib: hematologic- grade(G) 4 neutropenia greater than (\>)7days; Febrile neutropenia \>1 hour; G greater than or equal to (\>=)3 neutropenic infection, thrombocytopenia associated with G2 hemorrhage; G4 thrombocytopenia, anemia; G3 anemia required transfusion; daily dosing interrupted for \>=7 total days in first cycle for G3 neutropenia/thrombocytopenia. Non-hematologic: any G\>=3AE except non-clinically significant laboratory abnormalities, Non-hematologic AE deemed not clinically significant, nausea, vomiting, diarrhea responded to medical intervention within 72 hours, fatigue improved to G\>=2 within 7 days. Alanine/aspartate aminotransferase (ALT/AST)\>5\*upper limit of normal(ULN) and 2\*increases above baseline values; ALT/AST\>=3\*ULN concurrent with total bilirubin (TB)\>2\*ULN; TB\>5\*ULN; failure to deliver 75percent(%) of doses due to toxicities attributable to talazoparib.
Time frame: Cycle 1 (28 days)
Dose Expansion: Percentage of Participants With Confirmed Objective Response (OR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 by Investigator Assessment
Confirmed OR in participants was defined as the percentage of participants with complete response (CR) or partial response (PR) as best response determined by investigator as per RECIST v 1.1 and confirmed by a second image at least 4 weeks from the initial imaging showing response. As per RECIST v 1.1, CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<)10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From start of the treatment until disease progression or death (due to any cause) whichever occurred first (maximum duration: up to 502 days)
Number of Participants With Treatment Emergent Adverse Events (TEAE) Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.03
Adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event was the AE resulting in any of following outcomes/deemed significant for any other reason: death; initial /prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs were the events between first dose of study drug and up to 30 days after last dose or before start of new anticancer therapy, whichever occurred first. TEAE graded by CTCAE v 4.03 as Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death.
Time frame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy, whichever occurred first (Dose escalation: maximum duration- up to 286 days; Dose expansion: maximum duration- up to 502 days)
Number of Participants With Treatment Related Adverse Events Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.03
A treatment-related AE was any untoward medical occurrence attributed to the study drug in a participant who received study drug. Serious adverse event was the AE resulting in any of following outcomes/deemed significant for any other reason: death; initial /prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs were the events between first dose of study drug and up to 30 days after last dose or before start of new anticancer therapy, whichever occurred first. AE graded by CTCAE v 4.03 as Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death. Relatedness to study drug was assessed by the investigator.
Time frame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy, whichever occurred first (Dose escalation: maximum duration- up to 286 days; Dose expansion: maximum duration- up to 502 days)
Number of Participants With Grade 3 or Higher Treatment-Emergent Adverse Events (AEs) Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.03
AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were the events between first dose of study drug and up to 30 days after last dose or before start of new anticancer therapy, whichever occurred first. TEAE graded by CTCAE v 4.03 as Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death. In this outcome measure, number of participants with grade 3 or higher AEs were reported.
Time frame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy, whichever occurred first (Dose escalation: maximum duration- up to 286 days; Dose expansion: maximum duration- up to 502 days)
Number of Participants With Laboratory Abnormalities Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.03: Chemistry
Parameters: Alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, creatinine increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia. As per CTCAE v 4.03: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening. Only those categories in which at least one participant had data were reported in this outcome measure.
Time frame: Dose escalation: Baseline up to 286 days; Dose expansion: Baseline up to 502 days
Number of Participants With Laboratory Abnormalities Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.03: Hematology
Hematological parameters included: Anemia, Hemoglobin increased, Lymphocyte count decreased, Lymphocyte count increased, Neutrophil count decreased, Platelet count decreased, White blood cell decreased. As per CTCAE v 4.03: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening. Only those categories in which at least one participant had data were reported in this outcome measure.
Time frame: Dose escalation: Baseline up to 286 days; Dose expansion: Baseline up to 502 days
Dose Escalation: Number of Participants With Abnormalities in Vital Signs
Vital sign abnormalities: a) Sitting systolic blood pressure: \<90 millimeter of mercury (mmHg), decrease from baseline \>=30 mmHg, increase from baseline \>=30 mmHg; b) Sitting diastolic blood pressure: minimum \<50 mmHg, decrease from baseline \>=20 mmHg, increase from baseline \>=20 mmHg; c) Sitting pulse rate: minimum \<40 beats per minute (bpm), maximum \>120 bpm. Only those categories in which at least one participant had data were reported in this outcome measure.
Time frame: Baseline up to 286 days
Dose Escalation- Single Dose: Maximum Observed Plasma Concentration (Cmax) for Talazoparib
Cmax was defined as the maximum observed plasma concentration of talazoparib.
Time frame: Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10, 24, 48, 72 and 96 hours post dose on Day -7 of Cycle 1
Dose Escalation- Single Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax) for Talazoparib
Tmax was defined as the time to reach maximum observed plasma concentration of talazoparib.
