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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

French Innovative Leukemia Organization

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Decision date (initial)

2025-11-05

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety, Others

Evaluate efficacy of a short and fixed duration of ICT combined with pirtobrutinib.

Secondary objectives 5

1. To determine the kinetic evolution of the MRD at the end of treatment (month 15)
2. To determine the progression free survival (PFS), disease-free survival (DFS), event-free survival (EFS), overall survival (OS) and time to next treatment (TTNT)
3. To assess the specific efficacy of pirtobrutinib at month 9, month 18 and month 24 in term of response and MRD
4. To assess the specific cardiac toxicity of pirtobrutinib
5. To assess the safety of this global strategy (pirtobrutinib + FC + obinutuzumab) : - To evaluate the CHIP in CLL patients at inclusion; - To evaluate during the follow up the occurrence (%) of secondary malignancy specifically MDS and AML

Conditions and MedDRA coding

Patients with previously untreated symptomatic chronic lymphocytic leukemia.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. Participant must be ≥ 18 years at the time of screening
2. Immunophenotypically confirmed CLL according to IWCLL 2018 guidelines
3. 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
4. Absence of Del(17p) and TP53 mutation in NGS (cut off 1%)
5. ECOG performance status 0-2
6. CIRS (Cumulative Illness Rating Scale) ≤ 6
7. 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
8. 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
9. 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”
10. 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
11. 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
12. The patient is able to take oral medications
13. Signed written informed consent
14. Willing or able to participate in all required study evaluations and procedures.
15. 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)

Exclusion criteria 27

1. 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
2. Binet stage A without active disease according to IWCLL 2018 criteria
3. Life expectancy < 6 months
4. Current or past history or presence of clinically relevant disorder affecting the central nervous system (CNS)
5. Patient with history of confirmed progressive multifocal leukoencephalopathy (PML)
6. 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)
7. Concomitant disease requiring prolonged use of corticosteroids (> 1 month)
8. Patients treated by vitamin K antagonist or dual antiaggregant or anticoagulants (coumadin, warfarin)
9. History of bleeding diathesis (e.g. hemophilia or von Willebrand disease)
10. Prior solid organ transplantation
11. 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
12. 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).
13. Disease significantly affecting gastrointestinal function (malabsorption syndrome, stomach or small bowel resection)
14. Evidence for Richter syndrome
15. 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.
16. 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.
17. Major surgery within 30 days prior to the first dose of study treatment.
18. 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.
19. Have a known hypersensitivity to any of the excipients of pirtobrutinib or to any intended study medications.
20. 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
21. Treatment with another investigational agent or participating in another trial within 30 days prior to entering the study
22. No affiliate to social security
23. Currently pregnant (confirmed with positive pregnancy test) or breast feeding.
24. 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.
25. 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.
26. 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.
27. Lactation or plan to breastfeed during the study or within 1 week of the last dose of study treatment.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Peripheral blood with undetectable (<10-4) minimal residual disease at month 24.

Secondary endpoints 2

1. PB MRD at month 9 and 18 and BM MRD at month 24
2. Progression free survival (PFS), disease-free survival (DFS), event-free survival (EFS), overall survival (OS) and time to next treatment (TTNT)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

French Innovative Leukemia Organization

Sponsor organisation

French Innovative Leukemia Organization

Address

2 Boulevard Tonnelle

City

Tours

Postcode

37000

Country

France

Scientific contact point

Organisation

French Innovative Leukemia Organization

Contact name

Dr Anne-Sophie MICHALLET

Public contact point

Organisation

French Innovative Leukemia Organization

Contact name

FILO desk officer

Third parties 5

Locations

1 EU/EEA country · 31 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications