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

Phase 2
18 Years
Open (Enrolling)
Adult T-Cell Leukemia (ATL)

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Trial Information

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.

Inclusion Criteria


- Diagnosis of acute or lymphomatous ATL by flow cytometry of blood or
immunohistochemistry of biopsy tissue, confirmed by NCI Laboratory of Pathology, and
previously treated unless the patient is ineligible for or refuses other protocols or
treatments for ATL.

- Neutralizing antibodies less than or equal to 75% neutralization of 200 ng/ml of

- At least 18 years old.

- ECOG 0-2.

- Able to understand and give informed consent.

- Negative pregnancy test for females of childbearing potential.

- The transaminases ALT and AST must each be less than or equal to 2.5-times the upper
limits of normal or less than or equal to 10-times normal if due to ATL. Albumin must
be greater than or equal to 3.0 gm/dL. Total bilirubin must be less than or equal to
1.5 mg/dL except in patients with Gilbert's syndrome (as defined by greater than 80
percent unconjugated bilirubin) it must be less than 5mg/dl.

- Creatinine less than 2.0 mg/dL.

- ANC greater than or equal to 1000/uL and platelets greater than or equal to


- Prior therapy with LMB-2.

- Central nervous system disease as evidenced by clinical symptomatology.

- Cytotoxic chemotherapy, steroids or Mab within 3 weeks of enrollment, except anti Tac
Mab (i.e. daclizumab), which cannot be used within 12 weeks of enrollment.
Hydroxyurea is considered different from cytotoxic chemotherapy and may be used up to
the day before enrollment providing it is not increased during the week prior to
enrollment and that patients disease burden is not decreasing during that time.

- Uncontrolled infection.

- Untreated or uncontrolled 2nd malignancy.

- Patients who are pregnant or breast-feeding.

- Patients who have HIV or hepatitis C, since in these patients reductions in normal T-
or B-cells would increase the risk of exacerbation of their underlying disease.
Patients would not be excluded for hepatitis B surface antigen positivity if on
Lamivudine or Entecavir.

- Patients receiving warfarin (Coumadin [R])

- Patients with a left ventricular ejection fraction of less than 45%.

- Patients with a DLCO less than 50% of normal or an FEV1 less than 50% of normal.

- No concomitant use of alternative complimentary therapies or OTC agents allowed
without prior approval of the PI.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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.

Principal Investigator

Robert J Kreitman, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Federal Government

Study ID:




Start Date:

October 2008

Completion Date:

October 2013

Related Keywords:

  • Adult T-Cell Leukemia (ATL)
  • Immunotoxin
  • CD25
  • Immunogenicity
  • Neutralization
  • Neutralizing Antibodies
  • Adult T-Cell Leukemia
  • Leukemia
  • ATL
  • Leukemia
  • Leukemia, T-Cell
  • Leukemia-Lymphoma, Adult T-Cell



National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892