Time frame: Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10, 24, 48, 72 and 96 hours post dose on Day -7 of Cycle 1
Dose Escalation- Single Dose: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for Talazoparib
Area under the plasma concentration time-curve from time zero to the time of last measured concentration (AUClast).
Time frame: Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10, 24, 48, 72 and 96 hours post dose on Day -7 of Cycle 1
Dose Escalation- Single Dose: Area Under the Curve From Time Zero to Time Tau (AUCtau) for Talazoparib
Area under the plasma concentration curve from time 0 to end of dosing interval (AUCtau), where dosing interval was 24 hours.
Time frame: Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10 and 24 hours post dose on Day -7 of Cycle 1
Dose Escalation- Single Dose: Apparent Oral Clearance of Talazoparib (CL/F)
Clearance is a measure of the rate at which a drug was metabolized or eliminated by normal biological processes.
Time frame: Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10, 24, 48, 72 and 96 hours post dose on Day -7 of Cycle 1
Dose Escalation- Single Dose: Apparent Volume of Distribution (Vz/F) for Talazoparib
Volume of distribution is 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.
Time frame: Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10, 24, 48, 72 and 96 hours post dose on Day -7 of Cycle 1
Dose Escalation- Single Dose: Terminal Half-Life (t1/2) for Talazoparib
Terminal half-life (t1/2) is the time measured for the plasma concentration of a drug to decrease by half of its initial concentration.
Time frame: Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10, 24, 48, 72 and 96 hours post dose on Day -7 of Cycle 1
Dose Escalation- Single Dose: Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) for Talazoparib
AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre dose) to extrapolated infinite time (0-inf).
Time frame: Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10, 24, 48, 72 and 96 hours post dose on Day -7 of Cycle 1
Dose Escalation- Multiple Dose: Maximum Observed Plasma Concentration at Steady State (Css,Max) for Talazoparib
Css,max is maximum observed plasma concentration at steady state (post multiple dose) of Talazoparib.
Time frame: Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10 and 24 hours post dose on Day 22 of Cycle 1
Dose Escalation- Multiple Dose: Predose Concentration (Cmin) for Talazoparib
Pre dose plasma concentration of talazoparib.
Time frame: Pre dose on Day 22 of Cycle 1
Dose Escalation- Multiple Dose: Time for Maximum Observed Plasma Concentration at Steady State (Tss,Max) for Talazoparib
Tss,max = Time to reach Cmax for talazoparib at steady state (post multiple dose).
Time frame: Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10 and 24 hours post dose on Day 22 of Cycle 1
Dose Escalation- Multiple Dose: Area Under the Curve From Time Zero to Time Tau at Steady State (AUCss,Tau) for Talazoparib
Area under the plasma concentration curve from time 0 to end of dosing interval (AUCtau) at steady state (post multiple dose), where dosing interval was 24 hours.
Time frame: Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10 and 24 hours post dose on Day 22 of Cycle 1
Dose Escalation- Multiple Dose: Apparent Oral Clearance of Talazoparib at Steady State (CL/Fss)
Clearance is a measure of the rate at which a drug was metabolized or eliminated by normal biological processes.
Time frame: Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10 and 24 hours post dose on Day 22 of Cycle 1
Dose Escalation- Multiple Dose: Accumulation Ratio (Rac) of AUCtau for Talazoparib
Accumulation ratio for AUC was calculated as AUCtau for Day 22 divided by AUCtau for Day -7, where AUCtau was defined as area under the plasma concentration curve from time 0 to end of dosing interval, where dosing interval was 24 hours.
Time frame: Pre dose, 0.5, 0.75, 1, 2, 4, 6, 8, 10 and 24 hours post dose on Day -7 and Day 22 of Cycle 1
Dose Escalation- Multiple Dose: Linearity Ratio (Rss) of AUC for Talazoparib
Rss was calculated by dividing AUCtau at steady state (post multiple dosing on Day 22) by single dose AUCinf (on Day -7). AUCtau was defined as area under the plasma concentration curve from time 0 to end of dosing interval, where dosing interval was 24 hours. AUCinf was defined as area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf).
Time frame: Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10, 24, 48, 72 and 96 hours post dose on Day -7 of Cycle 1; Pre dose, 0.5, 0.75, 1, 2, 4, 6, 8, 10 and 24 hours post dose on Day 22 of Cycle 1
Dose Escalation: Percentage of Participants With Objective Response (OR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
OR in participants was defined as the percentage of participants with CR or PR as best response determined by investigator as per RECIST v 1.1. As per RECIST v 1.1, CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From start of the treatment until disease progression or death (due to any cause) whichever occurred first (maximum duration: up to 286 days)
Dose Escalation: Progression Free Survival (PFS)
PFS was defined as the time from the date of first dose of study drug to the earliest date of disease progression per RECIST v 1.1, or death due to any cause, whichever occurs first. PD = at least a 20% increase in the sum of diameters of measured lesions taking as references the smallest sum of diameters recorded on study (including baseline) and an absolute increase of \>=5 mm or appearance of at least 1 new lesion.
