Clonal Dynamics of Chronic Lymphocytic Leukaemia Treated With Pirtobrutinib After Previous Treatment With Zanubrutinib

NCT06812715 | Recruiting Phase 2 FDA Drug

• 1 other identifier: 23/028
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 3

Brief Summary

This is a multicentre single-arm prospective phase II trial evaluating pirtobrutinib in the treatment of relapsed/refractory (R/R) Chronic Lymphocytic Leukaemia (CLL) patients who have previously received zanubrutinib, and to specifically evaluate Bruton Tyrosine Kinase (BTK) mutational status (clonal dynamics) before, during and after treatment with pirtobrutinib.

Conditions

Chronic Lymphocytic Leukemia

Keywords

Pirtobrutinib; Bruton Tyrosine Kinase; BTK mutation; clonal dynamics; CLL; BTK inhibitor; Chronic Lymphocytic Leukaemia; Leukaemia

Outcome Measures

Primary Outcomes (1)

• Cloncal dynamics of BTK mutations in CLL before, during and after treatment with pirtobrutinib

  Before the start of treatment till end of study, up until the last registered patient has been on pirtobrutinib for 36 months without progressive disease

Secondary Outcomes (8)

• Overall response rate in CLL with pirtobrutinib after prior immediate zanubrutinib

  From the start of treatment till end of study, up until the last registered patient has been on pirtobrutinib for 36 months without progressive disease

• The efficacy as assessed by time to response (TTR)

  From the start of treatment till end of study, up until the last registered patient has been on pirtobrutinib for 36 months without progressive disease

• Efficacy as assessed by Duration of Response (DOR)

  From the start of treatment till end of study, up until the last registered patient has been on pirtobrutinib for 36 months without progressive disease

• Efficacy as assessed by Disease Control Rate (DCR)

  From the start of treatment till end of study, up until the last registered patient has been on pirtobrutinib for 36 months without progressive disease

• Efficacy as assessed by Time to next treatment (TTNT)

  From the start of treatment till end of study, up until the last registered patient has been on pirtobrutinib for 36 months without progressive disease

Other Outcomes (1)

• Additional elements of clonal dynamics in CLL

  From the start of treatment till end of study, up until the last registered patient has been on pirtobrutinib for 36 months without progressive disease

Study Arms (1)

Treatment Arm

EXPERIMENTAL

In this single-arm study, patients will receive 200mg of pirtobrutinib once daily on Day 1-28 of each 28-day cycle.

Drug: Pirtobrutinib

Interventions

Pirtobrutinib DRUG

Pirtobrutinib is a first-in-class, oral noncovalent Bruton tyrosine kinase (BTK) inhibitor (BTKi) that was approved in January 2023 in the United States for the treatment of relapsed/refractory (R/R) mantle cell lymphoma (MCL) and later that same year CLL. It is currently being investigated across several global randomised phase III trials for frontline and R/R chronic lymphocytic leukaemia (CLL).

Treatment Arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient has provided written informed consent using the PIPOZA Patient Information and Consent Form (PICF)
• Confirmed diagnosis of CLL according to iwCLL 2018 criteria, also including CLL with atypical immunophenotype
• Prior systemic therapy, which must include zanubrutinib as the most recent prior line of therapy. Patients must have received at least one cycle (28 days) of zanubrutinib
• Patients must have an indication for second- or subsequent-line treatment in the opinion of the investigator as defined by iwCLL 2018 criteria, including:
• Where the original indication for treatment has not resolved with initial therapy and it is considered reasonable to initiate second-line treatment without waiting for formal disease progression to be manifest
• Where the rate of disease progression is considered rapid, and initiation of subsequent therapy is considered acceptable before formal progression where there is substantial persisting disease burden
• Age 18 years of age or older at time of signing the PICF
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
• Must have adequate bone marrow function, as defined below:
• Absolute neutrophil count \> 0.75 × 109/L; if marrow is known to be infiltrated by CLL, granulocyte-colony stimulating factor (G-CSF) support may be used to achieve eligibility criteria
• Platelets ≥ 30 × 109/L independent of transfusions within 7 days prior to screening assessment
• Haemoglobin ≥ 70 g/L independent of transfusions within 7 days prior to screening assessment
• Normal hepatic function defined as:
• Total bilirubin ≤ 1.5× upper limit of normal (ULN) or ≤ 3.0 x ULN with documented liver involvement and/or Gilbert's Disease
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 3.0 × ULN or ≤ 5.0 × ULN with documented liver involvement

