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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02077166
Recruitment Status : Completed
First Posted : March 4, 2014
Results First Posted : February 4, 2022
Last Update Posted : February 4, 2022
Sponsor:
Collaborators:
Janssen Research & Development, LLC
Celgene Corporation
Information provided by (Responsible Party):
Pharmacyclics LLC.

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Relapsed Diffuse Large B-Cell Lymphoma Refractory Diffuse Large B-Cell Lymphoma Drug: Ibrutinib Drug: Lenalidomide Drug: Rituximab Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 138 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : March 13, 2014
Actual Primary Completion Date : December 17, 2020
Actual Study Completion Date : December 17, 2020


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: Ibrutinib
Drug: Lenalidomide
Drug: Rituximab
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: Ibrutinib
Drug: Lenalidomide
Drug: Rituximab
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: Ibrutinib
Drug: Lenalidomide
Drug: Rituximab
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: Ibrutinib
Drug: Lenalidomide
Drug: Rituximab
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: Ibrutinib
Drug: Lenalidomide
Drug: Rituximab
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: Ibrutinib
Drug: Lenalidomide
Drug: Rituximab
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: Ibrutinib
Drug: Lenalidomide
Drug: Rituximab



Primary Outcome Measures :
  1. 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) [ Time Frame: Estimated median time on study in Phase 1b was 59.6 months. ]
    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.

  2. Phase 1b: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and Discontinuations Due to TEAEs [ Time Frame: 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. ]
    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.

  3. Phase 2: Overall Response Rate (ORR) [ Time Frame: Estimated median time on study in Phase 2 was 35.0 months. ]
    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.


Secondary Outcome Measures :
  1. Phase 1b: ORR [ Time Frame: Estimated median time on study in Phase 1b was 59.6 months. ]
    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.

  2. Phase 1b: Complete Response (CR) Rate [ Time Frame: Estimated median time on Phase 1b study was 59.6 months. ]
    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.

  3. Phase 2: CR Rate [ Time Frame: Estimated median time on study in Phase 2 was 35.0 months. ]
    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.

  4. Phase 2: Duration of Response (DOR) [ Time Frame: Estimated median time on study in Phase 2 was 35.0 months. ]
    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.

  5. Phase 2: Progression Free Survival (PFS) [ Time Frame: Estimated median time on study in Phase 2 was 35.0 months. ]
    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.

  6. Phase 2: Overall Survival (OS) [ Time Frame: Estimated median time on study in Phase 2 was 35.0 months. ]
    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.

  7. Phase 2: Number of Participants With TEAEs, Serious TEAEs, and Discontinuations Due to TEAEs [ Time Frame: 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. ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02077166


Locations
Show Show 40 study locations
Sponsors and Collaborators
Pharmacyclics LLC.
Janssen Research & Development, LLC
Celgene Corporation
Investigators
Layout table for investigator information
Study Director: Jutta K. Neuenburg, MD, PhD Pharmacyclics LLC.
  Study Documents (Full-Text)

Documents provided by Pharmacyclics LLC.:
Study Protocol  [PDF] June 1, 2016
Statistical Analysis Plan  [PDF] April 20, 2020

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Pharmacyclics LLC.
ClinicalTrials.gov Identifier: NCT02077166    
Other Study ID Numbers: PCYC-1123-CA
2013-004341-17 ( EudraCT Number )
First Posted: March 4, 2014    Key Record Dates
Results First Posted: February 4, 2022
Last Update Posted: February 4, 2022
Last Verified: January 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
URL: http://yoda.yale.edu
Keywords provided by Pharmacyclics LLC.:
DLBCL
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Rituximab
Lenalidomide
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors