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

Refractory Diffuse Large B-Cell Lymphoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02077166
• Other study ID #: PCYC-1123-CA
• Secondary ID: 2013-004341-17
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: March 13, 2014
• Est. completion date: December 17, 2020

Study information

• Verified date: January 2022
• Source: Pharmacyclics LLC.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 138
• Est. completion date: December 17, 2020
• Est. primary completion date: December 17, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large B-Cell, Diffuse
• Refractory Diffuse Large B-Cell Lymphoma
• Relapsed Diffuse Large B-Cell Lymphoma

Intervention

Drug:
• Ibrutinib

• Lenalidomide

• Rituximab

Locations

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

Sponsors (3)

Lead Sponsor	Collaborator
Pharmacyclics LLC.	Celgene Corporation, Janssen Research & Development, LLC

Countries where clinical trial is conducted

United States,  Belgium,  Germany,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.
Primary	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.
Primary	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	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.