Study of Lenalidomide to Evaluate Safety and Effectiveness in Patients With Diffuse Large B-Cell Lymphoma (DLBCL)

Study Overview
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Brief Summary
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The purpose of this study is to compare lenalidomide to a control drug and see which one delays Diffuse Large B-Cell Lymphoma (DLBCL) disease progression longer.

Detailed Description
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This research study is for patients who have been diagnosed with Diffuse Large B-cell Lymphoma (DLBCL) that did not respond to (refractory) or that has come back after chemotherapy treatment (relapsed). Lymphoma is a cancer of a type of blood cell called lymphocytes. DLBCL is just one type of lymphoma. Within DLBCL there are two different subtypes called Germinal Center B-cell (GCB) and non-GCB which can be determined by cell surface marker tests or by gene expression tests. Scientists can look at cells and genes in the laboratory and see that the two kinds are different, but they don't know yet what the difference means. To patients and doctors these two kinds seem the same. Right now doctors don't usually do tests to find out which kind a patient has because the treatment is the same for both. This study will have two stages, 1 and 2. The main purpose of Stage 1 is to separate patients by subtype and then test whether patients taking lenalidomide or any one of four other drugs have a better response. It is possible that lenalidomide will work better than one of the other drugs in zero, one, or both subtypes. Stage 2 will further test only the subtype(s) from Stage 1 that showed a good response to lenalidomide. The main purpose of Stage 2 is to test how long patients are disease free on lenalidomide compared to one of the four other drugs. On 29 January 2013 the enrolment goal for the Stage 1 portion of the study was met and enrollment was stopped. The final analysis for Stage 1 was performed as of the 04 Jul 2013 data cutoff date. According to the Stage 1 results as assessed by the independent response adjudication committee (IRAC), neither subtype met the pre specified requirement to be further studied in Stage 2. Additionally, a suitable assay for the selection of participants for the Stage 2 study was not available. Therefore, on 6 January 2014, Celgene decided to not open Stage 2.

Official Title
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A Phase 2/3, Multicenter, Randomized, Open-label Study to Compare the Efficacy and Safety of Lenalidomide (Revlimid ®) Versus Investigator's Choice in Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma

Conditions
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Diffuse Large B-cell Lymphoma

Intervention / Treatment
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* Drug: Lenalidomide
* Drug: Gemcitabine
* Drug: Oxaliplatin
* Drug: Rituximab
* Drug: Etoposide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven Diffuse Large B-Cell Lymphoma (DLBCL). Relapsed or refractory to combination chemotherapy for DLBCL that contains rituximab and an anthracycline, and one additional combination chemotherapy or stem cell transplant. Measurable DLBCL disease by computed tomograph (CT) / magnetic resonance imagining (MRI). Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2. Exclusion Criteria: Diagnosis of lymphoma histologies other than DLBCL. History of malignancies, other than DLBCL, unless the patient has been disease free for 3 years or more. Eligible for autologous stem cell transplant. Known seropositive for, or history of, active human immunodeficiency virus (HIV) hepatitis B virus (HBV), hepatitis C virus (HCV) Neuropathy grade 4.

