PirtobrUtinib as frontline Therapy for elderly unfit/frail patient with MAntle cell lymphoma: a phase II study of the Fondazione Italiana Linfomi (FIL)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione Italiana Linfomi Ets

Participant type

Patients

Age range

65+ years

Gender

Male and Female

Therapeutic area

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

Decision date (initial)

2026-02-26

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Eli Lilly

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

To evaluate the efficacy, in terms of 12-month Progression Free Survival (1yr-PFS), of a treatment with Pirtobrutinib monotherapy in untreated elderly unfit/frail MCL patients

Secondary objectives 3

1. To assess the clinical response and survival endpoints after Pirtobrutinib in untreated elderly unfit/frail MCL patients
2. To evaluate the impact of Pirtobrutinib on quality of life of elderly unfit/frail MCL patients
3. To assess the safety profile of Pirtobrutinib in untreated elderly unfit/frail MCL patients

Conditions and MedDRA coding

Mantle Cell Lymphoma

Regulatory references

Plan to share IPD

Yes

IPD plan description

No identifiable data, such as name, address, hospital name, date of birth, or any other identifying data, will be shared and should not be requested). For each data sharing request, it is essential that a proforma (available on request) is completed that describes the general purpose, specific aims, data items requested, analysis plan and acknowledgment of the trial management team. Requests will be reviewed based on scientific merit and ethical principles. Requestors who are granted access to the data will be required to complete a data sharing agreement that will be signed by the requester and FIL. In compliance with the national ethics guideline and applicable legislation, individual deindentified patients’ data (including study protocol, statistical analysis plan and data coding) can be shared until 5 years after the publication of the study.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 19

1. Histologically documented diagnosis of nodal and extranodal mantle cell lymphoma (MCL) as defined in the 2022 edition of the World Health Organization (WHO) classification (For details refer to specific section in protocol)
2. ECOG performance status of 0- 2 (Appendix C)
3. Adequate hematologic function (unless caused by bone marrow infiltrate), defined as follows: a. Hemoglobin ≥ 8 g/dL (independent of transfusions within 7 days of screening assessment) b. White blood cells (WBC) > 2500/mmc with polymorphonuclear (cells) PMN≥750/ mmc) (independent of growth factor support within 7 days of screening assessment) c. Platelets count ≥ 50000/mmc (independent of transfusions within 7 days of screening assessment)
4. Adequate renal function: − Creatinine clearance ≥ 30 mL/min (Appendix B) or − Serum creatinine ≤ 2.5 mg /dL
5. 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
6. Adequate hepatic function: − ALT or AST ≤ 3 x the ULN or ≤ 5 x ULN with documented liver involvement; − Total bilirubin ≤ 1.5 x ULN or ≤ 3 x ULN with documented liver involvement and/or due to Gilbert’s Disease
7. Ability and willingness to comply with the study protocol procedure
8. Life expectancy > 6 months
9. The patient is able to take oral medications
10. The patient must give written informed consent
11. Male subjects must use highly effective contraception during sexual contact with a pregnant female or a female of childbearing potential from the start of study treatment and continuing for at least 3 months after the last dose of pirtobrutinib
12. Availability of biopsy material for central pathology revision and mutational analysis including TP53 mutations
13. Age ≥ 70 years
14. Previously untreated MCL
15. Active disease in need of treatment according to clinical practice (patients with leukemic with syntomatic leukemic non nodal disease may be included)
16. Ineligible to standard full-dose induction therapy (i.e. BR, R-CHOP, VR-CAP, RBAC500)
17. sGA assessment performed before starting treatment (Appendix H) FRAIL patients defined as follows: − Age ≥ 80 years − ADL <6 residual functions and/or − IADL <8 residual functions and/or − CIRS: ≥ 1 comorbidity of grade 3-4 or ≥ 5 comorbidities of grade 2; UNFIT patients defined as follows: − Age ≥ 80 years: − ADL 6 residual functions and − IADL 8 residual functions and − CIRS 0 comorbidities of grade 3-4 and <5 comorbidities of grade 2; or − Age < 80 years: − ADL < 5 residual functions and/or − IADL < 6 residual functions and/or − CIRS ≥ 1 comorbidity of grade 3-4 or >8 comorbidities of grade 2
18. Ann Arbor Stage I - IV (Appendix A)
19. At least one bi-dimensionally measurable lesion defined as > 1.5 cm in its largest dimension on CT scan

