A phase I study of 7-t-butyldimethylsilyl-10-hydroxycamptothecin in adult patients with refractory or metastatic solid malignancies

Abstract

Purpose: 7-t-Butyldimethylsilyl-10-hydroxycamptothecin (AR-67) is a novel third generation camptothecin selected for development based on the blood stability of its pharmacologically active lactone form and its high potency in preclinical models. Here, we report the initial phase I experience with i.v. AR-67 in adults with refractory solid tumors. EXPERIMENTAL DESIGN AND METHODS: AR-67 was infused over 1 hour daily five times, every 21 days, using an accelerated titration trial design. Plasma was collected on the 1st and 4th day of cycle 1 to determine pharmacokinetic parameters.

Results: Twenty-six patients were treated at nine dosage levels (1.2-12.4 mg/m(2)/d). Dose-limiting toxicities were observed in five patients and consisted of grade 4 febrile neutropenia, grade 3 fatigue, and grade 4 thrombocytopenia. Common toxicities included leukopenia (23%), thrombocytopenia (15.4%), fatigue (15.4%), neutropenia (11.5%), and anemia (11.5%). No diarrhea was observed. The maximum tolerated dosage was 7.5 mg/m(2)/d. The lactone form was the predominant species in plasma (>87% of area under the plasma concentration-time curve) at all dosages. No drug accumulation was observed on day 4. Clearance was constant with increasing dosage and hematologic toxicities correlated with exposure (P < 0.001). A prolonged partial response was observed in one subject with non-small cell lung cancer. Stable disease was noted in patients with small cell lung cancer, non-small cell lung cancer, and duodenal cancer.

Conclusions: AR-67 is a novel, blood-stable camptothecin with a predictable toxicity profile and linear pharmacokinetics. The recommended phase II dosage is 7.5 mg/m(2)/d five times every 21 days.

Figure 1

Pharmacokinetic analysis. (A) Mean plasma concentration-time profiles of total AR-67 in the MTD cohort (n=7). (B) The mean percent lactone in plasma at each time point for all patients. (C) Correlation plot of total and lactone AUC. (D) Relationship of administered AR-67 dosage with clearance. Solid lines in panels C and D represent linear regression lines.

Figure 2

Pharmacodynamic analysis of neutropenia and thrombocytopenia during cycle 1 in all patients. Percent decrease from baseline as a result of (A) increasing dosage level and (B) AUC (day 1 of cycle 1). Lines represent fit of a sigmoid Emax model to the data. (C) Logistic regression analysis demonstrating the probabilities of manifesting neutropenia and thrombocytopenia with increasing AR-67 exposure. The gray area encompasses the range of AR-67 AUC achieved at the MTD during day 1 of cycle 1.