PirtobrUtinib as Frontline Therapy for Elderly Unfit/Frail Patient With MAntle Cell Lymphoma (FIL_PUMA)

September 26, 2025 updated by: Fondazione Italiana Linfomi - ETS

PirtobrUtinib as Frontline Therapy for Elderly Unfit/Frail Patient With MAntle Cell Lymphoma: a Phase II Study of the Fondazione Italiana Linfomi (FIL)

This is a prospective, multicenter, phase II study, in elderly patients affected by Mantle cell lymphoma (MCL) defined as unfit/frail according to Simplified Geriatric Assessment (sGA) and previously untreated.

Patients will receive a treatment with Pirtobrutinib monotherapy until tumor progression, unacceptable adverse event, or patient decision for interruption.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

After providing written informed consent, patients will be evaluated for eligibility during a 28-day screening period. Patients will receive pirtobrutinib at a starting dose of 200 mg once daily (2 tablets q.d.). All treatment will be administered orally, and a cycle will be defined as 28 days in length and should be maintained regardless of dose interruptions. Treatment is meant to be administered until tumor progression, unacceptable adverse event, or patient decision for interruption.

Responses shall be assessed at month +3, +6 after start of treatment and then every 6 months using the radiologic method of tumor assessment consistent throughout the study and aligned with the baseline method (CT scan or ultrasound echography are acceptable). Positron Emission Tomography (PET) scan is mandatory at baseline and at month +3 after start of treatment to establish tumor response.

Study Type

Interventional

Enrollment (Estimated)

56

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Italy
      • Ancona, Italy
      • Avellino, Italy
        • Azienda Ospedaliera S.Giuseppe Moscati - S.C. Ematologia e Trapianto emopoietico
        • Contact:
        • Principal Investigator:
          • Sonya De Lorenzo, MD
      • Biella, Italy
      • Bologna, Italy
        • Policlinico S.Orsola-Malpighi - Istituto di Ematologia "Seragnoli"
        • Contact:
        • Principal Investigator:
          • Pier Luigi Zinzani, Prof.
      • Brescia, Italy
      • Catania, Italy
        • Azienda Ospedaliera Universitaria Policlinico - S. Marco - UOC di Ematologia
        • Contact:
        • Principal Investigator:
          • Annalisa Chiarenza, MD
      • Milan, Italy
        • Fondazione IRCCS Istituto Nazionale dei Tumori di Milano - Ematologia
        • Contact:
        • Principal Investigator:
          • Lucia Farina, MD
      • Palermo, Italy
        • A.O. Ospedali Riuniti Villa Sofia-Cervello - Divisione di Ematologia
        • Contact:
        • Principal Investigator:
          • Caterina Patti, MD
      • Parma, Italy
        • Parma - AOU di Parma - UOC Ematologia e CTMO
        • Contact:
        • Principal Investigator:
          • Giovanni Roti, Prof.
      • Pescara, Italy
        • P.O. Spirito Santo di Pescara - UOC Ematologia Dipartimento Oncologico Ematologico - ASL Pescara
        • Principal Investigator:
          • Elsa Pennese, MD
        • Contact:
      • Piacenza, Italy
        • Azienda USL Piacenza - UOC Ematologia e Centro Trapianti
        • Contact:
        • Principal Investigator:
          • Annalisa Arcari, MD
      • Reggio Emilia, Italy
        • Azienda Unitа Sanitaria Locale-IRCCS - Arcispedale Santa Maria Nuova - Ematologia
        • Contact:
        • Principal Investigator:
          • Angela Ferrari, MD
      • Siena, Italy
        • AOU Senese - U.O.C. Ematologia
        • Contact:
        • Principal Investigator:
          • Alberto Fabbri, MD
      • Terni, Italy
        • A.O. S. Maria di Terni - S.C. Oncoematologia
        • Contact:
        • Principal Investigator:
          • Arcangelo Liso, Prof.
      • Treviso, Italy
      • Varese, Italy
        • Ospedale di Circolo - U.O.C Ematologia
        • Contact:
          • Marta Coscia, Prof.
        • Principal Investigator:
          • Marta Coscia, Prof.
      • Verona, Italy
        • AOU Integrata di Verona - U.O. Ematologia
        • Contact:
        • Principal Investigator:
          • Carlo Visco, Prof.
      • Vicenza, Italy
        • Vicenza - ULSS 8 Berica - Ospedale S. Bortolo - Ematologia
        • Contact:
        • Principal Investigator:
          • Maria Chiara Tisi, MD
    • Forlì-Cesena
      • Meldola, Forlì-Cesena, Italy
        • IRCCS Istituto Romagnolo per lo studio dei Tumori "Dino Amadori" - IRST S.R.L. - Ematologia
        • Contact:
        • Principal Investigator:
          • Margherita Parolini, MD
    • Milano
      • Rozzano, Milano, Italy
        • Istituto Clinico Humanitas - U.O. Ematologia
        • Contact:
        • Principal Investigator:
          • Monica Balzarotti, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  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
  2. Availability of biopsy material for central pathology revision and mutational analysis including TP53 (Tumor Protein p53) mutations
  3. Age ≥ 70 years
  4. Previously untreated MCL
  5. Active disease in need of treatment according to clinical practice (patients with leukemic with symptomatic leukemic non nodal disease may be included)
  6. Ineligible to standard full-dose induction therapy (i.e. BR, R-CHOP, VR-CAP, RBAC500)

