A phase I study of pemetrexed in patients with relapsed or refractory acute leukemia

Abstract

Purpose: To investigate the toxicity profile, activity, pharmacokinetics, and pharmacodynamics of pemetrexed in leukemia.

Patients and methods: Patients with refractory or relapsed acute leukemia were eligible. A phase I 3+3 design was implemented. Pemetrexed was infused intravenously (IV) over 25 min with vitamin supplementation. Courses were repeated every 3 to 4 weeks according to toxicity and efficacy. The starting dose of 900 mg/m² was escalated by approximately 33% until the dose-limiting toxicity (DLT) was determined.

Results: Twenty patients with acute myeloid (AML) or lymphocytic (ALL) leukemia received therapy. The main non-hematologic adverse event was liver dysfunction at several dose levels, including 2 DLTs at 3,600 mg/m². One patient with ALL (3,600 mg/m² dose level) achieved a partial response. Pemetrexed pharmacokinetics were linear with escalated dosing. Elevated plasma deoxyuridine was observed in a subset of patients following pemetrexed infusion, but was not correlated with dose levels. Changes in the nucleotide pools of circulating mononuclear cells were observed, but were variable.

Conclusions: The recommended phase II dose of pemetrexed for future leukemia studies is 2,700 mg/m(2) IV over 25 min every 3 to 4 weeks with vitamin supplementation. Deoxyuridine levels did not increase with increasing pemetrexed dose, suggesting pemetrexed inhibition of thymidylate synthase (TS) may be saturated by the 900 mg/m² dose level. However, no firm conclusion can be made regarding TS saturation in tumor cells. While tolerable, pemetrexed monotherapy had limited activity in this highly refractory population. Exploration of pemetrexed in combination with other active agents in leukemia is a reasonable future endeavor.

Fig. 1

Dose-normalized pemetrexed plasma concentration versus time from dose after administration of pemetrexed 900, 1,500, 2,000, 2,700, or 3,600 mg/m². Twelve patients were included in the PK analysis. Pemetrexed PK evaluations used a 3-compartment model in non-linear mixed effects modeling (NONMEM). Estimates of pemetrexed systemic clearance (CL) and volume of distribution at steadystate (V_ss) based on this model for a “typical patient” (mean CrCL_{CG, std} [114 mL/min] and mean BSA [1.92 m²]) are 72 mL/min and 17 L, respectively)

Fig. 2

Correlation of pharmacokinetics/pharmacodynamics in Patient 100 (900 mg/m²). One patient was treated with a single dose of pemetrexed and blood was drawn at the indicated time points. Plasma pemetrexed, plasma deoxyuridine, and total intracellular pemetrexed (mononuclear cells) were determined as described in Methods. Shown are analyte concentration (plasma pemetrexed, intracellular pemetrexed, and plasma deoxyuridine) versus time following pemetrexed infusion

Fig. 3

Examples of cellular pharmacodynamics data. Three patients were treated with a single dose of pemetrexed (Panels a–b, 900 mg/m² or Panel c, 1,500 mg/m²) and blood was collected at the indicated time points. Panels a–b, Mononuclear cells were isolated and intracellular TTP and dGTP were extracted and measured as described in Methods. Panel c, Mononuclear cells were isolated and incorporation of radiolabelled deoxycytidine into mononuclear cell DNA was determined as described in Methods. Panels a–b, Shown are TTP and dGTP concentrations (uM) versus time following pemetrexed infusion; Panel c, Shown is the change of the amount of ³H-deoxycytidine taken up by mononuclear cells following pemetrexed administration expressed as percent of pretreatment value

Fig. 4

Pemetrexed pharmacodynamics analysis (representative samples). Four patients were treated with a single dose of pemetrexed (Panel a, 900 mg/m²; Panel b, 1,500 mg/m²; Panel c, 2,000 mg/m²; Panel d, 3,600 mg/m²) and blood was drawn at the indicated time points. Plasma pemetrexed and plasma deoxyuridine concentrations were determined as described in Methods. Shown is percent of baseline plasma deoxyuridine (left Y-axis) and plasma pemetrexed (right Y-axis) versus time following pemetrexed infusion