Pirtobrutinib + Obinutuzumab for Chronic Lymphocytic Leukemia

Not currently recruiting at 3 trial locations

Overseen By Heather A Walker, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Inhye Ahn

Must not be taking: Antiretrovirals, Immunosuppressants

Disqualifiers: Richter's transformation, Cardiovascular disease, 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: 1

Duration: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of medications, pirtobrutinib (Jaypirca) and obinutuzumab (Gazyva), to treat chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The goal is to determine if taking these drugs together for about a year can effectively treat these blood cancers. Individuals with CLL or SLL who have never received treatment and feel they need it now might be suitable candidates. Participants will begin with both medications, and if the cancer progresses, they may continue with just pirtobrutinib. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on certain immunosuppressive drugs or investigational agents, and there are restrictions on recent use of high-dose steroids and live vaccines.

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

Research shows that the combination of pirtobrutinib and obinutuzumab has been studied for safety and effectiveness in treating chronic lymphocytic leukemia (CLL). Previous studies have found that this combination is generally well-tolerated. For instance, a study involving pirtobrutinib, venetoclax, and obinutuzumab showed high rates of undetectable minimal residual disease (MRD), a positive result, without unexpected safety concerns.

The FDA has already approved pirtobrutinib for certain patients with CLL or small lymphocytic lymphoma (SLL), indicating a known safety profile. Obinutuzumab has also undergone extensive study, both alone and with other treatments, and has shown a manageable safety profile.

While the current trial is in an early phase, focusing mainly on safety, existing evidence suggests that the treatment is generally well-tolerated with no major safety issues reported so far. Clinical trial participants receive close monitoring, and researchers address any side effects quickly. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about pirtobrutinib and obinutuzumab for treating chronic lymphocytic leukemia (CLL) because they offer a unique approach to tackling the disease. Unlike the standard treatments that often involve chemotherapy or BTK inhibitors, pirtobrutinib is a next-generation BTK inhibitor that targets the BTK protein more selectively, potentially leading to fewer side effects and overcoming resistance seen with older drugs. Obinutuzumab, on the other hand, is a monoclonal antibody that enhances the immune system's ability to attack cancer cells. This combination could provide a more effective and potentially safer option for patients with CLL, especially those who have not responded well to existing treatments.

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

Research has shown that pirtobrutinib, when used as a second treatment option for chronic lymphocytic leukemia (CLL), yields promising results. This drug effectively blocks certain proteins that promote cancer cell growth. Obinutuzumab, another treatment, helps the immune system identify and attack cancer cells. In this trial, participants will receive a combination of pirtobrutinib and obinutuzumab, which may more effectively halt cancer cell growth. Although studies are ongoing, this combination is being tested as an initial treatment, and researchers remain hopeful about its potential benefits. ^{3 5 6 7 8}

Who Is on the Research Team?

Inhye Ahn

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

Adults over 18 with chronic lymphocytic leukemia or small lymphocytic lymphoma who need treatment and meet specific health guidelines. They should have no prior CLL/SLL treatments, be able to take pills, and have measurable disease. Excluded are those with other serious illnesses, recent major surgery, active infections like hepatitis B/C or HIV, bleeding disorders, significant heart issues, or pregnant/breastfeeding women.

Inclusion Criteria

Ability to understand and the willingness to sign a written informed consent document

I can take care of myself and am up and about more than half of my waking hours.

Currently have an indication for treatment as defined by the following 2018 IWCLL guidelines

Exclusion Criteria

Receiving any other investigational agents

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

I have an active, uncontrolled immune system disorder affecting my blood cells.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive 6 cycles of pirtobrutinib alone followed by 6 cycles of pirtobrutinib-obinutuzumab combination therapy

12 months

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Annual visits (in-person)

Retreatment

Participants with progressive CLL/SLL during follow-up will receive continuous pirtobrutinib monotherapy

As needed

What Are the Treatments Tested in This Trial?

Interventions

• Obinutuzumab
• Pirtobrutinib

Trial Overview The trial is testing a combination of two drugs—Pirtobrutinib and Obinutuzumab—for about a year as the first line of attack against chronic lymphocytic leukemia/small lymphocytic lymphoma. The effectiveness of this fixed-duration therapy given over 12 cycles will be evaluated.

How Is the Trial Designed?

Group I: Pirtobrutinib-Obinutuzumab Experimental Treatment 2 Interventions

Eligible participants will receive initial treatment with pirtobrutinib and obinutuzumab for 12 cycles. Participants with progressive chronic lymphocytuc leukemia or small lymphocytic lymphoma during the off-treatment follow-up will receive continuous pirtobrutinib monotherapy.

