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

• ClinicalTrials.gov Identifier: NCT00230282
• Recruitment Status: Completed
• First Posted: September 30, 2005
• Results First Posted: September 8, 2014
• Last Update Posted: October 6, 2014
• Sponsor: Steven E. Coutre
• Collaborator: Bayer
• Information provided by (Responsible Party): Steven E. Coutre, Stanford University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Leukemia; B-cell Leukemia; Chronic Leukemia; Chronic Lymphocytic Leukemia (CLL)	Drug: Alemtuzumab; Drug: Fludarabine; Drug: Cytoxan	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 25 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: July 2004
• Actual Primary Completion Date: December 2010
• Actual Study Completion Date: October 2011

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Number of Subjects Maintaining Partial Response (PR) or Complete Response (CR) [ Time Frame: 24 weeks ]

   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

Secondary Outcome Measures :

1. Duration of Response [ Time Frame: 105 months ]

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, California

Stanford University School of Medicine

Stanford, California, United States, 94305

Sponsors and Collaborators

Steven E. Coutre

Bayer

Investigators

• Principal Investigator: Steven Edward Coutre; Stanford University

More Information

• Responsible Party: Steven E. Coutre, Associate Professor of Medicine, Stanford University
• ClinicalTrials.gov Identifier: NCT00230282
• Other Study ID Numbers: IRB-13053; 31185 ( Other Identifier: Berlex Oncology ID ); 80071 ( Other Identifier: Stanford University Alternate IRB Approval Number ); HEMCLL0001 ( Other Identifier: OnCore )
• First Posted: September 30, 2005
• Results First Posted: September 8, 2014
• Last Update Posted: October 6, 2014
• Last Verified: September 2014

Additional relevant MeSH terms:

Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, B-Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Cyclophosphamide; Fludarabine; Alemtuzumab; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological