Clinical trial NCT03343054: A Phase 1 Study Of Talazoparib, PARP Inhibitor, In Japanese Patients With Advanced Solid Tumors
Official title: A PHASE 1 STUDY OF THE SAFETY, PHARMACOKINETICS AND ANTI-TUMOR ACTIVITY OF TALAZOPARIB, POLY (ADP-RIBOSE) POLYMERASE (PARP) INHIBITOR, IN JAPANESE PATIENTS WITH ADVANCED SOLID TUMORS
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neoplasms
Breast Neoplasms
Keywords: Phase 1
talazoparib
PF-06944076
MDV3800
BMN673
PARP inhibitor
Japanese
solid tumors
breast cancer
C3441030
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2017-11-17
Enrollment: 28
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: \[Dose Escalation Part\]

Inclusion Criteria:

* Histological or cytological diagnosis of locally advanced or metastatic solid tumor that is resistant to standard therapy or for which no standard therapy is available.
* ECOG Performance Status 0 or 1.
* Adequate Bone Marrow, Renal and Liver Function.

Exclusion Criteria:

* Patients with known symptomatic brain metastases requiring steroids.
* Current use of a strong P-gp inhibitor, strong P-gp inducer, or strong inhibitor of BCRP within 1 week or 5 half lives which ever is longer prior to the first dose of study treatment.
* Fertile male patients and female patients of childbearing potential who are unwilling or unable to use 2 highly effective methods of contraception.

\[Dose Expansion Part\]

Inclusion Criteria:

* Histologically or cytologically confirmed carcinoma of the breast.
* Locally advanced breast cancer that is not amenable to curative radiation or surgery and/or metastatic disease.
* Documentation of a deleterious, suspected deleterious, or pathogenic germline BRCA1 or BRCA2 mutation by Myriad Genetics' BRACAnalysis CDx test.
* No more than 3 prior chemotherapy-inclusive regimens for locally advanced or metastatic disease.
* Have measurable lesion by the RECIST v.1.1.
* ECOG Performance Status 0-2.
* Adequate Bone Marrow, Renal and Liver Function.

Exclusion Criteria:

* First-line locally advanced or metastatic breast cancer with no prior neoadjuvant and adjuvant chemotherapy.
* Prior treatment with a PARP inhibitor.
* Objective disease progression while receiving platinum chemotherapy administered for locally advanced or metastatic disease.
* HER2 positive breast cancer.
* Active inflammatory breast cancer.
* Central nervous system (CNS) metastases.
* Current or anticipated use within 7 days prior to the first dose of study treatment, or anticipated use during the study of strong P-gp inhibitors.
* Fertile male patients and female patients of childbearing potential who are unwilling or unable to use 2 highly effective methods of contraception.

