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Rituximab Plus Lenalidomide for Patients With Relapsed / Refractory Indolent Non-Hodgkin's Lymphoma (Follicular Lymphoma and Marginal Zone Lymphoma) (AUGMENT)

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ClinicalTrials.gov Identifier: NCT01938001
Recruitment Status : Active, not recruiting
First Posted : September 10, 2013
Results First Posted : August 13, 2019
Last Update Posted : August 13, 2019
Sponsor:
Information provided by (Responsible Party):
Celgene

Tracking Information
First Submitted Date  ICMJE September 5, 2013
First Posted Date  ICMJE September 10, 2013
Results First Submitted Date  ICMJE June 21, 2019
Results First Posted Date  ICMJE August 13, 2019
Last Update Posted Date August 13, 2019
Actual Study Start Date  ICMJE November 1, 2013
Actual Primary Completion Date June 22, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 19, 2019)
Kaplan Meier Estimate of Progression Free Survival Assessed by the Independent Review Committee (IRC) According to the 2007 International Working Group Response Criteria (IWGRC) [ Time Frame: From randomization of study drug up to disease progression or death, which occurred first; up to the data cut-off date of 22 June 2018; overall median follow-up time for all participants was 28.30 months (range: 0.1 to 51.3 months). ]
Progression-free survival (PFS) was defined as the time from date of randomization into the study to the first observation of documented disease progression or death due to any cause, whichever occurred first. PFS was based on the data from the IRC review using the modified 2007 International Working Group Response Criteria (IWGRC) using FDA censoring rules.
Original Primary Outcome Measures  ICMJE
 (submitted: September 9, 2013)
Progression free survival (PFS) for indolent lymphoma (Follicular lymphoma and Marginal zone lymphoma [ Time Frame: Up to 8 years ]
Progression-free survival is defined as the time from date of randomization to the first observation of disease progression or death due to any cause as assessed by an independent review committee.
Change History Complete list of historical versions of study NCT01938001 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 19, 2019)
  • Durable Complete Response Rate (DCCR) as Assessed by the IRC According to the 2007 IWGRC [ Time Frame: From first dose of investigational product (IP) to data cut-off date of 22 June 2018; the median treatment duration was 11.19 months in the rituximab/lenalidomiade arm and 11.04 months in the rituximab/placebo arm ]
    DCCR was defined as the percentage of participants with a best response of complete response (CR) that lasted no less than one year (≥ 48 weeks) during the study prior to administration of new anti-lymphoma therapy. A CR is defined as a complete disappearance of any disease-related symptoms and normalization of biochemical abnormalities.
  • Kaplan-Meier Estimate of Overall Survival (OS) [ Time Frame: From the date of randomization to the cut-off date of 22 June 2018; The overall median follow-up time for all participants was 28.30 months (range: 0.1 to 51.3 months) ]
    Overall survival 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 were lost to follow-up before death was documented.
  • Percentage of Participants With an Objective Response as Assessed by the IRC According to the 2007 IWGRC [ Time Frame: From date of first dose to data cut-off date of 22 June 2018; the median treatment duration was 11.19 months in the rituximab/lenalidomide arm and 11.04 months in the rituximab/placebo arm ]
    Percentage of participants with an objective response is defined as having a response of at least a PR during the study without administration of new anti-lymphoma therapy. A complete response = a complete disappearance of all detectable clinical and radiographic evidence of disease, disappearance of any disease-related symptoms, and normalization of biochemical abnormalities; a partial response (PR) = 50% decrease in SPD of the 6 largest dominant nodes or nodal masses. No increase in the size of other nodes, liver, or spleen. Splenic and hepatic nodules must regress by at least 50% in the SPD.
  • Percentage of Participants With a Best Response of Complete Response as Assessed by the IRC According to the 2007 IWGRC [ Time Frame: From date of first dose up to data cut-off date of 22 June 2018; the median treatment duration was 11.19 months in the rituximab/lenalidomide arm and 11.04 months in the rituximab/placebo arm ]
    Percentage of participants with a best response of at CR during the study without administration of new anti-lymphoma therapy. A CR = Complete disappearance of all detectable clinical and radiographic evidence of disease, disappearance of any disease-related symptoms, and normalization of biochemical abnormalities.
  • Kaplan-Meier Estimate of Duration of Objective Response as Assessed by the IRC According to the 2007 IWGRC [ Time Frame: From randomization up to data cut-off date of 22 June 2018; overall median follow-up time for all participants was 28.30 months (range: 0.1 to 51.3 months). ]
    Duration of response (DOR) was defined as the time from initial response (at least PR) until documented progressive disease (PD) or death. Participants who had not progressed at the time of analysis were censored at the last assessment date that the participant was known to be progression free. Participants who received a new treatment without documented progression were censored at the last assessment date that the participants was known to be progression free.
  • Kaplan-Meier Estimate of Duration of Complete Response (DOCR) as Assessed by the IRC According to the 2007 IWGRC [ Time Frame: From randomization up to data cut-off date of 22 June 2018; overall median follow-up time for all participants was 28.30 months (range: 0.1 to 51.3 months). ]
    DOCR was defined as the time from initial CR until documented PD or death. Participants who had not progressed at the time of analysis were censored at the last assessment date that the participant was known to be progression free. Participants who received a new treatment without documented progression were censored at the last assessment date that the participants was known to be progression free.
  • Kaplan Meier Estimate of Event Free Survival as Assessed by the IRC According to the 2007 IWGRC [ Time Frame: From date of randomization to data cut-off date of 22 June 2018; overall median follow-up time for all participants was 28.30 months (range: 0.1 to 51.3 months). ]
    Event-free survival (EFS) was defined as the time from date of randomization to date of first documented progression, relapse, institution of new anti-lymphoma treatment (chemotherapy, radiotherapy or immunotherapy) or death from any cause. Responding participants and those who were lost to follow up were censored at their last tumor assessment date.
  • Kaplan Meier Estimate of Time to Next Anti-Lymphoma Treatment (TTNLT) [ Time Frame: From randomization to data cut off of 22 Jun 2018; overall median follow-up time for all participants was 28.30 months (range: 0.1 to 51.3 months). ]
    Time to next anti-lymphoma treatment (TTNLT) was defined as the time from date of randomization to date of first documented administration of a new anti-lymphoma treatment (including chemotherapy, radiotherapy, radioimmunotherapy or immunotherapy). The time to the next anti-lymphoma treatment was of special interest to the study.
  • Number of Participants With Treatment Emergent Adverse Events (TEAEs) [ Time Frame: From the first dose of study drug up to 28 days after the last dose of IP and those SAEs made known at any time; the median treatment duration was 11.19 months in the rituximab/lenalidomide arm and 11.04 months in the rituximab/placebo arm ]
    TEAEs include AEs that started or worsened between the date of the first dose and 28 days after the date of the last dose. 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
Original Secondary Outcome Measures  ICMJE
 (submitted: September 9, 2013)
  • Overall response rate [ Time Frame: Up to 8 years ]
    Overall response rate is defined as proportion of subjects with best response of at least partial remission during the trial without administration of new anti-lymphoma therapy.
  • Durable complete response rate [ Time Frame: Up to 8 years ]
    Rate of durable complete response defined as complete response of at least 1 year's duration
  • Overall survival [ Time Frame: Up to 8 years ]
    Overall survival is defined as time from date of randomization to death from any cause
  • Duration of response [ Time Frame: Up to 8 years ]
    Duration of response is defined as time from initial response of at least a PR to documented progression/relapse
  • Event Free Survival [ Time Frame: Up to 8 years ]
    Event-free survival is defined as the time from the date of randomization to the first observation of disease progression, institution of new anti-lymphoma treatment, or death due to any cause
  • Time to next anti-lymphoma therapy (TTNLT) [ Time Frame: Up to 8 years ]
    TTNLT is defined as the time from date of randomization to institution of new anti-lymphoma treatment
  • Safety in Indolent Lymphoma [ Time Frame: Up to 8 years ]
    Incidence of Adverse Events
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Rituximab Plus Lenalidomide for Patients With Relapsed / Refractory Indolent Non-Hodgkin's Lymphoma (Follicular Lymphoma and Marginal Zone Lymphoma)
Official Title  ICMJE A Phase 3, Double-blind, Randomized Study to Compare the Efficacy and Safety of Rituximab Plus Lenalidomide (CC-5013) Versus Rituximab Plus Placebo in Subjects With Relapsed/Refractory Indolent Lymphoma
Brief Summary This double-blind randomized, parallel group study will evaluate the efficacy and safety of lenalidomide (Revlimid, CC-5013) in combination with rituximab (MabThera/Rituxan) in patients with relapsed or refractory follicular lymphoma or marginal zone lymphoma. Patients will be randomized to receive either lenalidomide or placebo for twelve 28-day cycles in combination with rituximab. Anticipated time on study treatment is 1 year.
Detailed Description Indolent lymphoma is a slow growing but incurable lymphoma which includes follicular lymphoma and marginal zone lymphoma. Follicular lymphoma and marginal zone lymphoma are cancers of the B lymphocyte, a type of white blood cell. Lenalidomide is an immunomodulatory drug (a drug that affects the immune system) which alters the body's immune system and it may also interfere with the development of tiny blood vessels involved in tumor growth. Therefore, lenalidomide may reduce or prevent the growth of cancer cells. Lenalidomide has also been shown to restore the immune cells' ability to attack and kill tumor cells, an ability that may be inhibited by follicular lymphoma and other lymphomas. The combination of rituximab and lenalidomide may eliminate the cancer while restoring the immune system's ability to attack tumor cells.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Lymphoma, Non-Hodgkin
Intervention  ICMJE
  • Drug: Rituximab
    Rituximab 375mg/m^2 IV every week in Cycle 1 (Days 1, 8, 15 and 22) on Day 1 of every 28 day cycle from Cycles 2 to 5
    Other Name: Rituxan
  • Drug: Lenalidomide
    Lenalidomide 20mg by mouth (PO) daily on Days 1 to 21 every 28 days up to 12 cycles
    Other Name: CC-5013, Revlimid
  • Drug: Placebo
    Placebo (identical matched capsule) PO daily on Days 1 to 21 every 28 days
Study Arms  ICMJE
  • Experimental: Rituximab and Lenalidomide
    Participants received rituximab 375 mg/m^2 intravenously (IV) every week in Cycle 1 (Days 1, 8, 15 and 22) and on Day 1 of every 28-day cycle from Cycles 2 to 5 plus lenalidomide 20 mg by mouth (PO) once daily on Days 1 to 21 every 28 days, up to 12 cycles (21-day treatment and 7-day rest period); if creatinine clearance (CrCl) was ≥ 30 mL/min but < 60 mL/min, participants received lenalidomide 10 mg capsules on days 1 to 21 every 28 days.
    Interventions:
    • Drug: Rituximab
    • Drug: Lenalidomide
  • Active Comparator: Rituximab and Placebo
    Participants received riituximab 375 mg/m^2 IV every week in Cycle 1 (Days 1, 8, 15 and 22) and on Day 1 of every 28-day cycle from cycle 2 to 5 plus placebo (identically matched capsule) once daily on Days 1 to 21 of every 28-day cycle up, to 12 cycles.
    Interventions:
    • Drug: Rituximab
    • Drug: Placebo
Publications * Leonard JP, Trneny M, Izutsu K, Fowler NH, Hong X, Zhu J, Zhang H, Offner F, Scheliga A, Nowakowski GS, Pinto A, Re F, Fogliatto LM, Scheinberg P, Flinn IW, Moreira C, Cabeçadas J, Liu D, Kalambakas S, Fustier P, Wu C, Gribben JG; AUGMENT Trial Investigators. AUGMENT: A Phase III Study of Lenalidomide Plus Rituximab Versus Placebo Plus Rituximab in Relapsed or Refractory Indolent Lymphoma. J Clin Oncol. 2019 May 10;37(14):1188-1199. doi: 10.1200/JCO.19.00010. Epub 2019 Mar 21.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: January 18, 2018)
358
Original Estimated Enrollment  ICMJE
 (submitted: September 9, 2013)
350
Estimated Study Completion Date  ICMJE December 28, 2021
Actual Primary Completion Date June 22, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age ≥18 years at the time of signing the informed consent document.
  • Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures are conducted.
  • Histologically confirmed marginal zone lymphoma or follicular lymphoma (grade 1, 2 or 3a; CD20+ by flow cytometry or histochemistry).
  • Previously treated with at least one prior systemic chemotherapy, immunotherapy or chemoimmunotherapy and have received at least 2 previous doses of rituximab.
  • Documented relapsed, refractory or progressive disease after treatment with systemic therapy and must not be rituximab-refractory.
  • Investigator considers rituximab monotherapy appropriate.
  • Bi-dimensionally measurable disease on cross sectional imaging by X-ray computed tomography (CT) or magnetic resonance imaging (MRI).
  • Need of treatment for relapsed, progressed or refractory disease as assessed by the investigator.
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
  • Adequate bone marrow function.
  • Willingness to follow study visit schedule, pregnancy precautions and other protocol requirements.

