A phase I study of intermittent infusion cladribine in patients with solid tumors

Cladribine (2-CdA, 2-chlorodeoxyadenosine), a chlorinated adenosine analog, is active in the treatment of hairy cell leukemia and other hematologic malignancies, but its use in treating solid tumors is still under investigation, as is the optimal schedule for administering this drug. The authors conducted a dose-finding study to define the maximal tolerated dose and toxicities of this agent when given to patients with refractory solid tumors having normal renal, hepatic, and bone marrow function.

Cladribine was given as a 1-hour intermittent infusion, repeated daily for 5 days, with a cycle length of 28 days. The initial dose was 4 mg/m2, with escalating doses by cohort. Three dosage levels (4, 6, and 8 mg/m2/day) were explored, and patients were observed to determine toxicity. The end points of the study were the definition of the maximally tolerated dose (MTD), toxicity profile, and establishment of a recommended Phase II dose (RPTD) for cladribine.

Eighteen patients were treated; the majority were patients with non-small cell lung cancer and colorectal cancer. The median Cycle-1 leukocyte nadirs for the 4, 6, and 8 mg/m2/day dosage levels were 3100, 2300, and 950 cells/microliters (range 800-3500), respectively, and the and 950 cells/microliters (range 800-3500), respectively, and the mean nadir absolute neutrophil counts were 1500, 936, and 482 cells/microliters (range 130-2241), respectively. Minimal thrombocytopenia was seen, and no evidence for cumulative myelosuppression was observed. Two patients were hospitalized for neutropenic fevers, both of whom received the 6 mg/m2/day dose. One patient who received the 4 mg/m2/day dose had a transient episode of blindness that occurred during the infusion on Day 3 of Cycle 3. Thorough evaluation of this problem did not reveal an etiology, and it did not recur with further administration of cladribine. No other significant nonhematologic toxicity has been noted. No responses were observed.

At the MTD (8 mg/m2/day), the dose-limiting toxicity of this agent is myelosuppression. The RPTD for further testing of this schedule is 6 mg/m2 daily x 5 days.