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

NCT ID: NCT00924170

Last Updated: 2023-11-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 18 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-10-31
• Study Completion Date: 2021-05-05

Brief 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.

Conditions

Adult T-Cell Leukemia (ATL)

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Fludarabine and Cyclophosphamide/LMB-2

Administer cycle 1 with Fludarabine and Cyclophosphamide (FC) alone. Two weeks after starting cycle 1, begin up to 6 cycles of FC plus LMB-2 at minimum 20-day intervals.

Group Type: EXPERIMENTAL

LMB-2

Intervention Type: DRUG

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.

Fludarabine

Intervention Type: DRUG

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

Cyclophosphamide

Intervention Type: DRUG

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

Interventions

LMB-2

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.

Intervention Type: DRUG

Fludarabine

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

Intervention Type: DRUG

Cyclophosphamide

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

Intervention Type: DRUG

Other Intervention Names

Fludara; Cytoxan

Eligibility Criteria

Inclusion Criteria

1. Diagnosis of acute or lymphomatous adult T-cell leukemia (ATL) by flow cytometry of blood or immunohistochemistry of biopsy tissue, confirmed by National Cancer Institute (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. Eastern Cooperative Oncology Group (ECOG) 0-2.

5. Able to understand and give informed consent.

6. Negative pregnancy test for females of childbearing potential.

7. The transaminases alanine aminotransferase (ALT) and aspartate aminotransferase (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 Gilberts 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. Absolute neutrophil count (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 calcium (Ca)++ > 2.73 or lactate dehydrogenase (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 monoclonal antibody (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 human immunodeficiency virus (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 diffusing capacity of the lungs for carbon monoxide (DLCO) less than 50% of normal or an forced expiratory volume 1 (FEV1) less than 50% of normal.

11. No concomitant use of alternative complimentary therapies or over the counter (OTC) agents allowed without prior approval of the principal investigator (PI).

12. Tumor or lymph node masses > 4 cm.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 100 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: lead

Responsible Party

Robert Kreitman, M.D.

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Robert J Kreitman, M.D.

Role: PRINCIPAL_INVESTIGATOR

National Cancer Institute (NCI)

Locations

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, United States

Countries

United States

References

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 Sezary leukemia, and their distinction using anti-Tac. Monoclonal antibody identifying the human receptor for T cell growth factor. J Clin Invest. 1984 Jun;73(6):1711-8. doi: 10.1172/JCI111379.

Reference Type: BACKGROUND

PMID: 6327770 (View on PubMed)

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. Nature. 1982 Nov 18;300(5889):267-9. doi: 10.1038/300267a0. No abstract available.

Reference Type: BACKGROUND

PMID: 6815536 (View on PubMed)

Proietti FA, Carneiro-Proietti AB, Catalan-Soares BC, Murphy EL. Global epidemiology of HTLV-I infection and associated diseases. Oncogene. 2005 Sep 5;24(39):6058-68. doi: 10.1038/sj.onc.1208968.

Reference Type: BACKGROUND

PMID: 16155612 (View on PubMed)

Kreitman RJ, Stetler-Stevenson M, Jaffe ES, Conlon KC, Steinberg SM, Wilson W, Waldmann TA, Pastan I. Complete Remissions of Adult T-cell Leukemia with Anti-CD25 Recombinant Immunotoxin LMB-2 and Chemotherapy to Block Immunogenicity. Clin Cancer Res. 2016 Jan 15;22(2):310-8. doi: 10.1158/1078-0432.CCR-15-1412. Epub 2015 Sep 8.

Reference Type: BACKGROUND

PMID: 26350263 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form: Eligibility Screening

View Document

Document Type: Informed Consent Form: Standard

View Document

Related Links

https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2009-C-0025.html

NIH Clinical Center Detailed Web Page

Other Identifiers

09-C-0025

Identifier Type: -

Identifier Source: secondary_id

090025

Identifier Type: -

Identifier Source: org_study_id

NCT00794833

Identifier Type: -

Identifier Source: nct_alias