Talazoparib for the Treatment of BRCA 1 / 2 Mutant Metastatic Breast Cancer
- Metastatic breast cancer with deleterious somatic BRCA 1 or 2 mutations detectable by cell-free circulating tumor DNA, by Clinical Laboratory Improvement Act (CLIA) certified clinical assay (including but not restricted to MGH-Snapshot cfDNA assay, Guardant360, Foundation One). The eligibility of a given assay and/or BRCA mutation could be discussed with the primary investigator (Dr. Vidula) and senior investigator (Dr. Bardia), who will provide the final discretion * Patients with germline BRCA 1 or 2 mutations will not be eligible * Patients with only a VUS (variant of unknown significance), or non-functional BRCA mutation, without a deleterious somatic BRCA 1 or 2 mutation will not be eligible
- The following disease subtypes are eligible: * Triple negative breast cancer (defined as estrogen receptor [ER] < 1%, progesterone receptor [PR] < 1%, HER2 negative, as per American Society of Clinical Oncology [ASCO] College of American Pathologists [CAP] guidelines), with disease progression on at least one prior chemotherapy regimen in the metastatic setting * Hormone receptor positive, HER2 negative disease with disease progression on at least one prior endocrine therapy in the metastatic setting or be considered inappropriate for endocrine therapy
- Patients must have evaluable or measurable disease
- Any number of prior lines of therapy are allowed
- Patients may have received prior platinum based chemotherapy (0-1 prior platinum based therapy). However, the patient must not have progressed while on platinum treatment (any setting), or within 6 months after end of treatment (neoadjuvant and/or adjuvant)
- At least two weeks from last systemic therapy for breast cancer, with recovery of all treatment related toxicity to grade 1 or less. Subjects with =< grade 2 neuropathy are an exception to this criterion
- At least two weeks from last radiation therapy, with recovery of all treatment related toxicity to grade 1 or less
- Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
- Absolute neutrophil count (ANC) >= 1,500 /mcL (within 10 days prior to treatment initiation)
- Platelets >= 100,000 / mcL (within 10 days prior to treatment initiation)
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment) (within 10 days prior to treatment initiation)
- Serum creatinine =< 1.5 X institutional upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (within 10 days prior to treatment initiation)
- Serum total bilirubin =< 1.5 X institutional ULN OR direct bilirubin =< institutional ULN for subjects with total bilirubin levels > 1.5 ULN (within 10 days prior to treatment initiation)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional ULN OR =< 5 X institutional ULN for subjects with liver metastases (within 10 days prior to treatment initiation)
- Prior central nervous system (CNS) disease is allowed if stable for at least one month since whole brain radiation therapy in patients who received whole brain radiation, or 2 weeks since stereotactic radiotherapy in patients who received stereotactic radiotherapy. Patients should not be requiring steroids. Patients whose CNS disease was surgically treated may be enrolled if stable for at least one month after surgery, and not requiring steroids
- Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
- Female subjects of childbearing potential must use an acceptable form of birth control per treating physician discretion or be surgically sterile, or abstain from heterosexual activity for the course of the study through 7 months after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
- Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 7 months after the last dose of study therapy. Additionally, male patients may not donate sperm during the duration of the study and through 7 months after the last dose of study therapy
- Willing and able to provide written informed consent
- Treatment with an investigational agent within 4 weeks of the first dose of treatment
- Patients must not have received prior treatment with a PARP inhibitor
- Patients must not have a germline BRCA 1 or 2 mutation
- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent. Note: Subjects with =< grade 2 neuropathy are an exception to this criterion * If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
- Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
- Has known, untreated central nervous system (CNS) metastases and/or carcinomatous meningitis
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 7 months after the last dose of trial treatment
- Has a known history of human immunodeficiency virus (HIV)
- Has known active hepatitis B or hepatitis C
- Patients should not be on strong P-glycoprotein inhibitors
- Patients should not be on any other anti-cancer therapy (chemotherapy, hormone therapy, immunotherapy, or alternate investigational therapy)
I. To evaluate the efficacy of talazoparib, as assessed by progression-free survival in patients with metastatic breast cancer harboring deleterious somatic BRCA 1 or 2 mutations, as detected by circulating cell-free deoxyribonucleic acid (cfDNA).
I. To evaluate the objective response rate (ORR) in patients with metastatic breast cancer and deleterious somatic BRCA 1 or 2 mutations treated with talazoparib.
II. To evaluate the safety/tolerability, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grading, in patients with metastatic breast cancer harboring deleterious somatic BRCA 1 or 2 mutations, as detected by cfDNA.
I. To prospectively monitor serial changes in BRCA mutant allelic fraction (MAF) by cfDNA in response to treatment with talazoparib, and correlate results with outcomes in patients with metastatic somatic BRCA cfDNA mutant breast cancer.
II. To assess the impact of pre-existing resistance mutations at baseline, particularly BRCA reversion mutations, based on pre-treatment cfDNA analysis, on clinical outcomes with talazoparib, in patients with somatic BRCA mutant metastatic breast cancer.
III. To compare paired pre-and post-treatment liquid biopsies, and to identify potential novel targets for future combination studies.
Patients receive talazoparib orally (PO) once daily (QD). Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, 90 days, then every 3 months up to 2 years.
Trial Phase Phase II
Trial Type Treatment
Dana-Farber Harvard Cancer Center
- Primary ID 19-188
- Secondary IDs NCI-2019-07732
- Clinicaltrials.gov ID NCT03990896