Fludarabine, Rituximab, and Lenalidomide in Minimally Treated/Untreated Patients With Chronic Lymphocytic Leukemia (CLL)

Sponsor
SCRI Development Innovations, LLC (Other)
Overall Status
Completed
CT.gov ID
NCT00536341
Collaborator
Celgene Corporation (Industry), Genentech, Inc. (Industry)
64
6
1
106
10.7
0.1

Study Details

Study Description

Brief Summary

This phase I/II trial will combine fludarabine, rituximab, and lenalidomide in untreated or minimally treated (Phase I only) CLL patients, employing fixed doses of fludarabine and rituximab, using a schedule similar to that examined by investigators at MD Anderson (J Clin Oncol 23(18):4079-88, 2005). Given that the optimal dose and schedule is not currently known, this trial will perform a phase I component followed by a phase II examination to further explore this regimen's activity.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Detailed Description

While progress has been made in treating CLL patients over the last decade, a cure remains elusive for many patients treated with standard therapies. The combination of fludarabine, a purine analog, and rituximab, a monoclonal antibody, is an effective and frequently used therapy for CLL. However, this drug combination is associated with increased toxicity. Lenalidomide has been shown to be less toxic and has been used to treat hematologic malignancies including CLL. We propose this Phase I/Phase II study to examine the combination of lenalidomide with a rituximab/fludarabine backbone.

Study Design

Study Type:
Interventional
Actual Enrollment :
64 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I/II Study of Fludarabine, Rituximab, and Lenalidomide in Minimally Treated and Untreated Patients With Chronic Lymphocytic Leukemia
Study Start Date :
Jan 1, 2008
Actual Primary Completion Date :
Apr 1, 2013
Actual Study Completion Date :
Nov 1, 2016

Arms and Interventions

Arm Intervention/Treatment
Experimental: lenalidomide, fludarabine, rituximab

Phase I Non-stratified, dose-escalation: >=3 patients per dose level. Safety and tolerability will be evaluated every 2 weeks during the active treatment. Doses of lenalidomide will be escalated, while the fludarabine and rituximab doses remain fixed. Phase II The Phase II regimen will be chosen following a review of the Phase I data. Following selection of the Phase II schedule, 40 treatment naive patients will be enrolled and treated with the Phase II regimen every 28 days for up to 6 courses. For those patients achieving a CR after 3 cycles, one additional cycle of treatment will be administered beyond CR confirmation.

Drug: lenalidomide
2.5 mg orally (PO) daily, Days 8-28, Cycle 1; 5.0 mg PO daily, Days 8-28 Cycles 2-6
Other Names:
  • Revlimid
  • Drug: Rituximab
    375 mg/m2 Cycle 1 (split over Day 1 & Day 2); 500 mg/m2 Day 1 of Cycles 2-6
    Other Names:
  • Rituxan
  • Drug: Fludarabine
    25 mg/m2 on Days 1, 2, and 3
    Other Names:
  • Fludara
  • Outcome Measures

    Primary Outcome Measures

    1. Number of Adverse Events as a Measure of Safety and Tolerability [63 months]

      Recorded from first treatment until 30 days after last treatment and assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

    2. Complete Response Rate [At 12 weeks during treatment and 2 months post-treatment until disease progression, projected 8 months]

      An improvement in complete response to at least 60% following treatment, assessed using CT scans, clinical/lab examinations, and bone marrow aspirations, as defined by National Cancer Institute Working Group Response Criteria.

    Secondary Outcome Measures

    1. Progression-Free Survival [Every 3 months during treatment until disease progression and every 6 months thereafter, up to 5 years]

      Measured from first treatment to disease progression and assessed using Kaplan-Meier methods.

    2. Overall Survival [Every 3 months until treatment discontinuation, expected average of 6 months and then every 6 months thereafter up to 5 years]

      Defined as the time from Day 1 of treatment administration to date of death from any cause, estimated using Kaplan-Meier methods.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Understand and voluntarily sign an informed consent form.

