Pirtobrutinib + VR for Chronic Lymphocytic Leukemia

(BRUIN CLL-322 Trial)

Recruiting at 314 trial locations

Overseen By Patient Advocacy

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Loxo Oncology, Inc.

Must not be taking: Warfarin, Strong CYP3A4 inhibitors

Disqualifiers: Richter's transformation, CNS involvement, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: Duration not specified

600 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial requires that you do not take certain medications, like strong CYP3A4 inhibitors or inducers, and you cannot be on therapeutic anticoagulation with warfarin or another Vitamin K antagonist. If you're on these, you may need to stop or switch medications.

Is the combination of Pirtobrutinib and Venetoclax safe for treating Chronic Lymphocytic Leukemia?

Pirtobrutinib and Venetoclax have been studied separately and in combination with other drugs for Chronic Lymphocytic Leukemia, showing a manageable safety profile. Venetoclax, often combined with Rituximab, has been effective and safe, with common side effects including diarrhea and liver enzyme changes. Pirtobrutinib has shown fewer severe side effects compared to Venetoclax in some studies. ^{1 2 3 4 5}

What makes the drug combination of Pirtobrutinib, Rituximab, and Venetoclax unique for treating chronic lymphocytic leukemia?

This drug combination is unique because Pirtobrutinib is a non-covalent (reversible) Bruton tyrosine kinase inhibitor designed to overcome limitations of previous inhibitors, and when combined with Venetoclax and Rituximab, it offers a novel approach that may improve response rates and safety profiles compared to existing treatments. ^{1 2 3 4 6}

Research Team

Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)

Principal Investigator

Eli Lilly and Company

Eligibility Criteria

This trial is for people with CLL/SLL who need treatment and have already tried at least one therapy. They should be in fairly good health (ECOG 0-2), have a certain level of blood cells, and their kidneys must work well enough (creatinine clearance ≥30 mL/min). People can't join if they've had certain infections, HIV, hepatitis B or C, previous venetoclax treatment, allergies to the drugs used here, recent live vaccines or stem cell transplants.

Inclusion Criteria

I have been treated with a specific cancer medication before.

Estimated creatinine clearance ≥30 milliliters per minute (mL/min)

My organs are working well.

Exclusion Criteria

I need blood thinners like warfarin for my condition.

My cancer has spread to my brain or spinal cord.

I have not received a live vaccine in the last 28 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Pirtobrutinib plus Venetoclax and Rituximab (Arm A) or Venetoclax and Rituximab (Arm B) for a fixed duration

Duration not specified

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to approximately 5 years

Treatment Details

Interventions

• Pirtobrutinib
• Rituximab
• Venetoclax

Trial Overview The study tests Pirtobrutinib combined with Venetoclax and Rituximab against just Venetoclax and Rituximab in patients previously treated for CLL/SLL. The goal is to see which combination works better and is safer over up to five years.

Participant Groups

Group I: Arm A (PVR) Experimental Treatment 3 Interventions

Fixed duration pirtobrutinib in combination with venetoclax and rituximab

Group II: Arm B (VR) Active Control 2 Interventions

Venetoclax with rituximab

Pirtobrutinib is already approved in United States for the following indications:

Approved in United States as Jaypirca for:

• Mantle Cell Lymphoma
• Chronic Lymphocytic Leukemia
• Small Lymphocytic Lymphoma

Who Is Running the Clinical Trial?

Loxo Oncology, Inc.

Lead Sponsor

Trials

72

Recruited

11,600+

Jacob Van Naarden

Loxo Oncology, Inc.

Chief Executive Officer since 2019

A.B. in Molecular Biology from Princeton University

Dr. Jennifer Low

Loxo Oncology, Inc.

Chief Medical Officer since 2014

MD and PhD from Georgetown University; Undergraduate degree from California Institute of Technology

Eli Lilly and Company

Industry Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Findings from Research

Pirtobrutinib, a non-covalent BTK inhibitor, showed a significantly higher objective response rate (80.2%) compared to venetoclax (64.8%) in patients with chronic lymphocytic leukemia (CLL) who had previously been treated with covalent BTK inhibitors, based on a comparison of 146 patients receiving pirtobrutinib and 91 patients receiving venetoclax.

