A Phase 3 Study of the Efficacy and Safety of Lenalidomide Maintenance for High-risk Patients With CLL Following First-line Therapy (CLLM1)

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2012 by German CLL Study Group
Sponsor:
Collaborator:
Celgene Corporation
Information provided by (Responsible Party):
German CLL Study Group
ClinicalTrials.gov Identifier:
NCT01556776
First received: March 14, 2012
Last updated: August 27, 2012
Last verified: August 2012
  Purpose

CLLM1 is a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study that compares the efficacy and safety of oral lenalidomide maintenance therapy to that of placebo maintenance therapy in high-risk subjects with Chronic Lymphocytic Leukemia (CLL) who have achieved at least a partial response (PR) and either:

  • MRD levels of ≥ 10-2 or
  • MRD levels of ≥ 10-4 - < 10-2 combined with at least one of the following factors:

    • an unmutated IGHV-status
    • 17p-deletion or
    • TP53 mutation after first line therapy with FCR, FR, BR or FC (in case of of contraindications to receive Rituximab).

Condition Intervention Phase
Chronic Lymphocytic Leukemia
Drug: lenalidomide
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: CLLM1-Protocol of the German CLL-Study Group (GCLLSG) A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Study of the Efficacy and Safety of Lenalidomide (Revlimid®) as Maintenance Therapy for High-risk Patients With Chronic Lymphocytic Leukemia Following First-line Therapy

Resource links provided by NLM:


Further study details as provided by German CLL Study Group:

Primary Outcome Measures:
  • Progression free survival [ Time Frame: up to 5 years ] [ Designated as safety issue: No ]

    Efficacy:

    All measurements will be compared with baseline values:

    • Lymph nodes, spleen and liver measurements by physical examination
    • Complete blood count (CBC)
    • Peripheral blood smear
    • Flow cytometry of peripheral blood for MRD assessment
    • Bone marrow aspirate/biopsy for standard histopathology and flow cytometry for MRD assessment
    • Computed tomography (CT) scans if clinically indicated
    • ECOG Performance Status
    • Assessment of constitutional symptoms


Secondary Outcome Measures:
  • Overall survival [ Time Frame: up to 5 years ] [ Designated as safety issue: No ]
    • date of last contact when patient was alive
    • date of death

  • safety [ Time Frame: up to five years ] [ Designated as safety issue: Yes ]
    • Vital signs
    • Clinical laboratory evaluations
    • Pregnancy testing for female subjects with childbearing potential
    • Electrocardiogram (ECG)
    • Concomitant medications
    • AEs by NCI CTCAE Version 4.0
    • Second Primary Malignancy. Subjects will be contacted 4 times per year during the survival follow up until the end of the study for observation for second primary malignancy.


Estimated Enrollment: 200
Study Start Date: July 2012
Estimated Study Completion Date: May 2017
Estimated Primary Completion Date: September 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Lenalidomide
lenalidomide maintenance following firstline treatment with FCR, BR, FR, or FC(if Rituximab is contraindicated)
Drug: lenalidomide
placebo or lenalidomide 5 mg daily on days 1-28 of the first 28-day cycle. If the 5 mg dose level is well tolerated, escalation to 10 mg daily on days 1-28 of cycle 2-6 is permitted; further escalations starting with the 7th cycle and up to the 12th cycle to 15 mg daily is permitted. If after 12 cycles of treatment subjects still present with MRD levels of ≥ 10-4 in peripheral blood and previous dose levels are well tolerated, starting with the 13th cycle up to progression 20 mg daily is permitted. If after 18 cycles of treatment for subjects still present with MRD.levels of ≥ 10-4 in peripheral blood and previous dose levels are well tolerated, starting with the 19th cycle up to progression 25 mg daily is permitted. 25 mg is the maximal daily dose of lenalidomide
Other Name: Revlimid
Placebo Comparator: Placebo
placebo
Drug: Placebo
placebo or lenalidomide 5 mg daily on days 1-28 of the first 28-day cycle. If the 5 mg dose level is well tolerated, escalation to 10 mg daily on days 1-28 of cycle 2-6 is permitted; further escalations starting with the 7th cycle and up to the 12th cycle to 15 mg daily is permitted. If after 12 cycles of treatment subjects still present with MRD levels of ≥ 10-4 in peripheral blood and previous dose levels are well tolerated, starting with the 13th cycle up to progression 20 mg daily is permitted. If after 18 cycles of treatment for subjects still present with MRD.levels of ≥ 10-4 in peripheral blood and previous dose levels are well tolerated, starting with the 19th cycle up to progression 25 mg daily is permitted. 25 mg is the maximal daily dose of lenalidomide
Other Name: Placebo

