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Trial record 1 of 1 for:    NCT00910910
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Study Of The Effectiveness & Safety Of Lenalidomide Versus Chlorambucil As First Line Therapy For Elderly Patients With B-Cell CLL (The ORIGIN Trial) (ORIGIN)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Celgene
ClinicalTrials.gov Identifier:
NCT00910910
First received: May 28, 2009
Last updated: January 30, 2017
Last verified: January 2017
  Purpose
The purpose of this study is to determine the safety and efficacy of lenalidomide as a first line therapy in treating patients with B-cell Chronic Lymphocytic Leukemia. This study will compare the effects (good and bad) of lenalidomide with chlorambucil.

Condition Intervention Phase
B-Cell Chronic Lymphocytic Leukemia (B-CLL)
Drug: Lenalidomide
Drug: Chlorambucil
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: A Phase 3, Multicenter, Randomized, Openlabel, Parallel-Group Study of the Efficacy and Safety of Lenalidomide (Revlimid®) Versus Chlorambucil as First-Line Therapy for Previously Untreated Elderly Patients With B-Cell Chronic Lymphocytic Leukemia (The Origin Trial)

Resource links provided by NLM:


Further study details as provided by Celgene:

Primary Outcome Measures:
  • Kaplan-Meier Estimate of Progression Free Survival (PFS) With a Later Cut-off of 31 March 2014 [ Time Frame: Data cut-off of 31 March 2014; up to approximately 53 months ]
    Progression-free survival was defined as the time from randomization to the first documented progression confirmed per investigator's assessment or death due to any cause on study, whichever occurred first. Progressive disease included lymphadenopathy, an appearance of any new lesion such as enlarged lymph nodes (> 1.5 cm), splenomegaly, hepatomegaly or other organ infiltrates, an increase by 50% or more in greatest determined diameter of any previous site or an increase by 50% or more in the sum of the product of diameters of multiple nodes. The progression date was assigned to the earliest time when any progression was observed without prior missing assessments. If withdrawal of consent or lost to follow-up occurred before documented progression or death, then these observations were censored at the date when the last complete tumor assessments determined a lack of progression.

  • Kaplan-Meier Estimate of Progression Free Survival (PFS) [ Time Frame: Data cut-off of 18 Feb 2013; up to approximately 39 months ]
    Progression-free survival was defined as the time from randomization to the first documented progression confirmed per investigator's assessment or death due to any cause on study, whichever occurred first. The progression date was assigned to the earliest time when any progression was observed without prior missing assessments. If withdrawal of consent or lost to follow-up occurred before documented progression or death, then these observations were censored at the date when the last complete tumor assessments determined a lack of progression


Secondary Outcome Measures:
  • Number of Participants With Adverse Events (AEs) [ Time Frame: From randomization up to data cut-off of 18 Feb 2013; Up to approximately 39 months; maximum duration of exposure for Lenalidomide was 1086 days and 406 days for Chlorambucil ]
    AEs = any noxious, unintended, or untoward medical occurrence that may appear or worsen during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, regardless of cause. Serious AE (SAE) = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs were graded based upon the participants symptoms according to the Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0); AEs were evaluated for severity according to the following scale: Grade 1 = Mild - transient or mild discomfort; no medical intervention required; Grade 2 = Moderate - mild to moderate limitation in activity; Grade 3 = Severe; Grade 4 = Life threatening; Grade 5 = Death

  • Number of Participants With Adverse Events (AEs) With a Later Cut-off of 31 March 2014 [ Time Frame: From randomization to the data cut-off of 31 March 2014; Up to 53 months; maximum duration of exposure for Lenalidomide was 1140 days and 406 days for Chlorambucil ]
    AEs = any noxious, unintended, or untoward medical occurrence that may appear or worsen during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, regardless of cause. Serious AE (SAE) = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs were graded based upon the participants symptoms according to the Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0); AEs were evaluated for severity according to the following scale: Grade 1 = Mild - transient or mild discomfort; no medical intervention required; Grade 2 = Moderate - mild to moderate limitation in activity; Grade 3 = Severe; Grade 4 = Life threatening; Grade 5 = Death

  • Kaplan-Meier Estimate for Duration of Response With a Later Cut-off of 31 March 2014 [ Time Frame: Up to data cut-off of 31 March 2014; up to approximately 53 months ]
    Duration of response was defined as the time from first nPR, PR, CRi, or CR to PD. Duration of response was censored at the last date that the patient was known to be progression-free for: 1) patients who had not progressed at the time of analysis; 2) patients who had withdrawn consent or were lost to follow-up prior to documentation of progression

  • Time to Response for a Later Cut-off of 31 March 2014 [ Time Frame: Up to data cut-off of 31 March 2014; up to approximately 53 months ]
    Time to response was calculated as the time from randomization to the first nPR, PR, CRi or CR based on IWCLL guidelines

  • Kaplan Meier Estimate for Overall Survival [ Time Frame: Up to data cut off of 18 Feb 2013; up to approximately 39 months; ]
    Overall Survival is defined as the time between randomization and death from any cause..

