Study of LOXO-305 Versus Investigator's Choice (IdelaR or BR) in Patients With Previously Treated Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

Study Overview
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Brief Summary
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This is a study for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) who have previously received treatment with at least a BTK inhibitor. The main purpose is to compare LOXO-305 to idelalisib plus rituximab or bendamustine plus rituximab. Participation could last up to four years, and possibly longer, if the disease does not progress.

Detailed Description
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This is a Phase 3 global, randomized, open-label study comparing LOXO-305 (Arm A) to investigator's choice of either idelalisib plus rituximab or bendamustine plus rituximab (Arm B) in CLL/SLL patients who have been treated with at least a covalent BTK inhibitor (BTKi). Patients may have discontinued the prior covalent BTKi due to disease progression (PD) or intolerance. Patients who have received venetoclax are eligible for the study. Eligible patients will be randomized in 1:1 to Arm A and Arm B.

Official Title
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A Phase 3 Open-Label, Randomized Study of LOXO-305 Versus Investigator's Choice of Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in BTK Inhibitor Pretreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (BRUIN CLL-321)

Conditions
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Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma

Intervention / Treatment
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* Drug: LOXO-305
* Drug: Idelalisib
* Drug: Bendamustine
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of CLL/SLL requiring therapy as defined by iwCLL 2018 criteria. Previously treated with a covalent BTK inhibitor. Eastern Cooperative Oncology Group (ECOG) 0-2. Absolute neutrophil count ≥ 0.75 × 10^9/L without granulocyte-colony-stimulating factor support, or ≥ 0.50 × 10^9/L in patients with documented bone marrow involvement considered to impair hematopoiesis. Granulocyte-colony-stimulating factor support is permitted in patients with documented bone marrow involvement. Hemoglobin ≥ 8 g/dL or ≥ 6 g/dL in patients with documented bone marrow involvement considered to impair hematopoiesis. Transfusion support is permitted in patients with bone marrow involvement. Platelets ≥ 50 × 10^9/L. If an investigator has chosen bendamustine/rituximab as the Arm B treatment, platelets must be ≥ 75 × 10^9/L. Patients may enroll below these thresholds if the Investigator determines the cytopenia is related to bone marrow involvement considered to impair hematopoiesis. Patients with a platelet count < 30 x 10^9/L are excluded. AST and ALT ≤ 3.0 x upper limit of normal (ULN). Total bilirubin ≤ 1.5 x ULN. Estimated creatinine clearance of ≥ 30 mL/min. Exclusion Criteria: Known or suspected Richter's transformation at any time preceding enrollment. Known or suspected history of central nervous system (CNS) involvement by CLL/SLL. Ongoing drug-induced liver injury. Active uncontrolled auto-immune cytopenia. Significant cardiovascular disease. History of allogeneic or stem cell transplantation (SCT) or chimeric antigen receptor-modified T cells (CAR-T) therapy within the past 60 days. Active hepatitis B or hepatitis C. Known active cytomegalovirus (CMV) infection. Active uncontrolled systemic bacterial, viral, fungal or parasitic infection. Known Human Immunodeficiency Virus (HIV) infection, regardless of CD4 count. Clinically significant active malabsorption syndrome or inflammatory bowel disease Prior exposure to 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. Vaccination with a live vaccine within 28 days prior to randomization. Patients with the following hypersensitivity: Known hypersensitivity, including anaphylaxis, to any component or excipient of LOXO-305. For patients planned to receive idelalisib, known hypersensitivity, including anaphylaxis, to any component or excipient of idelalisib. For patients planned to receive bendamustine, known hypersensitivity, including anaphylaxis, to any component or excipient of bendamustine. Prior significant hypersensitivity to rituximab.

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 in 1:1 into Arm A or Arm B. Patients randomized to Arm B who have disease progression (PD) confirmed by independent review committee (IRC) may be eligible to crossover into Arm A. Patients who discontinue treatment for toxicity may still be evaluated for cross over at the time of IRC-confirmed PD.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (LOXO-305)<br>Orally | Drug: LOXO-305<br>* Oral LOXO-305<br>* Other names: Pirtobrutinib;|
| Active Comparator: Arm B (Idelalisib plus rituximab [IdelaR] or bendamustine plus rituximab [BR])<br>Investigator's choice of idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR). | Drug: Idelalisib<br>* Oral<br>* Other names: Zydelig;Drug: Bendamustine<br>* IV<br>* Other names: Treanda, Treakisym, Ribomustin, Levact;Drug: Rituximab<br>* IV<br>* Other names: Rituxan, MabThera, Truxima;|

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 LOXO-305 monotherapy (Arm A) compared to investigator's choice of idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) (Arm B) | Assessed per iwCLL 2018 | Up to approximately 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the effectiveness of Arm A compared to Arm B based on Overall Response Rate (ORR) | Assessed per iwCLL 2018 | Up to approximately 36 months | 
| To evaluate the effectiveness of Arm A compared to Arm B based on Overall Survival (OS) | Assessed by survival | Up to approximately 36 months | 
| To evaluate the effectiveness of Arm A compared to Arm B based on Time to Next Treatment (TTNT) | Defined as time from randomization to next systemic anticancer therapy for CLL/SLL | Up to approximately 36 months | 
| 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 | Up to approximately 36 months | 
| Time to worsening (TTW) of physical function | Using the 5 physical function items identified from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30) questionnaire (also known as the EORTC IL 19 questionnaire), physical function will be measured. The range of raw scores for these items could be from 0-20 with the highest score indicating worst function. | Up to approximately 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lymphoma, non-Hodgkin's, Hematologic Disease, Lymphoma, B-cell, Lymphoma, Bruton's tyrosine kinase inhibitor, Ibrutinib, Acalabrutinib, Zanubrutinib, Pirtobrutinib