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lenalidomide<br>Lenalidomide 25 mg capsules by mouth on days 1-21 of each 28 day cycle. For patients with Creatinine Clearance ≥ 30 mL/min but < 60 mL/min, lenalidomide 10 mg (max escalation is 15 mg). | Drug: Lenalidomide<br>* Lenalidomide 25 mg orally for 21/28 days until Diffuse Large B-Cell Lymphoma (DLBCL) progressive disease. For patients with Creatinine Clearance ≥ 30 mL/min but < 60 mL/min, lenalidomide 10 mg (max escalation is 15 mg).<br>|
| Active Comparator: Investigators Choice<br>One of the following: Gemcitabine, Oxaliplatin, Rituximab, or Etoposide | Drug: Gemcitabine<br>* Suggested starting doses and regimens for Gemcitabine is 1,250 mg/m^2 intravenous (IV) administration on days 1, 8, 15 every 28 days for 6 Cycles or 1,000 mg/m^2 IV days 1 and 15 every 28 days for 6 Cycles<br>Drug: Oxaliplatin<br>* Suggested starting dose and regimen for Oxaliplatin is 100 mg/m^2 IV day 1 for 21 days for 6 Cycles<br>Drug: Rituximab<br>* Suggested starting dose for Rituximab is 375 mg/m^2 IV days 1, 8, 15, 22 during Cycle 1, and if stable disease at Week 12, also on Day 1 of Cycles 4, 6, 8, and 10 (CD20+ patients only)<br>Drug: Etoposide<br>* Suggested starting doses for Etoposide are: 100 mg/m^2 IV days 1-5 every 28 days for 6 Cycles, or 100 mg/m^2 IV days 1-3 every 28 days for 6 Cycles, or 50 mg/m^2 oral days 1-21 every 28 days for 6 Cycles, or 50 mg/m^2 oral days 1-14 every 28 days for 6 Cycles, or 50 mg/m^2 oral days 1-10 every 28 days for 6 Cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stage 1: Percentage of Participants With an Overall Response According to the International Working Group (IWG) Response Criteria for Non Hodgkin's Lymphoma (NHL), Cheson 1999 and Evaluated by the Independent Response Adjudication Committee (IRAC) | An overall response is a complete response (CR), unconfirmed complete response (CRu) or partial response (PR) and was evaluated by the IRAC. A CR = complete disappearance of disease and related symptoms. Lymph nodes and nodal masses regressed on computed tomography to normal size (≤ 1.5 cm in their greatest transverse diameter for nodes > 1.5 cm prior to therapy and ≤ 1.0 cm in their short axis for nodes 1.1-1.5 cm in their long axis and > 1.0 cm in their short axis prior to therapy). Spleen and/or liver not palpable on exam, normal size by imaging, and absence of nodules related to lymphoma. If bone marrow was involved prior to therapy, infiltrate must have cleared on repeat biopsy. PR = ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses. No increase in other nodes, liver, or spleen. Splenic and hepatic nodules regressed by ≥ 50% in their SPD or for single nodules, in the greatest transverse diameter;no new disease. | From the date of randomization to the data cut-off of 4 July 2013; when all patients reached the scheduled 16-week assessment or had progressed/died before the scheduled 16-week assessment); the median study duration was 27.0 and 19.7 weeks, respectively. | 
| Stage 1: Percentage of Participants With an Overall Response According to the IWG Response Criteria Based on the Investigators Assessment at the Final Data Cut During the Core Treatment Phase | Response was defined as having a CR, CRu or PR, based on IWG 1999 Response Criteria for NHL as evaluated by the investigators. CR = complete disappearance of disease and disease related symptoms. All lymph nodes and nodal masses regressed on computed tomography to normal size (≤ 1.5 cm in their greatest transverse diameter for nodes > 1.5 cm prior to therapy and ≤ 1.0 cm in their short axis for nodes 1.1-1.5 cm in their long axis and > 1.0 cm in their short axis prior to therapy). Spleen and/or liver not palpable on physical exam, normal size by imaging, and absence of nodules related to lymphoma. If BM was involved prior to therapy, infiltrate must have cleared on repeat biopsy. PR = ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses. No increase in the other nodes, liver, or spleen. Splenic and hepatic nodules regressed by ≥ 50% in their SPD or, for single nodules, in the greatest transverse diameter. No new disease. | From the date of randomization to the final data cut-off date of 18 May 2018; median study duration was 27.0 and 19.7 weeks, respectively. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | A TEAE was defined as an AE that begins or worsens in intensity of frequency on or after the first dose of study drug through 28 days after last dose of study drug. A serious adverse event (SAE) is any: Death; Life-threatening event; Any inpatient hospitalization or prolongation of existing hospitalization; Persistent or significant disability or incapacity; Congenital anomaly or birth defect; Any other important medical event The investigator determined the relationship of an AE to study drug based on the timing of the AE relative to drug administration and whether or not other drugs, therapeutic interventions, or underlying conditions could provide a sufficient explanation for the event.The severity of an AE was evaluated by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 4.03) where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death | From first dose of study drug to the final data cut-off date of 18 May 2018; median study duration was 27.0 and 19.7 weeks, respectively. | 
| Stage 2: Overall Response Rate (ORR) | ORR is defined as: Complete Response + Complete Response unconfirmed + Partial Response based on the International Lymphoma Workshop Response Criteria [IWRC] (Cheson 1999). | Approximately 3.5 years | 
| Stage 2: Duration of Response (DoR) | Length of time of overall response (Complete Response + Complete Response unconfirmed + Partial Response) based on the International Lymphoma Workshop Response Criteria [IWRC] (Cheson 1999). | Approximately 3.5 years | 
| Stage 2: Overall Survival (OS) | Overall survival was defined as time from randomization until death of any cause. | Approximately 3.5 years | 
| Stage 2: Duration of Complete Response | Length of time of complete response (Complete Response + Complete Response unconfirmed) based on the International Lymphoma Workshop Response Criteria [IWRC] (Cheson 1999). | Approximately 3.5 years | 
| Stage 2: Overall Response Rate for With a Duration of Response Lasting ≥ 16 Weeks | Complete Response + Complete Response unconfirmed + Partial Response for participants with a duration of response lasting ≥ 16 weeks based on the International Lymphoma Workshop Response Criteria [IWRC] (Cheson 1999). | Approximately 3.5 years | 
| Stage 2: Time to Progression | Length of time until disease progression occurs | Approximately 3.5 years | 
| Stage 2: Health Related Quality of Life Questionnaires | Quality of Life based on the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and the EQ-5D assessments | Approximately 3.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diffuse Large B-Cell Lymphoma, Non Hodgkin's Lymphoma, relapsed, refractory, relapsed/refractory, DLBCL, Diffuse Large B Cell Lymphoma