A Phase I Study With an Expansion Cohort of the PARP Inhibitor AZD2281 (KU-0059436) Combined With Carboplatin in Breast and Ovarian Cancer in BRCA1/2 Mutation Carriers (Familial Breast and Ovarian Cancer) and Sporadic Triple Negative Breast Cancer and Ovarian Cancer
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Enrollment
- 103
- Locations
- 1
- Primary Endpoint
- Safety/Toxicity
Study Overview
Brief 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.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 100 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
Arm 1
Standard dose escalation
Intervention: AZ2281 + Carboplatin (Drug)
Arm 2
Expanded cohort
Intervention: AZ2281 + Carboplatin (Drug)
Outcomes
Primary Outcomes
Safety/Toxicity
Time Frame: End of treatment
Determine the safety and toxicity of the combination of AZD2281 (KU- 0059436) and carboplatin in recurrent BRCA1/2-associated or familial breast and ovarian cancer patients, in recurrent low genetic risk serous ovarian cancer patients, and in recurrent low genetic risk triple negative breast cancer patients.
Secondary Outcomes
- Assess clinical activity of the combination; Determine biochemical changes in the poly(ADP-ribose) polymerase (PARP) and H2AX activity in mononuclear cells and in tumor in response to treatment(End of treatment)