    • Able to adhere to the study visit schedule and other protocol requirements.

    • Age >=18 years at the time of signing the informed consent form.

    • Patient must have histopathologically confirmed B-cell CLL

    • For Phase I only: Untreated or minimally treated patients (patients who have received only prior single agent rituximab) are eligible. For those patients who have had rituximab monotherapy, last dose must be greater than 90 days prior to beginning study treatment.

    • For Phase II only: Untreated B-cell CLL patients only.

    • Rai staging, will be employed. Patients must have Rai stage III/IV disease (irrespective of symptoms) OR symptomatic Rai stage 0-II disease, requiring therapy as defined by NCI 1996 guidelines.

    • Platelets must be > 75,000/mm3 and absolute neutrophil count must be > 1000/mm3 within 14 days of starting protocol treatment unless treating physicians deems the neutropenia is related to marrow involvement and then ANC > 750/mm3 is allowed.

    • Serum creatinine <=2.0 mg/dl obtained within 14 days of starting protocol treatment. Creatinine clearance as determined by the Cockroft-Gault formula, using ideal body weight, must be > 30 mL/minute.

    • AST or ALT must be < 3 x the upper limit of normal within 14 days of starting treatment.

    • ECOG performance of 0, 1 or 2.

    • Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to and again within 24 hours of starting lenalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure.

    • Disease free of prior malignancies for >= 2 years (including carcinoma in situ of the cervix or breast) treated with curative intent and anticipated 5 year disease-free survival is greater than 90%. Any basal cell or squamous cell carcinoma of the skin treated with curative intent is permitted.

    • Able to take aspirin (325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use low molecular weight heparin).

    Exclusion Criteria:
    • Major surgery less than 28 days prior to study treatment.

    • Any prior use of lenalidomide or thalidomide.

    • Concurrent use of other anti-cancer therapies.

    • Pregnant or breast feeding females. (Lactating females may be considered if they agree not to breast feed while receiving study treatment and until 12 months following last dose of rituximab).

    • History of pulmonary embolus or deep vein thrombosis.

    • Clinically significant heart dysfunction, defined as New York Heart Association class III or IV, at the time of screening, or history of myocardial infarction or heart failure within 6 months preceding the first study treatment (cardiac ejection fraction must be >= 50% within 8 weeks of beginning study treatment for any patient with a history of clinically significant heart dysfunction).

    • Known positive for HIV, hepatitis B surface Ag, hepatitis B core antibody, or hepatitis C. Mandatory testing is not required, but should be considered in patients deemed high risk or suspicious.

    • Active infection requiring oral or intravenous antibiotics at study entry. After infection resolves patient may be evaluated for enrollment.

    • Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura.

    • Richter's transformation.

    • CNS involvement.

    • Other severe, acute, or chronic medical or psychiatric condition, laboratory abnormality, or difficulty complying with protocol requirements that may increase the risk associated with study participation or study drug administration or may interfere with interpretation of study results that in the judgment of the investigator would make the patient inappropriate for this study or that would prevent the patient from signing the informed consent form.

    • Use of any other biologic agent or disease-modifying anti-rheumatic drugs (DMARDS).

    • Known anaphylaxis or IgE-mediated hypersensitivity to murine proteins or any component of rituximab.

    • Evidence of laboratory TLS by Cairo-Bishop criteria (subjects may be enrolled upon correction of electrolyte abnormalities).

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Florida Cancer Specialists Fort Myers Florida United States 33901
    2 Florida Hospital Cancer Institute Orlando Florida United States 32804
    3 Center for Cancer and Blood Disorders Bethesda Maryland United States 20817
    4 National Capital Clinical Research Consortium Bethesda Maryland United States 20817
    5 South Carolina Oncology Associates, PA Columbia South Carolina United States 29210
    6 Tennessee Oncology, PLLC Nashville Tennessee United States 37023

    Sponsors and Collaborators

    • SCRI Development Innovations, LLC
    • Celgene Corporation
    • Genentech, Inc.