Detailed Description:

CLLM1 is a phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the efficacy and safety of lenalidomide administered as maintenance treatment to subjects with CLL who have responded to first-line therapy (induction) achieving a response of at least PR and are at high risk of early progression. This study will compare the efficacy of lenalidomide maintenance treatment versus placebo at prolonging progression free survival (PFS); and as secondary endpoints assess overall survival, the safety of lenalidomide treatment and evaluate Minimal residual disease (MRD) kinetics in peripheral blood whilst subjects are on maintenance.

Although maintenance therapy has been established in recent years for the treatment of a subset of subjects with Non-Hodgkin's Lymphoma (NHL), it is a novel concept in the management of CLL. It is not regularly used and only a limited number of small studies have been conducted evaluating consolidation/maintenance therapy for limited periods of time with alemtuzumab or rituximab. Based on the limited amount of available data, it appears that maintenance therapy may improve the quality of remission in CLL subjects and prolong progression-free survival (PFS). A large phase 3 trial investigating lenalidomide as maintenance following response to second line therapy is ongoing. However, a large well-controlled study has not been conducted to investigate the beneficial effect of maintenance therapy following front line therapy; specifically in subjects with aggressive disease. This phase 3 study will evaluate whether lenalidomide maintenance therapy will prolong PFS in CLL subjects with a high risk of early progression following first line treatment.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Must understand and voluntarily sign an informed consent form.
  2. Age ≥ 18 years at the time of signing the informed consent form.
  3. Must be able to adhere to the study visit schedule and other protocol requirements.
  4. Must have a documented diagnosis of CLL (IWCLL guidelines for the diagnosis and treatment of chronic lymphocytic leukemia1).
  5. Must have been treated with one of the first line induction therapies: fludarabine/cyclophosphamide/rituximab, or bendamustine/rituximab or fludarabine/rituximab or fludarabine/cyclophosphamide,(in case of hypersensitivity reactions to Rituximab).
  6. Must have achieved a response of at least PR (IWCLL guidelines for the diagnosis and treatment of chronic lymphocytic leukemia [Hallek, 2008]) following completion (minimum 4 cycles) of first-line induction therapy prior to randomization (documentation of response status must be available).

    and have either:

    • MRD levels in the peripheral blood at final restaging of ≥ 10-2 or
    • MRD levels in the peripheral blood ≥ 10-4 - < 10-2 combined with at least one of the following factors:

      • an unmutated IGHV-status
      • 17p-deletion or
      • TP53 mutation1
  7. Must have completed last cycle of at least 4 cycles of first-line induction no less than 8 weeks (56 days) and no greater than 20 weeks (140 days) prior to randomization.
  8. Subjects who completed first line induction treatment with less than 6 but at least 4 cycles should document reason for early discontinuation
  9. Must have an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 2.
  10. Negative serological Hepatitis B test, negative testing of Hepatitis C RNA, negative HIV test within 6 weeks prior to registration.
  11. Females of childbearing potential (FCBP)† must:

    • Have two negative medically supervised pregnancy tests prior to starting of study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the subject practices complete and continued sexual abstinence.
    • Either commit to continued abstinence from heterosexual intercourse (which must be reviewed on a monthly basis) or agree to use, and be able to comply with, effective contraception without interruption (Highly effective methods: Intrauterine device (IUD), Hormonal (birth control pills, injections, implants), Tubal ligation, Partner's vasectomy, Additional effective methods: Male condom, Diaphragm, Cervical Cap), 28 days prior to starting study drug, during the study therapy (including dose interruptions), and for 28 days after discontinuation of study therapy.
  12. Male subjects must:

    • Agree to use a condom during sexual contact with a FCBP, even if they have had a vasectomy, throughout study drug therapy, during any dose interruption and after cessation of study therapy.
    • Agree to not donate semen during study drug therapy and for a period after end of study drug therapy.
  13. All subjects must:

    • Have an understanding that the study drug could have a potential teratogenic risk.
    • Agree to abstain from donating blood while taking study drug therapy and following discontinuation of study drug therapy.
    • Agree not to share study medication with another person.
    • Be counseled about pregnancy precautions and risks of fetal exposure.

