Phase 2 Fludarabine, Cytoxan and FCCAM <Alemtuzumab> in Untreated B-Cell Chronic Lymphocytic Leukemia

A Multi-Center Phase 2 Efficacy and Pharmacokinetic Study Evaluating Fludarabine, Cyclophosphamide, and Subcutaneous Campath (FCCam, Alemtuzumab) for Previously Untreated B-Cell Chronic Lymphocytic Leukemia

The primary objective of this study was to evaluate the safety and efficacy of the combination of fludarabine and cyclophosphamide in previously untreated CLL patients. Participants will receive fludarabine and cyclophosphamide on days 1, 2, and 3 of six 28-day cycles.

Study Overview

• Status: Completed
• Conditions: Leukemia; Chronic Lymphocytic Leukemia (CLL); Chronic Leukemia; B-cell Leukemia
• Intervention / Treatment: Drug: Alemtuzumab; Drug: Fludarabine; Drug: Cytoxan

Detailed Description

This single-arm study evaluated the safety and efficacy of the combination of fludarabine 25 mg/m2/d IV and cyclophosphamide 250 mg/m2/d SC in previously untreated CLL patients. Participants received fludarabine and cyclophosphamide on days 1, 2, and 3 of six 28-day cycles, followed by a no-treatment rest period (observation) for 3 to 12 weeks.

Responders entered a no-treatment rest period (observation) for 3 to 8 weeks, then depending on status, continued on follow-up or on-study to receive Campath stating at 3 mg/day with the dose adjusted to the maximum tolerated dose.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• ≥ age 18
• Karnofsky performance status 60% or above
• Confirmed immunohistological diagnosis of Chronic Lymphocytic Leukemia (CLL)

• Rai Stage I to IV as follows:

  • Advanced stage disease (Rai Stage III or IV, or modified Rai High Risk)
  • OR

  • Patients with Rai Stage I - II or (Modified Rai Intermediate-Risk) disease must have an indication for therapy based on 1996 NCI revised criteria for active disease as follows:

    • Any one of the following disease-related symptoms:

      1. Weight loss ≥ 10% body weight within the previous 6 months
      2. Extreme fatigue
      3. Fever greater than 100.5° F for ≥ 2 weeks without evidence of infection
      4. Night sweats without evidence of infection
    • Evidence of progressive marrow failure based on the development of worsening of anemia or thrombocytopenia
    • Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroid therapy
    • Massive (> 6 cm below the left costal margin) or progressive splenomegaly
    • Bulky (>10 cm in cluster) or progressive lymphadenopathy
    • Progressive lymphocytosis > 50% increase over 2 months, or anticipated doubling time < 6 months
• Patients with immunoglobulin VH gene in unmutated nucleotide sequence configuration, as defined by ≥ 98% homology with the nearest germline counterpart
• Serum creatinine ≤ 2x the upper limit of normal
• Total serum bilirubin ≤ 2x the upper limit of normal.
• AST ≤ 2x the upper limit of normal.
• ALT ≤ 2x the upper limit of normal.
• Signed written informed consent

Exclusion Criteria:

• Prior pharmacological treatment for CLL
• Past history of anaphylaxis following exposure to monoclonal antibodies
• Active secondary malignancy or a history of malignant disease (other than CLL or non-melanoma skin cancer) within the preceding 5 years
• Any medical condition requiring systemic corticosteroids
• Active systemic infection
• Major systemic or other illness (including Coombs positivity and active hemolysis) that would, in the opinion of the investigator, interfere with the patient's ability to comply with the protocol, compromise patient safety, or interfere with the interpretation of study results
• HIV positive by serologic testing
• Pregnant or nursing female
• Unwilling/unable to practice an acceptable form of contraception.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Fludarabine, cytoxan, then alemtuzumab; Fludarabine and cyclophosphamide days 1 to 3 for six 28-day cycles. Minimal residual disease positive responders continued on-treatment to receive alemtuzumab 30 mg weekly. MRD negative responders were observed.

Drug: Alemtuzumab; 3 to 30 mg, IV; Other Names: Campath; Campath-1H; Lemtrada; MabCampath; FCCam; Drug: Fludarabine; [(2R,3R,4S,5R)-5-(6-amino-2-fluoro-purin-9-yl)- 3,4-dihydroxy-oxolan-2-yl]methoxyphosphonic acid; Other Names: Fludara; Drug: Cytoxan; (RS)-N,N-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide; Other Names: Endoxan; Neosar; Revimmune; Cyclophosphamide; Procytox; cytophosphane

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects Maintaining Partial Response (PR) or Complete Response (CR)	Response criteria as per the NCI-WG Revised Guidelines for B-CLL Complete remission: No lymphadenopathy by physical exam No hepatomegaly or splenomegaly Absence of constitutional symptoms Polymorphonuclear leukocytes > 1,500/uL, Platelets > 100,000/uL, Hemoglobin > 11.0 g/dL Bone marrow aspirate and biopsy normocellular with < 30% lymphocytes Absent lymphoid nodules Partial remission: 50% decrease in peripheral blood lymphocyte count from the pretreatment baseline value; 50% reduction in lymphadenopathy and/or ≥ 50% reduction in the size of the liver and/or spleen AND one or more of the following Polymorphonuclear leukocytes > 1,500/uL or 50% improvement over baseline Platelets > 100,000/uL or 50% improvement over baseline Hemoglobin > 11.0 g/dL or 50% improvement over baseline	24 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Duration of Response	105 months

Collaborators and Investigators

• Sponsor: Steven E. Coutre
• Collaborators: Bayer
• Investigators: Principal Investigator: Steven Edward Coutre, Stanford University

Study record dates

Study Major Dates

• Study Start: July 1, 2004
• Primary Completion (Actual): December 1, 2010
• Study Completion (Actual): October 1, 2011

Study Registration Dates

• First Submitted: September 28, 2005
• First Submitted That Met QC Criteria: September 28, 2005
• First Posted (Estimate): September 30, 2005

Study Record Updates

• Last Update Posted (Estimate): October 6, 2014
• Last Update Submitted That Met QC Criteria: September 25, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Leukemia, B-Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Cyclophosphamide; Fludarabine; Alemtuzumab
• Other Study ID Numbers: IRB-13053; 31185 (Berlex Oncology ID); 80071 (Other Identifier: Stanford University Alternate IRB Approval Number); HEMCLL0001 (Other Identifier: OnCore)