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Phase I Study of 506U78 Administered on a Consecutive 5-Day Schedule in Children and Adults With Refractory Hematologic Malignancies

From the Duke University Medical Center, Durham; GlaxoSmithKline, Research Triangle Park; University of North Carolina, Chapel Hill, NC; Boston University Medical Center, Boston, MA; M.D. Anderson Cancer Center, Houston, TX; and Ohio Northern University, Ada, OH

Address reprint requests to Joanne Kurtzberg, MD, Professor of Pediatrics, Box 3350, Duke University Medical Center, Durham, NC 27710; e-mail: kurtz001{at}mc.duke.edu

PURPOSE: A phase I study was conducted to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacokinetics of a novel purine nucleoside, nelarabine, a soluble prodrug of 9-beta-D-arabinosylguanine (araG; Nelarabine), in pediatric and adult patients with refractory hematologic malignancies.

PATIENTS AND METHODS: Between April 1994 and April 1997, 93 patients with refractory hematologic malignancies were treated with one to 16 cycles of study drug. Nelarabine was administered daily, as a 1-hour intravenous infusion for 5 consecutive days, every 21 to 28 days. First-cycle pharmacokinetic data, including plasma nelarabine and araG levels, were obtained on all patients treated. Intracellular phosphorylation of araG was studied in samples of leukemic blasts from selected patients.

RESULTS: The MTDs were defined at 60 mg/kg/dose and 40 mg/kg/dose daily x 5 days in children and adults, respectively. Dose-limiting toxicity (DLT) was neurologic in both children and adults. Myelosuppression and other significant organ toxicities did not occur. Pharmacokinetic parameters were similar in children and adults. Accumulation of araGTP in leukemic blasts was correlated with cytotoxic activity. The overall response rate was 31%. Major responses were seen in patients with T-cell malignancies, with 54% of patients with T-lineage acute lymphoblastic leukemia achieving a complete or partial response after one to two courses of drug.

CONCLUSION: Nelarabine is a novel nucleoside with significant cytotoxic activity against malignant T cells. DLT is neurologic. Phase II and III trials in patients with T-cell malignancies are encouraged.

Supported by grants Nos. CA32839 and CA57629 from the National Cancer Institute.

Presented in part in Kisor et al¹⁸ and Gandhi et al.¹⁷

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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