Study PACIFIC: Fixed duration treatment with combined pirtobrutinib and short course immuno-chemotherapy in fit patients with previously untreated symptomatic chronic lymphocytic leukemia (CLL). A phase II FILO trial

Trial ID: 2025-521199-80-00
Protocol: FILOCLL016-PACIFIC
Sponsor: French Innovative Leukemia Organization

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Diseases & Conditions

Chronic lymphocytic leukaemia

Objectives

The primary objective is to evaluate the efficacy of a short and fixed duration of immuno-chemotherapy combined with pirtobrutinib in fit patients with previously untreated symptomatic chronic lymphocytic leukemia. This approach aims to assess whether combining a Bruton tyrosine kinase inhibitor with time-limited treatment can achieve meaningful clinical outcomes in this patient population.

The secondary objectives include:

• To determine the kinetic evolution of measurable residual disease at the end of treatment (month 15)

• To determine progression-free survival, disease-free survival, event-free survival, overall survival, and time to next treatment

• To assess the specific efficacy of pirtobrutinib at month 9, month 18, and month 24 in terms of response and measurable residual disease

• To assess the specific cardiac toxicity of pirtobrutinib

• To assess the safety of this global strategy (pirtobrutinib + fludarabine-cyclophosphamide + obinutuzumab), including evaluation of clonal hematopoiesis of indeterminate potential in chronic lymphocytic leukemia patients at inclusion and evaluation of the occurrence of secondary malignancies, specifically myelodysplastic syndromes and acute myeloid leukemia, during follow-up

Participants

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population includes **adult participants** aged **18 years and older** of **both genders** (male and female). Participants have **previously untreated symptomatic chronic lymphocytic leukemia** that has been immunophenotypically confirmed according to IWCLL 2018 guidelines. The trial population was selected based on specific disease characteristics, including **Binet stage C** or active disease in Binet stage A and B, with the absence of **Del(17p)** and **TP53 mutation**. Participants must demonstrate an **ECOG performance status** of 0-2 and a **Cumulative Illness Rating Scale (CIRS)** score of 6 or less. General health status requirements include adequate hematology values with **absolute neutrophil count** of at least 0.75 x 10⁹/L, **platelet count** of at least 50 x 10⁹/L, and **hemoglobin** of at least 80 g/L. Additional criteria include adequate liver and kidney function, with **creatinine clearance** of at least 30 mL/min and liver enzymes within specified limits. Participants must be able to take oral medications and have prior vaccination to SARS-CoV-2. The trial does not include vulnerable populations.

Plans and Procedures

This is a phase II clinical trial evaluating the efficacy and safety of a fixed duration treatment combining pirtobrutinib with short course immuno-chemotherapy in fit patients with previously untreated symptomatic chronic lymphocytic leukemia. The investigational medicinal product pirtobrutinib is administered as a film-coated tablet via the oral route, classified as an antineoplastic agent and protein kinase inhibitor. The maximum daily dose is 200 mg, with a maximum total dose of 84000 mg administered over a maximum treatment period of 420 days. The trial follows a phase II design to investigate the safety and efficacy of this potential therapeutic approach.

The primary objective of this study is to evaluate the efficacy of a short and fixed duration of immuno-chemotherapy combined with pirtobrutinib. The primary endpoint is defined as peripheral blood with undetectable minimal residual disease (less than 10-4) at month 24. Secondary endpoints include peripheral blood minimal residual disease at months 9 and 18, bone marrow minimal residual disease at month 24, and survival outcomes such as progression-free survival, disease-free survival, event-free survival, overall survival, and time to next treatment.

Eligible participants must be at least 18 years of age at the time of screening with immunophenotypically confirmed chronic lymphocytic leukemia according to IWCLL 2018 guidelines. Participants must have Binet stage C or Binet stage A and B with active disease meeting IWCLL 2018 criteria for treatment initiation. Key inclusion criteria include absence of Del(17p) and TP53 mutation in next-generation sequencing (cut-off 1%), ECOG performance status 0-2, and Cumulative Illness Rating Scale score of 6 or less. Participants must have adequate hematology values including absolute neutrophil count of at least 0.75 x 10⁹/L, platelet count of at least 50 x 10⁹/L, and hemoglobin of at least 80 g/L. Adequate coagulation is required, defined as activated partial thromboplastin time or partial thromboplastin time and prothrombin time or international normalized ratio not greater than 1.5 times the upper limit of normal. Calculated creatinine clearance must be at least 30 mL/min according to the Cockcroft-Gault formula. Adequate liver function is required with aspartate aminotransferase/alanine aminotransferase no more than 3 times the upper limit of normal or 5 times the upper limit of normal with documented liver involvement, and total bilirubin no more than 1.5 times the upper limit of normal or 3 times the upper limit of normal with documented liver involvement and/or Gilbert's Disease. Prior vaccination to the SARS-CoV-2 virus is required, and SARS-CoV-2 PCR testing with negative result before study treatment administration at each treatment cycle if clinically indicated. Participants must be able to take oral medications and provide signed written informed consent.

