Protocol Number: 09-C-0025
-CD25 (Tac or IL2R) is strongly expressed in virtually 100% of patients with adult T-cell leukemia/lymphoma (ATL), a highly aggressive 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 of 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 NCI, the MTD of LMB-2 was 40 micro g/Kg IV given every other day for 3 doses (QOD x3). 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 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 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+FC on normal B- and T-cell subsets by FACS. ELIGIBILITY: -CD25 plus ATL, untreated or with prior therapy -ECOG 0-2, 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 micro g/Kg x3. Escalate to 40 micro g/Kg if DLT in 0/3 or 1/6 at 30 micro g/Kg. Continue at 40 micro g/Kg if 0-1 of 6 have DLT at 40 micro g/Kg. -Repeat FC at minimum 20-day intervals for up to 7 cycles, and begin LMB-2 on the 2nd cycle of FC for up to 6 cycles. -Accrual goals: 29-37 patients, which includes 4 replacements.
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National Institutes of Health Clinical Center
Bethesda, Maryland 20892. Last update: 05/05/2009
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