A Phase I Study of Talvesta® (Talotrexin) in Relapsed or Refractory Leukemia or Myelodysplastic Syndrome.

Talvesta® is a novel, nonpolyglutamatable antifolate drug which has demonstrated improved antitumor activity in a broad spectrum of cancer models by targeting DHFR to inhibit tumor growth. Talvesta binds more tightly to DHFR than methotrexate (MTX), with a Ki of 0.35 pM, which is 15-fold lower than MTX. Talvesta enters cells by the reduced folate carrier (RFC) pathway. In CCRF-CEM leukemia cell lines, Talvesta compared to MTX exhibited an IC₅₀ of 1.1 nM and 11 nM, respectively. An open-label, dose escalation study of Talvesta administered as a 5–10 minute infusion on Days 1–5 on a 21-day cycle to patients with relapsed or refractory leukemias is ongoing. The primary objectives of this study are to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT), and evaluate the pharmacokinetics, safety and efficacy. Patients with AML, ALL, CLL, CML-BP, MDS, RAEB or RAEBT and CMML for whom no standard therapy resulting in a durable remission is available and with an ECOG PS 0–2, were enrolled. The starting dose was 0.2 mg/m² (1 mg/m² per cycle) based on preclinical data with dose escalation based on a modified Fibonacci sequence. Three patients were treated at each dose level in the absence of a DLT. All patients received folic acid and B₁₂ vitamin supplementation. Plasma Talvesta concentrations were analyzed by a validated LC/MS/MS method during cycle 1. To date, twenty-two (22) (16 male) heavily pre-treated patients (11 AML, 7 ALL, 1 CML-BP, 2 CLL, 1 Hairy Cell) median age 52 years (range, 19–84) have been enrolled and received a total of 29 cycles of Talvesta (median 1, range 1–4) at doses of 1 mg/m² to 4 mg/m² per cycle. Two patients experienced neutropenic fevers possibly/probably related to talvesta administration. Dose escalation continues in an attempt to identify a DLT with subsequent initiation of a Phase II study in patients with refractory ALL. One major response has been observed in a patient with refractory ALL. Pharmacokinetic parameters are pending analysis. Talvesta at the tested doses in this heavily pretreated leukemia patient population has been well tolerated.