A Pharmacokinetic/Pharmacodynamic Study With a Phase I Run-In With a PARP Inhibitor (Olaparib) in Combination With Carboplatin for Refractory or Recurrent Women's Cancers
- Olaparib (AZD2281) is an oral PARP-1/2 inhibitor (PARPi) that affects tumors by
impairing repair of single stranded DNA and causing double strand breaks. Carboplatin
covalently crosslinks DNA causing stalled replication forks repaired through nucleotide
excision repair and homologous recombination (HR).
- There is no published data on sequence-specificity of PARPi with platinums. Our
preclinical data indicate sequence may be important in growth inhibition and DNA damage
- We have demonstrated activity and safety with concomitant administration of olaparib
- We hypothesize that elucidation of sequence specificity may improve upon that clinical
benefit by optimizing drug administration and potentially safety.
- To determine safe dose of olaparib tablet with carboplatin.
- To estimate the pharmacokinetic (PK) and pharmacodynamic (PD) effects of two schedules
of olaparib and carboplatin using peripheral blood mononuclear cells (PBMCs).
- To determine the schedule-associated safety of olaparib and carboplatin in women's
- Adult women with recurrent/refractory epithelial ovarian cancer, fallopian, primary
peritoneal, uterine papillary serous cancer, or malignant mixed mullerian tumors, or
recurrent/refractory breast cancer that is metastatic or unresectable and for which
standard therapies do not exist or are no longer effective. BRCA1/2 mutation carriers
will be eligible with any metastatic disease.
- Patients must be off prior chemotherapy, radiation therapy, hormonal therapy, or
biological therapy for at least 4 weeks.
- ECOG performance status 0-2 and adequate organ and marrow function.
- A phase I 3 plus 3 safety run-in will optimize tablet olaparib dose (d1-7) in
combination with carboplatin on day 1. The carboplatin dose through the trial will be
- Subsequent accrual will randomize patients to one of 2 schedules on cycle 1 with the
other schedule on cycle 2. A: olaparib d1-7 > carbo d8; B: carbo d1 > olaparib d2-8.
- Cycle 3-8 will be schedule B. After 8 cycles of carboplatin, olaparib will be
administered alone on a daily basis.
- Research samples will be obtained for PD endpoints prior to and approximately 24 hours
after carboplatin infusion and prior to the 1st and 3rd of olaparib.
- Blood samples for olaparib PK will be obtained in all patients after the first dose of
olaparib in cycles 1 and 2.
- Patients will be evaluated for toxicity in clinic every 3 weeks and every two cycles
for response using RECIST criteria.
Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Determine the pharmacokinetics and pharmacodynamic effects of the sequence of administration of olaparib and carboplatin and the schedule-associated safety of the combination.
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|