A Trial of Pirtobrutinib (LOXO-305) Plus Venetoclax and Rituximab (PVR) Versus Venetoclax and Rituximab (VR) in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Study Overview
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Brief Summary
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The purpose of this study is to compare the efficacy and safety of fixed duration pirtobruitinib (LOXO-305) with VR (Arm A) compared to VR alone (Arm B) in patients with CLL/SLL who have been previously treated with at least one prior line of therapy. Participation could last up to five years.

Official Title
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A Phase 3 Open-Label, Randomized Study of Fixed Duration Pirtobrutinib (LOXO-305) Plus Venetoclax and Rituximab Versus Venetoclax and Rituximab in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (BRUIN CLL-322)

Conditions
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Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma

Intervention / Treatment
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* Drug: Pirtobrutinib
* Drug: Venetoclax
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of CLL/SLL requiring therapy per iwCLL 2018 criteria Previous treatment with at least one line of therapy that may include a covalent Bruton's tyrosine kinase (BTK) inhibitor Platelets greater than or equal to (≥)50 x 10⁹/liter (L), hemoglobin ≥8 grams/deciliter (g/dL) and absolute neutrophil count ≥1.0 x 10⁹/L Adequate organ function Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 Estimated creatinine clearance ≥30 milliliters per minute (mL/min) Exclusion Criteria: Known or suspected Richter's transformation at any time preceding enrollment Prior therapy with a non-covalent (reversible) BTK inhibitor Patients requiring therapeutic anticoagulation with warfarin or another Vitamin K antagonist Current treatment with strong cytochrome P450 (CYP) 3A4 (CYP3A4) inhibitors or inducers Prior therapy with venetoclax Central nervous system (CNS) involvement Active uncontrolled systemic bacterial, viral, fungal, or parasitic infection Known human immunodeficiency virus (HIV) infection, regardless of cluster of differentiation 4 (CD4) count Allogeneic stem cell transplantation (SCT) or chimeric antigen receptor (CAR)-T within 60 days Active hepatitis B or hepatitis C Known active cytomegalovirus (CMV) infection Uncontrolled immune thrombocytopenic purpura (ITP) or autoimmune hemolytic anemia (AIHA) Significant cardiovascular disease Vaccination with a live vaccine within 28 days prior to randomization Patients with the following hypersensitivity: Known hypersensitivity to any component or excipient of pirtobrutinib and venetoclax Prior significant hypersensitivity to rituximab Known allergy to allopurinol and inability to take uric acid lowering agent

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: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Eligible patients will be randomized 1:1 into Arm A and Arm B.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (PVR)<br>Fixed duration pirtobrutinib in combination with venetoclax and rituximab | Drug: Pirtobrutinib<br>* Oral<br>* Other names: LY3527727;Drug: Venetoclax<br>* Oral<br>* Other names: Venclyxto;Drug: Rituximab<br>* Intravenous (IV)<br>* Other names: Ruxience;|
| Active Comparator: Arm B (VR)<br>Venetoclax with rituximab | Drug: Venetoclax<br>* Oral<br>* Other names: Venclyxto;Drug: Rituximab<br>* Intravenous (IV)<br>* Other names: Ruxience;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate progression-free survival (PFS) of pirtobrutinib plus venetoclax and rituximab (Arm A) compared to venetoclax and rituximab (Arm B) | Assessed by blinded independent review committee (IRC) per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 | Up to approximately 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the efficacy of Arm A compared to Arm B: Progression-free survival (PFS) | Assessments of efficacy include PFS, assessed by investigator | Up to approximately 5 years | 
| To evaluate the efficacy of Arm A compared to Arm B: Overall survival (OS) | Assessments of efficacy include OS | Up to approximately 5 years | 
| To evaluate the efficacy of Arm A compared to Arm B: Time to next treatment (TTNT) | Assessments of efficacy include TTNT | Up to approximately 5 years | 
| To evaluate the efficacy of Arm A compared to Arm B: Event-free survival (EFS) | Assessments of efficacy include EFS | Up to approximately 5 years | 
| To evaluate the efficacy of Arm A compared to Arm B: Overall response rate (ORR) | Assessments of efficacy include ORR | Up to approximately 5 years | 
| To evaluate the effectiveness of Arm A compared to Arm B in patient-reported disease-related symptoms | Based on time to worsening of CLL/SLL-related symptoms | Up to approximately 5 years | 
| To evaluate the effectiveness of Arm A compared to Arm B in patient-reported physical functioning | Based on time to worsening of physical functioning | Up to approximately 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BTKi, Hematologic Disease, Lymphoma, non-Hodgkin's, Lymphoma, B-cell