Follicular Lymphoma
Conditions
Keywords
Follicular lymphoma, Non-Hodgkins Follicular Lymphoma, treatment for Follicular Lymphoma, rituximab treatment, rituximab and lenalidomide treatment
Brief summary
The purpose of this study is to evaluate the effect of the combined treatment of lenalidomide and rituximab in controlling the Follicular Lymphoma disease and also increase the length of response compared to the available standard combination chemotherapy treatment for Follicular Lymphoma.
Detailed description
Follicular Lymphoma (FL) is a cancer of a B lymphocyte, a type of white blood cell. FL is typically a slowly progressing but incurable disease. Follicular lymphoma cells produce a specific defect in the patient's immune system impairing their ability to control their cancer. Lenalidomide has been shown to reverse the specific immune defect caused by FL in the patient. By including lenalidomide, the RELEVANCE study aims to eliminate the cancer while restoring the patient's immune competence. The 'Relevance' cooperative group trial is being conducted as two companion studies: RV-FOL-GELARC-0683 (N=750) and RV-FOL-GELARC-0683C (N=250); the combined total of 1000 Follicular Lymphoma patients enrolled in both studies will be analyzed.
Interventions
DRUGRituximab
375 mg/m2 on days 1, 8, 15 and 22 of cycle 1, day 1 of cycles 2 to 6; 8 weeks later responding patients continue with 375 mg/m2 rituximab every 8 weeks for 12 cycles.
DRUGLenalidomide
20-mg on days 2-22 every 28 days x 6 cycles, if CR then 10-mg on days 2-22 every 28 days for 12 cycles. PR after 6 cycles, continue 20 mg for 3\ 6 cycles and then 10 mg on days 2-22 every 28-day cycles for upto 18 cycles
DRUGRituximab-CHOP
7 to 8 weeks later responding patients will continue with 375 mg/m2 rituximab every 8 weeks for 12 cycles.
DRUGRituximab-CVP
7 to 8 weeks later responding patients will continue with 375 mg/m2 rituximab every 8 weeks for 12 cycles.
DRUGRituximab-Bendamustine
7 to 8 weeks later responding patients will continue with 375 mg/m2 rituximab every 8 weeks for 12 cycles.
Sponsors
The Lymphoma Academic Research Organisation
Celgene
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed follicular lymphoma grade 1, 2 or 3a, Stage II-IV * Have no prior systemic treatment for lymphoma * Symptomatic follicular lymphoma requiring treatment. * Age ≥18 years * Eastern Cooperative oncology group performance status 0-2 * Willing to follow pregnancy precautions
Exclusion criteria
* Clinical evidence of transformed lymphoma or Grade 3b follicular lymphoma. * Major surgery (excluding lymph node biopsy) within 28 days prior to signing informed consent. * Known seropositive for or active viral infection with hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) * Known sensitivity or allergy to murine products. * Presence or history of central nervous system involvement by lymphoma * At high risk for a venous thromboembolic event (VTE) and not willing to take VTE prophylaxis * Any of the following laboratory abnormalities: * serum aspartate transaminase or alanine transaminase \> 3x upper limit of normal (ULN), except in patients with documented liver involvement by lymphoma * total bilirubin \> 2.0 mg/dl (34 µmol/L) except in cases of Gilberts Syndrome and documented liver or pancreatic involvement by lymphoma * creatinine clearance of \< 30 mL/min
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response Rate (CR/CRu) at 120 Weeks by Independent Central Review | At 120 weeks | The Complete Response Rate (CR/CRu) is the percentage of participants who achieve complete response (CR/CRu) at 120 weeks as assessed per Independent Central Review. * Complete Response (CR): Disappearance of all evidence of disease. * Complete Response Unconfirmed (CRu): Disappearance of all disease with the exception of residual lymph nodes that are 1.5 cm or less in greatest transverse diameter and/or indeterminate bone marrow findings. |
| Progression-free Survival (PFS) | From randomization into the study to the first observation of documented disease progression or death due to any cause (up to approximately 140 months). | Progression-free survival (PFS) is defined as the time from randomization into the study to the first observation of documented disease progression or death due to any cause. Progressive Disease (PD) is characterized by any of the following: * An increase of at least 50% in the sum of the products of the greatest diameters (SPD) of any previously identified abnormal lymph node(s) or other disease sites. * The appearance of any new lesion during or after treatment. * An increase of at least 50% in the longest diameter of a previously identified node that was 1 cm or more in its short axis. * An increase of at least 50% in the size of other lesions (e.g., splenomegaly, hepatomegaly). Based on Kaplan-Meier estimates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response Rate (CR) at 120 Weeks Per Independent Central Review | At 120 weeks | The Complete Response Rate (CR) is the percentage of participants who achieve confirmed complete response (CR) at 120 weeks as assessed per Independent Central Review. \- Complete Response (CR): Disappearance of all evidence of disease. |
