Phase II Trial of LMB-2, Fludarabine and Cyclophosphamide for Adult T-Cell Leukemia
Condition: Adult T-Cell Leukemia (ATL)
MeSH terms: Leukemia; Leukemia, T-Cell; Leukemia-Lymphoma, Adult T-Cell
Study type: Interventional
Phase: Phase 1/Phase 2

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....
    

Detailed description: 
      BACKGROUND:

        -  Cluster of differentiation 25 (CD25) (p55, Tac or interleukin receptor 2 (IL2Ra) 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 adult T-cell leukemia (ATL), the humanized anti-CD25 monoclonal antibody (Mab)
           daclizumab produced 13-14 % responses, and the anti-CD52 Mab Alemtuzumab (Campath- 1H)
           produced response lasting > 8 weeks 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 National Cancer Institute (NCI), the maximum tolerated dose (MTD)
           of LMB-2 was 40 mcg/Kg dose intravenous (IV) given every other day for 3 doses (every
           other day (QOD) x3). LMB-2 induced > 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 > 8 weeks 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 +FC on normal B- and T-cell subsets by FACS.

      ELIGIBILITY:

        -  CD25+ ATL, untreated or with prior therapy, leukemic type without malignant masses > 4
           cm.

        -  Eastern Cooperative Oncology Group (ECOG) 0-2, absolute neutrophil count (ANC),
           platelets and albumin at least 1000, 75,000, and 3.0 respectively.

      DESIGN:

        -  IV fludarabine and cyclophosphamide (FC) days 1-3 (doses listed respectively)

        -  Patients 1-7 and 10-14, and >18: 25 and 250 mg/m^2/day

        -  Patients 8-9: 30 and 300 mg/m^2/day

        -  Patients 15-17: 20 and 200 mg/m^2/day

        -  LMB-2 dose: Begin with 30 mcg/Kg IV on days 3,5 and 7. Escalate to 40 mcg/Kg if dose
           limiting toxicity (DLT) in 0/3 or 1/6 at 30 mcg/Kg. Continue at 40 mcg/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.
    

Intervention name(s): LMB-2; Fludarabine; Cyclophosphamide
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Begin with 30 mcg/Kg intravenous (IV) on days 3, 5 and 7. Escalate to 40 mcg/Kg if dose limiting toxicity (DLT) in 0/3 or 1/6 at 30 mcg/Kg. Continue at 40 mcg/Kg if 0-1 of 6 have DLT at 40 mcg/Kg.; Days 1-3:
Patients 1-7, 10-14, and >18:25mg/m^2/day Patients 8 - 9:30 mg/m^2/day Patients 15- 17:20 mg/m^2/day; Days 1-3:
Patients 1-7, 10 -14, and >18:250 mg/m^2/day Patients 8 - 9:300 mg/m^2/day Patients 15-17:200 mg/m^2/day
Other intervention name(s): Fludara; Cytoxan
Intervention MeSH terms: Cyclophosphamide; Fludarabine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Immunotoxin; CD25; Immunogenicity; Neutralization; Neutralizing Antibodies; Adult T-Cell Leukemia; Leukemia; ATL