Protocol Number: 09-C-0025

Title:

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

Number:

09-C-0025

Summary:

BACKGROUND:

-CD25 (Tac or IL2R) 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 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 NCI, the MTD of LMB-2 was 40 micro g/Kg IV given every other day for 3 doses (QOD x3). 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 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+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 micro g/Kg x3. Escalate to 40 micro g/Kg if DLT in 0/3 or 1/6 at 30 micro g/Kg. Continue at 40 micro g/Kg if 0-1 of 6 have DLT at 40 micro g/Kg.

-Repeat FC at minimum 20-day intervals for up to 7 cycles, and begin LMB-2 on the 2nd cycle of FC for up to 6 cycles.

-Accrual goals: 29-37 patients, which includes 4 replacements.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility 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 25% 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. 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% unconjugated bilirubin) it must be less than 5mg/dl.

-Creatinine less than 2.0.

-ANC greater than or equal to 1000 and Platelets greater than or equal to 50,000.

EXCLUSION CRITERIA:

-Prior therapy with LMB-2.

-Central nervous system disease as evidence 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.

-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.

-Patients receiving coumadin.

-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.

Special Instructions:

Currently Not Provided

Keywords:

Immunotoxin

CD25

Immunogenicity

Neutralization

Neutralizing Antibodies

Recruitment Keyword(s):

Adult T-Cell Leukemia

Leukemia

ATL

Condition(s):

Adult T-Cell Leukemia (ATL)

Investigational Drug(s):

LMB-2, anti-Tac(Fv)-PE38

Investigational Device(s):

None

Intervention(s):

Drug: LMB-2

Drug: Fludarabine

Drug: Cyclophosphamide

Drug: LMB-2, anti-Tac(Fv)-PE38

Supporting Site:

National Cancer Institute

Contact(s):

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
Phone: 1-888-NCI-1937
Fax: Not Listed
Electronic Address: ncicssc@mail.nih.gov

Citation(s):

Waldmann TA, Greene WC, Sarin PS, Saxinger C, Blayney DW, Blattner WA, Goldman CK, Bongiovanni K, Sharrow S, Depper JM, et al. Functional and phenotypic comparison of human T cell leukemia/lymphoma virus positive adult T cell leukemia with human T cell leukemia/lymphoma virus negative SŽzary leukemia, and their distinction using anti-Tac. Monoclonal antibody identifying the human receptor for T cell growth factor. 1: J Clin Invest. 1984 Jun;73(6):1711-8.

Leonard WJ, Depper JM, Uchiyama T, Smith KA, Waldmann TA, Greene WC. A monoclonal antibody that appears to recognize the receptor for human T-cell growth factor; partial characterization of the receptor. 1: Nature. 1982 Nov 18;300(5889):267-9.

Proietti FA, Carneiro-Proietti AB, Catalan-Soares BC, Murphy EL. Global epidemiology of HTLV-I infection and associated diseases. 1: Oncogene. 2005 Sep 5;24(39):6058-68.

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