| Event-free Survival (EFS) | From randomization to the date of first documented progression, relapse, and initiation of a new anti-lymphoma treatment or death by any cause (up to approximately 140 months). | Event Free Survival (EFS) is defined as the time a participant remains free from certain negative events (disease progression, relapse, initiation of a new anti-lymphoma treatment, or death) between the date of randomization to the date of first documented progression, relapse, and initiation of a new anti-lymphoma treatment or death by any cause. Responding participants and those lost to follow up were censored at their last tumor assessment date. Progressive Disease (PD) is characterized by any of the following: * An increase of at least 50% in the sum of the products of the greatest diameters (SPD) of any previously identified abnormal lymph node(s) or other disease sites. * The appearance of any new lesion during or after treatment. * An increase of at least 50% in the longest diameter of a previously identified node that was 1 cm or more in its short axis. * An increase of at least 50% in the size of other lesions (e.g., splenomegaly, hepatomegaly). Based on Kaplan-Meier estimates. |
| Overall Survival (OS) | From randomization to the date of death by any cause (up to approximately 144 months). | Overall survival (OS) is defined as the median length of time a participant stays alive from randomization. Participants who died, regardless of the cause of death, were considered to have had an event. Participants who withdrew consent for the study were considered censored at the time of withdrawal. Participants who completed the study and were still alive at the time of the clinical data cut-off date were censored. All participants who were lost to follow-up prior to the clinical data cut-off date were also considered censored at the time of last contact. Based on Kaplan-Meier estimates. |
| Time to Next Anti-Lymphoma Treatment (TTNLT) | From the date of randomization to the date of the first documented administration of any new anti-lymphoma treatment (up to approximately 140 months). | Time to Next Lymphoma Treatment (TTNLT) was measured from the date of randomization to the date of the first documented administration of any new anti-lymphoma treatment (such as chemotherapy, radiotherapy, radio-immunotherapy, or immunotherapy). Participants who continued to respond to treatment or who were lost to follow-up were considered censored on their last visit date. Participants who died (due to any cause) before receiving a new anti-lymphoma treatment were included in the statistical analysis, with death being counted as an event. Based on Kaplan-Meier estimates. |
Countries
Japan, United States
Participant flow
Pre-assignment details
1030 participants were randomized, 1010 participants were treated.
Participants by arm
| Arm | Count |
|---|---|
| Rituximab-Lenalidomide Rituximab, 375 mg/m\^2 on days
1, 8, 15 and 22 of cycle 1, day 1 of cycles 2 to 6; and 8 weeks later responding patients continue with 375 mg/m\^2 rituximab every 8 weeks for 12 cycles. Six cycles of lenalidomide 20 mg daily on days 2-22 every 28 days. | 513 |
| Investigator Choice Rituximab-CHOP: with six cycles of R-CHOP in 21 day cycles followed by two 21 day cycles of 375 mg/m\^2 rituximab and 7 weeks later responding patients continue with 375 mg/m\^2 rituximab every 8 weeks for 12 cycles, OR Rituximab-CVP: with eight cycles of R-CVP in 21 day cycles; and 7 weeks later responding patients continue with 375 mg/m\^2 rituximab every 8 weeks for 12 cycles, OR Rituximab-Bendamustine: with rituximab 375 mg/m\^2 (day 1) plus bendamustine 90 mg/m\^2 (days 1 + 2) every 28 days for six cycles; and 8 weeks later responding patients continue with 375 mg/m\^2 rituximab every 8 weeks for 12 cycles. | 517 |
| Total | 1,030 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment | Concurrent illness | 12 | 9 |
| Treatment | Death | 0 | 1 |
| Treatment | Insufficient response | 15 | 3 |
| Treatment | Major protocol violation | 1 | 6 |
| Treatment | Other reasons | 10 | 22 |
| Treatment | Progression | 64 | 71 |
| Treatment | Toxicity | 44 | 16 |
| Treatment | Voluntary treatment discontinuation | 8 | 4 |
| Treatment | Withdrawal by Subject | 3 | 14 |
Baseline characteristics
| Characteristic | Rituximab-Lenalidomide | Investigator Choice | Total |
|---|---|---|---|
| Age, Continuous | 58.5 Years STANDARD_DEVIATION 11.23 | 58.3 Years STANDARD_DEVIATION 11.38 | 58.4 Years STANDARD_DEVIATION 11.3 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 262 Participants | 266 Participants | 528 Participants |
| Sex: Female, Male Male | 251 Participants | 251 Participants | 502 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 88 / 513 | 71 / 372 | 7 / 28 | 12 / 117 |
| other Total, other adverse events | 496 / 507 | 351 / 365 | 26 / 26 | 108 / 112 |
| serious Total, serious adverse events | 181 / 507 | 109 / 365 | 7 / 26 | 32 / 112 |
Outcome results
Primary
Complete Response Rate (CR/CRu) at 120 Weeks by Independent Central Review
The Complete Response Rate (CR/CRu) is the percentage of participants who achieve complete response (CR/CRu) at 120 weeks as assessed per Independent Central Review. * Complete Response (CR): Disappearance of all evidence of disease. * Complete Response Unconfirmed (CRu): Disappearance of all disease with the exception of residual lymph nodes that are 1.5 cm or less in greatest transverse diameter and/or indeterminate bone marrow findings.