Time frame: From day of first dose until disease progression or death (due to any cause) whichever occur first (maximum duration: up to 286 days)
Dose Escalation: Duration of Response (DOR)
DOR was defined as the time between the date of the first documented objective response (PR or CR) and the date of the first documented progression or death (due to any cause) whichever occurs first. As per RECIST v 1.1: CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions.
Time frame: From date of first documented response to date of first documented PD or death (due to any cause) whichever occurred first (maximum duration: up to 286 days)
Dose Expansion: Percentage of Participants With Confirmed Objective Response (OR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Blinded Independent Central Review (BICR)
Confirmed OR in participants was defined as the percentage of participants with CR or PR as best response determined by BICR as per RECIST v 1.1 and confirmed by a second image at least 4 weeks from the initial imaging showing response. As per RECIST v 1.1, CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From start of the treatment until disease progression or death (due to any cause) whichever occurred first (maximum duration: up to 502 days)
Dose Expansion: Percentage of Participants With Confirmed Disease Control as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Investigator Assessment
Disease Control (DC) was defined as participants with a confirmed CR, confirmed PR and SD at 16 and 24 weeks as assessed by investigator as per RECIST v 1.1. As per RECIST v 1.1, CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (at least a 20% increase in the sum of diameters of target lesions) taking as reference the smallest sum diameters while on study.
Time frame: Baseline up to Week 16, Baseline up to Week 24
Dose Expansion: Percentage of Participants With Confirmed Disease Control as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Blinded Independent Central Review (BICR)
Disease Control (DC) was defined as participants with a confirmed CR, confirmed PR and SD at 16 and 24 weeks as assessed by BICR as per RECIST v 1.1. As per RECIST v 1.1, CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (at least a 20% increase in the sum of diameters of target lesions) taking as reference the smallest sum diameters while on study.
Time frame: Baseline up to Week 16, Baseline up to Week 24
Dose Expansion: Time-to-Tumor Response (TTR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Investigator Assessment
TTR was defined as the time (in months) from the date of first dose of study drug to the first documentation of objective response (CR or PR) as assessed by investigator according to RECIST v 1.1. As per RECIST v 1.1, CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From first dose of study drug until first documentation of CR or PR (maximum duration: up to 502 days)
Dose Expansion: Time-to-Tumor Response (TTR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Blinded Independent Central Review (BICR)
TTR was defined as the time (in months) from the date of first dose of study drug to the first documentation of objective response (CR or PR) as assessed by BICR according to RECIST v 1.1. As per RECIST v 1.1, CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From first dose of study drug until first documentation of CR or PR (maximum duration: up to 502 days)
Dose Expansion: Duration of Response (DOR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Investigator Assessment
DOR was defined as the time between the date of first documented objective response (PR or CR) and the date of first documented progression or death (due to any cause) whichever occurs first. As per RECIST v 1.1: CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions.
Time frame: From date of first documented response to date of first documented PD or death (due to any cause) whichever occurred first (maximum duration: up to 502 days)
Dose Expansion: Duration of Response (DOR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Blinded Independent Central Review (BICR)
DOR was defined as the time between the date of first documented objective response (PR or CR) and the date of first documented progression or death (due to any cause) whichever occurs first. As per RECIST v 1.1: CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions.
Time frame: From date of first documented response to date of first documented PD or death (due to any cause) whichever occurred first (maximum duration: up to 502 days)
Dose Expansion: Progression Free Survival (PFS) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Investigator Assessment
PFS was defined as the time from the date of first dose of study drug to the earliest date of disease progression per RECIST v 1.1, or death due to any cause, whichever occurs first. PD = at least a 20% increase in the sum of diameters of measured lesions taking as references the smallest sum of diameters recorded on study (including baseline) and an absolute increase of \>=5 mm or appearance of at least 1 new lesion.
Time frame: From day of first dose until disease progression or death (due to any cause) whichever occur first (maximum duration: up to 502 days)
Dose Expansion: Progression Free Survival (PFS) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Blinded Independent Central Review (BICR)
PFS was defined as the time from the date of first dose of study drug to the earliest date of disease progression per RECIST v 1.1, or death due to any cause, whichever occurs first. PD = at least a 20% increase in the sum of diameters of measured lesions taking as references the smallest sum of diameters recorded on study (including baseline) and an absolute increase of \>=5 mm or appearance of at least 1 new lesion.
Time frame: From day of first dose until disease progression or death (due to any cause) whichever occur first (maximum duration: up to 502 days)
Dose Expansion: Overall Survival (OS): Probability of Participants Who Were Event-Free at Month 12
OS was defined as the time from the first dose date to date of death due to any cause. Participant was considered as event (overall survival) free if participant was not died and was alive at Month 12. Probability of participants who were event free at Month 12 was estimated by Kaplan-Meier method and reported.
Time frame: At Month 12
Dose Expansion: Trough Concentrations (Ctrough) of Talazoparib
Pre dose plasma drug concentration.
Time frame: Pre dose at 0 hour on Day 1 of Cycle 2, 3, 4 and unplanned (any time during dose expansion period up to 502 days)
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