    Investigators

    • Study Chair: Ian W. Flinn, M.D., SCRI Development Innovations, LLC

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    SCRI Development Innovations, LLC
    ClinicalTrials.gov Identifier:
    NCT00536341
    Other Study ID Numbers:
    • SCRI CLL 02
    First Posted:
    Sep 27, 2007
    Last Update Posted:
    Jan 16, 2017
    Last Verified:
    Nov 1, 2016

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Dose Level 1 Dose Level 2
    Arm/Group Description Rituximab 375 mg/m^2 cycle 1 (split over Day 1 & Day 2), 500 mg/m^2 Day 1 of cycles 2-6 Fludarabine 25 mg/m^2 on days 1, 2 and 3 Lenalidomide 2.5 mg PO daily Days 8-28 all cycles 1-6 Rituximab 375 mg/m^2 cycle 1 (split over Day 1 & Day 2), 500 mg/m^2 Day 1 of cycles 2-6 Fludarabine 25 mg/m^2 on days 1, 2 and 3 Lenalidomide 2.5 mg PO daily Days 8-28 cycle 1, 5.0 mg PO days 8-28 cycles 2-6
    Period Title: Overall Study
    STARTED 10 54
    COMPLETED 5 43
    NOT COMPLETED 5 11

    Baseline Characteristics

    Arm/Group Title Dose Level 1 Dose Level 2 Total
    Arm/Group Description Rituximab 375 mg/m^2 cycle 1 (split over Day 1 & Day 2), 500 mg/m^2 Day 1 of cycles 2-6 Fludarabine 25 mg/m^2 on days 1, 2 and 3 Lenalidomide 2.5 mg PO daily Days 8-28 all cycles 1-6 Rituximab 375 mg/m^2 cycle 1 (split over Day 1 & Day 2), 500 mg/m^2 Day 1 of cycles 2-6 Fludarabine 25 mg/m^2 on days 1, 2 and 3 Lenalidomide 2.5 mg PO daily Days 8-28 cycle 1, 5.0 mg PO days 8-28 cycles 2-6 Total of all reporting groups
    Overall Participants 10 54 64
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    67
    63
    64
    Gender (Count of Participants)
    Female
    2
    20%
    25
    46.3%
    27
    42.2%
    Male
    8
    80%
    29
    53.7%
    37
    57.8%
    Region of Enrollment (participants) [Number]
    United States
    10
    100%
    54
    100%
    64
    100%

    Outcome Measures

    1. Primary Outcome
    Title Number of Adverse Events as a Measure of Safety and Tolerability
    Description Recorded from first treatment until 30 days after last treatment and assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
    Time Frame 63 months