You may not qualify if:

• Known or suspected Richter's Transformation to diffuse large B-cell lymphoma, prolymphocytic leukaemia, or Hodgkin lymphoma at any time prior to registration
• Known or suspected history of central nervous system involvement
• History of allogeneic or autologous stem cell transplant or chimeric antigen receptor T-cell (CAR-T) therapy within the past 60 days and/or with any of the following:
• Active graft versus host disease
• Cytopenias from incomplete blood cell count recovery post-transplant or CAR-T therapy
• Need for anti-cytokine therapy for toxicity from CAR-T therapy; residual symptoms of neurotoxicity Grade \> 1 from CAR-T therapy
• Ongoing immunosuppressive therapy
• Positive serology for human immunodeficiency virus (HIV) test in Screening 5. Concurrent anticancer therapy
• \. Use of ≥ 20 mg prednisone QD or equivalent dose of steroid per day within 7 days prior to the planned pirtobrutinib start date on Day 1 Cycle 1. Patients may not be on prednisone of any dose intended for antineoplastic use 7. Vaccination with a live vaccine within 28 days prior to registration 8. Prolongation of the corrected QT interval using the Fredericia formula (QTcF) \> 470 msec (QTcF is calculated using Fridericia's Formula: QTcF = QT / \[RR0.33\])
• Correction of suspected drug induced QTcF prolongation can be attempted at the investigator's discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation
• Manual correction for underlying bundle branch block is allowed Note: Patients with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker 9. Female patient who is pregnant or plans to become pregnant within 1 month after the last dose of study treatment 10. Female patient who is lactating or plans to breastfeed during the study or within 1 week after the last dose of study drug 11. Active second malignancy 12. Clinically significant active malabsorption syndrome including surgical resection of small intestine or other condition likely to affect gastrointestinal (GI) absorption of the oral administered study drugs 13. Active hepatitis B or C infection defined as:
• Hepatitis B virus (HBV): positive hepatitis B surface antigen (HbsAg) or hepatitis B core antibody (anti-HBc). If anti-HBc positive with surface antigen negative, patient will need to have a negative result for hepatitis B DNA before start of study therapy. Patients who are anti-HBc positive and hepatitis B polymerase chain reaction positive will be excluded
• Hepatitis C virus (HCV): positive hepatitis C antibody. If positive hepatitis C antibody result, patient will need to have a negative result for hepatitis C ribonucleic acid (RNA) before start of study therapy. Patients who are hepatitis C RNA positive will be excluded 14. Known active cytomegalovirus infection Note: Patients with an unknown or negative status are eligible 15. Evidence of other clinically significant uncontrolled condition(s) including, but not limited to, uncontrolled systemic infection (viral, bacterial, parasitic, or fungal) or other clinically significant active disease process which, in the opinion of the investigator, may pose a risk for patient participation. Screening for chronic conditions is not required 16. Active uncontrolled auto-immune cytopenia (e.g., autoimmune haemolytic anaemia, idiopathic thrombocytopenic purpura) where new therapy is introduced, or concomitant medication escalated within the 4 weeks prior to registration is required to maintain adequate blood counts. Stable controlled auto-immune cytopenias are allowed as long as required blood count criteria are met 17. Prior treatment with pirtobrutinib 18. Patients requiring therapeutic anticoagulation with warfarin or another vitamin K antagonist 19. Known hypersensitivity to any component or excipient of pirtobrutinib 20. Significant cardiovascular disease defined as:
• Unstable angina or acute coronary syndrome within the past 2 months prior to registration
• History of myocardial infarction within 3 months prior to registration

Sponsors & Collaborators

• Peter MacCallum Cancer Centre, Australia: lead
• Eli Lilly and Company: collaborator

Study Sites (3)

Peter MacCallum Cancer Centre

Melbourne, Victoria, 3000, Australia

RECRUITING

Alfred Hospital

Melbourne, Victoria, 3004, Australia

NOT YET RECRUITING

Monash Medical Centre

Melbourne, Victoria, 3168, Australia

NOT YET RECRUITING

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, B-Cell; Leukemia

Interventions

pirtobrutinib

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 2, 2025
• First Posted: February 6, 2025
• Study Start: May 5, 2025
• Primary Completion (Estimated): May 1, 2029
• Study Completion (Estimated): May 1, 2031
• Last Updated: August 6, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

AU (3)