Talazoparib for the Treatment of BRCA 1/2 Mutant Metastatic Breast Cancer
Talazoparib for the Treatment of BRCA 1/2 Mutant Metastatic Breast Cancer
This phase II trial studies how well talazoparib works for the treatment of breast cancer with a BRCA 1 or BRCA 2 gene mutation that has spread to other places in the body (metastatic). 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 that help repair deoxyribonucleic acid (DNA) mutations. PARP inhibitors, such as talazoparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. 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 tumor cells. Tumor cells may be killed by a study drug, like talazoparib, that stops the normal activity of PARPs. Talazoparib may be effective in the treatment of metastatic breast cancer with BRCA1 or BRCA2 mutations.
Breast
Phase II
Adults
Mol. targeted/Immunotherapy/Biologics
Talazoparib
Abramson, Vandana
National
Vanderbilt University
04-18-2023
Eligibility
18 Years
BOTH
NO
Inclusion Criteria:
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) or by a CLIA certified tumor tissue genotyping assay performed on a metastatic breast cancer specimen (including but not restricted to MGH-Snapshot assay, Foundation One, Caris). 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
>= 18 years of age on day of signing informed consent
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)
Measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 15 mL/min (within 10 days prior to treatment initiation)
Serum total bilirubin = 1.5 X institutional upper limit of normal (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
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 subjects 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)
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) or by a CLIA certified tumor tissue genotyping assay performed on a metastatic breast cancer specimen (including but not restricted to MGH-Snapshot assay, Foundation One, Caris). 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
>= 18 years of age on day of signing informed consent
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)
Measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 15 mL/min (within 10 days prior to treatment initiation)
Serum total bilirubin = 1.5 X institutional upper limit of normal (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
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 subjects 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)
