Chronic oral administration of CI-994: A phase 1 study

Objectives: CI-994 (N-acetyl dinaline, PD 123654) is a novel oral agent act ive in a broad variety of murine and human tumor xenografts. While cytotoxi c in the Brown Norway (BN) rat leukemia model, growth inhibition in other m urine and human tumor xenografts is predominantly cytostatic. Its specific mechanism of action remains unknown. Following CI-994 administration, inhib ition of both histone deacetylation and cellular proliferation at the G1 to S transition phase of the cell cycle are observed. This Phase 1 study in p atients with solid tumors was carried out to determine a maximum tolerated daily oral dose (MTD) for CI-994 administered on a chronic basis. Methods: Fifty-three patients received CI-994 daily for treatment durations ranging from 2 to 10 weeks. Dosage escalation proceeded in 2 phases; an Acute Dosin g Phase (n = 11) to define the MTD for CI-994 administered over 2 weeks and a Chronic Dosing Phase (n = 29) to define the MTD for daily administration for 8 weeks. Upon completion of the Chronic Dosing Phase, a third cohort o f patients (n = 13) received CI-994 at the recommended Phase 2 dose and sch edule with 2 additional single doses of drug administered separated by a 1- week washout to assess the effect of food on CI-994 pharmacokinetics. Resul ts: Thrombocytopenia was dose limiting at the MTD of 8 mg/m(2)/day for 8 we eks. Other toxicities included fatigue and gastrointestinal effects such as nausea, vomiting, diarrhea, constipation and mucositis. Pharmacokinetic st udies revealed that peak plasma levels and AUC's generally increased with d ose and that food intake did not affect the rate or extent of drug absorpti on. One patient with heavily pre-treated adenocarcinoma of the lung achieve d a Partial Response (PR) lasting over 2 years and 3 additional patients ac hieved Stable Disease (SD), 1 each with non-small cell lung, colorectal, an d renal cancer. Conclusions: The recommended Phase 2 starting dose is 8 mg/ m(2)/day for 8 weeks repeated after a 2-week drug-free interval.