Pirtobrutinib + VR for Chronic Lymphocytic Leukemia

(BRUIN CLL-322 Trial)

Not currently recruiting at 371 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the effectiveness and safety of a new treatment combination for individuals with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). Researchers compare a combination of three medications—pirtobrutinib (Jaypirca), venetoclax, and rituximab—against venetoclax and rituximab alone. Suitable candidates have previously received treatment for CLL/SLL but require additional management. The study will last up to five years and aims to discover better treatment options for those who have tried other therapies. As a Phase 3 trial, it represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

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 there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the combination of pirtobrutinib, venetoclax, and rituximab is generally well-tolerated by patients with chronic lymphocytic leukemia (CLL). Earlier studies demonstrated promising results, with patients achieving significant improvements. One study found no interactions between pirtobrutinib and venetoclax, supporting their safe use together.

For those considering venetoclax and rituximab without pirtobrutinib, these drugs already treat CLL and have a well-known safety record. Doctors understand the side effects well, which helps them manage these effects effectively.

Overall, while researchers continue to study these treatments, current data suggests they are generally safe with manageable side effects. Participants interested in joining a trial should talk to their healthcare provider to learn more about the potential risks and benefits. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about pirtobrutinib for treating chronic lymphocytic leukemia (CLL) because it offers a novel approach by targeting Bruton’s tyrosine kinase (BTK) in a reversible manner. Unlike current treatments, such as ibrutinib, which also target BTK but bind irreversibly and can lead to resistance, pirtobrutinib's reversible binding may overcome resistance and reduce side effects. Additionally, the combination of pirtobrutinib with venetoclax and rituximab—both known agents in CLL therapy—has the potential to enhance effectiveness and provide a more comprehensive treatment strategy. This makes the treatment a promising option for patients who may not respond well to existing therapies.

What evidence suggests that this trial's treatments could be effective for chronic lymphocytic leukemia?

In this trial, participants will join one of two treatment arms. Arm A receives a combination of pirtobrutinib, venetoclax, and rituximab. Research has shown that this combination is highly effective for patients with chronic lymphocytic leukemia (CLL) that has returned or not responded to previous treatments, often leading to significant cancer reduction or even disappearance. Arm B receives venetoclax and rituximab, a combination already proven effective in similar cases. Adding pirtobrutinib in Arm A appears to enhance the treatment's effectiveness, suggesting that this drug combination could greatly benefit people with CLL who have tried other treatments. ^{1 2 4 6 7}

Who Is on the 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

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12559276/

Pharmacological profiling in CLL patients during ... These data suggest that different targeted agents could be added or sequenced after several cycles of pirtobrutinib to enhance response. Disease ...

2. cllsociety.org cllsociety.org/2024/09/combination-pirtobrutinib-venetoclax-and-rituximab-for-cll/

Combination Pirtobrutinib, Venetoclax, and Rituximab for ... The combination of pirtobrutinib, venetoclax, and rituximab was very effective and produced deep remissions in patients with relapsed / refractory CLL.

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa2213093

First-Line Venetoclax Combinations in Chronic ... Venetoclax–obinutuzumab with or without ibrutinib was superior to chemoimmunotherapy as first-line treatment in fit patients with CLL.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04965493

NCT04965493 | A Trial of Pirtobrutinib (LOXO-305) Plus ... 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 ...

5. healthtree.org healthtree.org/cll/community/articles/sponsorstudy-pirtobrutinib-venetoclax-cll-phase-1

Two-Year Pirtobrutinib + Venetoclax for R/R CLL New study explores 2-year combo of pirtobrutinib + venetoclax ± rituximab for relapsed/refractory CLL. Promising early results.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38861666/

Fixed-duration pirtobrutinib plus venetoclax with or ... - PubMed Fixed-duration PV or PVR was well tolerated and had promising efficacy in patients with R/R CLL, including patients previously treated with a covalent BTKi.

7. mayo.edu mayo.edu/research/clinical-trials/diseases-conditions/chronic-lymphocytic-

Chronic Lymphocytic Clinical Trials The purpose of this study is to determine if a new drug combination, pirtobrutinib and venetoclax, will help Chronic Lymphocytic Leukemia (CLL) or Small ...