AZD2281 Plus Carboplatin to Treat Breast and Ovarian Cancer
Condition: Breast Cancer; Ovarian Cancer
MeSH terms: Breast Neoplasms; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Hereditary Breast and Ovarian Cancer Syndrome
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

        -  Carboplatin is approved by the Food and Drug Administration to treat cancer.

        -  AZD2281 is an experimental drug in a class of agents called PARP inhibitors. PARP is a
           protein that is -involved in repairing DNA damage; PARP inhibitors interfere with that
           process.

      Objectives:

        -  To determine the optimum doses of AZD2281 and carboplatin that can safely be used in
           patients with breast and ovarian cancer.

        -  To evaluate the response of the tumor to the drug combination and determine the side
           effects of the treatment.

      Eligibility:

      -Patients 18 years of age or older with breast or ovarian cancer who have a family history of
      cancer or who have a BRCA1 or BRCA2 mutation.

      Design:

        -  In this dose escalation study, the first small group of patients receives the smallest
           study doses of AZD2281 and carboplatin. Subsequent groups receive incrementally higher
           doses of first AZD2281 and then carboplatin as long as the preceding group has not
           experienced unacceptable side effects. When the highest safe dose is determined,
           additional patients receive that dose.

        -  Patients receive treatment in 21-day cycles as follows: AZD2281 by mouth twice a day
           every day; carboplatin thorough a vein on day 8 of each cycle. Treatment may continue
           until it is no longer beneficial.

        -  Evaluations during treatment include the following:

        -  Physical examination 1 week after starting treatment and then every 3 weeks.

        -  Blood tests weekly for the first 4 weeks of treatment and then every 3 weeks.

        -  CT scans or other imaging tests such as ultrasound or MRI every 6 weeks to evaluate the
           tumor.
    

Detailed description: 
      Background:

      AZD2281 (KU-0059436) is an oral PARP-1 and PART-2 inhibitor that affects tumor growth by
      impairing the ability of the cell to repair damaged DNA. Carboplatin causes covalent
      cross-linking of DNA with stalled replication forks that would usually be repaired through
      nucleotide excision repair and homologous recombination (HR).

      Sporadic breast (triple negative) and ovarian cancers have been shown to exhibit a BRCA1-like
      phenotype.

      BRCA1/2 proteins have a critical function in the homologous DNA repair pathway. BRCA1/2
      mutation carriers are at high risk for breast and ovarian cancer, and increased risk of
      pancreatic cancer and prostate cancer. Mutation carriers have been shown to have increased
      susceptibility to DNA damaging agents, such as the platinums.

      BRCA1/2 deficient cells have been shown to be sensitive to PARP inhibition alone and in
      combination with DNA damaging agents.

      Combining these two agents in a background of impaired HR in BRCA1/2 mutation potitive
      malignancies may result in synergistic anti-tumor effect.

      Objectives:

      Determine the safety and toxicity of the combination of AZD2281 and carboplatin in
      BRCA1/2-associated or familial recurrent breast and ovarian cancer patients (cohort 1, Group
      A), non-high risk serous ovarian cancer patients (Group B), and non-high risk triple negative
      breast cancer patients (Group C).

      Determine pharmacodynamics, estimates of biochemical changes in the apoptosis and PARP signal
      transduction pathways in tumor and stromal cells in response to treatment of an expansion
      cohort (cohort 2) at the MTD in a pilot fashion.

      Eligibility:

      Adults with breast or ovarian CA that is metastatic or unresectable and for which standard
      curativetherapies do not exist or are no longer effective.

      Documented deleterious BRCA1/2 mutation or a BRCAPRO score of greater than or equal to 30%.

      Non-high risk serous ovarian cancer (negative family history, BRCAPRO score of less than or
      equal to 20% or negative BRCA1/2 mutation test).

      Documented ER negative, PR negative, Her2neu negative breast cancer (negative family history
      and/or BRCAPRO score less than or equal to 10% (or negative BRCA1/2 mutation test).

      Patients must be off prior chemotherapy, radiation therapy, hormonal therapy, or biological
      therapy for at least 4 weeks.

      All patients enrolling in cohort 2 must have at least one lesion amenable to biopsy.

      ECOG performance status 0-2 and adequate organ and marrow function.

      Design:

      Patients will receive AZD2281 for days 1-7 of each 21 day cycle to maximize PARP inhibition
      with carboplatin administration on day 2. Carboplatin will then be administered q3weeks and
      with continuation AZD2281 BID on days 1-7 of each 21 day cycle.

      AZD2281 or carboplatin will be escalated sequentially in Cohort 1 (Groups A, B, and C), and
      after the maximum tolerated dose is determined, Cohort 2 will be enrolled for assessment of
      translational endpoints.

      Patients will be evaluated for toxicity in clinic every 3 weeks and every other cycle for
      response using RECIST criteria. The clinic visit will be changed to every 4 weeks when
      patients continue to stay on the study longer than two years with no or minimal disease.
      Imaging studies will be obtained every 3 cycles for patients who stay on the study longer
      than four years. The clinic visit will be changed to every two months (+/- 7 days) and the
      imaging studies will be obtained every four months (+/- 7 days) for patients who stay on the
      study longer than five years.

      Tumor biopsies and plasma and serum samples will be obtained from patients in Cohort 2 before
      treatment (biopsy mandatory), prior to treatment on cycle 2, day 1, and at time of disease
      progression (biopsies optional). Tumor biopsies (optional) will also be taken from "super
      responders" in Cohort 1 who have had a durable response longer than two years.

      A minimum of 84 and a maximum of 101 patients will be needed to achieve the objectives of the
      trial.
    

Intervention name(s): AZ2281 + Carboplatin
Intervention type(s): Drug
Intervention description(s): Cohort 1: Dose escalation: AZD2281 po bid qd + IV carboplatin D8 of each 21-day cycle.; Cohort 2: Expanded cohort treated at the MTD of the combination identified in Cohort 1.
Intervention MeSH terms: Carboplatin
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Genetic; BRCA; Ovarian Cancer, sporadic epithelial ovarian cancer; Breast Cancer, triple negative breast cancer; Metastatic; Breast Cancer; Ovarian Cancer