Phase II Trial of LMB-2, Fludarabine and Cyclophosphamide for Adult T-Cell Leukemia
- CD25 (p55, Tac or IL2R alpha) 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 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 microg/Kg IV given every other day for 3 doses (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.
-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.
- 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 FACS.
- CD25 plus ATL, untreated or with prior therapy
- ECOG 0-2, ANC, platelets and albumin at least 1000, 75,000, and 3.0.
- 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 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....
Adult T-Cell Leukemia (ATL)
Drug: LMB-2, anti-Tac(Fv)-PE38
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase II Trial of LMB-2, Fludarabine and Cyclophosphamide for Adult T-Cell Leukemia|
- To determine if 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.
- 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.
|Study Start Date:||October 2008|
|Estimated Study Completion Date:||October 2015|
|Estimated Primary Completion Date:||October 2015 (Final data collection date for primary outcome measure)|
Please refer to this study by its ClinicalTrials.gov identifier: NCT00924170
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Robert J Kreitman, M.D.||National Cancer Institute (NCI)|