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Phase II Protocol for CLL With Fludarabine and Cyclophosphamide With Rituximab (FCR) Plus Lenalidomide (FCR)

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ClinicalTrials.gov Identifier: NCT01723839
Recruitment Status : Active, not recruiting
First Posted : November 8, 2012
Last Update Posted : October 7, 2019
Sponsor:
Collaborator:
Celgene Corporation
Information provided by (Responsible Party):
Hackensack Meridian Health

Tracking Information
First Submitted Date  ICMJE November 6, 2012
First Posted Date  ICMJE November 8, 2012
Last Update Posted Date October 7, 2019
Actual Study Start Date  ICMJE February 22, 2012
Estimated Primary Completion Date December 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 2, 2014)
Complete Response [ Time Frame: 28 day cycle ]
Analysis of the Primary Endpoint: The complete responses will be estimated by the number of patients with CR divided by the total number of evaluable patients. Ninety-five percent confidence intervals for the true CR will be calculated
Original Primary Outcome Measures  ICMJE
 (submitted: November 7, 2012)
  • Complete Response
    Analysis of the Primary Endpoint: The complete responses will be estimated by the number of patients with CR divided by the total number of evaluable patients. Ninety-five percent confidence intervals for the true CR will be calculated
  • Toxicity
    All toxicities that were determined to be possibly, probably or definitely related to the treatment will be tabulated according to grade and type (according to the NCI Common Toxicity Criteria, Version 4.0). The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns
Change History Complete list of historical versions of study NCT01723839 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 22, 2013)
Overall Response Rate [ Time Frame: 4-6 28 day cycles ]
Analysis of the other Secondary Endpoints: The overall response rate will be estimated by the number of patients with complete and partial responses divided by the total number of evaluable patients. Ninety-five percent confidence intervals for the true success proportion will be calculated. Responses will be evaluated after 4 and 6 cycles of FCR plus lenalidomide and after 6 and 12 cycles of lenalidomide consolidation/maintenance. The overall survival (OS) is defined as the time interval between the treatment starting date and the documented date of death. For a surviving patient, OS is censored at the last follow-up date when the patient is documented to be alive. Progression-free survival (PFS) is defined as the time interval between the treatment starting date and the documented date of disease progression or death, whichever occurs first. For an alive and progression free patient, PFS is censored at the last follow-up date when patient is documented to be progression free.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 7, 2012)
Overall Response Rate
Analysis of the other Secondary Endpoints: The overall response rate will be estimated by the number of patients with complete and partial responses divided by the total number of evaluable patients. Ninety-five percent confidence intervals for the true success proportion will be calculated. Responses will be evaluated after 4 and 6 cycles of FCR plus lenalidomide and after 6 and 12 cycles of lenalidomide consolidation/maintenance. The overall survival (OS) is defined as the time interval between the treatment starting date and the documented date of death. For a surviving patient, OS is censored at the last follow-up date when the patient is documented to be alive. Progression-free survival (PFS) is defined as the time interval between the treatment starting date and the documented date of disease progression or death, whichever occurs first. For an alive and progression free patient, PFS is censored at the last follow-up date when patient is documented to be progression free.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase II Protocol for CLL With Fludarabine and Cyclophosphamide With Rituximab (FCR) Plus Lenalidomide
Official Title  ICMJE Phase II Clinical Protocol for the Treatment of Patients With Previously Untreated CLL With Four or Six Cycles of Fludarabine and Cyclophosphamide With Rituximab (FCR) Plus Lenalidomide Followed by Lenalidomide Consolidation/ Maintenance
Brief Summary In previously-untreated subjects with CLL, fludarabine and rituximab with or without cyclophosphamide (FR or FCR) produces complete responses (CR) of 40-80%. The major complication of FCR has been grade 3/4 neutropenia which was reduced using a lower dose of fludarabine and cyclophosphamide (FCR-Lite) The objective of this study is to evaluate the minimal residual disease (MRD) complete response rate (using the 2008 IWCLL guidelines) after 4 cycles of FCR-Lite plus lenalidomide in subjects with previously untreated CLL. Lenalidomide is active in frontline treatment of CLL as well as in patients with refractory disease. MRD has been demonstrated to be a sensitive surrogate marker for progression-free survival. If patients are MRD negative complete responders (CR) they will stop at 4 cycles of FCR-Lite followed by the lenalidomide consolidation/maintenance arm of the study. If they have a MRD positive CR or partial response (PR) they will continue with 2 additional cycles of FCR-Lite plus lenalidomide followed by lenalidomide consolidation/maintenance. They will be re-tested for MRD after the 6th cycle of FCR-Lite and after 6 and 12 months of lenalidomide monotherapy If they have no response (NR) or progressive disease (PD) following 4 cycles of FCR-Lite plus lenalidomide they will be removed from the study.
Detailed Description

STUDY OBJECTIVES:

Primary:

The primary objective is to evaluate the complete response rate following 4 cycles of FCR-Lite plus lenalidomide in previously untreated patients with CLL.

Secondary:

The first secondary objective is to evaluate the toxicity of patients with previously untreated CLL treated with FCR-Lite plus lenalidomide, followed by lenalidomide. The second is to evaluate the overall response rate and overall survival of patients with previously untreated CLL treated with FCR-Lite plus lenalidomide followed by lenalidomide. The third is to determine whether adding lenalidomide as a consolidation/maintenance therapy will eliminate bone marrow minimal residual disease in CR patients and whether patients who have a PR after 6 cycles of FCR-Lite plus lenalidomide will respond to 12 months of lenalidomide. The final secondary objective is to determine whether the expression of ZAP-70, CD38, and chromosomes correlate with response rate, duration of response, and survival for previously untreated patients with CLL.