While progression-free survival (PFS) and overall survival (OS) rates were comparable between pirtobrutinib and venetoclax, pirtobrutinib was associated with fewer grade ≥3 treatment-emergent adverse events, indicating it may be a safer option for patients with relapsed CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pirtobrutinib versus venetoclax in covalent Bruton tyrosine kinase inhibitor-pretreated chronic lymphocytic leukemia: a matching-adjusted indirect comparison. Al-Sawaf, O., Jen, MH., Hess, LM., et al.[2023]

The combination of venetoclax with rituximab showed remarkable efficacy and a manageable safety profile in treating chronic lymphocytic leukemia (CLL), both in relapsed/refractory cases and as a first-line therapy for high-risk patients.

Similarly, the combination of ibrutinib with venetoclax also demonstrated striking efficacy, suggesting that these combinations could become new standard treatment options for CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. Wanner, D., Steurer, M.[2020]

Venetoclax is an effective oral treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), showing durable responses and a manageable safety profile in clinical trials, including patients with poor prognostic factors.

In combination with rituximab, venetoclax significantly improved progression-free survival and achieved undetectable minimal residual disease compared to bendamustine plus rituximab, with benefits lasting for at least 36 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia. Scott, LJ.[2020]

Venetoclax is a highly effective treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), achieving response rates of about 80% in clinical trials involving 240 patients from 2011 to 2016.

While venetoclax has an acceptable safety profile, common side effects include neutropenia and diarrhea, and there is a risk of tumor lysis syndrome (TLS), which can be managed through careful dose ramp-up and patient education, leading to no reported TLS events in ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . Brumbaugh Paradis, H., Alter, D., Llerandi, D.[2018]

In a phase 1/2 clinical trial involving 46 patients with relapsed/refractory chronic lymphocytic leukemia (CLL), the combination therapy of venetoclax, umbralisib, and ublituximab (U2-VeN) demonstrated a remarkable overall response rate of 98%, with 42% achieving complete responses.

The treatment was found to be safe, with manageable adverse effects, including diarrhea in 50% of patients and liver enzyme elevations in 33%, but no cases of tumor lysis syndrome, indicating that this time-limited therapy can effectively control CLL while minimizing prolonged treatment risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response-Adapted, Time-Limited Venetoclax, Umbralisib and Ublituximab for Relapsed/Refractory Chronic Lymphocytic Leukemia. Hill, BT., Ma, S., Zent, CS., et al.[2023]

Ibrutinib has shown durable efficacy in treating relapsed/refractory chronic lymphocytic leukemia (CLL) over a 7-year follow-up, but patients with certain health conditions like cardiac disease or those on anticoagulants may not be suitable for this continuous therapy.

Venetoclax combined with rituximab offers an effective, chemo-free treatment option for R/R CLL with a fixed duration of up to 24 months, achieving deep responses in most patients and demonstrating a reassuring safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relapsed/Refractory Chronic Lymphocytic Leukemia: Chemoimmunotherapy, Treatment until Progression with Mechanism-Driven Agents or Finite-Duration Therapy? Cuneo, A., Foà, R.[2020]

References

1. Italy pubmed.ncbi.nlm.nih.gov

Pirtobrutinib versus venetoclax in covalent Bruton tyrosine kinase inhibitor-pretreated chronic lymphocytic leukemia: a matching-adjusted indirect comparison. [2023]

2. Austria pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. [2020]

3. France pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]

5. United States pubmed.ncbi.nlm.nih.gov

Response-Adapted, Time-Limited Venetoclax, Umbralisib and Ublituximab for Relapsed/Refractory Chronic Lymphocytic Leukemia. [2023]

6. Italy pubmed.ncbi.nlm.nih.gov

Relapsed/Refractory Chronic Lymphocytic Leukemia: Chemoimmunotherapy, Treatment until Progression with Mechanism-Driven Agents or Finite-Duration Therapy? [2020]