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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

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

Intervention / Treatment
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* Drug: Ibrutinib
* Drug: Lenalidomide
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1)<br>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<br> <br> Drug: Lenalidomide<br> <br> Drug: Rituximab<br> <br> |
| Experimental: Phase 1b: Enrolled at Lenalidomide Dose 10 mg (Dose Level -1)<br>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<br> <br> Drug: Lenalidomide<br> <br> Drug: Rituximab<br> <br> |
| Experimental: Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1+)<br>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<br> <br> Drug: Lenalidomide<br> <br> Drug: Rituximab<br> <br> |
| Experimental: Phase 1b: Enrolled at Lenalidomide Dose 20 mg (Dose Level 2)<br>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<br> <br> Drug: Lenalidomide<br> <br> Drug: Rituximab<br> <br> |
| Experimental: Phase 1b: Enrolled at Lenalidomide Dose 25 mg (Dose Level 3)<br>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<br> <br> Drug: Lenalidomide<br> <br> Drug: Rituximab<br> <br> |
| Experimental: Phase 2: Enrolled at Lenalidomide Dose 20 mg<br>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<br> <br> Drug: Lenalidomide<br> <br> Drug: Rituximab<br> <br> |
| Experimental: Phase 2: Enrolled at Lenalidomide Dose 25 mg<br>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<br> <br> Drug: Lenalidomide<br> <br> Drug: Rituximab<br> <br> |

What is the study measuring?
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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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DLBCL