Talazoparib in Treating Patients with BRCA1 and BRCA2 Wild-Type, Metastatic or Recurrent, Triple-Negative or HER2-Negative Breast Cancer or Other Solid Tumors
This phase II trial studies how well talazoparib works in treating patients with breast cancer (BRCA)1 and BRCA2 wild-type (lacking an inherited form of the BRCA1 or BRCA2 gene mutation), triple-negative (estrogen receptor-, progesterone receptor-, and HER2-negative) breast cancer or other solid tumors with faulty deoxyribonucleic acid repair mechanisms or HER2-negative breast cancer with evidence of a hereditary breast cancer syndrome or evidence of genetic changes in the tumor tissue that has come back (recurrent) or spread to other places in the body (metastatic). Talazoparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Inclusion Criteria
- Solid tumor by cohort as follows: * Cohort A: Tumor must be histologically confirmed triple negative breast cancer (estrogen receptor (ER) =< 5%; progesterone receptor (PR) =< 5%; AND HER2 negative via immunohistochemistry (IHC) or fluorescence in situ hybridization [FISH] per 2013 American Society of Clinical Oncology [ASCO]/College of American Pathologists [CAP] guidelines), with homologous recombination deficiency (HRD) score of >= 42 from a metastatic biopsy site. In the event that metastatic tumor biopsy is not feasible, the HRD score can be assessed from the primary breast biopsy. * Cohort B: Must be histologically confirmed metastatic or recurrent HER2 negative breast cancer (IHC or FISH per 2013 ASCO/CAP guidelines) or other histologically confirmed metastatic solid tumor. * Cohort B: Tumor must have a deleterious or suspected deleterious germline or somatic gene mutation implicated in the homologous recombination (HR) pathway (excluding BRCA1 or BRCA2), based on multiplex germline gene testing or direct tumor next generation DNA sequencing. The 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.
- No deleterious or suspected deleterious germline BRCA1 or BRCA2 gene mutation based on comprehensive testing including full sequencing and comprehensive rearrangement testing at an external reference laboratory. Patients with variants of unknown significance will be eligible significance will be eligible
- Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (computed tomographic [CT] chest abdomen pelvis [CAP] with contrast and bone scan or positron emission tomography (PET)/CT with intravenous (IV) contrast needed within 28 days of cycle 1 day 1. If patients have a history of brain metastases, a magnetic resonance imaging (MRI) brain or CT head with contrast is required.)
- 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 (e.g. carboplatin or cisplatin) or within 8 weeks of stopping platinum
- An 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 45 days after the last dose of study drug (hormonal contraception is not considered an acceptable method of contraception)
- If pre-menopausal, 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
- Availability of archival tumor tissue from primary breast cancer
- Adequate fresh or archival tumor tissue from metastatic biopsy site, if biopsy is technically feasible
Exclusion Criteria
- 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
- Any patient with a deleterious or suspected deleterious BRCA1 or BRCA2 gene mutation
- Prior treatment with a PARP inhibitor
- Pregnant or lactating
- Any anti-cancer therapy within the 21 days before the first day of treatment
- Prior progression on or within 8 weeks of the last dose of a platinum agent (ie, cisplatin or carboplatin) for recurrent or metastatic disease
- Brain or central nervous system (CNS) metastases OR leptomeningeal carcinomatosis * 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 allowed) 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
- Other malignancy that is either active or for which patient has received treatment in the last 5 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 (HIV)-positive
- Either known active hepatitis B or hepatitis C virus infection
- 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) version (v)5 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
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT02401347.
PRIMARY OBJECTIVES:
I. To determine whether single agent talazoparib produces better than expected responses in patients with advanced sporadic triple-negative breast cancer with homologous recombination deficiency as assessed by the homologous recombination deficiency (HRD) assay (Cohort A) and/or advanced HER2 negative (i.e. triple negative [TN] or estrogen receptor [ER]/progesterone receptor [PR] positive) breast cancer or other non-breast solid tumors with a germline or somatic mutation in the homologous recombination (HR) pathway, excluding BRCA1 or BRCA2 (Cohort B).
SECONDARY OBJECTIVES:
I. To determine clinical benefit rate (complete response, partial response or stable disease >= 24 weeks).
II. To determine progression-free survival in both cohorts.
III. To evaluate the safety of talazoparib in both patient populations.
CORRELATIVE OBJECTIVES:
I. To compare the rate of response in subjects with triple negative breast cancer (TNBC) with or without an underlying germline homologous recombination (HR) pathway mutation (Cohort A).
II. To compare the HRD scores in responders versus non-responders with underlying deleterious or suspected deleterious germline or somatic HR gene mutations (Cohort B).
III. To assess the concordance of the HRD scores in the primary tumor tissue with that in the metastatic tumor tissue.
IV. To assess in metastatic tumor biopsy samples, the RAD51 status of the tumor at baseline (absent or present) as a functional readout of HR capacity and correlate this with HRD and mutational status.
OUTLINE:
Patients receive talazoparib orally (PO) daily on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationStanford Cancer Institute Palo Alto
Principal InvestigatorMelinda L. Telli
- Primary IDBRS0050
- Secondary IDsNCI-2015-00036, 350
- ClinicalTrials.gov IDNCT02401347