The estimated recruitment start date is December 2025, with an estimated study completion date of December 2031. The maximum participant involvement period is 420 days of treatment, with follow-up assessments extending to month 24 for the primary endpoint evaluation. Study visits include a screening visit to assess eligibility criteria, treatment visits during the active treatment period, and follow-up visits at months 9, 18, and 24 for minimal residual disease assessment. The end-of-study visit occurs at the completion of the follow-up period or upon early termination from the study.

Treatment

**Pirtobrutinib** is administered as a **film-coated tablet** via the **oral route**. The active substance is pirtobrutinib, a chemical entity classified as an **antineoplastic agent** and **protein kinase inhibitor**. The maximum daily dose is **200 mg**. The maximum total dose over the treatment period is **84000 mg**. The maximum treatment duration is **420 days**. Pirtobrutinib serves as the **investigational medicinal product** in this clinical trial and is combined with **immuno-chemotherapy** as part of a fixed-duration treatment regimen for patients with previously untreated symptomatic **chronic lymphocytic leukemia**.

Efficacy

Efficacy will be assessed using minimal residual disease (MRD) levels measured in peripheral blood and bone marrow at specified timepoints throughout the study. The primary endpoint is the achievement of undetectable MRD in peripheral blood, defined as less than 10^-4, at month 24. Secondary efficacy endpoints include peripheral blood MRD levels at months 9 and 18, as well as bone marrow MRD at month 24. Additional secondary endpoints comprise progression-free survival, disease-free survival, event-free survival, overall survival, and time to next treatment. These parameters will be evaluated to determine the efficacy of short and fixed-duration immuno-chemotherapy combined with pirtobrutinib in patients with previously untreated symptomatic chronic lymphocytic leukemia.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Participant must be ≥ 18 years at the time of screening
Immunophenotypically confirmed CLL according to IWCLL 2018 guidelines
Binet stage C or Binet stage A and B with active disease could be considered for inclusion according to IWCLL 2018 for initiation of treatment
Absence of Del(17p) and TP53 mutation in NGS (cut off 1%)
ECOG performance status 0-2
CIRS (Cumulative Illness Rating Scale) ≤ 6
Adequate coagulation: defined as activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) and prothrombin (PT) or (international normalized ratio (INR) not greater than 1.5 x ULN
Calculated creatinine clearance ≥ 30 ml/min according to Cockcroft/Gault Formula: (140 – age) × body weight (kg) × 0.85 (if female) serum creatinine (mg/dL) × 72
Adequate liver function: a. Aspartate aminotransferase (AST)/alanine aminotransferase or (ALT) ≤ 3 × the ULN or ≤ 5 × ULN with documented liver involvement ; b. Total bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN with documented liver involvement and/or "Gilbert’s Disease”
Adequate hematology values: a. Absolute neutrophil count ≥ 0.75 x 109/L ; b. Platelet count ≥ 50 x 109/L (accordance to the coordinator if linked to the disease) ; c. Hemoglobin ≥ 80g/L
Prior vaccination to the SARS-Cov-2 virus and SARS-CoV-2 PCR testing (if clinically indicated) and negative result before study treatment administration at each treatment cycle
The patient is able to take oral medications
Signed written informed consent
Willing or able to participate in all required study evaluations and procedures.
Ability to understand the purpose and risks of the study and to provide a signed and dated informed consent form and authorization to use protected health information (in accordance with national and local subject privacy regulations)

