A Study to Investigate the Sequencing Strategy of Pirtobrutinib After Disease Progression on First-line Acalabrutinib Treatment for Adult Participants With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (BOSS)

BOSS: BTK Inhibitor Optimal Sequencing Study Phase II Open-label Single Arm Trial of Pirtobrutinib in Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma After First-line Acalabrutinib Progression

To assess the efficacy and safety of pirtobrutinib in participants with CLL/SLL who have progressed on first-line treatment with acalabrutinib.

Study Overview

• Status: Withdrawn
• Conditions: Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma
• Intervention / Treatment: Drug: Pirtobrutinib; Drug: Acalabrutinib

Detailed Description

The purpose of this study is to assess the efficacy and safety of pirtobrutinib in participants with CLL/SLL who have progressed on first-line treatment with acalabrutinib. A subset of participants who have disease progression on pirtobrutinib will be retreated with acalabrutinib to assess whether relapsed CLL can be re-sensitized to a covalent irreversible BTK inhibitor such as acalabrutinib, and thereby, remain on treatment within the BTK inhibitor class rather than transition into another CLL/SLL treatment.

• The study duration for each participant will be up to 3 years in total.
• For participants who receive pirtobrutinib alone, the visit frequency will be approximately every month for the first 6 months. After that, the visit frequency will be reduced to one visit approximately every 3 months for the subsequent 12 months. The final part of the Treatment Phase has 2 visits in the space of 6 months. There is one visit to the site after the Treatment Phase.
• Participants who have disease progression on pirtobrutinib and go on to receive acalabrutinib retreatment will visit the site approximately once every month for the first 6 months. After that, the visit frequency will be reduced to 2 visits in the space of 6 months. There is one visit to the site after the Treatment Phase.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Saint Petersburg, Florida, United States, 33709
      • Research Site
  • Iowa
    • Ames, Iowa, United States, 50010
      • Research Site
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Research Site
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Research Site
    • Winston-Salem, North Carolina, United States, 27103
      • Research Site
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Research Site
  • Oregon
    • Medford, Oregon, United States, 97504
      • Research Site
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Research Site
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • Research Site
    • Richmond, Virginia, United States, 23219
      • Research Site
  • Washington
    • Seattle, Washington, United States, 98109
      • Research Site
    • Spokane, Washington, United States, 99208
      • Research Site
    • Tacoma, Washington, United States, 98405
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Participant must be ≥ 18 at the time of signing the informed consent.
• Participants must have received acalabrutinib monotherapy as first-line treatment for CLL/SLL, have progressed per the iwCLL Criteria (Hallek et al 2018) and be eligible for second-line treatment by the same criteria.
• ECOG performance status of 0, 1, or 2.
• Adequate organ and BM function.
• Adequate coagulation, defined as aPTT or PTT and PT or INR not greater than 1.5 × ULN.
• Participants have a clearly defined, documented and accessible start date of their first line acalabrutinib monotherapy for CLL/SLL.
• Participants are eligible for the acalabrutinib retreatment phase only if they have progressed on pirtobrutinib monotherapy per iwCLL Criteria.

Exclusion Criteria:

• Major surgical procedure within 30 days before and not recovered adequately the first dose of study drug.
• Participants who experienced a major bleeding event or Grade ≥ 3 arrhythmia on prior treatment with a BTK inhibitor.
• History of bleeding diathesis (eg, hemophilia, von Willebrand disease).
• History of stroke or intracranial hemorrhage within 6 months before first dose of study drug.
• Significant cardiovascular disease.
• History of PML.
• Any active significant infection.
• HIV positive
• Active HBV or HCV infection.
• Active CNS involvement by lymphoma, leptomeningeal disease, or spinal cord compression.
• Active auto-immune cytopenia.
• History of prior or current malignancy.
• Requires or receiving therapeutic anticoagulation with warfarin or equivalent vitamin K antagonists.
• Received a live virus vaccination within 28 days of first dose of study drug.
• Requires treatment with a strong CYP3A inhibitor or inducer. The use of strong CYP3A inhibitors within 1 week or strong CYP3A inducers within 3 weeks of the first dose of study drug is prohibited.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Pirtobrutinib and Acalabrutinib; 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.

Drug: Pirtobrutinib; Patients will receive pirtobrutinib orally with dosing schedule as prescribed; Other Names: JAYPIRCA; Drug: Acalabrutinib; Patients will receive acalabrutinib orally with dosing schedule as prescribed.; Other Names: CALQUENCE®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR) in participants with CLL/SLL.	ORR is defined as the proportion of participants who achieve best response of CR, CRi, nPR, or PR per the iwCLL Criteria as assessed by the investigator.	ORR will be assessed after 12 cycles (each cycle lasts 28 days) of pirtobrutinib.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Investigator assessed ORR in participants with CLL/SLL.	ORR is defined as the proportion of participants who achieve best response of CR, CRi, nPR, or PR per the iwCLL Criteria as assessed by the investigator.	ORR will be assessed after 24 cycles (each cycle is 28 days) of pirtobrutinib and at 3 years from Cycle 1: Day 1 of pirtobrutinib.
Progression free Survival (PFS) in participants with CLL/SLL.	PFS is defined as time from date of the first dose of pirtobrutinib until disease progression per the iwCLL Criteria as assessed by the investigator, or death due to any cause in the absence of disease progression.	PFS will be assessed at 24 months of pirtobrutinib treatment.
Safety and tolerability of pirtobrutinib in CLL/SLL following disease progression on first-line acalabrutinib in participants with CLL/SLL.	Safety and tolerability will be evaluated as the number of participants with Adverse Events (AEs), Serious Adverse Events (SAEs), and AE leading to treatment discontinuation.	Safety and tolerability will be evaluated at every visit starting from pirtobrutinib treatment through the study completion (for 3 years)
Safety of acalabrutinib retreatment following disease progression on pirtobrutinib in participants with CLL/SLL.	Safety will be evaluated as the number of participants with Adverse Events (AEs), Serious Adverse Events (SAEs), and AE leading to treatment discontinuation.	Safety will be evaluated at every visit starting from acalabrutinib treatment through the study completion (for 3 years)

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Eli Lilly and Company

Study record dates

Study Major Dates

• Study Start (Estimated): June 30, 2025
• Primary Completion (Estimated): July 28, 2028
• Study Completion (Estimated): July 29, 2030

Study Registration Dates

• First Submitted: January 21, 2025
• First Submitted That Met QC Criteria: February 17, 2025
• First Posted (Actual): February 21, 2025

Study Record Updates

• Last Update Posted (Estimated): June 5, 2025
• Last Update Submitted That Met QC Criteria: June 3, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Chronic Disease; Disease Attributes; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia; Lymphoma; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Tyrosine Kinase Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Acalabrutinib; Pirtobrutinib
• Other Study ID Numbers: D8220R00065

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No