Phase II Trial of Talazoparib in BRCA1/2 Wild-type HER2-negative Breast Cancer and Other Solid Tumors

Sponsor

Melinda Telli (Other)

Overall Status

Recruiting

CT.gov ID

NCT02401347

Collaborator

BioMarin Pharmaceutical (Industry), Pfizer (Industry)

Enrollment

Location

Arms

100

Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The aim of this single-arm phase 2 clinical trial is to evaluate the anti-cancer activity of Talazoparib (also known as BMN 673) in patients with advanced breast cancer with specific genetic or tumor genomic alterations. Patients with either triple-negative or HER2-negative breast cancer are eligible.

Condition or Disease	Intervention/Treatment	Phase
Advanced Breast Cancer HER2/Neu Negative Triple-Negative Breast Cancer	Drug: Talazoparib Tosylate	Phase 2

Detailed Description

Talazoparib (BMN 673) is a novel, dual-mechanism PARP inhibitor that potently inhibits the PARP enzyme and effectively traps PARP on DNA. Talazoparib has shown promising single-agent anti-tumor efficacy in several BRCA1/2 mutation-associated advanced cancers. The efficacy of PARP inhibition in BRCA1/2 wild-type TNBC with homologous recombination (HR) defects and in breast tumors with mutations in other non-BRCA1/2 HR pathway genes is currently unknown.

This phase 2 trial explores the activity of single agent talazoparib in BRCA1/2 wild-type BC patients using an optimal Simon two-stage design. Eligible subjects will be assigned to one of two parallel cohorts: 1) Cohort A: Subjects (n=29) with advanced TNBC with underlying HR defects as assessed by the HRD assay and, 2) Cohort B: Subjects (n=29) with advanced HER2-negative BC with a somatic or germline mutation in a non-BRCA1/2 HR pathway gene. Gene mutations of interest are: PTEN, PALB2, CHEK2, ATM, NBN, BARD1, BRIP1, RAD50, RAD51C, RAD51D, MRE11, ATR, Fanconi anemia complementation group of genes (FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase II Clinical Trial of the PARP Inhibitor Talazoparib in BRCA1 and BRCA2 Wild Type Patients With Advanced Triple Negative Breast Cancer and Homologous Recombination Deficiency or Advanced HER2 Negative Breast Cancer or Other Solid Tumors With a Mutation in Homologous Recombination Pathway Genes

Study Start Date :

Aug 1, 2015

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Dec 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort A - Triple-negative Breast Cancer Participants with advanced triple-negative breast cancer (TNBC) with homologous recombination deficiency (HRD) based on the Myriad HRD Assay. Participants receive talazoparib 1 mg by mouth daily.	Drug: Talazoparib Tosylate Participants receive Talazoparib tosylate at 1 mg by mouth daily. Other Names: BMN 673
Experimental: Cohort B - HER2-negative solid tumor Participants with advanced HER2-negative solid tumor with a deleterious hereditary or cancer somatic mutation in one of the following genes: PTEN, PALB2, CHEK2, ATM, NBN, BARD1, BRIP1, RAD50, RAD51C, RAD51D, MRE11, ATR, Fanconi anemia complementation group of genes. Participants receive talazoparib 1 mg by mouth daily.	Drug: Talazoparib Tosylate Participants receive Talazoparib tosylate at 1 mg by mouth daily. Other Names: BMN 673

Arm

Intervention/Treatment

Experimental: Cohort A - Triple-negative Breast Cancer

Participants with advanced triple-negative breast cancer (TNBC) with homologous recombination deficiency (HRD) based on the Myriad HRD Assay. Participants receive talazoparib 1 mg by mouth daily.

Drug: Talazoparib Tosylate

Participants receive Talazoparib tosylate at 1 mg by mouth daily.

Other Names:

BMN 673

Experimental: Cohort B - HER2-negative solid tumor

Participants with advanced HER2-negative solid tumor with a deleterious hereditary or cancer somatic mutation in one of the following genes: PTEN, PALB2, CHEK2, ATM, NBN, BARD1, BRIP1, RAD50, RAD51C, RAD51D, MRE11, ATR, Fanconi anemia complementation group of genes. Participants receive talazoparib 1 mg by mouth daily.

Drug: Talazoparib Tosylate

Participants receive Talazoparib tosylate at 1 mg by mouth daily.

Other Names:

BMN 673

Outcome Measures

Primary Outcome Measures

Objective response rate (ORR) [Up to 3 years]
Objective response rate (ORR) will be assessed and is defined as complete response or partial response per RECIST 1.1

Secondary Outcome Measures

Clinical benefit rate [After at least 24 weeks]
Clinical benefit rate >= 24 weeks will be assessed and is defined as complete response, partial response or stable disease as assessed after at least 24 weeks per RECIST 1.1
Progression-free survival (PFS) [From randomization to documented disease progression or death]
Incidence of adverse events, graded according to CTCAE v4.0 [Up to 3 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

INCLUSION CRITERIA:

No deleterious germline BRCA1 or BRCA2 mutation based on full sequencing and comprehensive rearrangement testing at an external reference laboratory; patients with variants of unknown significance will be eligible
Measurable disease per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1
Must have progressed on at least 1 prior chemotherapy regimen for the treatment of advanced breast cancer; there is no upper limit on the number of prior therapies
If prior platinum agent (eg, carboplatin or cisplatin) has been administered, no evidence of progression, or within 8 weeks of stopping platinum treatment
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN); if liver function abnormalities are due to hepatic metastasis, then AST and ALT ≤ 5 x ULN
Total serum bilirubin ≤ 1.5 x ULN (≤ 3 x ULN for Gilbert's syndrome)
Calculated creatinine clearance ≥ 30 mL/min or serum creatinine ≤ 1.5 mg/dL
Hemoglobin ≥ 9.0 g/dL with last transfusion at least 14 days before day 1 of study drug
Absolute neutrophil count (ANC) ≥ 1500/mm^3
Platelet count ≥ 100,000/mm^3
Able to take oral medications
Willing and able to provide written, signed informed consent after the nature of the study has been explained, and prior to any research-related procedures
Sexually active patients of childbearing potential must be willing to use an acceptable method of contraception such as an intrauterine device or double barrier contraception during treatment and for 30 days after the last dose of study drug
Females of childbearing potential must have a negative serum pregnancy test at screening and be willing to have additional serum pregnancy tests during the study; females considered not of childbearing potential include those who have been in menopause at least 2 years, or had tubal ligation at least 1 year prior to screening, or who have had total hysterectomy
Willing and able to comply with all study procedures
COHORT A SPECIFIC ELIGIBILITY CRITERIA:
Histologically-confirmed metastatic or recurrent triple-negative breast cancer (defined as estrogen receptor ≤ 5%, progesterone receptor ≤ 5%, HER2-negative via immunohistochemistry [IHC] or fluorescent in situ hybridization [FISH])
An homologous recombination deficiency (HRD) score ≥ 42 on the HRD Assay as assessed on a tumor biopsy sample; in the case that obtaining an adequate metastatic tumor biopsy is not possible, we will assess the HRD score from the primary breast tumor
COHORT B SPECIFIC ELIGIBILITY CRITERIA:
Histologically-confirmed metastatic or recurrent HER2-negative (via IHC or FISH) breast cancer or other histologically-confirmed metastatic solid tumor
Deleterious germline or somatic mutation implicated in the homologous recombination (HR) pathway, excluding BRCA1 or BRCA2, based on germline multiplex gene testing or direct tumor next generation DNA sequencing. Genes of interest include: PTEN, PALB2, CHEK2, ATM, NBN, BARD1, BRIP1, RAD50, Rad51c, Rad51d, MRE11, ATR, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL, plus other HR-related genes at the discretion of the primary investigators.

EXCLUSION CRITERIA:

Any patient with a deleterious mutation in BRCA1 or BRCA2
Hormone receptor positive and/or HER2 positive breast cancer (Cohort A only)
HER2 positive breast cancer (Cohort B only)
Prior treatment with a PARP inhibitor
Non-measurable disease only
Pregnant or nursing patients
Any anti-cancer therapy within the past 21 days of the first day of treatment
Brain or central nervous system (CNS) metastases
Exception: Adequately treated brain metastases documented by baseline computed tomography (CT) or magnetic resonance imaging (MRI) scan that have not progressed since previous scans and do not require corticosteroids (except prednisone ≤ 5 mg/day or equivalent) for management of CNS symptoms. A repeated CT or MRI following the identification of CNS metastases (obtained at least 2 weeks after definitive therapy) must document adequately treated brain metastases
Subjects with leptomeningeal carcinomatosis are not permitted
Other malignancy that is either active or for which patient has received treatment in the last five years excluding non-melanoma skin cancer and carcinoma in situ of the cervix
Radiation therapy in the last 14 days
Known to be human immunodeficiency virus positive
Known active hepatitis C virus
Known active hepatitis B virus
Use of any investigational product or investigational medical device within 28 days before day 1 of study drug
Major surgery requiring a prolonged hospitalization or recovery within 21 days before day 1 of study drug
Concurrent disease or condition that would interfere with study participation or safety, such as any of the following:
Active, clinically significant infection either grade > 2 by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 or requiring the use of parenteral anti-microbial agents within 7 days before day 1 of study drug
Clinically significant bleeding diathesis or coagulopathy, including known platelet function disorders
Known hypersensitivity to any of the components of BMN 673