    Outcome Measure Data

    Analysis Population Description
    All treated patients
    Arm/Group Title Dose Level 1 Dose Level 2
    Arm/Group Description Rituximab 375 mg/m^2 cycle 1 (split over Day 1 & Day 2), 500 mg/m^2 Day 1 of cycles 2-6 Fludarabine 25 mg/m^2 on days 1, 2 and 3 Lenalidomide 2.5 mg PO daily Days 8-28 all cycles 1-6 Rituximab 375 mg/m^2 cycle 1 (split over Day 1 & Day 2), 500 mg/m^2 Day 1 of cycles 2-6 Fludarabine 25 mg/m^2 on days 1, 2 and 3 Lenalidomide 2.5 mg PO daily Days 8-28 cycle 1, 5.0 mg PO days 8-28 cycles 2-6
    Measure Participants 10 54
    Fatigue
    8
    80%
    40
    74.1%
    Neutropenia
    7
    70%
    41
    75.9%
    Anemia
    8
    80%
    34
    63%
    Leukopenia
    7
    70%
    34
    63%
    Thrombocytopenia
    8
    80%
    30
    55.6%
    Rash
    6
    60%
    27
    50%
    Nausea
    7
    70%
    25
    46.3%
    Constipation
    3
    30%
    15
    27.8%
    Anorexia
    4
    40%
    12
    22.2%
    Fever
    3
    30%
    13
    24.1%
    Hyperhidrosis
    3
    30%
    13
    24.1%
    Arthralgia
    1
    10%
    14
    25.9%
    Edema Limbs
    3
    30%
    12
    22.2%
    Pruritus
    0
    0%
    15
    27.8%
    Back pain
    3
    30%
    11
    20.4%
    Headache
    1
    10%
    13
    24.1%
    Chills
    2
    20%
    11
    20.4%
    Insomnia
    2
    20%
    11
    20.4%
    Vomiting
    2
    20%
    11
    20.4%
    Dysgeusia
    1
    10%
    11
    20.4%
    Abdominal Pain
    2
    20%
    9
    16.7%
    Allergic Reaction
    4
    40%
    7
    13%
    Diarrhea
    3
    30%
    8
    14.8%
    Cough
    2
    20%
    8
    14.8%
    Dizziness
    2
    20%
    8
    14.8%
    Dyspnea
    0
    0%
    10
    18.5%
    Hypotension
    1
    10%
    9
    16.7%
    Myalgia
    2
    20%
    8
    14.8%
    2. Primary Outcome
    Title Complete Response Rate
    Description An improvement in complete response to at least 60% following treatment, assessed using CT scans, clinical/lab examinations, and bone marrow aspirations, as defined by National Cancer Institute Working Group Response Criteria.
    Time Frame At 12 weeks during treatment and 2 months post-treatment until disease progression, projected 8 months

    Outcome Measure Data

    Analysis Population Description
    All patients deemed evaluable and evaluated for response
    Arm/Group Title Dose Level 1 Dose Level 2
    Arm/Group Description Rituximab 375 mg/m^2 cycle 1 (split over Day 1 & Day 2), 500 mg/m^2 Day 1 of cycles 2-6 Fludarabine 25 mg/m^2 on days 1, 2 and 3 Lenalidomide 2.5 mg PO daily Days 8-28 all cycles 1-6 Rituximab 375 mg/m^2 cycle 1 (split over Day 1 & Day 2), 500 mg/m^2 Day 1 of cycles 2-6 Fludarabine 25 mg/m^2 on days 1, 2 and 3 Lenalidomide 2.5 mg PO daily Days 8-28 cycle 1, 5.0 mg PO days 8-28 cycles 2-6
    Measure Participants 9 41
    Number [participants]
    4
    40%
    9
    16.7%
    3. Secondary Outcome
    Title Progression-Free Survival
    Description Measured from first treatment to disease progression and assessed using Kaplan-Meier methods.
    Time Frame Every 3 months during treatment until disease progression and every 6 months thereafter, up to 5 years

    Outcome Measure Data

    Analysis Population Description
    All treated patients, all dose levels
    Arm/Group Title All Patients
    Arm/Group Description
    Measure Participants 64
    Median (95% Confidence Interval) [months]
    24.64
    4. Secondary Outcome
    Title Overall Survival
    Description Defined as the time from Day 1 of treatment administration to date of death from any cause, estimated using Kaplan-Meier methods.
    Time Frame Every 3 months until treatment discontinuation, expected average of 6 months and then every 6 months thereafter up to 5 years

    Outcome Measure Data

    Analysis Population Description
    All treated patients, all dose levels
    Arm/Group Title All Patients
    Arm/Group Description
    Measure Participants 64
    Median (95% Confidence Interval) [months]
    NA

