Study of Lenalidomide to Evaluate Safety and Efficacy in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and effectiveness of different dose regimens of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).

Official Title
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A Phase 2, Multi-Center, Randomized, Double-Blinded, Parallel Group Study of the Safety and Efficacy of Different Lenalidomide (REVLIMID®) Dose Regimens in Subjects With Relapsed or Refractory B-Cell Chronic Lymphocytic Leukemia

Conditions
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Relapsed or Refractory Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: lenalidomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years at the time of signing the informed consent form Must be able to adhere to the study visit schedule and other protocol requirements Must have a documented diagnosis of B-cell CLL Must be relapsed or refractory to at least 1 regimen for treatment of CLL. At least one of the prior treatments must have included a purine analog-based or bendamustine-based regimen Must have an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 2. Exclusion Criteria: Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form Active infections requiring systemic antibiotics Systemic treatment for B-cell CLL within 28 days of initiation of lenalidomide treatment Alemtuzumab therapy within 120 days of initiating lenalidomide treatment Prior therapy with lenalidomide History of grade 4 rash due to prior thalidomide treatment Planned autologous or allogeneic bone marrow transplantation Central nervous system (CNS) involvement as documented by spinal fluid cytology or imaging. Uncontrolled hyperthyroidism or hypothyroidism Venous thromboembolism within 12 months ≥ Grade 2 neuropathy Uncontrolled autoimmune hemolytic anemia or thrombocytopenia Disease transformation [i.e. Richter's Syndrome (lymphomas) or prolymphocytic leukemia] Participation in any clinical study or having taken any investigational therapy within 28 days prior to initiating lenalidomide therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lenalidomide 5 mg<br>Participants received a starting dose of 5 mg lenalidomide orally once a day. Lenalidomide dose was escalated by 5 mg in a step-wise manner every 28 days up to a maximum dose of 25 mg daily based on tolerability. Participants continued receiving study drug until disease progression or unacceptable toxicity, unless they withdrew consent or had other reasons to discontinue from study drug | Drug: lenalidomide<br>* Depending on the starting dose, subjects will be allocated in a double-blind fashion to three different regimens and will escalate every 28 days, based on individual subject tolerability, as follows: Treatment Arm 1: 5 mg →10 mg →15 mg →20 mg →25 mg/daily Treatment Arm 2: 10 mg →15 mg →20 mg →25 mg/daily Treatment Arm 3: 15 mg →20 mg →25 mg/daily Subjects will continue treatment until disease progression or unacceptable toxicity<br>|
| Experimental: Lenalidomide 10 mg<br>Participants received a starting dose of 10 mg lenalidomide orally once a day. Lenalidomide dose was escalated by 5 mg in a step-wise manner every 28 days up to a maximum dose of 25 mg daily based on tolerability. Participants continued receiving study drug until disease progression or unacceptable toxicity, unless they withdrew consent or had other reasons to discontinue from study drug | Drug: lenalidomide<br>* Depending on the starting dose, subjects will be allocated in a double-blind fashion to three different regimens and will escalate every 28 days, based on individual subject tolerability, as follows: Treatment Arm 1: 5 mg →10 mg →15 mg →20 mg →25 mg/daily Treatment Arm 2: 10 mg →15 mg →20 mg →25 mg/daily Treatment Arm 3: 15 mg →20 mg →25 mg/daily Subjects will continue treatment until disease progression or unacceptable toxicity<br>|
| Experimental: Lenalidomide 15 mg<br>Participants received a starting dose of 15 mg lenalidomide orally once a day. Lenalidomide dose was escalated by 5 mg in a step-wise manner every 28 days up to a maximum dose of 25 mg daily based on tolerability. Participants continued receiving study drug until disease progression or unacceptable toxicity, unless they withdrew consent or had other reasons to discontinue from study drug | Drug: lenalidomide<br>* Depending on the starting dose, subjects will be allocated in a double-blind fashion to three different regimens and will escalate every 28 days, based on individual subject tolerability, as follows: Treatment Arm 1: 5 mg →10 mg →15 mg →20 mg →25 mg/daily Treatment Arm 2: 10 mg →15 mg →20 mg →25 mg/daily Treatment Arm 3: 15 mg →20 mg →25 mg/daily Subjects will continue treatment until disease progression or unacceptable