Time frame: At 120 weeks
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab-Lenalidomide | Complete Response Rate (CR/CRu) at 120 Weeks by Independent Central Review | 48.1 Percent of participants |
| Investigator Choice | Complete Response Rate (CR/CRu) at 120 Weeks by Independent Central Review | 53.0 Percent of participants |
p-value: 0.128Cochran-Mantel-Haenszel
Primary
Progression-free Survival (PFS)
Progression-free survival (PFS) is defined as the time from randomization into the study to the first observation of documented disease progression or death due to any cause. Progressive Disease (PD) is characterized by any of the following: * An increase of at least 50% in the sum of the products of the greatest diameters (SPD) of any previously identified abnormal lymph node(s) or other disease sites. * The appearance of any new lesion during or after treatment. * An increase of at least 50% in the longest diameter of a previously identified node that was 1 cm or more in its short axis. * An increase of at least 50% in the size of other lesions (e.g., splenomegaly, hepatomegaly). Based on Kaplan-Meier estimates.
Time frame: From randomization into the study to the first observation of documented disease progression or death due to any cause (up to approximately 140 months).
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rituximab-Lenalidomide | Progression-free Survival (PFS) | 120.2 Months |
| Investigator Choice | Progression-free Survival (PFS) | 123.8 Months |
p-value: 0.40695% CI: [0.756, 1.12]Log Rank
Secondary
Complete Response Rate (CR) at 120 Weeks Per Independent Central Review
The Complete Response Rate (CR) is the percentage of participants who achieve confirmed complete response (CR) at 120 weeks as assessed per Independent Central Review. \- Complete Response (CR): Disappearance of all evidence of disease.
Time frame: At 120 weeks
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab-Lenalidomide | Complete Response Rate (CR) at 120 Weeks Per Independent Central Review | 27.7 Percent of participants |
| Investigator Choice | Complete Response Rate (CR) at 120 Weeks Per Independent Central Review | 32.7 Percent of participants |
Secondary
Event-free Survival (EFS)
Event Free Survival (EFS) is defined as the time a participant remains free from certain negative events (disease progression, relapse, initiation of a new anti-lymphoma treatment, or death) between the date of randomization to the date of first documented progression, relapse, and initiation of a new anti-lymphoma treatment or death by any cause. Responding participants and those lost to follow up were censored at their last tumor assessment date. Progressive Disease (PD) is characterized by any of the following: * An increase of at least 50% in the sum of the products of the greatest diameters (SPD) of any previously identified abnormal lymph node(s) or other disease sites. * The appearance of any new lesion during or after treatment. * An increase of at least 50% in the longest diameter of a previously identified node that was 1 cm or more in its short axis. * An increase of at least 50% in the size of other lesions (e.g., splenomegaly, hepatomegaly). Based on Kaplan-Meier estimates.
Time frame: From randomization to the date of first documented progression, relapse, and initiation of a new anti-lymphoma treatment or death by any cause (up to approximately 140 months).
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rituximab-Lenalidomide | Event-free Survival (EFS) | 130.6 Months |
| Investigator Choice | Event-free Survival (EFS) | 132.3 Months |
95% CI: [0.854, 1.261]
Secondary
Overall Survival (OS)
Overall survival (OS) is defined as the median length of time a participant stays alive from randomization. Participants who died, regardless of the cause of death, were considered to have had an event. Participants who withdrew consent for the study were considered censored at the time of withdrawal. Participants who completed the study and were still alive at the time of the clinical data cut-off date were censored. All participants who were lost to follow-up prior to the clinical data cut-off date were also considered censored at the time of last contact. Based on Kaplan-Meier estimates.
Time frame: From randomization to the date of death by any cause (up to approximately 144 months).
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rituximab-Lenalidomide | Overall Survival (OS) | NA Months |
| Investigator Choice | Overall Survival (OS) | NA Months |
95% CI: [0.775, 1.395]
Secondary
Time to Next Anti-Lymphoma Treatment (TTNLT)
Time to Next Lymphoma Treatment (TTNLT) was measured from the date of randomization to the date of the first documented administration of any new anti-lymphoma treatment (such as chemotherapy, radiotherapy, radio-immunotherapy, or immunotherapy). Participants who continued to respond to treatment or who were lost to follow-up were considered censored on their last visit date. Participants who died (due to any cause) before receiving a new anti-lymphoma treatment were included in the statistical analysis, with death being counted as an event. Based on Kaplan-Meier estimates.
Time frame: From the date of randomization to the date of the first documented administration of any new anti-lymphoma treatment (up to approximately 140 months).
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rituximab-Lenalidomide | Time to Next Anti-Lymphoma Treatment (TTNLT) | NA Months |
| Investigator Choice | Time to Next Anti-Lymphoma Treatment (TTNLT) | NA Months |
95% CI: [0.651, 1.006]Regression, Cox