Ibrutinib in Combination With Lenalidomide and Rituximab in Participants With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

A Multicenter Open-Label Phase 1b/2 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Combination With Lenalidomide and Rituximab in Subjects With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

This Phase 1b/2 study is designed to assess the safety and efficacy of ibrutinib in combination with lenalidomide and rituximab in subjects with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) not eligible for transplant.

Study Overview

• Status: Completed
• Conditions: Refractory Diffuse Large B-Cell Lymphoma; Relapsed Diffuse Large B-Cell Lymphoma
• Intervention / Treatment: Drug: Rituximab; Drug: Lenalidomide; Drug: Ibrutinib

Detailed Description

Phase 1b: In the dose escalation portion of the study, various cohorts with escalating doses of lenalidomide may be explored, using the 3+3+3 principle for dose determination.

Phase 2: This will be conducted as an international, multicenter, open-label study. Eligible subjects will receive ibrutinib, lenalidomide and rituximab.

• Study Type: Interventional
• Enrollment (Actual): 138
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Antwerpen, Belgium, 2060
    • Ziekenhuis Netwerk Antwerpen - Campus Stuivenberg
  • Brussels, Belgium
    • CHU Brugmann
  • Brussels, Belgium
    • Cliniques Universitaires Saint-luc
  • Gent, Belgium
    • Universitair Ziekenhuis Gent
  • Leuven, Belgium
    • UZ Leuven
• Germany
  • Baden-Wuerttemberg
    • Ulm, Baden-Wuerttemberg, Germany, 89081
      • Universiaetsklinikum Ulm
  • Bayern
    • Muenchen, Bayern, Germany, 81377
      • Klinikum der Universitaet Muenchen - Campus Grosshadern
    • Muenchen, Bayern, Germany, 81675
      • Klinikum rechts der Isar - Technische Universitaet Muenchen, III. Medizinische Klinik und Polyklinik
    • Wuerzburg, Bayern, Germany, 97080
      • Universitaetsklinikum Wuerzburg, Medizinische Klinik Und Poliklinik II
• United Kingdom
  • Birmingham, United Kingdom
    • University Hospitals Birmingham NHS Foundation Trust
  • Cardiff, United Kingdom
    • University Hospital of Wales
  • Harrow, United Kingdom
    • Northwick Park Hospital
  • Leeds, United Kingdom
    • The Leeds Teaching Hospitals
  • London, United Kingdom
    • Kings College Hospital
  • London, United Kingdom
    • University College London Hospitals
  • Manchester, United Kingdom
    • The Christie Nhs Foundation Trust
  • Southampton, United Kingdom
    • University Hospital Southampton NHS Foundation Trust
  • Sutton, United Kingdom
    • The Royal Marsden NHS Foundation Trust
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • Banner MD Anderson Cancer Center
  • California
    • Los Angeles, California, United States, 90095
      • UCLA Medical Center
    • Los Angeles, California, United States, 90048
      • Cedar Sinai Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute
  • Nevada
    • Las Vegas, Nevada, United States, 89169
      • Comprehensive Cancer Center of Nevada
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
    • Morristown, New Jersey, United States, 07960
      • Summit Medical Group
  • New York
    • New York, New York, United States, 10065
      • Weill Cornell Medical Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Levine Cancer Institute
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati Health Barrett Center
    • Columbus, Ohio, United States, 43219
      • Mid-Ohio Oncology/ Hematology
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • University of TN Medical Center
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt Ingram Cancer Center
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor Charles Sammons Cancer Center
    • Houston, Texas, United States, 77030
      • The University of Texas, MD Anderson Cancer Center
  • Washington
    • Spokane, Washington, United States, 99208
      • Medical Oncology Associates, PS
    • Tacoma, Washington, United States, 98405
      • Northwest Medical Specialities, PLLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Pathologically confirmed relapsed/ refractory DLBCL
• Must have previously received first line treatment regimen
• Must be ineligible for high dose therapy/ stem cell transplantation
• Measurable disease sites on computed tomography (CT) scan (>1.5 cm in longest dimension)
• prothrombin time/international normalized ratio (PT/INR) < 1.5 x upper limit of normal (ULN) and partial thromboplastin time (PTT; activated partial thromboplastin time [aPTT]) <1.5 x ULN
• Men and women ≥18 years of age
• Eastern Cooperative Oncology Group (ECOG) < 2
• Adequate hepatic and renal function
• Adequate hematologic function

Exclusion Criteria:

• Medically apparent central nervous system lymphoma or leptomeningeal disease
• History of allogeneic stem-cell (or other organ) transplantation
• Any chemotherapy, external beam radiation therapy, or anticancer antibodies within 2 weeks
• Radio- or toxin-immunoconjugates within 10 weeks
• Concurrent enrollment in another therapeutic investigational study or have previously taken ibrutinib and/or lenalidomide.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SEQUENTIAL
• Masking: NONE

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1); Ibrutinib 560 mg administered orally (PO) once daily (QD) beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 15 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered intravenously (IV) on Day 1 of each 28-day cycle for 6 cycles.	Drug: Rituximab; Drug: Lenalidomide; Drug: Ibrutinib
EXPERIMENTAL: Phase 1b: Enrolled at Lenalidomide Dose 10 mg (Dose Level -1); De-escalation cohort: Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 10 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.	Drug: Rituximab; Drug: Lenalidomide; Drug: Ibrutinib
EXPERIMENTAL: Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1+); Re-escalation cohort: Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 15 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.	Drug: Rituximab; Drug: Lenalidomide; Drug: Ibrutinib
EXPERIMENTAL: Phase 1b: Enrolled at Lenalidomide Dose 20 mg (Dose Level 2); Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 20 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.	Drug: Rituximab; Drug: Lenalidomide; Drug: Ibrutinib
EXPERIMENTAL: Phase 1b: Enrolled at Lenalidomide Dose 25 mg (Dose Level 3); Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 25 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.	Drug: Rituximab; Drug: Lenalidomide; Drug: Ibrutinib
EXPERIMENTAL: Phase 2: Enrolled at Lenalidomide Dose 20 mg; Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 20 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.	Drug: Rituximab; Drug: Lenalidomide; Drug: Ibrutinib
EXPERIMENTAL: Phase 2: Enrolled at Lenalidomide Dose 25 mg; Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 25 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.	Drug: Rituximab; Drug: Lenalidomide; Drug: Ibrutinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1b: Recommended Phase 2 Dose of Lenalidomide in Combination With Fixed Doses of Ibrutinib and Rituximab in Participants With Relapsed or Refractory Diffuse Large B Cell Lymphoma (DLBCL)	The dose levels of lenalidomide were explored, and dose escalation of lenalidomide followed the 3+3+3 dose escalation schema. A Dose Level Review Committee evaluated safety data following completion of each dose observation period of the Phase 1b portion.	Estimated median time on study in Phase 1b was 59.6 months.
Phase 1b: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and Discontinuations Due to TEAEs	An adverse event (AE) is any untoward medical occurrence, which does not necessarily have a causal relationship with treatment. A serious AE is any untoward medical occurrence that at any dose: results in death; is life-threatening; requires in-patient hospitalization > 24 hours or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is an important medical event. AEs that started or worsened during the treatment-emergent period and all possibly related or related AEs were considered TEAEs. Related events were those that were considered possibly related or related to study drug per investigator's judgment. Events were graded per the national Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.03: Grade 1=mild; grade 2=moderate; grade 3=severe; grade 4=life-threatening; grade 5=death.	From first dose of study drug up to 30 days after last dose of study drug. Phase 1b median duration of ibrutinib exposure was 4.4 months; median duration of lenalidomide exposure was 4.4 months; median total number of doses of rituximab received was 4.0.
Phase 2: Overall Response Rate (ORR)	The ORR was defined as the percentage of participants who achieve either a partial response (PR) or complete response (CR), according to the Revised International Working Group Response Criteria for Malignant Lymphoma or Lugano Classification (Cheson 2014), as assessed by the investigator in response-evaluable population. The 95% confidence interval (CI) was calculated using the exact method.	Estimated median time on study in Phase 2 was 35.0 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1b: ORR	The ORR was defined as the percentage of participants who achieve either a PR or CR, according to the Revised International Working Group Response Criteria for Malignant Lymphoma (Cheson 2007), as assessed by the Investigator in response-evaluable population, where CR=disappearance of all evidence of disease and PR=regression of measurable disease and no new sites. The 95% CI was calculated using the exact method.	Estimated median time on study in Phase 1b was 59.6 months.
Phase 1b: Complete Response (CR) Rate	The CR rate was defined as the percentage of participants who achieve a CR, according to the Revised International Working Group Response Criteria for Malignant Lymphoma (Cheson 2007), as assessed by the Investigator in response-evaluable population, where CR=disappearance of all evidence of disease, as assessed by the Investigator.	Estimated median time on Phase 1b study was 59.6 months.
Phase 2: CR Rate	The CR rate was defined as the percentage of participants who achieve a CR, according to the Revised International Working Group Response Criteria for Malignant Lymphoma or Lugano Classification (see Cheson, 2014 for detailed criteria) in response-evaluable population, as assessed by the Investigator.	Estimated median time on study in Phase 2 was 35.0 months.
Phase 2: Duration of Response (DOR)	DOR is defined as the time from the date of the first documented response (CR or PR) to the first documented evidence of disease progression (PD) according to the Revised International Working Group Response Criteria for Malignant Lymphoma or Lugano Classification (Cheson 2014) or death from any cause. For participants who had achieved an overall response but did not die or progress at the time of analysis, DOR was censored on the date of the last adequate post-baseline disease assessment, or on the date of the first occurrence of response (CR or PR) if there was no disease assessment afterwards. 2-sided 95% CI is estimated by Kaplan-Meier method.	Estimated median time on study in Phase 2 was 35.0 months.
Phase 2: Progression Free Survival (PFS)	PFS is defined as the time from the date of the first dose of study drug to confirmed PD according to the Revised International Working Group Response Criteria for Malignant Lymphoma or Lugano Classification (Cheson 2014) or death from any cause, whichever occurred first. For participants without disease progression or death, PFS data was censored at the date of the last tumor assessment. 2 sided 95% CI is estimated by Kaplan-Meier method.	Estimated median time on study in Phase 2 was 35.0 months.
Phase 2: Overall Survival (OS)	OS is defined as the time from the date of the first dose of study drug to the date of death due to any cause. For participants not known to have died at or prior to the database lock date, OS data was censored at the date last known alive. Participants who withdrew consent prior to study closure were censored on the date of the consent withdrawal. 2-sided 95% CI was estimated by Kaplan-Meier method.	Estimated median time on study in Phase 2 was 35.0 months.
Phase 2: Number of Participants With TEAEs, Serious TEAEs, and Discontinuations Due to TEAEs	An adverse event (AE) is any untoward medical occurrence, which does not necessarily have a causal relationship with treatment. A serious AE is any untoward medical occurrence that at any dose: results in death; is life-threatening; requires in-patient hospitalization > 24 hours or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is an important medical event. AEs that started or worsened during the treatment-emergent period and all possibly related or related AEs were considered TEAEs. Related events were those that were considered possibly related or related to study drug per investigator's judgment. Events were graded per the national Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.03: Grade 1=mild; grade 2=moderate; grade 3=severe; grade 4=life-threatening; grade 5=death.	From first dose of study drug up to 30 days after last dose of study drug. Phase 2 median duration of ibrutinib exposure was 4.9 months; median duration of lenalidomide exposure was 4.7 months; median total number of doses of rituximab received was 5.0.

