Phase II Study of Pirtobrutinib as Frontline Therapy in Elderly Unfit or Frail Patients with Mantle Cell Lymphoma

Trial ID: 2025-521666-10-01
Protocol: FIL_PUMA
Sponsor: Fondazione Italiana Linfomi Ets

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Diseases & Conditions

Mantle cell lymphoma

Objectives

The primary objective is to evaluate the efficacy of pirtobrutinib monotherapy in terms of 12-month progression-free survival in untreated elderly patients with mantle cell lymphoma who are classified as unfit or frail. 5, 3

Secondary objectives include:

Assessment of clinical response and survival endpoints.
Evaluation of the impact on quality of life.
Assessment of the safety profile.

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Participants

The sponsor did not provide information regarding the total number of participants. The study population consists of male and female patients diagnosed with mantle cell lymphoma. Eligible participants are aged 70 years or older and are classified as either unfit or frail based on clinical assessments of functional status and comorbidities. The study focuses on individuals with previously untreated disease who are ineligible for standard full-dose induction therapy. Inclusion requires histologically documented nodal or extranodal disease according to WHO classification, an ECOG performance status of 0-2, and at least one bi-dimensionally measurable lesion. Participants must demonstrate adequate hematologic, renal, hepatic, and coagulation functions. Additionally, the population must have a life expectancy exceeding 6 months and the ability to administer oral medications.

Plans and Procedures

This phase II clinical trial is designed to evaluate the efficacy of pirtobrutinib monotherapy in patients with previously untreated mantle cell lymphoma who are classified as elderly, unfit, or frail. The primary objective is to assess 12-month progression-free survival. The study methodology involves an initial screening visit to confirm eligibility through histological diagnosis, biopsy material availability for mutational analysis, and assessment of clinical status via the sGA tool. Following screening, participants receive an oral dose of 200 mg of pirtobrutinib. The study includes various follow-up evaluations to monitor overall response rate, overall survival, event-free survival, and duration of response. Additionally, secondary endpoints include the assessment of adverse events and health-related quality of life. Participation may be discontinued due to treatment failure, toxicity, or patient preference. The trial is estimated to occur between February 2026 and February 2030.

Treatment

The experimental treatment consists of pirtobrutinib administered at a dosage of 200 mg. The medication is delivered via an oral route of administration.

Efficacy

The primary efficacy endpoint is 12-month progression-free survival (PFS), defined as the interval from the initiation of treatment to the first documented instance of recurrence, disease progression, or death from any cause. Secondary efficacy assessments include the overall response rate (ORR), comprising the complete response (CR) and partial response (PR) rates determined according to the Lugano criteria. Additional secondary parameters involve the complete response rate (CRR), overall survival (OS), and event-free survival (EFS), which is defined as the time from treatment onset to treatment failure, including disease progression or discontinuation due to toxicity, patient preference, death, or initiation of new therapy without documented progression. The duration of response (DOR) is measured from the first documentation of tumor response until disease progression or death.

Health-related quality of life (HRQoL) will be evaluated using the EuroQol 5-Dimension Scale (EQ-5D-5L) and the Functional Assessment of Cancer Therapy for Patients with Lymphoma (FACT-Lym) standardized questionnaire. The study will also monitor the drop-out rate and the rate of treatment discontinuation related to adverse events (AE) or intolerance. The frequency and severity of AEs and serious adverse events (SAE) are to be classified according to the Common Terminology Criteria for Adverse Events (CTCAE).

Inclusion and Exclusion Criteria

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Inclusion Criteria

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)
ECOG performance status of 0- 2 (Appendix C)
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)
Adequate renal function: − Creatinine clearance ≥ 30 mL/min (Appendix B) or − Serum creatinine ≤ 2.5 mg /dL
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
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
Ability and willingness to comply with the study protocol procedure
Life expectancy > 6 months
The patient is able to take oral medications
The patient must give written informed consent
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
Availability of biopsy material for central pathology revision and mutational analysis including TP53 mutations
Age ≥ 70 years
Previously untreated MCL
Active disease in need of treatment according to clinical practice (patients with leukemic with syntomatic leukemic non nodal disease may be included)
Ineligible to standard full-dose induction therapy (i.e. BR, R-CHOP, VR-CAP, RBAC500)
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
Ann Arbor Stage I - IV (Appendix A)
At least one bi-dimensionally measurable lesion defined as > 1.5 cm in its largest dimension on CT scan

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Exclusion Criteria

Candidate to watch and wait due to indolent presentation
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.
Known active cytomegalovirus (CMV) infection. Unknown or negative status are eligible
HIV positivity
Clinically significant active malabsorption syndrome or other conditions likely to affect gastrointestinal (GI) absorption of the study drug
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
Major surgery within 4 weeks prior to investigation treatment
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
Patients who experienced grade ≥ 3 arrhythmia.
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)
Active herpes zoster infection; previously infected patients is accepted only with concomitant treatment with Valacyclovir
FIT patients according to sGA eligible to standard full dose therapy
Leukemic non-nodal MCL that has stable asymptomatic disease should not be included in this study
Histological diagnosis different from MCL or leukemic non-nodal MCL
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
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
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
Any other co-existing medical or psychological condition that would preclude participation in the study or compromise ability to give informed consent
Candidate or eligible to full-dose BR, R-CHOP, VR-CAP, RBAC500 or any other full dose intensive chemotherapy
Suspect or clinical evidence of CNS involvement by lymphoma
Contraindication to the use BTKi
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
History of stroke or intracranial hemorrhage within 6 months of investigation treatment
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)
Evidence of any severe active acute or chronic infection
Absence of caregivers in non-autonomous patients
Need of anticoagulation with warfarin or another vitamin K antagonist
Vaccination with live vaccine within 28 days prior to investigation treatment
Have a known hypersensitivity to any of the excipients of Pirtobrutinib or to any intended study medications