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)

Phase 3

Active, not recruiting

• Conditions: Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma
• Interventions: Drug: Pirtobrutinib; Drug: Venetoclax; Drug: Rituximab

• Registration Number: NCT04965493
• Lead Sponsor: Loxo Oncology, Inc.

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2021-07-15
• Study First Submitted QC: 2021-07-15
• Study First Posted: 2021-07-16
• Study Start: 2021-09-20
• Status Verified: 2025-08
• Last Update Submitted: 2025-08-29
• Last Update Posted: 2025-09-02
• Primary Completion: 2026-04
• Study Completion: 2027-01-01

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 600

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A (PVR)	Pirtobrutinib	Fixed duration pirtobrutinib in combination with venetoclax and rituximab
Arm A (PVR)	Venetoclax	Fixed duration pirtobrutinib in combination with venetoclax and rituximab
Arm A (PVR)	Rituximab	Fixed duration pirtobrutinib in combination with venetoclax and rituximab
Arm B (VR)	Venetoclax	Venetoclax with rituximab
Arm B (VR)	Rituximab	Venetoclax with rituximab

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (272)

Ironwood Physicians, Ironwood Cancer and Research Centers; 🇺🇸 Chandler, Arizona, United States

Mayo Clinic Hospital; 🇺🇸 Phoenix, Arizona, United States

University of California Irvine Medical Center; 🇺🇸 Orange, California, United States

Providence Medical Foundation; 🇺🇸 Santa Rosa, California, United States

Stamford Hospital; 🇺🇸 Stamford, Connecticut, United States

Florida Cancer Specialists; 🇺🇸 Fort Myers, Florida, United States

Cancer Specialists of North Florida -St Augustine; 🇺🇸 Saint Augustine, Florida, United States

Florida Cancer Specialists East; 🇺🇸 West Palm Beach, Florida, United States

Mission Cancer and Blood; 🇺🇸 Des Moines, Iowa, United States

Pikeville Medical Center, Inc.; 🇺🇸 Pikeville, Kentucky, United States

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