    Adverse Events

    Time Frame 63 months
    Adverse Event Reporting Description
    Arm/Group Title Dose Level 1 Dose Level 2
    Arm/Group Description Rituximab 375 mg/m^2 cycle 1 (split over Day 1 & Day 2), 500 mg/m^2 Day 1 of cycles 2-6 Fludarabine 25 mg/m^2 on days 1, 2 and 3 Lenalidomide 2.5 mg PO daily Days 8-28 all cycles 1-6 Rituximab 375 mg/m^2 cycle 1 (split over Day 1 & Day 2), 500 mg/m^2 Day 1 of cycles 2-6 Fludarabine 25 mg/m^2 on days 1, 2 and 3 Lenalidomide 2.5 mg PO daily Days 8-28 cycle 1, 5.0 mg PO days 8-28 cycles 2-6
    All Cause Mortality
    Dose Level 1 Dose Level 2
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    Dose Level 1 Dose Level 2
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/10 (20%) 16/54 (29.6%)
    Gastrointestinal disorders
    Abdominal pain 1/10 (10%) 1/54 (1.9%)
    Diarrhea 0/10 (0%) 1/54 (1.9%)
    Mucositis 0/10 (0%) 1/54 (1.9%)
    Nausea 0/10 (0%) 1/54 (1.9%)
    General disorders
    Chills 0/10 (0%) 1/54 (1.9%)
    Edema limbs 0/10 (0%) 1/54 (1.9%)
    Fatigue 0/10 (0%) 1/54 (1.9%)
    Fever 0/10 (0%) 2/54 (3.7%)
    Immune system disorders
    Allergic Reaction 0/10 (0%) 1/54 (1.9%)
    Infections and infestations
    Bronchial Infection 0/10 (0%) 2/54 (3.7%)
    Infections and infestations - Other, gastrointestinal infection NOS 0/10 (0%) 1/54 (1.9%)
    Infections and infestations - Other, pneumonia 1/10 (10%) 1/54 (1.9%)
    Infections and infestations - Other, unspecified 0/10 (0%) 1/54 (1.9%)
    Sepsis 0/10 (0%) 1/54 (1.9%)
    Investigations
    Lymphocyte count decreased 0/10 (0%) 1/54 (1.9%)
    Neutrophil count decreased 0/10 (0%) 1/54 (1.9%)
    White blood cell decreased 0/10 (0%) 2/54 (3.7%)
    Metabolism and nutrition disorders
    Tumor Lysis Syndrome 0/10 (0%) 1/54 (1.9%)
    Musculoskeletal and connective tissue disorders
    Generalized muscle weakness 0/10 (0%) 1/54 (1.9%)
    Skin and subcutaneous tissue disorders
    Rash 0/10 (0%) 2/54 (3.7%)
    Other (Not Including Serious) Adverse Events
    Dose Level 1 Dose Level 2
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 10/10 (100%) 54/54 (100%)
    Blood and lymphatic system disorders
    Anemia 8/10 (80%) 34/54 (63%)
    Febrile neutropenia 0/10 (0%) 4/54 (7.4%)
    Gastrointestinal disorders
    Nausea 7/10 (70%) 25/54 (46.3%)
    Constipation 3/10 (30%) 15/54 (27.8%)
    Vomiting 2/10 (20%) 11/54 (20.4%)
    Abdominal pain 2/10 (20%) 9/54 (16.7%)
    Diarrhea 3/10 (30%) 8/54 (14.8%)
    Gastroesophageal reflux disease 1/10 (10%) 7/54 (13%)
    Mucositis 0/10 (0%) 6/54 (11.1%)
    General disorders
    Fatigue 8/10 (80%) 40/54 (74.1%)
    Fever 3/10 (30%) 13/54 (24.1%)
    Edema limbs 3/10 (30%) 12/54 (22.2%)
    Chills 2/10 (20%) 11/54 (20.4%)
    Immune system disorders
    Allergic reaction 4/10 (40%) 7/54 (13%)
    Infections and infestations
    Sinusitis 0/10 (0%) 7/54 (13%)
    Infections and infestations - Other, unspecified 1/10 (10%) 4/54 (7.4%)
