A Phase II Clinical Trial of the PARP Inhibitor Talazoparib in BRCA1 and BRCA2 Wild-Type Patients

The Talazoparib Beyond BRCA (TBB), a phase II proof-of-concept clinical trial, was designed to test the efficacy of talazoparib, a potent, orally bioavailable PARP inhibitor, with an established Phase II recommended dose, in the treatment of advanced BRCA wildtype (WT), HER2-negative breast cancer and other solid tumors with homologous recombination (HR) deficiency. Eligible patients had advanced HER2-negative breast cancer or other solid tumors with a germline or somatic mutation in a gene linked to the HR pathway. Patients identified as harboring a deleterious or suspected deleterious germline or somatic mutation in the HR pathway were treated with single agent talazoparib until disease progression. Primary and metastatic tumor samples were sequenced with panel sequencing and exome sequencing to detect commonly mutated genes and those associated with DNA repair deficiency. In addition, ctDNA was sequenced at baseline and progression. Fastq files for tumor and ctDNA sequencing are deposited. ]]>
Inclusion Criteria

Individuals (men and women) aged 18 years or older
No deleterious or suspected 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.
Patients must have measurable disease per RECIST 1.1
Must have progressed on at least 1 prior systemic therapy regimen for the treatment of advanced breast or other non-breast metastatic cancer. There is no upper limit on the number of prior therapies.
No evidence of progression on a platinum agent (eg. carboplatin or cisplatin) or within 8 weeks of stopping platinum
An ECOG performance status of 0-2
Adequate organ function as defined below:

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/mm3
Platelet count ≥ 100,000/mm3

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 45 days after the last dose of study drug (hormonal contraception is not allowed)
Females of childbearing potential must have a negative urine pregnancy test at screening and be willing to have additional urine 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 B Specific Eligibility Criteria

Histologically confirmed metastatic or recurrent HER2-negative (via IHC or FISH per ASCO/CAP guidelines 2013) breast cancer or histologically confirmed metastatic solid tumor
Deleterious or suspected deleterious germline or somatic gene mutation implicated in the HR pathway, excluding BRCA1 or BRCA2, based on multiplex germline gene testing or direct tumor next generation DNA sequencing. These genes include: 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), plus other HR-related genes at the discretion of the primary investigators.
At least 10 HER2-negative breast cancer patients will be enrolled in this cohort

Exclusion Criteria

Any patient with a deleterious mutation in BRCA1 or BRCA2
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
Prior progression on or within 8 weeks of the last dose of a platinum agent (i.e. cisplatin or carboplatin) for recurrent or metastatic disease
Brain or CNS metastases

Exception: Adequately treated brain metastases documented by baseline CT or 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, or known active hepatitis B virus
Use of any investigational product (IP) 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) v4.0 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 talazoparib

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This investigator-initiated phase II clinical trial enrolled patients at Stanford Women’s Cancer Center from August 2015 to December 2018 (Trial Registration ID: NCT02401347). The study adhered to good clinical practice guidelines, as well as applicable laws and regulations, and in accordance with the Declaration of Helsinki. The trial was approved by the Stanford Institutional Review Board. All patients provided written informed consent prior to enrollment. The trial was designed by the academic authors as an independent sponsored research agreement supported by BioMarin Pharmaceutical Inc., Medivation and Pfizer, Inc. The cohort B study enrolled in 2 stages: 10 subjects were enrolled, then if at least 2 responses were observed, an additional 10 subjects were enrolled. Cohort A opened later, and accrual is ongoing, with results to be reported separately.]]>