Phase II Trial of LMB-2, Fludarabine and Cyclophosphamide for Adult T-Cell Leukemia
- CD25 (p55, Tac or IL2Ralpha) is strongly expressed in virtually 100 percent 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
percent of responses, and the anti-CD52 Mab Alemtuzumab (Campath- 1H) produced response
lasting > 2 months in of 30 percent 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 mcg/Kg(Bullet)dose IV given every
other day for 3 doses (QOD times 3). LMB-2 induced > 90 percent 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.
- 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 > 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 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.
- IV fludarabine days 1-3
- patients 1-7 and 10-14: 25mg/m1/day
- patients 8-9: 30mg/m2/day
- patient 15 on: 20mg/m2/day
- IV cyclophosphamide days 1-3
- patients 1-7 and 10-14: 250mg/m2/day
- patients 8-9: 300mg/m2/day
- patients 15 on: 200mg/m2/day
- LMB-2 dose: Begin with 30mcg/Kg IV on days 3,5 and 7. Escalate to 40 mcg/Kg if DLT in
0/3 or 1/6 at 30mcg/Kg. Continue at 40mcg/Kg if 0-1 of 6 have DLT at 40 mcg/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.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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.
Robert J Kreitman, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|