Patient case: 73-year-old female with breast cancer; genetic feature: CDKN2A

Clinical trial: Pilot Trial of BMN 673, an Oral PARP Inhibitor, in Patients With Advanced Solid Tumors and Deleterious BRCA Mutations

Summary: Background:
  -  The poly (ADP-ribose) polymerase (PARP) family of enzymes is critical for maintaining genomic stability by regulating a variety of DNA damage repair mechanisms.
  -  BMN 673 is a PARP inhibitor with greater in vitro activity than any other PARP inhibitor currently in development. BMN 673 has been shown to cause single-agent synthetic lethality in BRCA1/2- and PTEN-deficient cell lines, and has potent antitumor activity in animal models of tumors harboring mutations in DNA repair pathways.
  -  BMN 673 is showing promising single-agent activity in patients with advanced ovarian and breast cancer harboring deleterious BRCA mutations.
  -  This pilot study will evaluate the pharmacodynamic effects of BMN 673 on DNA damage and apoptosis markers in tumor biopsy tissue.
  Primary Objective:
  -Determine the pharmacodynamic effect of BMN 673 in tumor biopsies from patients with advanced ovarian, breast, or other solid tumor and deleterious BRCA mutations.
  Secondary Objectives:
  -  Determine the response rate (CR + PR) of treatment with BMN 673 in patients with advanced ovarian or primary peritoneal carcinoma and deleterious BRCA mutations.
  -  Determine the response rate (CR + PR) of treatment with BMN 673 in patients with advanced breast carcinoma and deleterious BRCA mutations.
  -  Determine the response rate (CR + PR) of treatment with BMN 673 in patients with advanced solid tumor (other than breast or ovarian) and deleterious BRCA mutations.
  Eligibility:
  -  Adult patients with documented deleterious BRCA 1 or 2 mutations with histologically confirmed ovarian, primary peritoneal, breast, prostate, pancreas, gastric or other solid tumor whose disease has progressed following at least one standard therapy or who have no acceptable standard treatment options.
  -  No major surgery, radiation, or chemotherapy within 4 weeks prior to study enrollment, and recovered from toxicities of prior therapies to at least eligibility levels.
  -  Age greater than or equal to 18 years of age; ECOG performance status less than equal to 2
  -  Adequate organ function.
  -  Willingness to undergo tumor biopsies.
  Study Design:
  -  BMN 673 will be administered orally each day in 28-day cycles.
  -  Dosing will be at the established recommended Phase II dose of 1000 mcg/day each day for
  28 days.
  -  We plan to accrue a total of 12 evaluable patients per cohort for a total of 36 patients. To allow for some patients who will not be evaluable, the accrual ceiling is 42 patients.
  -  Tumor biopsies will be mandatory at baseline (pre-dose), and then approximately 3-6 hours post BMN 673 on day 8. An optional tumor biopsy may also be collected at time of disease progression.
  SCHEMA
  -  BMN 673 is administered orally each day in 28-day cycles
  -  Tumor biopsies will be performed at baseline (pre-treatment) and 3-6 hrs post dose on cycle 1 day 8. An optional tumor biopsy may also be collected at time of disease progression. Tumor biopsies will be evaluated for PAR levels, DNA damage response markers such as >=H2AX, cleaved caspase 3, ERCC1, pNbs1, XPF, RAD51, and pT1989ATR, and, as indicators of ATR/ATM activation, chk1 and chk2
  -  Blood samples for CTC analyses will be collected at baseline (pre-treatment), on cycle 1 day 1(3-6 hours post dose), on cycle 1 day 8 (3-6 hours post dose), and on cycle 2 day 1 (3-6 hours post dose)
  -  Blood samples for PK analysis will be collected on cycle 1 day 1 pre-dose and 0.5, 1, 2, 3, 4, 6,8, and 24 hours post-dose, on cycle 1 day 8 (3-6 hours post dose), and on cycle 2 day 1 predose and 3-6 hours post dose.