STUDY DESIGN:

2-stage phase 2 study-design. 19 subjects are treated in stage-1 with FCR-Lite plus 5mg lenalidomide increasing to 10mg and 15mg in subsequent cycles depending on toxicity. If there are at least 5 CRs the study will accrue an additional 35 subjects (see statistical section). A secondary objective of this study will be to determine if MRD positive patients will become MRD negative with lenalidomide consolidation/maintenance and whether PR patients will convert to CRs Lenalidomide will begin 2 months after the last dose of FCR-Lite in all subjects with CR. It may begin as soon as 1 month after FCR-Lite plus lenalidomide in subjects with PR. Lenalidomide is given in 28 d cycles increasing the dose from 5 mg/d to 10 mg/d in cycle 2 and to 15mg in cycles 3-6 if well- tolerated (no grade-3 or -4 toxicity). Patients with creatinine clearance ≥30ml/min and <60ml/min will start at 2.5mg daily increasing to 5 and 10mg in subsequent cycles . Reduction to the prior dose is allowed for grade-3/-4 toxicity. MRD will be studied by flow cytometry from bone marrow and peripheral blood samples following 4 and 6 cycles of FCR-Lite and after 6 and 12 months of lenalidomide in CR patients.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Chronic Lymphocytic Leukemia (CLL)
Intervention  ICMJE Drug: Fludarabine, Cyclophosphamide, Rituximab, Lenalidomide
19 subjects are treated in stage-1 with FCR plus 5mg lenalidomide increasing to 10mg and 15mg in subsequent cycles depending on toxicity.
Other Name: FCR + Lenalidomide
Study Arms  ICMJE FCR with Lenalidomide
Fludarabine, Cyclophosphamide, Rituximab, Lenalidomide - 19 subjects are treated in stage-1 with FCR plus 5mg lenalidomide increasing to 10mg and 15mg in subsequent cycles depending on toxicity. If there are at least 5 CRs after 4 cycles of FCR plus lenalidomide the study will accrue an additional 35 subjects.
Intervention: Drug: Fludarabine, Cyclophosphamide, Rituximab, Lenalidomide
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: April 11, 2019)
21
Original Estimated Enrollment  ICMJE
 (submitted: November 7, 2012)
54
Estimated Study Completion Date  ICMJE December 2019
Estimated Primary Completion Date December 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients must have diagnosis of CLL (as defined by the NCI Criteria below:

    • Patients must have peripheral blood absolute lymphocyte count of >5,000/mm3 obtained within 2 weeks prior to start of study.
    • The lymphocytosis must consist of small, mature lymphocytes, with ≤55% (not greater than 55%) prolymphocytes.
  • Patients must have phenotypically characterized CLL as defined as:

    1. The predominant population of cells share B-cell antigens with CD5 in the absence of other pan-T-cell markers (CD3, CD2, etc.);
    2. Surface immunoglobulin (slg) and CD20 with low-cell surface density expression.
    3. If surface immunoglobulin can be demonstrated, the leukemic cells are restricted to expression of either kappa or lambda.
  • Splenomegaly, hepatomegaly or lymphadenopathy are not required for the diagnosis of CLL
  • Patients must require chemotherapy
  • Patients must not have received prior treatment cytotoxic, immunotherapy or investigational therapy.
  • Patients must not have history of corticosteroid treatment for CLL, Autoimmune thrombocytopenia, or autoimmune hemolytic anemia.
  • Calculated creatinine clearance ≥30ml/min by Cockcroft-Gault formula
  • Bilirubin must be ≤1.5mg/dl, unless secondary to tumor, obtained within 2 weeks prior to registration
  • Platelets ≥75x109/L, unless due to CLL involvement of bone marrow
  • Neutrophils ≥1.5x109/L, unless due to CLL involvement of bone marrow
  • AST or ALT < 2x upper limit of normal, unless related to CLL
  • Age ≥18 years
  • ECOG performance status 0-2
  • Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test
  • Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy
  • Able to take aspirin (81mg or 325mg) daily as prophylactic anticoagulation
  • Subject must provide written informed consent
  • All study participants must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist®

Exclusion Criteria:

  • Patients with autoimmune hemolytic anemia or autoimmune thrombocytopenia are not eligible
  • No prior immunotherapy, investigational or cytotoxic chemotherapy
  • Patients with a history of steroid treatment for CLL/SLL autoimmune hemolytic anemia, or autoimmune thrombocytopenia are not eligible
  • Patients with active infections requiring oral or intravenous (IV) antibiotics until resolution of the infection and completion of therapeutic antibiotics
  • Women of childbearing potential and sexually active males who both refuse to use an accepted and effective method of contraception or women who are breastfeeding
  • Patients with a second malignancy other than basal cell carcinoma or squamous cell carcinoma of the skin or in situ carcinoma of the cervix are not eligible unless the tumor was treated with curative intent at least two years previously
  • History of known HIV
  • History or presence CNS disease
  • Evidence of laboratory TLS by Cairo-Bishop definition of Tumor Lysis Syndrome
  • History of corticosteroid treatment for CLL, Autoimmune thrombocytopenia, or autoimmune hemolytic anemia.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01723839
Other Study ID Numbers  ICMJE Pro00002262 RV-CLL-PI-0530
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Hackensack Meridian Health
Study Sponsor  ICMJE Hackensack Meridian Health
Collaborators  ICMJE Celgene Corporation
Investigators  ICMJE
Principal Investigator: Andre Goy, MD John Theurer Cancer Center at HackensackUMC
PRS Account Hackensack Meridian Health
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP