Phase II Trial of LMB-2, Fludarabine and Cyclophosphamide for Adult T-Cell Leukemia

Detailed Summary

BACKGROUND: * Cluster of differentiation 25 (CD25) (p55, Tac or interleukin 2 receptor (IL2R) alpha) is strongly expressed in virtually 100% of patients with adult T-cell leukemia/lymphoma (ATL), a highly aggressive human T-lymphotropic virus type 1 (HTLV-1) related malignancy responding poorly to chemotherapy. * In ATL, the humanized anti-CD25 monoclonal antibody (Mab) daclizumab produced 13-14% responses, and the anti-CD52 Mab Alemtuzumab (Campath-1H) produced response lasting greater than 2 months in 30% of 23 patients. * LMB-2 is an anti-CD25 recombinant immunotoxin containing variable domains of murine MAb anti-Tac and truncated Pseudomonas exotoxin. * In a phase I trial at National Cancer Institute (NCI), the maximum tolerated dose (MTD) of LMB-2 was 40 microg/Kg intravenous (IV) given every other day for 3 doses (every other day (QOD) times 3). LMB-2 induced greater than 90% tumor reduction rapidly in all 3 ATL patients on protocol, but achieved only 1 partial response due to rapid tumor progression and/or immunogenicity. * In preclinical models, response from recombinant immunotoxins is limited by high concentrations of soluble receptor in the blood and especially in the interstitial space of the tumor. Synergism was observed with chemotherapy and immunotoxins, possibly due to reduction of soluble receptor in tumor interstitium. OBJECTIVES: -To determine, in nonrandomized fashion, if after verifying its safety, fludarabine and cyclophosphamide (FC) prior to LMB2 for ATL can result in low immunogenicity and a rate of major response lasting greater than 2 months, which may be an improvement over that demonstrated previously from Alemtuzumab (CAMPATH). Secondary objectives: * To determine the effect of 1 cycle of FC alone in ATL. * To examine progression-free and overall survival in ATL after FC/LMB-2. * Evaluate pharmacokinetics, toxicity, and monitor soluble CD25 and other tumor marker levels in the serum. * To study the effects of LMB-2 plus FC on normal B- and T-cell subsets by fluorescence-activated cell sorting (FACS). ELIGIBILITY: * CD25 plus ATL, untreated or with prior therapy * Eastern Cooperative Oncology Group (ECOG) 0-2, absolute neutrophil count (ANC), platelets and albumin at least 1000, 75,000, and 3.0. DESIGN: * Fludarabine 25 mg/m(2) IV days 1-3 * Cyclophosphamide 250 mg/m(2) IV days 1-3 * LMB-2 30-40 micro g/Kg IV days 3, 5 and 7. * LMB-2 dose: Begin with 30 microg/Kg times 3. Escalate to 40 microg/Kg if dose limiting toxicity (DLT) in 0/3 or 1/6 at 30 microg/Kg. Continue at 40 microg/Kg if 0-1 of 6 have DLT at 40 microg/Kg. * Administer cycle 1 with FC alone. Two weeks after starting cycle 1, begin up to 6 cycles of FC plus LMB-2 at minimum 20-day intervals. * Accrual goals: 29-37 patients, which includes 4 replacements....

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