Exclusion Criteria:

  • Histology other than follicular or marginal zone lymphoma or clinical evidence of transformation or Grade 3b follicular lymphoma.
  • Subjects taking corticosteroids during the last week prior to study treatment, unless administered at a dose equivalent to < 20 mg/day prednisone or prednisolone.
  • Systemic anti-lymphoma therapy within 28 days or use of antibody agents within 8 weeks use of radioimmunotherapy within 6 months.
  • Known seropositive for or active viral infection with hepatitis B virus (HBV) or/and human immunodeficiency virus (HIV).
  • Known hepatitis C virus (HCV) positive with chronic HCV or active viral infection with HCV hepatitis requiring anti-viral medication (at time of randomization).
  • Life expectancy < 6 months.
  • Known sensitivity or allergy to murine products.
  • Prior history of malignancies, other than follicular or marginal zone lymphoma, unless the subject has been free of the disease for ≥ 5 years.
  • Prior use of lenalidomide.
  • Known allergy to thalidomide.
  • Neuropathy > Grade 1.
  • Presence or history of central nervous system involvement by lymphoma.
  • Subjects who are at a risk for a thromboembolic event and are not willing to take prophylaxis for it.
  • Uncontrolled intercurrent illness.
  • Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent document.
  • Pregnant or lactating females.
  • Any condition that places the subject at unacceptable risk if he/she were to participate in the study or that confounds the ability to interpret data from the study.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Brazil,   China,   Czechia,   France,   Germany,   Israel,   Italy,   Japan,   Poland,   Portugal,   Puerto Rico,   Russian Federation,   Spain,   Turkey,   United Kingdom,   United States
Removed Location Countries Czech Republic
 
Administrative Information
NCT Number  ICMJE NCT01938001
Other Study ID Numbers  ICMJE CC-5013-NHL-007
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Celgene
Study Sponsor  ICMJE Celgene
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Stacey Kalambakas, MD Celgene
PRS Account Celgene
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP