Patient case: 64-year-old female with ovarian cancer; genetic feature: BRCA1

Clinical trial: Neoadjuvant Talazoparib for Patients With a BRCA Deleterious Mutation

Summary: The goal of this clinical research study is to learn if talazoparib can help to control breast cancer that has a BRCA mutation (genetic change). The safety of talazoparib will also be studied.
  This is an investigational study. Talazoparib is not FDA-approved or commercially available. It is currently being used for research purposes only. The study doctor can explain how the study drug is designed to work.
  Up to 20 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed description: Main Study:
  Study Drug Administration:
  Each study cycle is 28 days.
  If you are found to be eligible to take part in this study, you will take talazoparib capsules by mouth 1 time each day at about the same time every morning. While it is not required, if you have a caregiver, you should advise them to wear gloves when handling the talazoparib capsules.
  You will be given a study drug diary to write down what time you take talazoparib and if you miss or vomit any doses. You will return your completed study drug diary and study drug bottles with any unused study drug to each study visit. While it is not required, if you have a caregiver, you should advise them to wear gloves when handling the talazoparib capsules.
  If you have side effects, the study doctor may decide to lower your study drug dose or have you stop taking the drug. You may be able to restart the study drug at the same or a lower dose. The study doctor will discuss this with you.
  On the days that you have study visits, you will take your dose of study drug at the clinic. Do not take your dose of study drug at home on these days.
  Study Visits:
  On Day 1 of all cycles:
  -  You will have a physical exam.
  -  Blood (about 1 tablespoon) will be drawn for routine tests.
  Every week, blood (about 1 tablespoon) will be drawn for routine tests. If the study doctor approves it, you may not have to return to the clinic on Days 8 and 15 of Cycle 2. You may have these blood draws done at a local laboratory and have the results sent to the study doctor. Your study doctor will discuss this with you.
  On Days 1, 8, and 22 of Cycle 1, blood (about 1-2 tablespoons) will be drawn for biomarker, PGt, and proteomic testing. Biomarkers are found in the blood and tissue and may be related to your reaction to the study drug.
  On Day 1 of Cycle 2,you will have an ultrasound of your breast(s) to check the status of the disease.
  Within 7 days before completing treatment with talazoparib:
  -  Blood (about 1-2 tablespoons) will be drawn for biomarker, PGt, and proteomic testing.
  -  You will have a core biopsy and an image-guided FNA to check the status of the disease and for biomarker, PGt, and proteomic testing.
  After your last dose of Cycle 2:
  -  You will have a physical exam.
  -  Blood (about 1 tablespoon) will be drawn for routine tests.
  -  You will have an ultrasound of your breast(s) to check the status of the disease.
  After Cycle 2, you will receive chemotherapy and/or have surgery to remove the tumor as part of the standard of care for the disease. You will be given a separate consent form that describes this procedure and its risks. During the surgery, some of the tissue that is removed will be collected to check the status of the disease and for biomarker, PGt, and proteomic testing. After the surgery, you may be called by the study doctor to ask how you are doing. This call should last about 10 minutes.
  Cell lines will be created using your collected tissue. Cell lines are blood or tissue cells that are grown in a laboratory or in research animals.
  Xenograft models will be created using your collected tissue. A xenograft is taking a graft of tissue from one donor and transplanting it into another. For this study, we will take a graft of your tissue and transplant it into a mouse to help us better understand BRCA mutations.
  After surgery, you will receive chemotherapy as part of the standard of care for the disease.
  Length of Treatment:
  You will receive up to 2 cycles of study drug.You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.
  If you stop taking the study drug because the disease got worse, you will have an image-guided core biopsy and FNA performed for biomarker testing, including genetic biomarkers, proteomic testing, and PGt testing. This will be performed before you start any new chemotherapy treatments as part of your standard care.
  Your participation on the study will be over after the surgery.
  Expansion Cohort:
  Study Visits:
  Each study cycle is 28 days.
  If you are found to be eligible to take part in this study, you will take talazoparib capsules by mouth 1 time each day at about the same time every morning. While it is not required, if you have a caregiver, you should advise them to wear gloves when handling the talazoparib capsules.
  You will be given a study drug diary to write down what time you take talazoparib and if you miss or vomit any doses. You will return your completed study drug diary and study drug bottles with any unused study drug to each study visit.
  If you have side effects, the study doctor may decide to lower your study drug dose or have you stop taking the drug. You may be able to restart the study drug at the same or a lower dose. The study doctor will discuss this with you.
  On the days that you have study visits, you will take your dose of study drug at the clinic. Do not take your dose of study drug at home on these days.
  Study Visits:
  On Day 1 of all cycles:
  -  You will have a physical exam
  -  Blood (about 1 tablespoon) will be drawn for routine tests.
  On Days 1 and 15 of Cycle 1 only, blood (about 1 tablespoon) will be drawn for routine tests. You may have these blood draws done at a local laboratory and have the results sent to the study doctor. Your study doctor will discuss this with you.
  On Day 1 of Cycle 1 and Cycle 3 only, blood (about 1-2 tablespoons) will be drawn for biomarker, PGt, and proteomic testing. Biomarkers are found in the blood and tissue and may be related to your reaction to the study drug.
  On Day 1 of Cycle 3 and Day 1 of Cycle 5, you will have an ultrasound of your breast(s) to check the status of the disease.
  After receiving study drug for up to 6 cycles, you will have surgery to remove the tumor as part of the standard of care for the disease. You will be given a separate consent form that describes this procedure and its risks. During the surgery, some of the tissue that is removed will be collected to check the status of the disease and for biomarker, PGt, and proteomic testing. After the surgery, you may be called by the study doctor to ask how you are doing. This call should last about 10 minutes.
  Cell lines will be created using your collected tissue. Cell lines are blood or tissue cells that are grown in a laboratory or in research animals.
  Xenograft models will be created using your collected tissue. A xenograft is taking a graft of tissue from one donor and transplanting it into another. For this study, we will take a graft of your tissue and transplant it into a mouse to help us better understand BRCA mutations.
  After surgery, you will receive chemotherapy as part of the standard of care for the disease.
  Length of Treatment:
  You will receive up to 6 cycles of study drug.You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.
  If you stop taking the study drug because the disease got worse, you will have an image-guided core biopsy and FNA performed for biomarker testing, including genetic biomarkers, proteomic testing, and PGt testing. This will be performed before you start any new chemotherapy treatments as part of your standard care.
  Your participation on the study will be over after the surgery.