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Exclusion Criteria

Presence of Clonal hematopoiesis of indetermined potential or CHIP (To define patients with CHIP: Presence of a myeloid mutation (whatever the mutation) with a VAF >2% in the granular fraction
Binet stage A without active disease according to IWCLL 2018 criteria
Life expectancy < 6 months
Current or past history or presence of clinically relevant disorder affecting the central nervous system (CNS)
Patient with history of confirmed progressive multifocal leukoencephalopathy (PML)
Evidence of other clinically significant uncontrolled condition(s) including, but not limited to: - Uncontrolled and/or active systemic infection (viral, bacterial or fungal): Known history of human immunodeficiency virus, serologic status reflecting active hepatitis B virus or hepatitis C virus infection, any uncontrolled active systemic infection along with subjects who are on ongoing anti-infective treatment and subjects who have received vaccination with a live attenuated vaccine within 4 weeks before the first dose of study treatment : a. Subjects who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antibody (anti-HBs) negative will need to have a negative hepatitis B virus PCR result before enrollment. Those who are hepatitis B surface antigen (HBsAg) positive or hepatitis B virus PCR positive will be excluded ; b. Subjects who are hepatitis C virus antibody positive will need to have a negative hepatitis C virus PCR result before enrollment. Those who are hepatitis C virus PCR positive will be excluded ; - Known active cytomegalovirus (CMV) infection. Unknown or negative status are eligible ; - Active and uncontrolled autoimmune cytopenia, including autoimmune hemolytic anemia (AIHA) (isolated positive DAT is not an exclusion criteria) and idiopathic thrombocytopenic purpura (ITP)
Concomitant disease requiring prolonged use of corticosteroids (> 1 month)
Patients treated by vitamin K antagonist or dual antiaggregant or anticoagulants (coumadin, warfarin)
History of bleeding diathesis (e.g. hemophilia or von Willebrand disease)
Prior solid organ transplantation
Concurrent severe diseases which exclude the administration of therapy: - Heart insufficiency NYHA grade III/IV, LVEF < 50% and or RF < 30%, myocardial infarction within the past 6 months prior to study - Significant cardiovascular disease such as symptomatic arrhythmias (including atrial fibrillation), congestive heart failure, unstable angina or acute coronary syndrome within the past 2 months prior to randomization or myocardial infarction within 6 months of Screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional (Subjects with controlled, asymptomatic atrial fibrillation are allowed to enroll on study) ; - Prolongation of the QT interval corrected for heart rate (QTcF) > 470 msec. QTcF is calculated using Fridericia’s Formula (QTcF): QTcF = QT/(RR0.33). ; a. 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. ; b. Correction for underlying bundle branch block (BBB) allowed ; - Severe chronic obstructive lung disease with hypoxemia ; - History of stroke or intra-cranial hemorrhage within the last 6 months ; - Severe diabetes mellitus ; - Uncontrolled hypertension ; - Impaired renal function with creatinine clearance < 30 ml/min according the formula of Cockroft and Gault
Patient who requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole (unless of separate dosing of pirtobrutinib capsules with antacids by at least 2 hours. Pirtobrutinib capsules should be taken 2 hours before an H2-receptor antagonist. Avoid co-administration of pirtobrutinib capsules with proton pump inhibitors).
Disease significantly affecting gastrointestinal function (malabsorption syndrome, stomach or small bowel resection)
Evidence for Richter syndrome
Treatment with any of the following within 7 days prior to the first dose of study drug: steroid therapy (refer to criteria 7 of the non-inclusion criteria) for anti-neoplastic intent.
A significant history of renal, neurologic, psychiatric, endocrine, metabolic, immunologic, cardiovascular, or hepatic disease that, in the opinion of the investigator, would adversely affect the patient’s participation in this study or interpretation of study outcomes.
Major surgery within 30 days prior to the first dose of study treatment.
History of prior other malignancy that could affect compliance with the protocol or interpretation of results, with the exception of the following: - Curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix at any time prior to study. - Other cancers not specified above that have been curatively treated by surgery and/or radiation therapy from which patient is disease-free for ≥ 5 years without further treatment.
Have a known hypersensitivity to any of the excipients of pirtobrutinib or to any intended study medications.
Persons deprived of their liberty by judicial or administrative decision, persons subject to a legal protection measure (guardianship, curatorship, legal protection), persons under psychiatric care
Treatment with another investigational agent or participating in another trial within 30 days prior to entering the study
No affiliate to social security
Currently pregnant (confirmed with positive pregnancy test) or breast feeding.
Women of Childbearing Potential (WOCBP) unless the following criteria are met- a negative pregnancy test is required for all WOCBP within 21 days before start of study intervention, followed by immediate highly effective contraception; further pregnancy testing will be performed monthly.
Fertile men or WOCBP unless the following criteria are met: Willing to use 2 methods of reliable contraception, including one highly effective contraceptive method (Pearl Index < 1) and one additional effective (barrier) method during study intervention and for 1 month after last pirtobrutinib dose (for WOCBP). Men must refrain from sperm donation during the study.
Fertile male and female patients who cannot or do not wish to use an effective method of contraception, during and for 12 months after the final treatment used for the purposes of the study.
Lactation or plan to breastfeed during the study or within 1 week of the last dose of study treatment.