An Early Phase 1 Study of ABT-888 in Combination With Carboplatin and Paclitaxel in Patients With Hepatic or Renal Dysfunction and Solid Tumors
The poly (ADP-ribose) polymerase (PARP) family of enzymes is critical for maintaining
genomic stability by regulating a variety of DNA repair mechanisms. The
carboplatin/paclitaxel combination has demonstrated a wide spectrum of clinical antitumor
activity, making it an ideal platform for evaluation with novel agents, such as the PARP
To determine the pharmacokinetics and pharmacodynamics of ABT-888 in patients with varying
degrees of renal or hepatic dysfunction.
To determine the maximum tolerated dose (MTD) of ABT-888 in combination with carboplatin and
paclitaxel for patients with varying degrees of liver or kidney dysfunction.
To provide dosing recommendations for ABT-888 in combination with carboplatin and paclitaxel
based on degree of hepatic and renal impairment.
To define the dose-limiting toxicity and other toxicities associated with the use of this
combination in patients with varying degrees of renal or hepatic dysfunction.
To evaluate the pharmacokinetic parameters of ABT-888, carboplatin and paclitaxel when
administered as a combination in patients with varying degrees of renal or hepatic
To evaluate the pharmacodynamic measurement of PAR and platinum adducts in peripheral blood
mononuclear cells (PBMC) and tumor cells associated with the use of this combination
in patients with varying degrees of renal or hepatic dysfunction.
Patients must have histologically confirmed malignancy that is metastatic or unresectable,
for which standard curative or palliative measures do not exist or are no longer effective,
and for which there is expectation of response to the combination of carboplatin/paclitaxel
(e.g., lung, ovarian, breast, and melanoma).
Patients must have adequate bone marrow function.
Patients with normal organ function, patients with all degrees of renal dysfunction, and
patients with mild to severe hepatic dysfunction are allowed.
ABT-888 (80 mg) will be given orally on day -6 ( 1 day) of cycle 1 in all cohorts. ABT-888
in varying doses will then be given on days 1-7 of each cycle, with the dose depending on
each patient's degree of renal or hepatic dysfunction.
Fixed doses of chemotherapy will be given intravenously on day 3 of each cycle. For patients
with renal dysfunction, carboplatin will be given at AUC of 6 and paclitaxel at 175 mg/m2.
For patients with hepatic dysfunction, carboplatin will be given at AUC of 6 and paclitaxel
at doses adjusted to each patient's degree of hepatic dysfunction.
The dose of ABT-888 will be escalated to determine the MTD of the combination.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine the pharmacokinetics and pharmacodynamics of ABT-888 in patients with varying degrees of renal or hepatic dysfunction. To determine the MTD of ABT-888 with carboplatin and paclitaxel in these patients.
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|
|University of Pittsburgh Cancer Center||Pittsburgh, Pennsylvania 15232|