Exclusion Criteria:

  1. A CIRS Score of more than 6 or a single score of 4 for an organ system limiting the ability to receive an intensive therapy for CLL
  2. Active infections requiring systemic antibiotics.
  3. Systemic infection CTC grade 3 or 4 that has not resolved > 2 months prior to randomization in spite of adequate anti-infective therapy.
  4. Autologous or allogeneic bone marrow transplant as first line therapy.
  5. Pregnant or lactating females.
  6. Systemic treatment for CLL in the interval between completing the last cycle of first-line induction therapy and randomization.
  7. Participation in any clinical study or having taken any investigational therapy which would interfere with the study drug for a disease other than CLL within 28 days prior to initiating maintenance therapy.
  8. Known presence of alcohol and/or drug abuse.
  9. Central nervous system (CNS) involvement as documented by spinal fluid cytology or imaging. Subjects who have signs or symptoms suggestive of leukemic meningitis or a history of leukemic meningitis must have a lumbar puncture procedure performed within two weeks prior to randomization.
  10. Prior history of malignancies, other than CLL, unless the subject has been free of the disease for ≥ 5 years. Exceptions include the following:

    • Basal cell carcinoma of the skin
    • Squamous cell carcinoma of the skin
    • Carcinoma in situ of the cervix
    • Carcinoma in situ of the breast
    • Incidental histological finding of prostate cancer (TNM stage of T1a or T1b)
  11. History of renal failure requiring dialysis.
  12. Prior therapy with lenalidomide.
  13. Any of the following laboratory abnormalities:

    • Calculated (method of Cockroft-Gault) creatinine clearance of < 60 mL/min
    • Absolute neutrophil count (ANC) < 1,000/μL (1.0 X 109/L)
    • Platelet count < 50,000/μL (50 X 109/L)
    • Serum aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase (SGPT) > 3.0 x upper limit of normal (ULN)
    • Serum total bilirubin > 2.0 mg/dL (with the exception of Gilbert's Syndrome)
  14. Uncontrolled hyperthyroidism or hypothyroidism
  15. Venous thromboembolism within one year
  16. ≥ Grade-2 neuropathy
  17. Uncontrolled autoimmune hemolytic anemia or thrombocytopenia
  18. Disease transformation (active) (i.e. Richter's Syndrome, prolymphocytic leukemia)
  19. Known allergy to allopurinol, if the subject has bulky disease
  20. Prisoners or subjects who are institutionalized by regulatory or court order
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01556776

Contacts
Contact: Central Study Office GCLLSG +4922147888220 cllstudie@uk-koeln.de

Locations
Germany
German CLL Study Group Recruiting
Cologne, Germany, 50937
Principal Investigator: Barbara Eichhorst, MD         
University Hospital Cologne Recruiting
Cologne, Germany, 50924
Contact: Barbara Eichhorst, MD    49 (0)221-478-88220    cllstudie@uk-koeln.de   
Principal Investigator: Michael Hallek, MD         
Sponsors and Collaborators
German CLL Study Group
Celgene Corporation
Investigators
Study Chair: Anna Fink, MD German CLL Study Group
Principal Investigator: Barbara Eichhorst, MD German CLL Study Group
  More Information

No publications provided

Responsible Party: German CLL Study Group
ClinicalTrials.gov Identifier: NCT01556776     History of Changes
Other Study ID Numbers: CLLM1 Protocol of the GCLLSG, 2011-004698-98, RV-CLL-GCLLSG-0725
Study First Received: March 14, 2012
Last Updated: August 27, 2012
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by German CLL Study Group:
CLL
High Risk
Maintenance

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Leukemia, B-Cell
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lenalidomide
Thalidomide
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Leprostatic Agents
Anti-Bacterial Agents
Anti-Infective Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors

ClinicalTrials.gov processed this record on July 20, 2014