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

Study Overview
=================
Brief Summary
-----------------
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.

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.

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)

Conditions
-----------------
B-Cell Chronic Lymphocytic Leukemia

Intervention / Treatment
-----------------
* Drug: Lenalidomide
* Drug: Chlorambucil


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Must sign an informed consent form. Age ≥ 65 years Must be able to adhere to the study visit schedule and other protocol requirements. Must have a documented diagnosis of B-cell CLL. Must have an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤2. Must agree to follow pregnancy precautions as required by the protocol. Must agree to receive counseling related to teratogenic and other risks of lenalidomide. Must agree not to donate blood or semen as defined by the protocol Exclusion Criteria: Prior treatment for B-cell CLL. Any medical condition, that would prevent the subject from signing the informed consent form. Active infections requiring systemic antibiotics. Systemic infection that has not resolved > 2 months prior to initiating lenalidomide Pregnant or lactating females. Participation in any clinical study or having taken any investigational therapy within 28 days. Known presence of alcohol and/or drug abuse. Central nervous system (CNS) involvement. 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) History of renal failure requiring dialysis. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and/or Hepatitis C Virus (HCV) infection. Prior therapy with lenalidomide. Evidence of TLS at screening Presence of specific hematology and/or chemistry abnormalities Uncontrolled hyperthyroidism or hypothyroidism Venous thromboembolism within one year ≥ Grade-2 neuropathy Uncontrolled autoimmune hemolytic anemia or thrombocytopenia Disease transformation [i.e. Richter's Syndrome (lymphomas) or prolymphocytic leukemia]

Ages Eligible for Study
-----------------
Minimum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1 - Lenalidomide<br>1 - Lenalidomide | Drug: Lenalidomide<br>* 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.<br>* Other names: Revlimid;|
| Active Comparator: 2- Chlorambucil<br>2- Chlorambucil | Drug: Chlorambucil<br>* 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).<br>* Other names: Leukeran;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kaplan-Meier Estimate of Progression Free Survival (PFS) | 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 | From first dose of study drug to date of data cut-off of 18 Feb 2013; up to approximately 39 months | 
| Kaplan-Meier Estimate of Progression Free Survival (PFS) With a Later Cut-off Date of 14 March 2014 | 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. | From randomization to data cut off date of 31 March 2014; median follow up time for all participants was 12.6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) | 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 | 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 | 
| Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 | 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 | From randomization to the data cut-off date of 31 March 2014; Up to 53 months; maximum duration of exposure for Lenalidomide was 1140 days and 406 days for Chlorambucil | 
| Percentage of Participants With the Best Overall Response Based on the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Guidelines | 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 | Up to data cut-off date of 18 Feb 2013; approximately 39 months | 
| Percentage of Participants With a Best Overall Response Based on IWCLL Guidelines With a Later Cut-off Date of 31 March 2014 | 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 | Up to data cut-off of 31 March 2014; approximately 53 months | 
| Kaplan-Meier Estimate for Duration of Response | 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) participants who had not progressed at the time of analysis; 2) participants who had withdrawn consent or were lost to follow-up prior to documentation of progression | Up to data cut-off of 18 Feb 2013; up to approximately 39 months | 
| Kaplan-Meier Estimate for Duration of Response With a Later Cut-off Date of 31 March 2014 | 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 | Up to data cut-off of 31 March 2014; up to approximately 53 months | 
| Time to Response | Time to response was calculated as the time from randomization to the first nPR, PR, CRi or CR based on IWCLL guidelines | Up to data cut-off of 18 Feb 2013; up to approximately 39 months | 
| Time to Response for a Later Cut-off Date of 31 March 2014 | Time to response was calculated as the time from randomization to the first nPR, PR, CRi or CR based on IWCLL guidelines | Up to data cut-off of 31 March 2014; up to approximately 53 months | 
| Kaplan Meier Estimate of Overall Survival | Overall Survival is defined as the time between randomization and death from any cause. | Up to data cut off of 31 March 2014; median follow-up for all participants was 18.8 months | 
| Kaplan Meier Estimate for Overall Survival at the Final Analysis | Overall Survival is defined as the time between randomization and death from any cause. Overall survival was censored at the last date that the subject was known to be alive for participants who were alive as of the data cutoff date and for participants who were lost to follow-up before death was documented. | Up to the last patient last visit date of 19 May 2018; median follow-up for all participants was 46.7 months | 
| Functional Assessment of Cancer Therapy-General to Create the FACT-Leukemia (FACT-Leu) Quality of Life Instrument | 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). | Day 1 and once every 8 weeks | 
| Euro Quality of Life Five Dimension (EQ-5D) Questionnaire | 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. | Day 1 and once every 8 weeks | 
| Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Subsequent anti-cancer therapies administered to participants following the discontinuation of study drug (either Lenalidomide or Chlorambucil) | Up to the last patient last visit date of 19 May 2018; median follow-up for all participants was 46.7 months |