Triple Therapy for Chronic Lymphocytic Leukemia

Overseen By Nitin Jain, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Warfarin, Strong CYP3A4 inhibitors

Disqualifiers: HIV, Hepatitis B, Hepatitis C, 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: 6-12 months

60 Participants Needed

Trial Summary

What is the purpose of this trial?

To learn if the combination of pirtobrutinib (also called LOXO-305), venetoclax, and obinutuzumab is safe and effective when given to patients with chronic lymphocytic leukemia (CLL) or Richter transformation (RT) who have not previously received treatment.

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) for strong CYP3A4 inhibitors or inducers and certain P-gp inhibitors before starting the study. If you are taking these medications, you will need to stop them for a specific period before joining the trial.

What data supports the effectiveness of the drug combination of Obinutuzumab, Pirtobrutinib, and Venetoclax for treating Chronic Lymphocytic Leukemia?

Research shows that Venetoclax, when combined with Obinutuzumab, is effective for treating Chronic Lymphocytic Leukemia (CLL), leading to longer progression-free survival and higher response rates compared to other treatments. Venetoclax also shows promise in combination with other drugs like rituximab, providing durable responses in relapsed or refractory CLL. ^{1 2 3 4 5}

Is the triple therapy for Chronic Lymphocytic Leukemia safe for humans?

The combination of venetoclax and obinutuzumab has been shown to have an acceptable safety profile in treating Chronic Lymphocytic Leukemia (CLL), with manageable side effects like neutropenia (low white blood cell count). Pirtobrutinib, another component of the triple therapy, also demonstrated a lower rate of severe side effects compared to venetoclax in some studies. ^{1 2 4 6 7}

What makes the triple therapy of Obinutuzumab, Pirtobrutinib, and Venetoclax unique for treating chronic lymphocytic leukemia?

This triple therapy combines Obinutuzumab, an antibody that targets cancer cells, with Pirtobrutinib, a new type of drug that blocks signals helping cancer cells grow, and Venetoclax, which helps kill cancer cells by targeting a specific protein. This combination is unique because it uses different mechanisms to attack the cancer, potentially offering a more effective treatment option for patients with chronic lymphocytic leukemia. ^{1 2 3 4 8}

Research Team

Nitin Jain, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with untreated chronic lymphocytic leukemia (CLL) or Richter transformation (RT). Participants must have certain levels of bilirubin, renal function, and blood counts. They should not have active hepatitis B/C, HIV, uncontrolled infections or autoimmune diseases requiring high-dose steroids. Pregnant women are excluded and participants must agree to use effective contraception.

Inclusion Criteria

I am 18 years old or older.

My blood tests show enough platelets, hemoglobin, and neutrophils.

My kidneys work well, with a creatinine clearance rate of 50 ml/min or more.

Exclusion Criteria

I have a condition that affects how my body absorbs medication.

I have a serious heart condition that is not under control.

I have not had major surgery in the last 4 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pirtobrutinib, venetoclax, and obinutuzumab in 28-day cycles

6-12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• Obinutuzumab
• Pirtobrutinib
• Venetoclax

Trial Overview The study tests a combination of three drugs: Pirtobrutinib, Venetoclax, and Obinutuzumab in patients who haven't been treated before for CLL or RT. It aims to determine the safety and effectiveness of this drug regimen.

Participant Groups

Group I: Pirtobrutinib plus Venetoclax plus Obinutuzumab (combination) Experimental Treatment 5 Interventions

Participants will receive the study drugs in cycles. Each cycle is 28 days.

Obinutuzumab is already approved in United States, European Union for the following indications:

Approved in United States as Gazyva for:

• Chronic Lymphocytic Leukemia (CLL)
• Follicular Lymphoma

Approved in European Union as Gazyva for:

• Chronic Lymphocytic Leukemia (CLL)
• Follicular Lymphoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

The Leukemia and Lymphoma Society

Collaborator

Trials

87

Recruited

26,200+

Loxo Oncology, Inc.

Industry 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

Findings from Research

In the phase III CLL14 trial, a 12-month treatment with venetoclax combined with obinutuzumab significantly improved progression-free survival and rates of undetectable minimal residual disease compared to traditional chemoimmunotherapy with chlorambucil and obinutuzumab in patients with untreated chronic lymphocytic leukaemia.

Venetoclax + obinutuzumab is a well-tolerated, chemotherapy-free treatment option for CLL, with manageable side effects like neutropenia, making it suitable for patients who cannot undergo intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. Blair, HA.[2021]

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]

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]

In a phase 2 trial involving 70 patients with chronic lymphocytic leukaemia, both 12 cycles of venetoclax consolidation and minimal residual disease-guided consolidation showed similar effectiveness, with around 50% of patients achieving undetectable minimal residual disease in bone marrow after treatment.

While consolidation treatment did not lead to treatment-related deaths, it was associated with a higher incidence of adverse events, particularly infections, indicating that while it may extend treatment duration, it does not significantly improve disease response or reduce relapse risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (HOVON 139/GiVe): primary endpoint analysis of a multicentre, open-label, randomised, parallel-group, phase 2 trial. Kersting, S., Dubois, J., Nasserinejad, K., et al.[2022]

The combination of venetoclax and obinutuzumab has been approved as a superior first-line treatment for elderly, unfit patients with chronic lymphocytic leukaemia (CLL), showing better efficacy than chlorambucil/obinutuzumab based on a phase-III trial.

For patients with high-risk features like deletion 17p or TP53 mutations, targeted therapies such as ibrutinib or venetoclax/obinutuzumab are recommended due to their poor response to traditional chemotherapy, highlighting the importance of personalized treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Current diagnosis and treatment of chronic lymphocytic leukaemia]. Cramer, P., von Tresckow, J., Eichhorst, B., et al.[2021]

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]

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]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. [2021]

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

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

3. Austria pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. [2020]

4. France pubmed.ncbi.nlm.nih.gov

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

5. England pubmed.ncbi.nlm.nih.gov

Venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (HOVON 139/GiVe): primary endpoint analysis of a multicentre, open-label, randomised, parallel-group, phase 2 trial. [2022]

6. Germany pubmed.ncbi.nlm.nih.gov

[Current diagnosis and treatment of chronic lymphocytic leukaemia]. [2021]

7. 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]

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

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