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Relapsed Diffuse Large B-Cell LymphomaPhase 1/2NCT02077166

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

A Phase 1/2 study testing Ibrutinib, Lenalidomide and Rituximab in people with Relapsed Diffuse Large B-Cell Lymphoma and Refractory Diffuse Large B-Cell Lymphoma, run by Pharmacyclics LLC. at 40 sites in 4 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Ibrutinib, Lenalidomide and Rituximab
Could I receive a placebo?
No, everyone receives an active treatment
How many people
138 participants
Where
40 sitesin 4 countries
Study dates
13 Mar 2014to 17 Dec 2020
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 9Show fewer
  • Eastern Cooperative Oncology Group (ECOG) < 2
  • Adequate hepatic and renal function
  • Adequate hematologic function

Who cannot join

  • 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.

Trial locations and contacts

40 sites in 4 countries.

40 sites in 4 countries

United States22 sites

  • University of Alabama

    Birmingham, Alabama, 35294

  • Levine Cancer Institute

    Charlotte, North Carolina, 28204

  • Rush University Medical Center

    Chicago, Illinois, 60612

  • University of Cincinnati Health Barrett Center

    Cincinnati, Ohio, 45267

  • Mid-Ohio Oncology/ Hematology

    Columbus, Ohio, 43219

  • Baylor Charles Sammons Cancer Center

    Dallas, Texas, 75246

  • Karmanos Cancer Institute

    Detroit, Michigan, 48201

  • University of Florida

    Gainesville, Florida, 32610

  • Banner MD Anderson Cancer Center

    Gilbert, Arizona, 85234

  • Hackensack University Medical Center

    Hackensack, New Jersey, 07601

  • The University of Texas, MD Anderson Cancer Center

    Houston, Texas, 77030

  • University of Iowa

    Iowa City, Iowa, 52242

  • University of TN Medical Center

    Knoxville, Tennessee, 37920

  • Comprehensive Cancer Center of Nevada

    Las Vegas, Nevada, 89169

  • Cedar Sinai Medical Center

    Los Angeles, California, 90048

  • UCLA Medical Center

    Los Angeles, California, 90095

  • Summit Medical Group

    Morristown, New Jersey, 07960

  • Vanderbilt Ingram Cancer Center

    Nashville, Tennessee, 37232

  • Tulane Medical Center

    New Orleans, Louisiana, 70112

  • Weill Cornell Medical Center

    New York, New York, 10065

  • Medical Oncology Associates, PS

    Spokane, Washington, 99208

  • Northwest Medical Specialities, PLLC

    Tacoma, Washington, 98405

Other trials in United States

United Kingdom9 sites

  • University Hospitals Birmingham NHS Foundation Trust

    Birmingham

  • University Hospital of Wales

    Cardiff

  • Northwick Park Hospital

    Harrow

  • The Leeds Teaching Hospitals

    Leeds

  • Kings College Hospital

    London

  • University College London Hospitals

    London

  • The Christie NHS Foundation Trust

    Manchester

  • University Hospital Southampton NHS Foundation Trust

    Southampton

  • The Royal Marsden NHS Foundation Trust

    Sutton

Other trials in United Kingdom

Belgium5 sites

  • Ziekenhuis Netwerk Antwerpen - Campus Stuivenberg

    Antwerp, 2060

  • CHU Brugmann

    Brussels

  • Cliniques Universitaires Saint-Luc

    Brussels

  • Universitair Ziekenhuis Gent

    Ghent

  • UZ Leuven

    Leuven

Other trials in Belgium

Germany4 sites

  • Klinikum der Universitaet Muenchen - Campus Grosshadern

    Munich, Bavaria, 81377

  • Klinikum rechts der Isar - Technische Universitaet Muenchen, III. Medizinische Klinik und Polyklinik

    Munich, Bavaria, 81675

  • Universiaetsklinikum Ulm

    Ulm, Baden-Wurttemberg, 89081

  • Universitaetsklinikum Wuerzburg, Medizinische Klinik und Poliklinik II

    Würzburg, Bavaria, 97080

Other trials in Germany

About this study

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

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.

Read the 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.

Keywords
DLBCL
Medical subject headings
Lymphoma, Large B-Cell, Diffuse

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Study groups in NCT02077166
Study groupRoleWhat they receive
Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1)ExperimentalIbrutinib 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.
Receives: Drug: Ibrutinib; Drug: Lenalidomide; Drug: Rituximab
Phase 1b: Enrolled at Lenalidomide Dose 10 mg (Dose Level -1)ExperimentalDe-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.
Receives: Drug: Ibrutinib; Drug: Lenalidomide; Drug: Rituximab
Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1+)ExperimentalRe-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.
Receives: Drug: Ibrutinib; Drug: Lenalidomide; Drug: Rituximab
Phase 1b: Enrolled at Lenalidomide Dose 20 mg (Dose Level 2)ExperimentalIbrutinib 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.
Receives: Drug: Ibrutinib; Drug: Lenalidomide; Drug: Rituximab
Phase 1b: Enrolled at Lenalidomide Dose 25 mg (Dose Level 3)ExperimentalIbrutinib 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.
Receives: Drug: Ibrutinib; Drug: Lenalidomide; Drug: Rituximab
Phase 2: Enrolled at Lenalidomide Dose 20 mgExperimentalIbrutinib 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.
Receives: Drug: Ibrutinib; Drug: Lenalidomide; Drug: Rituximab
Phase 2: Enrolled at Lenalidomide Dose 25 mgExperimentalIbrutinib 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.
Receives: Drug: Ibrutinib; Drug: Lenalidomide; Drug: Rituximab

What is being measured

The primary outcome is the main question the study is designed to answer.

  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)

    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.

    Measured: Estimated median time on study in Phase 1b was 59.6 months.

  2. 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.

    Measured: 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.

  3. 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.

    Measured: Estimated median time on study in Phase 2 was 35.0 months.

Secondary outcomes (7)

  1. 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.

    Measured: Estimated median time on study in Phase 1b was 59.6 months.

  2. 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.

    Measured: Estimated median time on Phase 1b study was 59.6 months.

  3. 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.

    Measured: Estimated median time on study in Phase 2 was 35.0 months.

  4. 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.

    Measured: Estimated median time on study in Phase 2 was 35.0 months.

  5. 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.

    Measured: Estimated median time on study in Phase 2 was 35.0 months.

  6. 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.

    Measured: Estimated median time on study in Phase 2 was 35.0 months.

  7. 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.

    Measured: 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.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted4 Mar 2014 (estimated)
  2. Study start13 Mar 2014
  3. Primary completion17 Dec 2020
  4. Study completion17 Dec 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Masking
None (open label)
Enrolment
138 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02077166
Sponsor's protocol ID
PCYC-1123-CA
Other IDs
2013-004341-17
Status last verified
Jan 2022
First submitted
10 Feb 2014
Last updated
4 Feb 2022
Data monitoring committee
Yes
Individual data sharing
Yes: 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.

Publications

  • Ramchandren R, Johnson P, Ghosh N, Ruan J, Ardeshna KM, Johnson R, Verhoef G, Cunningham D, de Vos S, Kassam S, Fayad L, Radford J, Bailly S, Offner F, Morgan D, Munoz J, Ping J, Szafer-Glusman E, Eckert K, Neuenburg JK, Goy A. The iR2 regimen (ibrutinib plus lenalidomide and rituximab) for relapsed/refractory DLBCL: A multicentre, non-randomised, open-label phase 2 study. EClinicalMedicine. 2022 Dec 26;56:101779. doi: 10.1016/j.eclinm.2022.101779. eCollection 2023 Feb.

    PubMed 36618900

  • 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.

    PubMed 31331917

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Ibrutinib, Lenalidomide and Rituximab in people with Relapsed Diffuse Large B-Cell Lymphoma and Refractory Diffuse Large B-Cell Lymphoma, run by Pharmacyclics LLC. at 40 sites in 4 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 4 Feb 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 40 sites in United States, United Kingdom, Belgium, Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 4 Feb 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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 study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02077166, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Feb 2022; AzTrials last refreshed its copy on 7 Nov 2026.

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