  • Kaplan Meier Estimate of Overall Survival for a Later Cut-off of 31 March 2014 [ Time Frame: Up to data cut off of 31 March 2014; up to approximately 53 months; median follow-up was 18.8 months ]
    Overall Survival is defined as the time between randomization and death from any cause.

  • Functional Assessment of Cancer Therapy-General to Create the FACT-Leukemia (FACT-Leu) Quality of Life Instrument [ Time Frame: Day 1 and once every 8 weeks ]
    The FACT-Leu scale is a valid, reliable, and efficient measure of leukemia-specific health-related quality of life for acute and chronic disease. The FACT-Leu is described as including 27 items that assess 17 physical symptoms (fevers, bleeding, general pain, stomach pain, chills, night sweats, bruising, lymph node swelling, weakness, tiredness, weight loss, appetite, shortness of breath, functional ability, diarrhea, concentration, and mouth sores) and 10 emotional/social concerns (frustration with activity limitation, discouraged by illness, future planning, uncertainty, worry about illness, emotional lability, isolation, infertility concern, family worry, and worry about infections).

  • Euro Quality of Life Five Dimension (EQ-5D) Questionnaire [ Time Frame: Day 1 and once every 8 weeks ]
    The standardized extended version of EQ-5D was designed for the collection of health state values using a visual analogue scale (VAS) rating scale - a vertical 20 cm visual analogue scale with the end points labeled best imaginable health state at the top and worst imaginable health state at the bottom having numeric values of 100 and 0 respectively. The participant is asked to indicate his/her health state by ticking (or placing a cross) in the box against the most appropriate statement in each of the 5 dimensions.

  • Percentage of Participants With the Best Overall Response Based on the International Workshop on Chronic Lymphocytic Leukemia Guidelines (IWCLL) Guidelines [ Time Frame: Up to data cut-off of 18 Feb 2013; approximately 39 months ]

    A best overall response rate is a CR, CRi, nPR or PR and is defined as:

    Complete Remission (CR):

    • No lymphadenopathy
    • No hepatomegaly or splenomegaly
    • Absence of constitutional symptoms
    • Polymorphonuclear leukocytes ≥ 1500/ul
    • No circulating clonal B-lymphocytes
    • Platelets > 100,000/ul
    • Hemoglobin > 11.0 g/dl
    • Normocellular <30% lymphocytes, no B-lymphoid nodules;

    Incomplete Clinical Response (CRi):

    • CR without bone marrow biopsy confirmation.

    Nodular Partial Response (nPR):

    • CR with the presence of residual clonal nodules.

    Partial Response (PR) requires:

    • ≥ 50% decrease in peripheral blood lymphocyte count
    • ≥ 50% reduction in lymphadenopathy
    • ≥ 50% reduction in size of liver and/or spleen
    • 1 or more of the following:
    • Polymorphonuclear leukocytes ≥ 1500/ul
    • Platelets >100,000/ul

  • Percentage of Participants With Overall Response Based on IWCLL Guidelines With a Later Cut-off of 31 March 2014 [ Time Frame: Up to data cut-off of 31 March 2014; approximately 53 months ]

    A best overall response rate is a CR, CRi, nPR or PR and is defined as:

    Complete Remission (CR):

    • No lymphadenopathy
    • No hepatomegaly or splenomegaly
    • Absence of constitutional symptoms
    • Polymorphonuclear leukocytes ≥ 1500/ul
    • No circulating clonal B-lymphocytes
    • Platelets > 100,000/ul
    • Hemoglobin > 11.0 g/dl
    • Normocellular <30% lymphocytes, no B-lymphoid nodules;

    Incomplete Clinical Response (CRi):

    • CR without bone marrow biopsy confirmation.

    Nodular Partial Response:

    • CR with the presence of residual clonal nodules.

    Partial Response requires:

    • ≥ 50% decrease in peripheral blood lymphocyte count
    • ≥ 50% reduction in lymphadenopathy
    • ≥ 50% reduction in size of liver and/or spleen
    • 1 or more of the following:
    • Polymorphonuclear leukocytes ≥ 1500/ul
    • Platelets >100,000/ul

  • Kaplan-Meier Estimate for Duration of Response [ Time Frame: Up to data cut-off of 18 Feb 2013; up to approximately 39 months ]
    Duration of response was defined as the time from first nPR, PR, CRi, or CR to PD. Duration of response was censored at the last date that the patient was known to be progression-free for: 1) patients who had not progressed at the time of analysis; 2) patients who had withdrawn consent or were lost to follow-up prior to documentation of progression

  • Time to Response [ Time Frame: Up to data cut-off of 18 Feb 2013; up to approximately 39 months ]
    Time to response was calculated as the time from randomization to the first nPR, PR, CRi or CR based on IWCLL guidelines

  • Number of Participants With Subsequent Anti-cancer Therapies Received Post Treatment [ Time Frame: Up to data cut-off of 31 March 2014; up to approximately 53 months ]
    Subsequent anti-cancer therapies administered to participants following the discontinuation of study drug (either Lenalidomide or Chlorambucil)


Enrollment: 450
Study Start Date: October 2009
Estimated Study Completion Date: April 2018
Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1 - Lenalidomide
1 - Lenalidomide
Drug: Lenalidomide

For patients with normal renal function (defined as CrCl ≥ 60 mL/min), 5 mg once daily on Days 1 through 28 of the first 28-day cycle, 10 mg once daily on Days 1 through 28 starting at the second cycle, 15 mg once daily starting at the third cycle and for the remainder of the study until PD or unacceptable toxicity, whichever occurs first.

For patients with moderate renal impairment (defined as CrCl ≥ 30 to < 60 mL/min), 2.5 mg once daily on Days 1 through 28 of the first 28-day cycle, 5 mg once daily on Days 1 through 28 starting at the second cycle, 7.5 mg once daily starting at the third cycle and for the remainder of the study until PD or unacceptable toxicity, whichever occurs first.

Other Name: Revlimid
Active Comparator: 2- Chlorambucil
2- Chlorambucil
Drug: Chlorambucil
Patients assigned to the chlorambucil arm will receive oral chlorambucil tablets at 0.8 mg/kg on Days 1 and 15 of each 28-day cycle for a total duration of 12 months (approximately 13 cycles).
Other Name: Leukeran

Detailed Description:
After notification from the US Food and Drug Administration (FDA) on 12 July 2013, Celgene agreed to discontinue the lenalidomide treatment for all patients due to an imbalance in the number of deaths in patients treated with lenalidomide versus patients treated with chlorambucil. No specific causality for this imbalance has been identified to date. Investigators were instructed to immediately discontinue all participants from experimental lenalidomide treatment and inform their patients accordingly. Participants on the Chlorambucil arm may continue up to 12 months (13 cycles) with the last participant completing in March 2014. All randomized participants will continue to be followed for overall survival and secondary primary malignancies.
  Eligibility

Ages Eligible for Study:   65 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Must sign an informed consent form.
  2. Age ≥ 65 years
  3. Must be able to adhere to the study visit schedule and other protocol requirements.
  4. Must have a documented diagnosis of B-cell CLL.
  5. Must have an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤2.
  6. Must agree to follow pregnancy precautions as required by the protocol.
  7. Must agree to receive counseling related to teratogenic and other risks of lenalidomide.
  8. Must agree not to donate blood or semen as defined by the protocol

Exclusion Criteria:

  1. Prior treatment for B-cell CLL.
  2. Any medical condition, that would prevent the subject from signing the informed consent form.
  3. Active infections requiring systemic antibiotics.
  4. Systemic infection that has not resolved > 2 months prior to initiating lenalidomide
  5. Pregnant or lactating females.
  6. Participation in any clinical study or having taken any investigational therapy within 28 days.
  7. Known presence of alcohol and/or drug abuse.
  8. Central nervous system (CNS) involvement.
  9. Prior history of malignancies, other than CLL, unless the subject has been free of the disease for ≥3 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 histologic finding of prostate cancer (TNM stage of T1a or T1b)
  10. History of renal failure requiring dialysis.
  11. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and/or Hepatitis C Virus (HCV) infection.
  12. Prior therapy with lenalidomide.
  13. Evidence of TLS at screening
  14. Presence of specific hematology and/or chemistry abnormalities
  15. Uncontrolled hyperthyroidism or hypothyroidism
  16. Venous thromboembolism within one year
  17. ≥ Grade-2 neuropathy
  18. Uncontrolled autoimmune hemolytic anemia or thrombocytopenia
  19. Disease transformation [i.e. Richter's Syndrome (lymphomas) or prolymphocytic leukemia]
  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: NCT00910910

  Show 165 Study Locations
Sponsors and Collaborators
Celgene
Investigators
Study Director: Ken Takeshita, MD Celgene Corporation
  More Information

Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT00910910     History of Changes
Other Study ID Numbers: CC-5013-CLL-008
2008-003079-32 ( EudraCT Number )
Study First Received: May 28, 2009
Results First Received: September 23, 2015
Last Updated: January 30, 2017

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

ClinicalTrials.gov processed this record on April 24, 2017