  7. sGA assessment performed before starting treatment

    FRAIL patients defined as follows:

    • Age ≥ 80 years
    • Activities of Daily Living (ADL) <6 residual functions and/or
    • Instrumental Activities of Daily Living (IADL) <8 residual functions and/or
    • Cumulative Illness Rating Scale (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
  8. Ann Arbor Stage I - IV
  9. At least one bi-dimensionally measurable lesion defined as > 1.5 cm in its largest dimension on CT scan
  10. Eastern Cooperative Oncology Group (ECOG) performance status of 0- 2

  11. Adequate hematologic function (unless caused by bone marrow infiltrate), defined as follows:

    1. Hemoglobin ≥ 8 g/dL (independent of transfusions within 7 days of screening assessment)
    2. White blood cells (WBC) > 2500/mmc with polymorphonuclear (cells) PMN≥750/ mmc) (independent of growth factor support within 7 days of screening assessment)
    3. Platelets count ≥ 50000/mmc (independent of transfusions within 7 days of screening assessment)

  12. Adequate renal function:

    • Creatinine clearance ≥ 30 mL/min or
    • Serum creatinine ≤ 2.5 mg /dL
  13. 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 upper limit of normal (ULN)

  14. Adequate hepatic function:

    • Alanine aminotransferase (ALT) or Aspartate aminotransferase (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
  15. Ability and willingness to comply with the study protocol procedure
  16. Life expectancy > 6 months
  17. The patient is able to take oral medications
  18. The patient must give written informed consent
  19. 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

Exclusion Criteria:

Patients who meet any of the following criteria are not eligible to enroll:

  1. Candidate to watch and wait due to indolent presentation
  2. Leukemic non-nodal MCL that has stable asymptomatic disease should not be included in this study
  3. Histological diagnosis different from MCL or leukemic non-nodal MCL
  4. Fit patients according to sGA eligible to standard full dose therapy
  5. Candidate or eligible to full-dose Bendamustine+Rituximab (BR), Rituximab + Cyclophosphamide, Hydroxydaunorubicin (doxorubicin), Oncovin (vincristine) e Prednisone (R-CHOP), bortezomib, rituximab, cyclophosphamide, doxorubicin, prednisone (VR-CAP), Rituximab, Bendamustine, Cytarabine (RBAC500) or any other full dose intensive chemotherapy
  6. Suspect or clinical evidence of central nervous system (CNS) involvement by lymphoma
  7. Contraindication to the use Bruton Tyrosine Kinase Inhibitor (BTKi)
  8. HBsAg positivity; HBsAg-negative patients with anti-hepatitis B core antigen (HBc) antibody can be enrolled if Hepatitis B Virus (HBV)-DNA are negative and prophylactic antiviral treatment is provided
  9. HIV positivity
  10. Active herpes zoster infection; previously infected patients is accepted only with concomitant treatment with Valacyclovir
  11. Major surgery within 4 weeks prior to investigation treatment
  12. 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
  13. Patients who experienced grade ≥ 3 arrhythmia.
  14. 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)
  15. History of stroke or intracranial hemorrhage within 6 months of investigation treatment

  16. History of Chimeric Antigen Receptor T-cell therapy (CAR-T) within 60 days of investigation treatment or presence of any of the following, regardless of prior Stem Cell Transplantation (SCT) and/or CAR-T therapy timing:

    1. active graft versus host disease (GVHD);
    2. cytopenia from incomplete blood cell count recovery post-transplant;
    3. need for anti-cytokine therapy for toxicity from CAR-T therapy; residual symptoms of neurotoxicity > Grade 1 from CAR-T therapy;
    4. ongoing immunosuppressive therapy (> 20 mg prednisone or equivalent daily)
  17. Evidence of any severe active acute or chronic infection
  18. 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.
  19. Known active cytomegalovirus (CMV) infection. Unknown or negative status are eligible
  20. Clinically significant active malabsorption syndrome or other conditions likely to affect gastrointestinal (GI) absorption of the study drug
  21. 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
  22. 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