toxicity<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events | Adverse events (AEs) were graded for severity by the investigator according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0 with the exceptions of hematologic toxicities and tumor lysis syndrome, according to the following scale: Grade 1 = Mild Grade 2 = Moderate Grade 3 = Severe Grade 4 = Life Threatening or disabling AE Grade 5 = Death The investigator determined the relationship of each AE to study drug based on the timing of the AE and whether other medications, therapeutic interventions, or underlying conditions could provide a sufficient explanation for the observed event. | From first dose of study drug to 30 days after the last dose; the maximum duration of treatment was 251, 265, and 267 weeks in the 5 mg, 10 mg, and 15 mg treatment groups respectively. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR was defined as the percentage of patients with a complete response (CR), CR with incomplete bone marrow (BM) recovery (CRi) or partial response (PR) during treatment. Response was assessed according to the 2008 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines. Per the guidelines, a CR required peripheral blood lymphocytes below 4 x 10^9/L, absence of lymphadenopathy, no hepatomegaly or splenomegaly, absence of disease and blood counts neutrophils >1.5 x 10^9/L, platelets >100 x 10^9/L, hemoglobin (hgb) >11g/dL) and BM at least normocellular for age. CRi = CR with incomplete BM recovery. PR = required at least 2 months from end of treatment, a ≥50% decrease in peripheral blood lymphocyte count from the pre-treatment value and either a ≥ 50% reduction in lymphadenopathy or ≥50% reduction of liver enlargement or ≥50% reduction of spleen enlargement plus neutrophils >1.5 x 10^9/ or ≥50% increase, platelets >100 x 10^9/L or ≥50% increase, hgb 11 g/dL. | Response was assessed after 3 cycles of therapy (Week 12) and every 4 weeks thereafter until disease progression. Maximum time on study was 91 months. | 
| Kaplan-Meier Estimate of Duration of Response | Duration of response (DOR) was defined as the time from the first visit where PR, CRi, or CR was documented to progressive disease (PD). Duration of response was censored at the last date that the participant was known to be progression-free for participants who had not progressed at the time of analysis or who withdrew consent or were lost to follow-up prior to documentation of progression. | Response was assessed after 3 cycles of therapy (Week 12) and every 4 weeks thereafter until disease progression. Maximum time on study was 91 months. | 
| Time to Response | Time to response (TTR) was calculated as the time from randomization to the first documented date of response (PR, CRi or CR) based on iwCLL guidelines for participants with an objective response during the treatment period. | Response was assessed after 3 cycles of therapy (Week 12) and every 4 weeks thereafter until disease progression. Maximum time on study was 91 months. | 
| Kaplan-Meier Estimate of Time to Progression | Time to progression (TTP) was defined as the time from randomization to the first documented progression. For participants who did not progress during the study, TTP was censored at the last adequate response assessment showing evidence of no disease progression. | From randomization until the end of the study; maximum time on study was 91 months. | 
| Kaplan-Meier Estimate of Event-Free Survival | Event-free survival (EFS) is the interval between the start of treatment to the first sign of disease progression, or treatment for relapse or death (whichever occurred first). If withdrawal of consent or loss 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 until the end of the study; maximum time on study was 91 months. | 
| Kaplan-Meier Estimate of Progression Free Survival | Progression-free survival (PFS) was calculated as the time from randomization to the first documented progression or death due to any cause during or after the treatment period, whichever occurred first. The progression date was assigned to the earliest time when any progression is observed without prior missing assessments. If withdrawal of consent or loss 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 until the end of the study; maximum time on study was 91 months. | 
| Kaplan-Meier Estimate of Overall Survival | Overall survival (OS) was defined as the time from randomization to death from any cause. Overall survival was censored at the last date that the participant was known to be alive for participants who were alive at the time of analysis and for participants who had withdrawn consent or were lost to follow-up before death was documented. | From randomization until the end of the study; maximum time on study was 91 months. |