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?

Inhye Ahn

Lead Sponsor

Trials

2

Recruited

60+

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

Published Research Related to This Trial

Obinutuzumab, a novel humanized anti-CD20 antibody, has been shown to significantly improve overall survival when combined with chlorambucil in untreated comorbid patients with chronic lymphocytic leukemia (CLL).

This antibody enhances antibody-dependent cellular cytotoxicity and directly induces cell death more effectively than previous type I antibodies, marking a significant advancement in CLL treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted treatment for chronic lymphocytic leukemia: clinical potential of obinutuzumab. Smolej, L.[2020]

In a study of 56 patients with relapsed/refractory follicular lymphoma, obinutuzumab combined with chemotherapy (either G-CHOP or G-FC) resulted in high response rates of 93% to 96%, indicating strong efficacy for this treatment approach.

The safety profile was acceptable, with most adverse events being mild infusion-related reactions; however, G-FC was associated with more adverse events compared to G-CHOP, suggesting that while both regimens are effective, G-CHOP may be better tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab (GA101) plus CHOP or FC in relapsed/refractory follicular lymphoma: results of the GAUDI study (BO21000). Radford, J., Davies, A., Cartron, G., et al.[2022]

In a study of 158 previously untreated CLL patients, the combination of obinutuzumab and bendamustine (G-B) showed an overall response rate of 81.0% and a 2-year progression-free survival rate of 81.8%, indicating strong clinical efficacy.

While G-B treatment had manageable toxicity, with 82.3% of patients experiencing grade ≥3 adverse events, careful monitoring for tumor lysis syndrome (TLS) was necessary due to its occurrence in 8.2% of patients, including two fatalities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab plus bendamustine in previously untreated patients with CLL: a subgroup analysis of the GREEN study. Stilgenbauer, S., Leblond, V., Foà, R., et al.[2023]

Ibrutinib has shown high effectiveness as a first-line treatment for chronic lymphocytic leukemia in real-world settings, with 12-month overall survival rates between 95% and 96% and progression-free survival rates ranging from 89% to 93% across various studies involving 112 to 2033 patients.

The treatment demonstrated a strong response rate, with 71% to 90% of patients responding positively, and a significant majority (91% at 12 months and 87% at 24 months) did not require new treatment, indicating its sustained efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic Literature Review of Real-World Effectiveness Results Data for First-Line Ibrutinib in Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma. Lee, P., Kistler, KD., Douyon, L., et al.[2023]

Obinutuzumab, a next-generation CD20 antibody, has been engineered to enhance its ability to kill B cells, showing significant efficacy in treating chronic lymphocytic leukemia (CLL) and other B-cell lymphoproliferative disorders (LPDs).

Clinical trials indicate that obinutuzumab is well tolerated by patients, and its novel mechanism of action may provide advantages over the previously used antibody rituximab, with ongoing studies aimed at optimizing its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab for the treatment of chronic lymphocytic leukemia and other B-cell lymphoproliferative disorders. Said, R., Tsimberidou, AM.[2023]

Obinutuzumab treatment in patients with chronic lymphocytic leukemia and follicular lymphoma led to a significant decrease in natural killer (NK) cell levels in peripheral blood, dropping below the normal range.

Subcutaneous rituximab resulted in a less pronounced reduction of NK cells compared to intravenous rituximab, suggesting that the method of administration may influence NK cell levels during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Battle of Thermopylae: 300 Spartans (natural killer cells plus obinutuzumab) versus the immortal warriors (chronic lymphocytic leukemia cells) of Xerxes' army. García-Muñoz, R., Nájera, MJ., Feliu, J., et al.[2022]

Obinutuzumab, a new type II fully humanized CD20 antibody, shows promise in treating chronic lymphocytic leukemia (CLL) by inducing greater antibody-dependent cell-mediated cytotoxicity (ADCC) compared to the older antibody rituximab.

Clinical trials have demonstrated that obinutuzumab leads to more effective B-cell depletion in CLL patients, suggesting it may provide more durable responses and potentially improve long-term outcomes in CLL therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab in chronic lymphocytic leukemia: design, development and place in therapy. Al-Sawaf, O., Fischer, K., Engelke, A., et al.[2018]

The Phase IIIb GREEN trial demonstrated that obinutuzumab (GA101) has a manageable toxicity profile in both first-line and relapsed/refractory chronic lymphocytic leukaemia (CLL) patients, with no new safety signals identified in the final analysis involving 630 first-line and 341 relapsed/refractory patients.

