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

This study has suspended participant recruitment.
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT00924170
First received: June 17, 2009
Last updated: June 28, 2014
Last verified: February 2014
  Purpose

BACKGROUND:

  • 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.

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 plus 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 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....

Condition Intervention Phase
Adult T-Cell Leukemia (ATL)
Drug: LMB-2
Drug: Fludarabine
Drug: Cyclophosphamide
Drug: LMB-2, anti-Tac(Fv)-PE38
Phase 2

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • 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.

Secondary Outcome Measures:
  • 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.

Enrollment: 15
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)
Intervention Details:
    Drug: LMB-2
    N/A
    Drug: Fludarabine
    N/A
    Drug: Cyclophosphamide
    N/A
    Drug: LMB-2, anti-Tac(Fv)-PE38
    N/A
Detailed Description:

BACKGROUND:

  • 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 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.

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 > 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.

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:

  • 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.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • 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 LMB-2.
  • 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 50,000/uL.

EXCLUSION CRITERIA:

  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00924170

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Investigators
Principal Investigator: Robert J Kreitman, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT00924170     History of Changes
Obsolete Identifiers: NCT00794833
Other Study ID Numbers: 090025, 09-C-0025
Study First Received: June 17, 2009
Last Updated: June 28, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Immunotoxin
CD25
Immunogenicity
Neutralization
Neutralizing Antibodies
Adult T-Cell Leukemia
Leukemia
ATL

Additional relevant MeSH terms:
Leukemia
Leukemia, T-Cell
Leukemia-Lymphoma, Adult T-Cell
Neoplasms by Histologic Type
Neoplasms
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Fludarabine monophosphate
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites

ClinicalTrials.gov processed this record on July 10, 2014