Detailed description: Background:
  -  The poly (ADP-ribose) polymerase (PARP) family of enzymes is critical for maintaining genomic stability by regulating a variety of DNA damage repair mechanisms.
  -  BMN 673 is a PARP inhibitor with greater in vitro activity than any other PARP inhibitor currently in development. BMN 673 has been shown to cause single-agent synthetic lethality in BRCA1/2- and PTEN-deficient cell lines, and has potent antitumor activity in animal models of tumors harboring mutations in DNA repair pathways.
  -  BMN 673 is showing promising single-agent activity in patients with advanced ovarian and breast cancer harboring deleterious BRCA mutations.
  -  This pilot study will evaluate the pharmacodynamic effects of BMN 673 on DNA damage and apoptosis markers in tumor biopsy tissue.
  Primary Objective:
  -Determine the pharmacodynamic effect of BMN 673 in tumor biopsies from patients with advanced ovarian, breast, or other solid tumor and deleterious BRCA mutations.
  Secondary Objectives:
  -  Determine the response rate (CR + PR) of treatment with BMN 673 in patients with advanced ovarian or primary peritoneal carcinoma and deleterious BRCA mutations.
  -  Determine the response rate (CR + PR) of treatment with BMN 673 in patients with advanced breast carcinoma and deleterious BRCA mutations.
  -  Determine the response rate (CR + PR) of treatment with BMN 673 in patients with advanced solid tumor (other than breast or ovarian) and deleterious BRCA mutations.
  Eligibility:
  -  Adult patients with documented deleterious BRCA 1 or 2 mutations with histologically confirmed ovarian, primary peritoneal, breast, prostate, pancreas, gastric or other solid tumor whose disease has progressed following at least one standard therapy or who have no acceptable standard treatment options.
  -  No major surgery, radiation, or chemotherapy within 4 weeks prior to study enrollment, and recovered from toxicities of prior therapies to at least eligibility levels.
  -  Age greater than or equal to 18 years of age; ECOG performance status less than equal to 2
  -  Adequate organ function.
  -  Willingness to undergo tumor biopsies.
  Study Design:
  -  BMN 673 will be administered orally each day in 28-day cycles.
  -  Dosing will be at the established recommended Phase II dose of 1000 g/day each day for
  28 days.
  -  We plan to accrue a total of 12 evaluable patients per cohort for a total of 36 patients. To allow for some patients who will not be evaluable, the accrual ceiling is 42 patients.
  -  Tumor biopsies will be mandatory at baseline (pre-dose), and then approximately 3-6 hours post BMN 673 on day 8. An optional tumor biopsy may also be collected at time of disease progression.
  SCHEMA
  -  BMN 673 is administered orally each day in 28-day cycles
  -  Tumor biopsies will be performed at baseline (pre-treatment) and 3-6 hrs post dose on cycle 1 day 8. An optional tumor biopsy may also be collected at time of disease progression. Tumor biopsies will be evaluated for PAR levels, DNA damage response markers such as >=H2AX, cleaved caspase 3, ERCC1, pNbs1, XPF, RAD51, and pT1989ATR, and, as indicators of ATR/ATM activation, chk1 and chk2
  -  Blood samples for CTC analyses will be collected at baseline (pre-treatment), on cycle 1 day 1(3-6 hours post dose), on cycle 1 day 8 (3-6 hours post dose), and on cycle 2 day 1 (3-6 hours post dose, plus/minus 3 days for scheduling conflicts), on day 1 of every subsequent cycle before drug administration (day 1 of every 3 cycles for patients on study for more than 12 months), and at time of disease progression.
  -  Blood samples for PK analysis will be collected on cycle 1 day 1 pre-dose and 0.5, 1, 2, 3, 4, 6,8, and 24 hours post-dose, on cycle 1 day 8 (3-6 hours post dose), and on cycle 2 day 1 predose and 3-6 hours post dose.

Eligibility: -  INCLUSION CRITERIA:
  Adult patients with documented deleterious BRCA 1 or 2 mutations with histologically confirmed ovarian, primary peritoneal, breast, prostate, pancreas, gastric or other solid tumor whose disease has progressed following at least one standard therapy or who have no acceptable standard treatment options.
  Patients should be either platinum-naive or should have received platinum-based therapy at least 6 months or greater prior to the time of enrollment; patients who received platinum as part of adjuvant therapy should not have had recurrent disease within 6 months of completing adjuvant therapy.
  Patients with metastatic disease must have received at least one line of standard of care (SOC) treatment for metastatic disease prior to enrollment
  -  Age greater than or equal to 18 years of age.
  -  ECOG performance status less than or equal to 2
  -  Life expectancy of greater than 3 months.
  -  Patients must have normal organ and marrow function as defined below:
  -  leukocytes greater than or equal to 3,000/mcL
  -  absolute neutrophil count greater than or equal to 1,500/mcL
  -  platelets greater than or equal to 100,000/mcL
  -  total bilirubin less than or equal to 1.5 times institutional upper limit of normal
  -  AST(SGOT)/ALT(SGPT) less than or equal to 3 times institutional upper limit of normal
  -  creatinine less than or equal to 1.5 times institutional upper limit of normal
  OR
  -creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with creatinine levels above institutional normal.
  The effects of BMN 673 on the developing human fetus are unknown. For this reason and because PARP inhibitors are known to be teratogenic, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 30 days after completing study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for 3 months after completion of BMN 673 administration.
  -  Patients must be able to swallow whole tablets or capsules. Nasogastric or G-tube administration is not allowed. Any gastrointestinal disease which would impair ability to swallow, retain, or absorb drug is not allowed.
  -  Ability to understand and the willingness to sign a written informed consent document.
  -  Patients with HER2-positive advanced breast cancer or ovarian cancer should have received at least two lines of systemic therapy in the advanced setting.
  EXCLUSION CRITERIA:
  -  Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. Patients who have had prior treatment with any PARP inhibitors are ineligible.
  -  Patients who are receiving any other investigational agents.
  -  Patients with known active brain metastases or carcinomatous meningitis are excluded from this clinical trial. Patients whose brain metastatic disease status has remained stable for greater than or equal to 4 weeks following treatment of brain metastases are eligible to participate at the discretion of the principal investigator.
  -  Eligibility of subjects receiving any medications or substances with the potential to affect the activity or pharmacokinetics of BMN 673 will be determined following review by the principal investigator.
  -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  -  Pregnant women are excluded from this study because the effects of the study drugs on the developing fetus are unknown.
  -  HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with BMN 673. In addition, these patients are at increased risk of lethal infections when treated with marrow suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
  -  Patients who require use of coumarin-derivative anticoagulants such as warfarin are excluded. Low molecular weight heparin is permitted for prophylactic or therapeutic use. Low-dose warfarin (less than or equal to 1 mg/day) is permitted.
  -  Women who are currently lactating

Relevance to patient case: not relevant