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Protocol Details

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

This study is NOT currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

09-C-0025

Sponsoring Institute

National Cancer Institute (NCI)

Recruitment Detail

Type: Completed Study; data analyses ongoing
Gender: Male & Female
Min Age: 18 Years
Max Age: N/A

Referral Letter Required

No

Population Exclusion(s)

Children;
Fetuses;
Pregnant Women

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

Investigational Device(s)

None

Intervention(s)

Drug: LMB-2
Drug: Fludarabine
Drug: Cyclophosphamide

Supporting Site

National Cancer Institute

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.

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Eligibility

INCLUSION CRITERIA:

1. 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.

2. Neutralizing antibodies less than or equal to 75% neutralization of 200 ng/ml of LMB-2.

3. At least 18 years old.

4. ECOG 0-2.

5. Able to understand and give informed consent.

6. Negative pregnancy test for females of childbearing potential.

7. The transaminases ALT and AST must each be less than or equal to 3-times the upper limits of normal (UNL) 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.

8. Creatinine less than 2.0 mg/dL.

9. ANC greater than or equal to 1000/uL and platelets greater than or equal to 50,000/uL.

10. Current or prior features of acute ( corrected Ca++ > 2.73 or LDH 2- fold above ULN) or chronic (LDH 1.5-2-fold above ULN or absolute lymphocyte count >4 x10^9/L with T-cells >3.5 x10^9/L) ATL. Patients with smoldering ATL (no acute or chronic features) and symptomatic ATL skin lesions are also eligible.

EXCLUSION CRITERIA:

1. Prior therapy with LMB-2.

2. Central nervous system disease as evidenced by clinical symptomatology.

3. 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.

4. Uncontrolled infection.

5. Untreated or uncontrolled 2nd malignancy.

6. Patients who are pregnant or breast-feeding.

7. 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.

8. Patients receiving warfarin (Coumadin [R])

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

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

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

12. Tumor or lymph node masses > 4 cm.


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Citations:

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 S(SqrRoot)(Copyright)zary 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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Contacts:

Principal Investigator

Referral Contact

For more information:

Robert J. Kreitman, M.D.
National Cancer Institute (NCI)
NIHBC 10 - CLINICAL CENTER BG RM 13N248A
10 CENTER DR
BETHESDA MD 20892
(301) 480-6187
kreitmar@mail.nih.gov

Julie C. Feurtado, R.N.
National Cancer Institute (NCI)
National Institutes of Health
Building 10
Room 12N214
10 Center Drive
Bethesda, Maryland 20892
(301) 480-6186
julie.feurtado@nih.gov

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
1-888-NCI-1937

Clinical Trials Number:

NCT00924170

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