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
Overview
- Phase
- Phase 1
- Intervention
- Ibrutinib
- Conditions
- Relapsed Diffuse Large B-Cell Lymphoma
- Sponsor
- Pharmacyclics LLC.
- Enrollment
- 138
- Locations
- 40
- Primary Endpoint
- 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)
- Status
- Completed
- Last Updated
- 4 years ago
Overview
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.
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.
Investigators
Eligibility 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.
Arms & Interventions
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.
Intervention: Ibrutinib
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.
Intervention: Lenalidomide
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.
Intervention: Rituximab
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.
Intervention: Ibrutinib
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.
Intervention: Lenalidomide
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.
Intervention: Rituximab
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.
Intervention: Ibrutinib
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.
Intervention: Lenalidomide
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.
Intervention: Rituximab
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.
Intervention: Ibrutinib
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.
Intervention: Lenalidomide
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.
Intervention: Rituximab
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.
Intervention: Ibrutinib
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.
Intervention: Lenalidomide
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.
Intervention: Rituximab
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.
Intervention: Ibrutinib
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.
Intervention: Lenalidomide
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.
Intervention: Rituximab
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.
Intervention: Ibrutinib
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.
Intervention: Lenalidomide
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.
Intervention: Rituximab
Outcomes
Primary Outcomes
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.
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.
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 Outcomes
- Phase 1b: ORR(Estimated median time on study in Phase 1b was 59.6 months.)
- Phase 1b: Complete Response (CR) Rate(Estimated median time on Phase 1b study was 59.6 months.)
- Phase 2: CR Rate(Estimated median time on study in Phase 2 was 35.0 months.)
- Phase 2: Duration of Response (DOR)(Estimated median time on study in Phase 2 was 35.0 months.)
- Phase 2: Progression Free Survival (PFS)(Estimated median time on study in Phase 2 was 35.0 months.)
- Phase 2: Overall Survival (OS)(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(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.)