Pirtobrutinib for Chronic Lymphocytic Leukemia

(BOSS Trial)

No longer recruiting at 12 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: AstraZeneca

Must be taking: Acalabrutinib

Must not be taking: Warfarin, Strong CYP3A inhibitors

Disqualifiers: Significant cardiovascular disease, HIV, 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

Compensation: Varies

Number of Visits: 12

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the effectiveness of a new treatment, pirtobrutinib, for individuals with chronic lymphocytic leukemia (CLL) who have previously received acalabrutinib and require a second option. The study evaluates the efficacy and safety of pirtobrutinib, with some participants trying acalabrutinib again if pirtobrutinib proves ineffective. It suits those who have progressed on their initial acalabrutinib treatment and are ready for a second-line therapy. Participants should not have undergone major surgery recently or have certain heart problems or infections. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group, offering participants the opportunity to benefit from a promising new therapy.

Will I have to stop taking my current medications?

The trial does not specify if you must stop all current medications, but you cannot take strong CYP3A inhibitors or inducers close to starting the study drug. If you're on these, you may need to stop them 1 to 3 weeks before the trial.

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

Earlier research found pirtobrutinib to be safe for individuals with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Studies show it works well even for patients with certain genetic changes and is generally easy for patients to handle. Another study demonstrated that pirtobrutinib is safer compared to some other treatments.

Real-world studies have shown acalabrutinib to be safe and effective for CLL. Its safety surpasses some older treatments, particularly regarding heart-related side effects. Patients using acalabrutinib have generally tolerated it well.

Both treatments have shown good safety results in studies, making them promising options for those considering participation in a clinical trial. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for chronic lymphocytic leukemia?

Pirtobrutinib is unique because it targets Bruton’s tyrosine kinase (BTK) in a new way. Unlike current chronic lymphocytic leukemia treatments, which often face resistance issues, pirtobrutinib is designed to overcome these problems by binding differently to the BTK enzyme. Researchers are excited about this treatment because it offers hope for patients who have stopped responding to existing therapies like ibrutinib and acalabrutinib, potentially providing a more effective and durable option.

What evidence suggests that pirtobrutinib might be an effective treatment for chronic lymphocytic leukemia?

Research has shown that pirtobrutinib, which participants in this trial may receive, effectively treats chronic lymphocytic leukemia (CLL). One study found that it reduced cancer in 62% of patients and prevented disease progression for an average of 20 months. This indicates that more than half of the patients experienced tumor shrinkage. Pirtobrutinib has also improved survival rates compared to standard treatments in previously untreated patients. Acalabrutinib is another treatment option in this trial, and studies suggest it is highly effective. Specifically, it prevented disease progression for 12 months in 92% of high-risk CLL patients and achieved a 94% overall survival rate. Both treatments show promise in effectively managing CLL. ^{1 2 6 7 8}

Are You a Good Fit for This Trial?

This trial is for adults with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma who have seen their disease progress after first-line treatment with Acalabrutinib. Specific eligibility criteria are not provided, but typically include factors like age, health status, and previous treatments.

Inclusion Criteria

I can care for myself and am up and about more than 50% of my waking hours.

My organs and bone marrow are working well.

Adequate coagulation, defined as aPTT or PTT and PT or INR not greater than 1.5 × ULN

Exclusion Criteria

I have a bleeding disorder such as hemophilia.

I have not had a stroke or brain bleed in the last 6 months.

Active HBV or HCV infection

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment with Pirtobrutinib

Participants receive pirtobrutinib for up to 24 cycles or until disease progression, unacceptable toxicity, death, or withdrawal of consent

24 months

Monthly visits for the first 6 months, then every 3 months for 12 months, and 2 visits in the last 6 months

Retreatment with Acalabrutinib

Participants who progress on pirtobrutinib receive acalabrutinib for up to 12 cycles or until disease progression, death, intolerance, unacceptable toxicity, or withdrawal of consent

12 months

Monthly visits for the first 6 months, then 2 visits in the last 6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

One visit after the treatment phase

Open-label extension (optional)

Participants can continue receiving treatment off-trial if beneficial, in consultation with their physician

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• Pirtobrutinib

Trial Overview The study is testing the effectiveness and safety of Pirtobrutinib in patients whose CLL/SLL has worsened despite initial treatment with Acalabrutinib. It's likely a sequential study where Pirtobrutinib follows as a second-line therapy.

How Is the Trial Designed?

Group I: Pirtobrutinib and Acalabrutinib Experimental Treatment 2 Interventions

Participants will receive dose A of pirtobrutinib starting Cycle 1 Day 1 for up to 24 cycles or until disease progression, unacceptable toxicity, death, or withdrawal of consent. If they progress on pirtobrutinib, a subset will receive dose B of acalabrutinib starting Cycle 1 Day 1 for up to 12 cycles or until disease progression, death, intolerance, unacceptable toxicity, or withdrawal of consent. Those benefiting from treatment will enter the Disease Follow-up period, continuing with pirtobrutinib or acalabrutinib until disease progression, unacceptable toxicity, death, or withdrawal of consent. After 36 months from starting pirtobrutinib, participants can continue receiving treatment off-trial if beneficial, in consultation with their physician.

Who Is Running the Clinical Trial?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

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

Non-covalent Bruton's tyrosine kinase inhibitors (ncBTKi), like pirtobrutinib, offer a promising alternative for treating chronic lymphocytic leukemia (CLL) due to their reversible binding, which may reduce toxicity and resistance issues associated with covalent inhibitors (cBTKi).

Pirtobrutinib has demonstrated strong safety and preliminary efficacy in clinical trials for CLL, particularly for patients who have developed resistance to previous treatments, highlighting its potential role in addressing unmet needs in CLL therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-Covalent Bruton's Tyrosine Kinase Inhibitors in the Treatment of Chronic Lymphocytic Leukemia. Montoya, S., Thompson, MC.[2023]

In a meta-analysis of 2456 CLL patients, ibrutinib was found to have a similar risk of anemia, thrombocytopenia, and neutropenia compared to control treatments, indicating a favorable safety profile for these adverse effects.

However, patients treated with ibrutinib experienced significantly higher rates of abdominal issues and diarrhea, suggesting that while it is effective, monitoring for gastrointestinal side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse drug events associated with ibrutinib for the treatment of elderly patients with chronic lymphocytic leukemia: A systematic review and meta-analysis of randomized trials. Zhou, Y., Lu, H., Yang, M., et al.[2022]

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]

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]

Pirtobrutinib, a noncovalent BTK inhibitor, demonstrated a 73.3% overall response rate in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had previously failed covalent BTK inhibitor treatments, indicating its efficacy as a new therapeutic option.

The treatment was generally well-tolerated, with only 2.8% of patients discontinuing due to adverse events, and common side effects included infections and bleeding, while serious side effects like hypertension and major hemorrhage were relatively infrequent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia. Mato, AR., Woyach, JA., Brown, JR., et al.[2023]

Pirtobrutinib received accelerated FDA approval for treating adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two prior therapies, showing a 50% overall response rate in a study of 120 patients.

While effective, pirtobrutinib has potential side effects including fatigue, diarrhea, and increased risk of infections and bleeding, necessitating postmarketing studies to further assess its long-term safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pirtobrutinib for Relapsed or Refractory Mantle Cell Lymphoma. Telaraja, D., Kasamon, YL., Collazo, JS., et al.[2023]

Pilaralisib, a pan-PI3K inhibitor, was found to have an acceptable safety profile in a study of 25 patients with chronic lymphocytic leukemia (CLL) and lymphoma, with common side effects including diarrhea (92%) and pyrexia (52%).

The treatment showed preliminary efficacy, with 50% of CLL patients achieving a partial response and 60% experiencing significant nodal shrinkage, indicating potential for further development in these cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Trial of the Pan-PI3K Inhibitor Pilaralisib (SAR245408/XL147) in Patients with Chronic Lymphocytic Leukemia (CLL) or Relapsed/Refractory Lymphoma. Brown, JR., Davids, MS., Rodon, J., et al.[2021]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40736551/

Real-world efficacy and safety outcomes of acalabrutinib in ... NAOS, a real-world study, complements these trials with real-world (rw) acalabrutinib data generated from clinical practice.

2. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/5151/503709/Real-World-Effectiveness-and-Safety-Outcomes-of

Real-World Effectiveness and Safety Outcomes of ... The 18-month OS rate was 90% and 85% for the 1L and 2L+ cohorts, respectively ( Figure 2). After initiation of acalabrutinib treatment, the incidence rates of ...

3. tandfonline.com tandfonline.com/doi/full/10.1080/1120009X.2024.2357980

Meta-analysis of the efficacy and adverse effects ... The results demonstrate that acalabrutinib shows efficacy in the treatment of R/R CLL with tolerable adverse reaction rates.

4. rarediseaseadvisor.com rarediseaseadvisor.com/news/acalabrutinib-improved-outcomes-high-risk-chronic-lymphocytic-leukemia/

Acalabrutinib Improved Outcomes in High-Risk CLL With a 12-month progression-free survival (PFS) rate of 92% and overall survival (OS) rate of 94%, these results underscore the utility of ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S2473952923002422

Real-world comparative effectiveness of acalabrutinib and ... Patients with CLL receiving acalabrutinib demonstrated lower rates of discontinuation and a prolonged time to discontinuation vs those receiving ibrutinib.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04008706

NCT04008706 | Acalabrutinib Safety Study in Untreated ... To evaluate the safety and tolerability of acalabrutinib monotherapy in participants with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia.

7. hematologyadvisor.com hematologyadvisor.com/news/chronic-leukemia-cll-safety-profile-acalabrutinib-superior-chemoimmunotherapy/

Safety Profile of Acalabrutinib Superior to ... The cardiovascular safety profile of acalabrutinib is superior to that of chemoimmunotherapy in treating patients with chronic lymphocytic leukemia (CLL).

8. sciencedirect.com sciencedirect.com/science/article/pii/S2950328024000645

Real-world safety profile of therapy with ibrutinib or ... Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial