Safety and Efficacy Study of a BTK Inhibitor in Subjects With Relapsed or Refractory Diffuse Large B-cell Lymphoma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy of ibrutinib (PCI-32765) in relapsed/refractory de novo activated B-cell (ABC) and germinal-cell B-Cell (GCB) Diffuse Large B-cell Lymphoma (DLBCL).

Detailed Description
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The primary objectives of this study were to evaluate the efficacy of ibrutinib administered at 560 mg once per day in relapsed or refractory de novo ABC and GCB DLBCL, and to evaluate the efficacy of ibrutinib administered at 840 mg once per day in relapsed or refractory de novo ABC DLBCL. The secondary objective was to evaluate the safety and tolerability of a fixed daily oral dosing regimen of ibrutinib in relapsed/refractory de novo DLBCL.

Official Title
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A Multicenter, Open-label, Phase 2, Safety and Efficacy Study of the Bruton's Tyrosine Kinase (Btk) Inhibitor, PCI-32765, in Subjects With Relapsed or Refractory or de Novo Diffuse Large B-cell Lymphoma (DLBCL)

Conditions
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Diffuse Large Cell B-lymphoma

Intervention / Treatment
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* Drug: ibrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women ≥ 18 years of age. ECOG performance status ≤ 2. Pathologically confirmed de novo DLBCL Subjects must have available tissue for central pathology review to be eligible. Treatment Group 2: Subjects will be eligible if they have the non-GCB phenotype, as confirmed by Central IHC testing by the Hans method. Relapsed or refractory disease, defined as either: 1) recurrence of disease after a CR, or 2) PR, SD, or progressive disease (PD) at completion of the treatment regimen preceding entry to the study (residual disease): Subjects must have previously received an appropriate first-line treatment regimen. Subjects who have not received HDT/ASCT must be ineligible for HDT/ASCT Treatment Group 1: Subjects must have ≥ 1 measurable (> 2 cm in longest dimension) disease sites on CT scan. Treatment Group 2: Subjects must have ≥ 1 measurable (> 1.5 cm in longest dimension) disease sites on CT scan. Exclusion Criteria: Transformed DLBCL or DLBCL with coexistent histologies (eg, FL or MALT). Primary mediastinal (thymic) large B-cell lymphoma. Known central nervous system lymphoma. In addition, for subjects in Treatment Group 2, known leptomeningeal involvement is exclusionary. Certain exclusions on prior therapy Major surgery within 2 weeks of first dose of study drug. Any of the following laboratory abnormalities: ANC < 0.75 x 10^9/L. Treatment Group 2: Eligible subjects must be independent of growth factor support for 7 days prior to the screening lab tests. Platelet count < 50 x 10^9/L independent of transfusion support. Treatment Group 2 only: Eligible subjects must be independent of transfusion support for 7 days prior to the screening lab tests. AST or ALT ≥ 3.0 x upper limit of normal (ULN) Creatinine > 2.0 x ULN Treatment Group 2 only: Hemoglobin < 8.0 g/dL Treatment Group 2 only: Total Bilirubin > 1.5 x ULN Requires or has received anticoagulation treatment with warfarin or equivalent Vitamin K antagonists (eg, phenprocoumon) Treatment Group 2: Requires treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor Treatment Group 2: Known bleeding diathesis, eg, von Willebrand's disease, hemophilia.

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PCI-32765: 560 mg<br>Treatment Group 1: Subjects received 560 mg of ibrutinib once daily, on a continuous basis. | Drug: ibrutinib<br>* ibrutinib is an inhibitor of BTK<br>* Other names: PCI-32765, Imbruvica;|
| Experimental: PCI-32765: 840 mg<br>Treatment Group 2: Subjects received 840 mg of ibrutinib once daily, on a continuous basis. | Drug: ibrutinib<br>* ibrutinib is an inhibitor of BTK<br>* Other names: PCI-32765, Imbruvica;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With an Overall Response to Study Drug | The primary endpoint of the study was overall response rate (ORR), defined as the proportion of participants who achieved a best overall response of complete response (CR) or partial response (PR), according to the revised International Working Group Criteria for non-Hodgkin's lymphoma (Cheson et al, 2007), as assessed by the investigator. | The median follow up time on the study for all treated participants is 1.7 months (range 0.1- 32.3 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Adverse Events as a Measure of Safety and Tolerability | Participants will be followed until progression of the disease or start of another anticancer treatment. The clinical database captured all AEs from baseline through end of treatment. Treatment Emergent AEs were collected pre-dose, at the beginning of each cycle and 30 days post last dose of study drug, unless related to study drug. | Adverse events determined to be related to study drug are collected from first dose until study exit (approximately 3 years). | 
| Ibrutinib and Its Metabolite (PCI-45227) AUC0-24h After Repeat Dosing of PCI-32765 | Treatment Group 1 PK collection schedule: Cycle 1 Day 1: Pre-dose, 1, 2, 4, 7, and 24 hours post-dose Cycle 1 Day 8: Pre-dose, 1, 2, 4, 7, and 24 hours post-dose Cycle 1 Day 15: Pre-dose and 2 hours post-dose Cycle 1 Day 22: Pre-dose and 2 hours post-dose Treatment Group 2 PK collection schedule: Cycle 1 Day 8: Pre-dose, 1, 2, 4 and 7 hours post-dose Cycle 1 Day 15: Pre-dose and 2 hours post-dose Cycle 1 Day 22: Pre-dose and 2 hours post-dose Cycle 3 Day 1: Pre-dose, 1, 2, and 4 hours post-dose | Performed during the first month of receiving study drug. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PCI-32765, Lymphoma, B-Cell, Bruton's Tyrosine Kinase, Non Hodgkin's Lymphoma, Germinal Center B-Cell, Activated B-Cell