Collaborators and Investigators

• Sponsor: Pharmacyclics LLC.
• Collaborators: Janssen Research & Development, LLC; Celgene Corporation
• Investigators: Study Director: Jutta K. Neuenburg, MD, PhD, Pharmacyclics LLC.

Publications and helpful links

General Publications

• Goy A, Ramchandren R, Ghosh N, Munoz J, Morgan DS, Dang NH, Knapp M, Delioukina M, Kingsley E, Ping J, Beaupre DM, Neuenburg JK, Ruan J. Ibrutinib plus lenalidomide and rituximab has promising activity in relapsed/refractory non-germinal center B-cell-like DLBCL. Blood. 2019 Sep 26;134(13):1024-1036. doi: 10.1182/blood.2018891598. Epub 2019 Jul 22.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 13, 2014
• Primary Completion (ACTUAL): December 17, 2020
• Study Completion (ACTUAL): December 17, 2020

Study Registration Dates

• First Submitted: February 10, 2014
• First Submitted That Met QC Criteria: February 28, 2014
• First Posted (ESTIMATE): March 4, 2014

Study Record Updates

• Last Update Posted (ACTUAL): February 4, 2022
• Last Update Submitted That Met QC Criteria: January 6, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: DLBCL
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Lenalidomide; Rituximab
• Other Study ID Numbers: PCYC-1123-CA; 2013-004341-17 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Requests for access to individual participant data from clinical studies conducted by Pharmacyclics LLC, an AbbVie Company, can be submitted through Yale Open Data Access (YODA) Project site at the following link.