A Study of Pirtobrutinib (LOXO-305) Versus Ibrutinib in Participants With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (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 pirtobruitinib (LOXO-305) to ibrutinib in participants with CLL/SLL. Participants may or may not have already had treatment for their cancer. Participation could last up to six years.

Official Title
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A Phase 3 Open-Label, Randomized Study of Pirtobrutinib (LOXO-305) Versus Ibrutinib in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (BRUIN-CLL-314)

Conditions
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Chronic Lymphocytic Leukemia, Leukemia, Lymphocytic, Leukemia, B-cell, Small Lymphocytic Lymphoma

Intervention / Treatment
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* Drug: Pirtobrutinib
* Drug: Ibrutinib


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 Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 Adequate organ function Platelets greater than or equal to (≥)50 x 10⁹/liter (L) or ≥30 x 10⁹/L in participants with documented bone marrow involvement considered to impair hematopoiesis, Hemoglobin ≥8 grams/deciliter (g/dL) or ≥6 g/dL in participants with documented bone marrow involvement considered to impair hematopoiesis Absolute neutrophil count ≥0.75 x 10⁹/L or ≥0.50 × 10⁹/L in participants with documented bone marrow involvement considered to impair hematopoiesis Kidney function: Estimated creatinine clearance ≥30 milliliters per minute (mL/min) Exclusion Criteria: Known or suspected Richter's transformation to diffuse large B-cell lymphoma (DLBCL), prolymphocytic leukemia, or Hodgkin's lymphoma at any time preceding enrollment Known or suspected central nervous system (CNS) involvement A significant history of renal, neurologic, psychiatric, endocrine, metabolic or immunologic disease Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia [AIHA], idiopathic thrombocytopenic purpura [ITP]) Significant cardiovascular disease including ejection fraction < 40% and any grade ongoing atrial fibrillation or atrial flutter Hepatitis B or hepatitis C testing indicating active/ongoing infection, based on Screening laboratory tests Active cytomegalovirus (CMV) infection Active uncontrolled systemic bacterial, viral, or fungal infection Known human immunodeficiency virus (HIV) infection, regardless of cluster of differentiation 4 (CD4) count Clinically significant active malabsorption syndrome or other condition likely to affect GI absorption of the oral-administered study treatments Ongoing inflammatory bowel disease Prior exposure to BTK inhibitor (covalent or noncovalent) Concurrent use of investigational agent or anticancer therapy except hormonal therapy Participants requiring therapeutic anticoagulation with warfarin or another Vitamin K antagonist Use of ≥ 20 mg prednisone daily or equivalent dose of steroid at the time of first dose of study drug Vaccination with a live vaccine within 28 days prior to randomization Participants receiving chronic therapy with a strong cytochrome P450 (CYP)3A inhibitor (except posaconazole and voriconazole) which cannot be stopped within 3-5 half lives of the CYP3A inhibitor therapy prior to start of study drug treatment Participants with known hypersensitivity, including anaphylaxis, to any component or excipient of pirtobrutinib or ibrutinib

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pirtobrutinib<br>Administered orally. | Drug: Pirtobrutinib<br>* Administered orally.<br>* Other names: LY3527727;|
| Active Comparator: Ibrutinib<br>Administered orally. | Drug: Ibrutinib<br>* Administered orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Complete Response (CR), Complete Remission with Incomplete Hematologic Recovery (Cri), Nodular Partial Remission (nPR) or Partial Response (PR): Overall Response Rate (ORR) | ORR as assessed by independent review committee (IRC) per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria | Baseline to best overall response at or before the initiation of subsequent anti-cancer therapy (if any) (approximately 3 years and 5 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-Free Survival (EFS) | EFS by IRC per iwCLL 2018 criteria | Randomization to first occurrence of treatment discontinuation due to adverse event/toxicity, treatment-emergent atrial fibrillation or atrial flutter of any grade, progressive disease (PD) or death (approximately 4 years) | 
| Progression-Free Survival (PFS) | PFS by IRC per iwCLL 2018 criteria | Randomization to PD (per iwCLL 2018 criteria) or death from any cause (approximately 5 years 8 months) | 
| Duration of Response (DOR) | DOR | Time from the date of the first documented response of CR, CRi, nPR or PR to the earlier of documentation of definitive PD (per iwCLL 2018 criteria) or death from any cause (approximately 2 years) | 
| Overall Survival (OS) | OS | Randomization to death from any cause (approximately 6 years) | 
| Time to Next Treatment (TTNT) | TTNT | Randomization to initiation of the next systemic anticancer therapy for CLL/SLL or death from any cause, whichever occurs first (approximately 6 years) | 
| Time to Worsening (TTW) of CLL/SLL Related Symptoms | Using symptom questions identified from the EORTC item library. The range of raw scores for these items could be from 0 to 52 with highest score being worse symptoms. | Randomization to time to worsening symptoms (approximately 6 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