  23. Significant cardiovascular disease defined as:

    1. unstable angina or acute coronary syndrome within the past 2 months prior to study enrollment
    2. history of myocardial infarction within 3 months prior to study enrollment or
    3. documented left ventricular ejection fraction (LVEF) by any method of ≤ 40% in the 12 months prior to study enrollment
    4. ≥ Grade 3 New York Heart Association (NYHA) functional classification system of heart failure
    5. Uncontrolled or symptomatic arrhythmias

  24. Prolongation of the QT interval corrected for heart rate (QTcF) > 470 msec. QTcF is calculated using Fridericia's Formula (QTcF): QTcF = QT/(RR0.33):

    1. 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.
    2. 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
  25. Any other co-existing medical or psychological condition that would preclude participation in the study or compromise ability to give informed consent
  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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Experimental
Pirtobrutinib monotherapy in untreated elderly unfit/frail MCL patients.
Drug: Pirtobrutinib
Patients will receive pirtrobrutinib at a starting dose of 200 mg once daily (q.d). All treatment will be administered orally and a cycle will be defined as 28 days in length and should be maintained regardless of dose interruptions. Treatment is meant to be administered until tumor progression, unacceptable adverse event, or patient decision for interruption.
Other Names:
  • Jaypirca

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression Free Survival (PFS)
Time Frame: 48 months
PFS defined as the time between the start of treatment and the first documentation of recurrence, progression or death for any cause
48 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall response rate (ORR)
Time Frame: 48 months
Overall Response Rate (ORR) will be defined as the proportion of patients achieving either a Complete Response (CR) or a Partial Response (PR), according to the Lugano 2014 criteria for response assessment in lymphoma.
48 months
Complete response rate (CRR)
Time Frame: 48 months
Complete response rate (CRR) refers to the proportion of patients whose disease completely disappears following treatment, as determined by clinical, imaging, or pathological assessments. It indicates a full remission of detectable disease.
48 months
Overall survival (OS)
Time Frame: 48 months
Overall survival (OS) is defined as the time between the start of treatment and death from any cause
48 months
Event free survival (EFS)
Time Frame: 48 months
Event free survival (EFS) is 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).
48 months
Duration of response (DOR)
Time Frame: 48 months
Duration of response (DOR) is defined as the time from the first documentation of tumor response to disease progression or death from any cause.
48 months
Drop-out rate
Time Frame: 48 months
Proportion of participants who withdraw from the study for any reason before completing the planned treatment/intervention period.
48 months
Rate of treatment discontinuation due to Adverse Event (AE) or treatment intolerance.
Time Frame: 48 months
Proportion of participants who permanently discontinue the assigned treatment due to adverse events (AEs) or treatment intolerance during the study period.
48 months
Frequency and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time Frame: 48 months
Frequency and severity of AEs and SAEs classified as per latest version of CTCAE
48 months
Health-Related Quality of Life Assessed by the EuroQol 5-Dimension 5-Level (EQ-5D-5L) Questionnaire
Time Frame: 48 months
The EQ-5D-5L is a standardized instrument for measuring generic health status. It includes five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each with five levels. The outcome will be reported as the EQ-5D-5L index score. Higher scores indicate better health status.
48 months
Health-Related Quality of Life Assessed by the Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Questionnaire
Time Frame: 48 months
The FACT-Lym is a disease-specific instrument assessing quality of life in patients with lymphoma. It includes physical, social/family, emotional, and functional well-being, plus lymphoma-specific concerns. The outcome will be reported as the total FACT-Lym score. Higher scores indicate better quality of life.
48 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fondazione Italiana Linfomi - ETS

Investigators

  • Principal Investigator: Carlo Visco, Prof., Verona - AOU Integrata di Verona - U.O. Ematologia
  • Principal Investigator: Guido Gini, Dott., Ancona - AOU Ospedali Riuniti - Clinica di Ematologia

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

February 1, 2026

Primary Completion (Estimated)

February 1, 2028

Study Completion (Estimated)

February 1, 2030

Study Registration Dates

First Submitted

September 17, 2025

First Submitted That Met QC Criteria

September 26, 2025

First Posted (Estimated)

October 6, 2025

Study Record Updates

Last Update Posted (Estimated)

October 6, 2025

Last Update Submitted That Met QC Criteria

September 26, 2025

Last Verified

September 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • FIL_PUMA

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (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 deidentified patients' data (including study protocol, statistical analysis plan and data coding) can be shared until 5 years after the publication of the study.

IPD Sharing Time Frame

In compliance with the domestic ethics guideline and applicable legislation, individual deidentified patients' data underlying the results reported in the publication article (including study protocol, statistical analysis plan and data coding) can be shared until 5 years after the publication of the article.

IPD Sharing Access Criteria

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.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ANALYTIC_CODE

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Mantle Cell Lymphoma

Clinical Trials on Pirtobrutinib

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Madagascar

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe