A Phase I Study With an Expansion Cohort of the PARP Inhibitor AZD2281 Combined With Carboplatin in BRCA1/2 Familial Breast and Ovarian Cancer and Sporadic Triple Negative Breast and Ovarian Cancer
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
BRCA1/2 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.
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
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.
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
Patients will be evaluated for toxicity in clinic every 3 weeks and every 6 weeks for
response using RECIST criteria.
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).
A minimum of 84 and a maximum of 101 patients will be needed to achieve the objectives of
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Determine the safety and toxicity of the combination of AZ2281 (KU-0059436) and carboplatin in BRCA 1/2-associated recurrent breast and ovarian cancer patients
Elise C Kohn, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|