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

NCT00924170 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 09002509-C-0025
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

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....

Conditions

Adult T-Cell Leukemia (ATL)

Keywords

Immunotoxin; CD25; Immunogenicity; Neutralization; Neutralizing Antibodies; Adult T-Cell Leukemia; Leukemia; ATL

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With a Minimally Durable Clinical Response Rate

  Response is based on the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma and must last \>8 weeks to meet the primary endpoint of the study. Complete remission (CR) is complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease related symptoms if present before therapy and normalization of those biochemical abnormalities definitely assignable to the lymphoma. Partial response is reduction by ≥50% of leukemia cell count or ≥50% reduction in the size of all measurable lesions, and no increase in size of any measurable or evaluable lesion or appearance of new lesion. Stable disease is neither a response nor progressive disease. Progressive disease is appearance of new lesions, or an increase of 50% or greater in the sum of the product of the perpendicular diameters of the measurable lesions or persistent (at least two determinations) doubling of the peripheral blood leukemic cell count.

  8 weeks

Secondary Outcomes (15)

• Peak Level of LMB-2 in Adult T-Cell Lymphoma

  First 24 hours after the dose given on Cycle 2, day 1

• Progression Free Survival (PFS)

  70 months

• Overall Survival (OS)

  70 months

• Number of Participants With Serious and Non-serious Adverse Events

  7 years and 12 days

• Number of Participants With Dose Limiting Toxicity (DLT)

  30 days after last dose of LMB2

Study Arms (1)

Fludarabine and Cyclophosphamide/LMB-2

EXPERIMENTAL

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.

Drug: LMB-2; Drug: Fludarabine; Drug: Cyclophosphamide

Interventions

LMB-2 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 and Cyclophosphamide/LMB-2

Fludarabine 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

Also known as: Fludara

Fludarabine and Cyclophosphamide/LMB-2

Cyclophosphamide 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

Also known as: Cytoxan

Fludarabine and Cyclophosphamide/LMB-2

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Neutralizing antibodies less than or equal to 75% neutralization of 200 ng/ml of LMB-2.
• At least 18 years old.
• Eastern Cooperative Oncology Group (ECOG) 0-2.
• Able to understand and give informed consent.
• Negative pregnancy test for females of childbearing potential.
• 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.
• Creatinine less than 2.0 mg/dL.
• Absolute neutrophil count (ANC) greater than or equal to 1000/uL and platelets greater than or equal to 50,000/uL.
• 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.

You may not qualify if:

• Prior therapy with LMB-2.
• Central nervous system disease as evidenced by clinical symptomatology.
• 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.
• Uncontrolled infection.
• Untreated or uncontrolled 2nd malignancy.
• Patients who are pregnant or breast-feeding.
• 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.
• Patients receiving warfarin (Coumadin \[R\])
• Patients with a left ventricular ejection fraction of less than 45%.
• 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.
• No concomitant use of alternative complimentary therapies or over the counter (OTC) agents allowed without prior approval of the principal investigator (PI).
• Tumor or lymph node masses \> 4 cm.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• 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.

  PMID: 6327770 BACKGROUND

• 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.

  PMID: 6815536 BACKGROUND

• 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.

  PMID: 16155612 BACKGROUND

• 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.

  PMID: 26350263 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Leukemia-Lymphoma, Adult T-Cell; Leukemia

Interventions

B3(Fv)-PE38KDEL recombinant immunotoxin; fludarabine; fludarabine phosphate; Cyclophosphamide

Condition Hierarchy (Ancestors)

Leukemia, T-Cell; Leukemia, Lymphoid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Results Point of Contact

• Title: Dr. Robert Kreitman
• Organization: National Cancer Institute

Robert_Kreitman@nih.gov

301-496-6947

Study Officials

• Robert J Kreitman, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 17, 2009
• First Posted: June 18, 2009
• Study Start: October 31, 2008
• Primary Completion: January 2, 2016
• Study Completion: May 5, 2021
• Last Updated: November 14, 2023
• Results First Posted: September 8, 2017

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely.
• Access Criteria: Clinical data will be made available via subscription to Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI).

Locations

US (1)