Exclusion criteria 29

1. Candidate to watch and wait due to indolent presentation
2. Hepatitis C virus (HCV): positive hepatitis C antibody. If positive hepatitis C antibody result, HCV-RNA is required. Only patients with HCV-RNA negative are accepted.
3. Known active cytomegalovirus (CMV) infection. Unknown or negative status are eligible
4. HIV positivity
5. Clinically significant active malabsorption syndrome or other conditions likely to affect gastrointestinal (GI) absorption of the study drug
6. Evidence of other clinically significant uncontrolled condition(s) including but not limited to, uncontrolled systemic bacterial, viral, fungal or parasitic infection (except for fungal nail infection), or other clinically significant active disease process which in the opinion of the investigator and medical monitor may pose a risk for patient participation. Screening for chronic conditions is not required
7. Major surgery within 4 weeks prior to investigation treatment
8. Any history of other malignancies unless in remission and with life expectancy > 2 years prior to study entry except for adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer
9. Patients who experienced grade ≥ 3 arrhythmia.
10. History of severe bleeding diathesis (major bleeding event) NOTE: Major bleeding is defined as bleeding having one or more of the following features: potentially life-threatening bleeding with signs or symptoms of hemodynamic compromise; bleeding associated with a decrease in the hemoglobin level of at least 2 g per deciliter; or bleeding in a critical area or organ (e.g., retroperitoneal, intraarticular, pericardial, epidural, or intracranial bleeding or intramuscular bleeding with compartment syndrome)
11. Active herpes zoster infection; previously infected patients is accepted only with concomitant treatment with Valacyclovir
12. FIT patients according to sGA eligible to standard full dose therapy
13. Leukemic non-nodal MCL that has stable asymptomatic disease should not be included in this study
14. Histological diagnosis different from MCL or leukemic non-nodal MCL
15. Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia [AIHA], idiopathic thrombocytopenic purpura [ITP]) for which new therapy was introduced or existing therapy was escalated within the 4 weeks prior to study enrollment to maintain adequate blood counts
16. Significant cardiovascular disease defined as: a) unstable angina or acute coronary syndrome within the past 2 months prior to study enrollment b) history of myocardial infarction within 3 months prior to study enrollment or c) documented left ventricular ejection fraction (LVEF) by any method of ≤ 40% in the 12 months prior to study enrollment d) ≥ Grade 3 NYHA functional classification system of heart failure e) Uncontrolled or symptomatic arrhythmias
17. 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. Note: Patients with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker
18. Any other co-existing medical or psychological condition that would preclude participation in the study or compromise ability to give informed consent
19. Candidate or eligible to full-dose BR, R-CHOP, VR-CAP, RBAC500 or any other full dose intensive chemotherapy
20. Suspect or clinical evidence of CNS involvement by lymphoma
21. Contraindication to the use BTKi
22. HBsAg positivity; HBsAg-negative patients with anti-HBc antibody can be enrolled if Hepatitis B Virus (HBV)-DNA are negative and prophylactic antiviral treatment is provided
23. History of stroke or intracranial hemorrhage within 6 months of investigation treatment
24. History of CAR-T within 60 days of investigation treatment or presence of any of the following, regardless of prior SCT and/or CAR-T therapy timing: a) active graft versus host disease (GVHD); b) cytopenia from incomplete blood cell count recovery post-transplant; c) need for anti-cytokine therapy for toxicity from CAR-T therapy; residual symptoms of neurotoxicity > Grade 1 from CAR-T therapy; d) ongoing immunosuppressive therapy (> 20 mg prednisone or equivalent daily)
25. Evidence of any severe active acute or chronic infection
26. Absence of caregivers in non-autonomous patients
27. Need of anticoagulation with warfarin or another vitamin K antagonist
28. Vaccination with live vaccine within 28 days prior to investigation treatment
29. Have a known hypersensitivity to any of the excipients of Pirtobrutinib or to any intended study medications

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. PFS defined as the time between the start of treatment and the first documentation of recurrence, progression or death for any cause

Secondary endpoints 9

1. Overall response rate [ORR = complete response (CR) + partial response (PR) rate) (according to Lugano, 2014 criteria)]
2. Complete response rate (CRR)
3. Overall survival (OS) defined as the time between the start of treatment and death from any cause
4. Event free survival (EFS) defined as the time between the start of treatment and treatment failure including disease progression, or discontinuation of treatment for any reason (e.g., disease progression, toxicity, patient preference, initiation of new treatment without documented progression, or death)
5. Duration of response (DOR) defined as the time from the first documentation of tumor response to disease progression or death from any cause
6. Drop-out rate
7. Rate of treatment discontinuation due to AE or treatment intolerance
8. Frequency and severity of AEs and SAEs classified as per latest version of CTCAE
9. The health-related quality of life (HRQoL) as measured by the EuroQol 5-Dimension Scale (EQ-5D-5L) and the Functional Assessment of Cancer Therapy for Patients with Lymphoma (FACTLym) standardized questionnaire on health status

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione Italiana Linfomi Ets

Sponsor organisation

Fondazione Italiana Linfomi Ets

Address

Piazza Filippo Turati 5

City

Alexandria

Postcode

15121

Country

Italy

Scientific contact point

Organisation

Fondazione Italiana Linfomi Ets

Contact name

Prof. Carlo Visco

Public contact point

Organisation

Fondazione Italiana Linfomi Ets

Contact name

Start Up office

Locations

1 EU/EEA country · 20 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 13 files

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

Application history

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