A PHASE-I STUDY OF INTERMITTENT INFUSION CLADRIBINE IN PATIENTS WITH SOLID TUMORS

Background. Cladribine (2-CdA, 2-chlorodeoxyadenosine), a chlorinated adenosine analog, is active in the treatment of hairy cell leukemia an d other hematologic malignancies, but its use in treating solid tumors is still under investigation, as is the optimal schedule for administ ering 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, an d bone marrow function. Methods. Cladribine was given as a 1-hour inte rmittent infusion, repeated daily for 5 days, with a cycle length of 2 8 days. The initial dose was 4 mg/m(2), with escalating doses by cohor t. Three dosage levels (4, 6, and 8 mg/m(2)/day) were explored, and pa tients were observed to determine toxicity. The end points of the stud y were the definition of the maximally tolerated dose (MTD), toxicity profile, and establishment of a recommended Phase II dose (RPTD) for c ladribine. Results. Eighteen patients were treated; the majority were patients with non-small. cell lung cancer and colorectal cancer. The m edian Cycle-1 leukocyte nadirs for the 4, 6, and 8 mg/m(2)/day dosage levels were 3100, 2300, and 950 cells/mu l (range 800-3500), respectiv ely, and the mean nadir absolute neutrophil counts were 1500, 936, and 482 cells/mu l (range 130-2241), respectively. Minimal thrombocytopen ia was seen, and no evidence for cumulative myelosuppression was obser ved. Two patients were hospitalized for neutropenic fevers, both of wh om received the 6 mg/m(2)/day dose. One patient who received the 4 mg/ m(2)/day dose had a transient episode of blindness that occurred durin g the infusion on Day 3 of Cycle 3. Thorough evaluation of this proble m did not reveal an etiology, and it did not recur with further admini stration of cladribine. No other significant nonhematologic toxicity h as been noted. No responses were observed. Conclusions, At the MTD (8 mg/m(2)/day), the dose-limiting toxicity of this agent is myelosuppres sion. The RPTD for further testing of this schedule is 6 mg/m(2) daily X 5 days.