Pirtobrutinib + Venetoclax + Obinutuzumab for Chronic Lymphocytic Leukemia

Overseen By Alessandra Ferrajoli, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Warfarin, Vitamin K antagonists

Disqualifiers: Richter's syndrome, CNS involvement, others

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

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 13 cycles (approximately 13 months)

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if a combination of three drugs—pirtobrutinib, venetoclax, and obinutuzumab—can control chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that has returned after treatment. The trial includes two groups: one for individuals who have not used venetoclax before and another for those who have. Suitable candidates are those previously treated for CLL or SLL and now require additional therapy. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Do I have to stop taking my current medications for the trial?

The trial requires a washout period (time without taking certain medications) for some treatments before starting. Specifically, you need to stop targeted agents, investigational agents, therapeutic monoclonal antibodies, or cytotoxic chemotherapy for 5 half-lives or 2 weeks, whichever is shorter. Additionally, certain other treatments like immunoconjugated antibody treatment and radiation have specific washout periods.

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

Research shows that the combination of pirtobrutinib, venetoclax, and obinutuzumab holds promise for treating chronic lymphocytic leukemia (CLL). Some studies indicate that patients have tolerated this combination well. Many have experienced deep remissions, where their disease significantly decreases or temporarily disappears.

Although patients in earlier studies generally tolerated the treatment well, side effects can still occur. These studies are ongoing, and researchers continue to learn about patient responses and potential side effects. It is crucial to consult a healthcare provider to understand the potential risks and benefits before considering joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Pirtobrutinib, Venetoclax, and Obinutuzumab for Chronic Lymphocytic Leukemia (CLL) because it offers a fresh approach compared to existing treatments. Pirtobrutinib is a next-generation Bruton's tyrosine kinase (BTK) inhibitor that targets cancer cells more precisely, potentially reducing side effects. Venetoclax works by inducing cancer cell death through a different pathway, specifically targeting BCL-2 proteins, which makes it a powerful partner in this cocktail. Obinutuzumab, an antibody that directly attacks cancerous B-cells, complements these mechanisms. This triple combination aims to provide a more comprehensive attack on CLL, potentially leading to better outcomes than current standard treatments like Ibrutinib or Rituximab-based regimens.

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

Research shows that a combination of three drugs—pirtobrutinib, venetoclax, and obinutuzumab—may be promising for treating chronic lymphocytic leukemia (CLL). In this trial, participants will be divided into two groups: those who are venetoclax-naive and those previously exposed to venetoclax. Studies have found that using venetoclax and obinutuzumab together can lead to long-lasting periods without treatment, with 53% of patients not experiencing disease progression for six years. Adding pirtobrutinib to this mix has demonstrated high rates of minimal residual disease negativity, indicating very low levels of cancer cells in the bone marrow after six to twelve months. This suggests that the combination could effectively control CLL. Early results also indicate that patients tolerate the treatment well, with manageable side effects. ^{4 6 7 8 9}

Who Is on the Research Team?

Alessandra Ferrajoli, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with recurrent CLL/SLL who have previously undergone treatment. Specific eligibility criteria are not provided, but typically include factors like age, health status, and disease characteristics.

Inclusion Criteria

I have been diagnosed with CLL/SLL according to 2018 standards.

I have CLL needing treatment as per 2018 guidelines.

My side effects from previous treatments are mild, except for hair loss and some nerve pain.

Exclusion Criteria

I had a major bleeding event on a previous BTK inhibitor treatment.

I need blood thinners like warfarin for my condition.

I don't have major kidney, brain, mental health, hormone, metabolism, or immune issues that could affect my study participation.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Pirtobrutinib, Venetoclax, and Obinutuzumab in cycles, with primary objectives measured at the end of Cycle 13

13 cycles (approximately 13 months)

Follow-up

Participants are monitored for safety, progression-free survival, and overall survival

12 months

What Are the Treatments Tested in This Trial?

Interventions

• Obinutuzumab
• Pirtobrutinib
• Venetoclax

Trial Overview

The study tests a combination of three drugs: Pirtobrutinib, Venetoclax, and Obinutuzumab (PVO), to see if they can effectively control relapsed Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL).

How Is the Trial Designed?

Group I: V-Naive Experimental Treatment 3 Interventions

Venetoclax Naive: Treatment with Pirtobrutinib+Venetoclax+Obinutuzumab Q4W

Group II: V-Exposed Experimental Treatment 3 Interventions

Venetoclax Exposed: Treatment with Pirtobrutinib+Venetoclax+Obinutuzumab Q4W

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

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

Citations

1.

clinicaltrials.gov

clinicaltrials.gov/study/NCT05536349

Study Details | NCT05536349 | Time-limited Triplet ...

To learn if the combination of pirtobrutinib (also called LOXO-305), venetoclax, and obinutuzumab is safe and effective when given to patients with chronic ...

2.

ashpublications.org

ashpublications.org/blood/article/144/18/1924/516941/Venetoclax-obinutuzumab-for-previously-untreated

6-year results of the randomized phase 3 CLL14 study | Blood

One-year fixed-duration Ven-Obi results in durable treatment-free remissions, with a 6-year PFS rate of 53% and TTNT rate of 65%, in CLL. End-of ...

3.

ash.confex.com

ash.confex.com/ash/2024/webprogram/Paper211454.html

Combined Pirtobrutinib, Venetoclax, and Obinutuzumab As ...

We observed a very high rate of BM U-MRD6 at 6-months and 12-months of combined treatment. Adverse event profile was similar to what was noted ...

4.

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.

5.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11551846/

6-year results of the randomized phase 3 CLL14 study

Patients who received VO have better quality of life, better global health status, and improved survival, with no significant excess of second cancers.

6.

clinicaltrials.gov

clinicaltrials.gov/study/NCT05536349

Study Details | NCT05536349 | Time-limited Triplet ...

To learn if the combination of pirtobrutinib (also called LOXO-305), venetoclax, and obinutuzumab is safe and effective when given to patients with chronic ...

7.

cllsociety.org

cllsociety.org/2025/03/first-line-pirtobrutinib-venetoclax-obinutuzumab-for-cll/

First-Line Pirtobrutinib-Venetoclax-Obinutuzumab for CLL

A combination of pirtobrutinib, venetoclax, and obinutuzumab produces deep remissions in most patients with CLL as a first-line treatment.

8.

nejm.org

nejm.org/doi/full/10.1056/NEJMoa2213093

First-Line Venetoclax Combinations in Chronic ...

Three-year progression-free survival was 90.5% in the venetoclax–obinutuzumab–ibrutinib group and 75.5% in the chemoimmunotherapy group (hazard ...

9.

cancernetwork.com

cancernetwork.com/view/pirtobrutinib-triplet-improves-mrd-outcomes-in-cll

Pirtobrutinib Triplet Improves MRD Outcomes in CLL

Phase 2 results showed high undetectable MRD rates with pirtobrutinib, venetoclax, and obinutuzumab for patients with chronic lymphocytic leukemia.