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

Sponsor

Hackensack Meridian Health (Other)

Overall Status

Completed

CT.gov ID

NCT01723839

Collaborator

Celgene Corporation (Industry)

Enrollment

Location

Arm

111.5

Actual Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Chronic Lymphocytic Leukemia (CLL)	Drug: Fludarabine, Cyclophosphamide, Rituximab, Lenalidomide	Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

21 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Feb 22, 2012

Actual Primary Completion Date :

Jun 8, 2021

Actual Study Completion Date :

Jun 8, 2021

Arms and Interventions

Arm	Intervention/Treatment
Other: 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.	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 Names: FCR + Lenalidomide

Arm

Intervention/Treatment

Other: 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.

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 Names:

FCR + Lenalidomide

Outcome Measures

Primary Outcome Measures

Complete Response [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

Secondary Outcome Measures

Overall Response Rate [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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:

The predominant population of cells share B-cell antigens with CD5 in the absence of other pan-T-cell markers (CD3, CD2, etc.);
Surface immunoglobulin (slg) and CD20 with low-cell surface density expression.
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.