Phase I Study of Continuous-Infusion Nelarabine in Patients with Advanced Lymphoid Malignancies

Abstract 4239

Nelarabine is a prodrug of arabinosylguanine (ara-G), a cytotoxic nucleoside analogue that targets T-cells. In vitro investigations and clinical trials in pediatric and adult patients (pt) demonstrated activity in T-cell acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (T-LBL) resulting in FDA approval for the treatment of refractory or relapsed T-ALL/T-LBL. The schedule of drug infusion was daily × 5 or on days 1, 3, 5 with an infusion-duration of two hours. While this bolus infusion was clinically effective, the dose-limiting toxicity was neurotoxicity: which can manifest as somnolence, seizures, paralysis, or most commonly chronic peripheral neuropathy. Based on experience with similar nucleoside analogues such as cytarabine, we hypothesized that neurotoxicity with nelarabine could be dosing schedule-related and a continuous infusion (C.I.), rather than bolus, may mitigate this toxicity. A phase I trial was designed to determine the safety, pharmacokinetics (PK), and maximum tolerated dose (MTD) of nelarabine given as a C.I. for 5 days. We report the preliminary results of clinical efficacy and PK and pharmacodynamics (PD) from a dose-escalation study of C.I. nelarabine. Four dose levels are planned, starting at 200mg/m²/d for 5 days (d) on a 28 d cycle, escalating according to the classic 3+3 design (200, 300, 400, and 500 mg/m²/d). The starting dose (200 mg/m²/d × 5 d) is 22% of the recommended bolus-infusion dose (1500 mg/m²/d on days 1, 3, 5 of a 21 d cycle). Six pts (1 female) have been enrolled thus far with a median age of 29 (range 24–70 yrs). Five pts (83%) had a diagnosis of relapsed T-ALL, and 1 had relapsed T-prolymphocytic leukemia (PLL). The median number of prior therapies is 1 (1–3). All 6 patients were treated at the first dose level (including 3 in an expansion cohort) and all patients received at least one course of therapy. Five patients are evaluable for toxicity and response after completion of cycle 1. Overall, the infusion was well tolerated with no infusion reactions. All patients experienced myelosuppression. Most non-hematologic toxicities were grade 1 or 2 in severity: 1 occurrence of grade 1 respiratory distress, and 1 grade 1 neuropathy. One patient was admitted for neutropenic fever, sepsis, and grade 3 renal dysfunction related to sepsis. One patient developed grade 3 peripheral neuropathy, which was defined as a dose limiting toxicity. At this starting dose level, 2 patients with T-ALL had stable disease, 1 had a partial response, and 1 had a complete response for an overall response rate of 40% (2/5). The patient with T-PLL had progressive disease. The 2 patients with T-ALL who achieved a response were both able to go onto allogeneic stem cell transplant. Plasma pharmacokinetics of nelarabine and steady-state ara-G are being analyzed. Cellular pharmacokinetics data (n = 5) suggest that the triphosphate of ara-G (ara-GTP) increased for 2–3 days without reaching a steady-state level. Ara-GTP accumulation in leukemia cells continued throughout the 6-day infusion in 3 patients. The C_max concentration of ara-GTP was 109 uM (range 58 – 205 μ M). In conclusion, preliminary evaluation of continuous-infusion nelarabine suggests that the safety profile is acceptable for the selected patient population. Clinical activity has been observed at a low dose with C.I., and additional pts are needed to be evaluated to establish utility of this schedule. Continued dose escalation is planned.