Common serious adverse events included neutropenia and thrombocytopenia, but the safety profile remained consistent with existing risk management strategies, while efficacy analyses indicated that certain treatment combinations, like obinutuzumab with fludarabine and cyclophosphamide, may lead to better outcomes in specific patient subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of obinutuzumab alone or with chemotherapy in previously untreated or relapsed/refractory chronic lymphocytic leukaemia patients: Final analysis of the Phase IIIb GREEN study. Stilgenbauer, S., Bosch, F., Ilhan, O., et al.[2021]

Obinutuzumab combined with chlorambucil shows better treatment outcomes for patients with untreated chronic lymphocytic leukemia compared to rituximab plus chlorambucil, while maintaining a similar safety profile.

Infusion-related reactions (IRRs) are more common with obinutuzumab, particularly during the first infusion, but these reactions are generally manageable with proper monitoring and management strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Managing Infusion-Related Reactions for Patients With Chronic Lymphocytic Leukemia Receiving Obinutuzumab. Dawson, K., Moran, M., Guindon, K., et al.[2017]

Pirtobrutinib, a noncovalent Bruton tyrosine kinase inhibitor, has shown high response rates in patients with chronic lymphocytic leukemia and mantle cell lymphoma who are resistant to conventional covalent BTK inhibitors, addressing a significant unmet need in this population.

The early studies indicate that pirtobrutinib has a favorable toxicity profile, suggesting it may be suitable for use in combination therapies, and it has recently received accelerated FDA approval for use in mantle cell lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pirtobrutinib: a new hope for patients with BTK inhibitor-refractory lymphoproliferative disorders. Thompson, PA., Tam, CS.[2023]

The combination of the BTK inhibitor ibrutinib with traditional chemoimmunotherapy shows significant benefits for patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma, enhancing treatment effectiveness.

This study highlights the potential of combining targeted therapies like ibrutinib with established treatment methods to improve patient outcomes in CLL, suggesting a promising approach for future cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted drugs in concert with chemo: opposites attract. Wendtner, CM., Fischer, K.[2021]

Ibrutinib is a targeted therapy specifically designed for treating chronic lymphocytic leukemia (CLL), which is a type of cancer that affects the blood and bone marrow.

This novel treatment works by inhibiting Bruton's tyrosine kinase (BTK), a key enzyme that helps cancer cells survive and proliferate, leading to improved patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib (imbruvica): a novel targeted therapy for chronic lymphocytic leukemia. Parmar, S., Patel, K., Pinilla-Ibarz, J.[2021]

Ibrutinib, a BTK inhibitor, has been shown to significantly improve clinical outcomes for patients with chronic lymphocytic leukemia, as demonstrated in two phase III trials.

When used alone or in combination with rituximab, ibrutinib enhances progression-free survival compared to traditional chemoimmunotherapy regimens, suggesting it should be considered a standard treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-Line Ibrutinib Confirmed for CLL. [2019]

Citations

1. onclive.com onclive.com/view/pirtobrutinib-offers-potential-second-line-treatment-in-cll

Pirtobrutinib Offers Potential Second-Line Treatment in CLL Jennifer A. Woyach, MD, discusses the potential of pirtobrutinib as a second-line option for patients with CLL.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06333262?utm_source=trialradar

Fixed Duration Pirtobrutinib and Obinutuzumab in Chronic ... This study will evaluate fixed-duration therapy with pirtobrutinib and obinutuzumab given over 12 cycles (approximately 1 year) as first-line treatment of ...

3. healthtree.org healthtree.org/cll/community/articles/first-time-treated-cll-pirtobrutinib-obinutuzumab

First-Time Treated CLL Pirtobrutinib Obinutuzumab Dr. Inhye Ahn is conducting a clinical trial utilizing pirtobrutinib combined with obinutuzumab for CLL patients needing treatment for the ...

4. dana-farber.org dana-farber.org/clinical-trials/24-017

A phase 2 study of fixed duration therapy with pirtobrutinib ... This study will evaluate fixed-duration therapy with pirtobrutinib and obinutuzumab given over 12 cycles (approximately 1 year) as first-line treatment of ...

5. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-03573

Pirtobrutinib in Combination with Obinutuzumab for the ... This phase II trial studies side effects and how well pirtobrutinib in combination with obinutuzumab works in treating patients with previously untreated ...

6. 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.

7. 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 ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6278964/

Safety of obinutuzumab alone or combined with ... The safety of obinutuzumab, alone or with chemotherapy, was studied in a non-randomized, open-label, non-comparative, phase IIIb study (GREEN) in previously ...