Primary outcomes:
measure: Dose Escalation: Number of Participants With Dose-Limiting Toxicities (DLT)
timeFrame: Cycle 1 (28 days)
measure: 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
timeFrame: From start of the treatment until disease progression or death (due to any cause) whichever occurred first (maximum duration: up to 502 days)
Secondary outcomes:
measure: 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
timeFrame: 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)
measure: Number of Participants With Treatment Related Adverse Events Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.03
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: Number of Participants With Laboratory Abnormalities Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.03: Chemistry
timeFrame: Dose escalation: Baseline up to 286 days; Dose expansion: Baseline up to 502 days
measure: Number of Participants With Laboratory Abnormalities Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.03: Hematology
timeFrame: Dose escalation: Baseline up to 286 days; Dose expansion: Baseline up to 502 days
measure: Dose Escalation: Number of Participants With Abnormalities in Vital Signs
timeFrame: Baseline up to 286 days
measure: Dose Escalation- Single Dose: Maximum Observed Plasma Concentration (Cmax) for Talazoparib
timeFrame: 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
measure: Dose Escalation- Single Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax) for Talazoparib
timeFrame: 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
measure: Dose Escalation- Single Dose: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for Talazoparib
timeFrame: 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
measure: Dose Escalation- Single Dose: Area Under the Curve From Time Zero to Time Tau (AUCtau) for Talazoparib
timeFrame: Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10 and 24 hours post dose on Day -7 of Cycle 1
measure: Dose Escalation- Single Dose: Apparent Oral Clearance of Talazoparib (CL/F)
timeFrame: 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
measure: Dose Escalation- Single Dose: Apparent Volume of Distribution (Vz/F) for Talazoparib
timeFrame: 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
measure: Dose Escalation- Single Dose: Terminal Half-Life (t1/2) for Talazoparib
timeFrame: 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
measure: Dose Escalation- Single Dose: Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) for Talazoparib
timeFrame: 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
measure: Dose Escalation- Multiple Dose: Maximum Observed Plasma Concentration at Steady State (Css,Max) for Talazoparib
timeFrame: Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10 and 24 hours post dose on Day 22 of Cycle 1
measure: Dose Escalation- Multiple Dose: Predose Concentration (Cmin) for Talazoparib
timeFrame: Pre dose on Day 22 of Cycle 1
measure: Dose Escalation- Multiple Dose: Time for Maximum Observed Plasma Concentration at Steady State (Tss,Max) for Talazoparib
timeFrame: Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10 and 24 hours post dose on Day 22 of Cycle 1
measure: Dose Escalation- Multiple Dose: Area Under the Curve From Time Zero to Time Tau at Steady State (AUCss,Tau) for Talazoparib
timeFrame: Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10 and 24 hours post dose on Day 22 of Cycle 1
measure: Dose Escalation- Multiple Dose: Apparent Oral Clearance of Talazoparib at Steady State (CL/Fss)
timeFrame: Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10 and 24 hours post dose on Day 22 of Cycle 1
measure: Dose Escalation- Multiple Dose: Accumulation Ratio (Rac) of AUCtau for Talazoparib
timeFrame: 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
measure: Dose Escalation- Multiple Dose: Linearity Ratio (Rss) of AUC for Talazoparib
timeFrame: 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
measure: Dose Escalation: Percentage of Participants With Objective Response (OR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
timeFrame: From start of the treatment until disease progression or death (due to any cause) whichever occurred first (maximum duration: up to 286 days)
measure: Dose Escalation: Progression Free Survival (PFS)
timeFrame: From day of first dose until disease progression or death (due to any cause) whichever occur first (maximum duration: up to 286 days)
measure: Dose Escalation: Duration of Response (DOR)
timeFrame: 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)
measure: 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)
timeFrame: From start of the treatment until disease progression or death (due to any cause) whichever occurred first (maximum duration: up to 502 days)
measure: Dose Expansion: Percentage of Participants With Confirmed Disease Control as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Investigator Assessment
timeFrame: Baseline up to Week 16, Baseline up to Week 24
measure: 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)
timeFrame: Baseline up to Week 16, Baseline up to Week 24
measure: Dose Expansion: Time-to-Tumor Response (TTR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Investigator Assessment
timeFrame: From first dose of study drug until first documentation of CR or PR (maximum duration: up to 502 days)
measure: 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)
timeFrame: From first dose of study drug until first documentation of CR or PR (maximum duration: up to 502 days)
measure: Dose Expansion: Duration of Response (DOR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Investigator Assessment
timeFrame: 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)
measure: Dose Expansion: Duration of Response (DOR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Blinded Independent Central Review (BICR)
timeFrame: 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)
measure: Dose Expansion: Progression Free Survival (PFS) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Investigator Assessment
timeFrame: From day of first dose until disease progression or death (due to any cause) whichever occur first (maximum duration: up to 502 days)
measure: Dose Expansion: Progression Free Survival (PFS) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Blinded Independent Central Review (BICR)
timeFrame: From day of first dose until disease progression or death (due to any cause) whichever occur first (maximum duration: up to 502 days)
measure: Dose Expansion: Overall Survival (OS): Probability of Participants Who Were Event-Free at Month 12
timeFrame: At Month 12
measure: Dose Expansion: Trough Concentrations (Ctrough) of Talazoparib
timeFrame: 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)
Other outcomes:
Locations:
city: Nagoya
country: Japan
facility: Aichi Cancer Center Hospital
state: Aichi
city: Kashiwa
country: Japan
facility: National Cancer Center Hospital East
state: Chiba
city: Sapporo
country: Japan
facility: National Hospital Organization Hokkaido Cancer Center
state: Hokkaido
city: Yokohama
country: Japan
facility: Kanagawa Cancer Center
state: Kanagawa
city: Kitaadachi-gun
country: Japan
facility: Saitama Cancer Center
state: Saitama
city: Chuo-Ku
country: Japan
facility: National Cancer Center Hospital
state: Tokyo
city: Kagoshima
country: Japan
facility: Hakuaikai Medical Corporation Sagara Hospital
city: Osaka
country: Japan
facility: National Hospital Organization Osaka National Hospital
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: Kotani H, Masuda N, Yamashita T, Naito Y, Taira T, Inoue K, Takahashi M, Yonemori K, Toyoizumi S, Mori Y, Nagasawa T, Hori N, Iwata H. Efficacy and safety of talazoparib in Japanese patients with germline BRCA-mutated locally advanced or metastatic breast cancer: results of the phase 1 dose-expansion study. Breast Cancer. 2022 Nov;29(6):1088-1098. doi: 10.1007/s12282-022-01390-w. Epub 2022 Jul 30.
citation: Naito Y, Kuboki Y, Ikeda M, Harano K, Matsubara N, Toyoizumi S, Mori Y, Hori N, Nagasawa T, Kogawa T. Safety, pharmacokinetics, and preliminary efficacy of the PARP inhibitor talazoparib in Japanese patients with advanced solid tumors: phase 1 study. Invest New Drugs. 2021 Dec;39(6):1568-1576. doi: 10.1007/s10637-021-01120-7. Epub 2021 Jun 23.