Eligibility: Inclusion Criteria:
  1. Signed written informed consent
  2. Histologically confirmed primary invasive adenocarcinoma of the breast with the size of the primary tumor being at least 1 cm on imaging by either mammography, ultrasound or breast MRI
  3. Negative HER-2/neu- disease defined as patients with FISH ratio <2.0 or <6.0 HER2 gene copies per nucleus, and IHC staining scores of 0, 1+, or 2+.
  4. No treatment for current primary invasive adenocarcinoma of the breast such as irradiation, chemotherapy, immunotherapy, investigational therapy or surgery. Previous treatment for breast an/or ovarian cancer with chemotherapy, endocrine therapy, surgery and radiation are allowed if >/=3 years prior to current diagnosis and there is no clinical evidence of metastatic disease.
  5. ECOG performance status of 0-1
  6. Baseline MUGA or echocardiogram scans with LVEF of > 50%.
  7. Patient must have adequate organ function as determined by the following laboratory values: a. ANC>/=1,500 /uL b. Platelets >/=100,000 / uL c. Hgb >/= 9 g/dL d. Creatinine clearance >50 ml/min e. Total bilirubin </= 1.5 X ULN f. ALT and AST < 2.5 X ULN
  8. Men or women 18 years of age or older.
  9. Negative serum or urine pregnancy test for women within 7 days of receiving the first dose of the study medication for women of childbearing potential. Women will be considered not of childbearing potential and exempt from pregnancy testing if they are either a) older than 50 and amenorrheic for at least 12 consecutive months following cessation of all exogenous hormonal treatments, or b) have documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy, but not tubal ligation.
  10. Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 8 weeks after the last dose of investigational product. Men on study also must be using contraception.
  11. Identified deleterious mutation in BRCA 1 or 2 genes ( this does not include variants of uncertain significance).
  12. Eligible to receive standard of care chemotherapy and/or surgery based upon standard practices or institutional guidelines.
  Exclusion Criteria:
  1. Women who are pregnant (including positive pregnancy test at enrollment or prior to study drug administration) or breast-feeding.
  2. Disease free of prior malignancy for < 3 years with the exception of curatively treated basal carcinoma of the skin or carcinoma in situ of the cervix.
  3. Any other previous antitumor therapies for the current cancer event.
  4. Has had major surgery within 21 days before Cycle 1 Day 1
  5. Gastrointestinal tract disease or defect with associated malabsorption syndrome
  6. Uncontrolled inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)
  7. Myocardial infarction within 6 months before starting therapy, symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or unstable cardiac arrhythmia requiring medication
  8. Serious intercurrent infections or non-malignant medical illness that are uncontrolled or the control of which may be jeopardized by this therapy
  9. Psychiatric disorders or other conditions rendering the subject incapable of complying with the requirements of the protocols
  10. Unable to take oral medications
  11. Known to be human immunodeficiency virus positive
  12. Known active hepatitis C virus, or known active hepatitis B virus
  13. 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) v4.03 or requiring the use of parenteral anti-microbial agents within 14 days before Day 1 of study drug • Clinically significant bleeding diathesis or coagulopathy, including known platelet function disorders • Non-healing wound, ulcer, or bone fracture
  14. Known hypersensitivity to any of the components of talazoparib

Relevance to patient case: not relevant