A Phase I Combination Study of AZD2281 and Cisplatin Plus Gemcitabine in Adults With Solid Tumors
- Poly (ADP-ribose) polymerase-enzyme (PARP-1) recognizes and rapidly binds to DNA
single- and double-strand breaks and has been shown to participate in other DNA-related
functions, including gene amplification, cell division, differentiation, apoptosis, and
DNA base-excision repair.
- Increased PARP activity is one of the mechanisms by which tumor cells avoid apoptosis
caused by DNA damaging agents, and drug resistance has been linked to higher
expressions of PARP in cancer cells. This differential expression of PARP supports the
observed selectivity of PARP inhibitors to affect proliferating tumor cells. AZD2281 is
an orally administered potent inhibitor of PARP-1 and PARP-2, and its combination with
cisplatin and gemcitabine may overcome some of the resistance associated with these
- Establish the safety, tolerability, and maximum tolerated dose (MTD) of AZD2281 in
combination with cisplatin and gemcitabine in patients with solid tumors.
- Evaluate the effect of cisplatin-gemcitabine, with or without AZD2281, on PAR and
gamma- H2AX levels in tumor biopsies and peripheral blood mononuclear cells (PBMCs)
pre- and post-treatment.
- Evaluate the pharmacokinetics (PK) of AZD2281 with and without cisplatin and gemcitabine.
- Patients (greater than or equal to 18 years) must have histologically confirmed solid
tumor malignancy that is metastatic or unresectable for which standard curative
measures do not exist, or are associated with minimal patient survival benefit.
- Patients who have previously received cisplatin or gemcitabine, or both, are eligible.
- Cycle 1 and subsequent cycles: AZD2281 will be administered orally every 12 hours (Q 12
hours) on day 1, while gemcitabine will be administered intravenously (IV) over 1 hour
(600 mg/m(2)/hour) on day 1 and 8 of each cycle and cisplatin over 1 hour on day 1
- Dose escalation will proceed in cohorts of 3-6 patients to a minimum of 27 and a
maximum of 42 patients.
- Patients will have a maximum of six cycles of treatment.
- Tumor biopsies will be collected in cycle 1 only, while blood for PBMC samples will be
collected in cycle 1 and before drug administration, 24 and 48 hours post
administration, in cycle 2, day 1. If Dose Level 3 is achieved additional time points
will be collected in cycle 1, day 8 - before drug administration, 6, 24 and 48 hours
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Establish the safety and tolerability of AZD2281 in combination with cisplatin and gemcitabine in patients with solid tumors. Establish the maximum tolerated dose (MTD) for the combination of AZD2281 with cisplation and gemcitabine.
Steven A Rosenberg, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|