This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of an investigational drug to learn whether the drug works in treating a
specific disease. "Investigational" means that the drug is being studied.
The U.S. Food and Drug Administration (FDA) has not approved talazoparib for the
participants' specific disease but it has been approved for metastatic breast cancer with a
germline (inherited) BRCA mutation.
Talazoparib is a study drug that inhibits (stops) the normal activity of certain proteins
called "poly (ADP-ribose) polymerases" also called "PARPs". PARPs are proteins (made from
genes which are part of your DNA) that are found in all normal and cancer cells that are
involved in the repair of DNA. PARPs are needed to repair mistakes that can happen in DNA
when cells divide. If the mistakes are not repaired, the defective cell will usually die and
be replaced. Cells with mistakes in their DNA that do not die can become cancer cells. Cancer
cells may be killed by a study drug, like talazoparib, that stops the normal activity of
PARPs. In clinical trials, the use of talazoparib and other PARP inhibitors have shown that
these drugs can reduce tumor size and slow tumor growth in some cancer patients with BRCA1 or
BRCA2 mutations.
In this research study, the investigators are examining how effective talazoparib is in
patients with metastatic breast cancer with a BRCA mutation in their tumor.
Inclusion Criteria:
- Metastatic breast cancer with deleterious somatic BRCA 1 or 2 mutations detectable by
cell-free circulating tumor DNA, by 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 ER < 1%, PR < 1%, HER2 negative, as per
ASCO 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.
-≥ 18 years of age on day of signing informed consent.
- ECOG performance status of ≤2.
- Adequate organ function as defined in Table 1 within 10 days prior to treatment
initiation.
- Adequate Organ Function Laboratory Values
- SYSTEM LABORATORY VALUE
- Hematological
- Absolute neutrophil count (ANC) ≥1,500 /mcL
- Platelets ≥100,000 / mcL
- Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7
days of assessment)
- Renal
--Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be
used in place of creatinine or CrCl) ≤1.5 X institutional upper limit of normal (ULN)
OR ≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN
- Hepatic
- Serum total bilirubin ≤ 1.5 X institutional ULN OR Direct bilirubin ≤
institutional ULN for subjects with total bilirubin levels > 1.5 ULN
- AST (SGOT) and ALT (SGPT) ≤ 2.5 X institutional ULN OR ≤ 5 X institutional ULN
for subjects with liver metastases
- Prior 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.
Exclusion Criteria:
- 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).
