Purpose: To determine maximum tolerated dose of CI-994, a novel oral histone deacetylase inhibitor, in combination with carboplatin and paclitaxel in patients with advanced solid tumors.
Patients and methods: Patients with advanced solid tumors who had received two or fewer prior chemotherapy regimens were eligible for trial. Five cohorts of patients were treated with escalating doses (4-6 mg/m2) and alternative schedules (7 days or 14 days) of CI-994. Dose escalation of paclitaxel was performed to achieve tolerability of CI-994 with a paclitaxel dose of 225 mg/m2 when administered in combination with carboplatin. Pharmacokinetic assessment of CI-994 was performed by using liquid chromatography/mass spectrometry. Histone deacetylation inhibition was determined by Western blot analysis.
Results: A total of 30 patients (median age 58 years) were entered into five treatment cohorts. Maximum tolerated dose of CI-994 was determined to be 4 mg/m2 administered for 7 consecutive days following paclitaxel at a dose of 225 mg/m2 and carboplatin at an area under the curve (AUC) of 6 every 21 days. Neutropenia, thrombocytopenia, and grade 3 respiratory insufficiency limited further dose escalation of CI-994. Pharmacokinetics showed that CI-994 absorption and disposition were unaffected by carboplatin and paclitaxel coadministration. Association between histone H3 acetylation levels and disease response was suggested. A subset of patients with lymphocyte H3 acetylation levels at least 1.5-fold times baseline all achieved either a clinical response or stable disease. All evaluable patients with progressive disease (PD) had H3 acetylation levels <1.5-fold times baseline. Twenty-four of the 30 patients received greater than one cycle of treatment. Five of these patients achieved a partial response (3 nonsmall cell lung cancer, 1 colorectal cancer, and 1 unknown primary) and 2 patients achieved a complete response (esophageal and bladder cancer).
Conclusion: The combination of CI-994 at a dose of 4 mg/m2 administered orally for 7 consecutive days can be safely coadministered with paclitaxel at a dose of 225 mg/m2 and carboplatin at an AUC of 6 on day 1 of a 21-day cycle. Evidence of antitumor activity is suggested and may correlate with histone modulation.