    Upper respiratory infection 0/10 (0%) 4/54 (7.4%)
    Investigations
    Neutrophil count decreased 7/10 (70%) 41/54 (75.9%)
    White blood cell decreased 7/10 (70%) 34/54 (63%)
    Platelet count decreased 8/10 (80%) 30/54 (55.6%)
    Aspartate aminotransferase increased 0/10 (0%) 8/54 (14.8%)
    Alanine aminotransferase increased 1/10 (10%) 5/54 (9.3%)
    Alkaline phosphatase increased 1/10 (10%) 5/54 (9.3%)
    Investigations - Other, LDH increased 0/10 (0%) 5/54 (9.3%)
    Blood bilirubin increased 0/10 (0%) 4/54 (7.4%)
    Metabolism and nutrition disorders
    Anorexia 4/10 (40%) 12/54 (22.2%)
    Hyperkalemia 2/10 (20%) 6/54 (11.1%)
    Dehydration 0/10 (0%) 5/54 (9.3%)
    Hyperglycemia 0/10 (0%) 4/54 (7.4%)
    Hyponatremia 1/10 (10%) 3/54 (5.6%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 1/10 (10%) 14/54 (25.9%)
    Back pain 3/10 (30%) 11/54 (20.4%)
    Myalgia 2/10 (20%) 8/54 (14.8%)
    Pain in extremity 1/10 (10%) 7/54 (13%)
    Flank pain 1/10 (10%) 3/54 (5.6%)
    Nervous system disorders
    Headache 1/10 (10%) 13/54 (24.1%)
    dysgeusia 1/10 (10%) 11/54 (20.4%)
    Dizziness 2/10 (20%) 8/54 (14.8%)
    Peripheral sensory neuropathy 2/10 (20%) 7/54 (13%)
    Tremor 1/10 (10%) 4/54 (7.4%)
    Psychiatric disorders
    Insomnia 2/10 (20%) 11/54 (20.4%)
    depression 0/10 (0%) 5/54 (9.3%)
    Respiratory, thoracic and mediastinal disorders
    Cough 2/10 (20%) 8/54 (14.8%)
    Dyspnea 0/10 (0%) 10/54 (18.5%)
    Allergic rhinitis 3/10 (30%) 4/54 (7.4%)
    Nasal congestion 1/10 (10%) 6/54 (11.1%)
    Epistaxis 0/10 (0%) 4/54 (7.4%)
    Sore throat 2/10 (20%) 2/54 (3.7%)
    Skin and subcutaneous tissue disorders
    Rash 6/10 (60%) 27/54 (50%)
    Hyperhidrosis 3/10 (30%) 13/54 (24.1%)
    Pruritus 0/10 (0%) 15/54 (27.8%)
    Dry skin 0/10 (0%) 7/54 (13%)
    Skin and subcutaneous tissue disorders - Other, erythema 3/10 (30%) 1/54 (1.9%)
    Vascular disorders
    Hypotension 1/10 (10%) 9/54 (16.7%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The sponsor can review/embargo results communications prior to public release for a period that is >60 but =180 days from date submitted to sponsor, who may require changes to the communication in order to remove specifically identified confidential information (other than study data) and/or delay the proposed publication to enable the sponsor to seek patent protection for inventions. The PI may not publish its results until 18 mos. after the trial has been completed at all sites

    Results Point of Contact

    Name/Title John D Hainsworth, MD
    Organization Sarah Cannon Research Institute
    Phone 1-877-691-7274
    Email asksarah@scresearch.net
    Responsible Party:
    SCRI Development Innovations, LLC
    ClinicalTrials.gov Identifier:
    NCT00536341
    Other Study ID Numbers:
    • SCRI CLL 02
    First Posted:
    Sep 27, 2007
    Last Update Posted:
    Jan 16, 2017
    Last Verified:
    Nov 1, 2016