Clinical Trial to Evaluate the Efficacy and Safety of Pirtobrutinib With Rituximab in Patients With Mantle Cell Lymphoma

Inclusion Criteria:

1. Adult patients (≥18 years of age).
2. Written informed consent must be obtained before any study-specific assessment is performed.
3. Subjects with confirmed diagnosis of Mantle Cell Lymphoma according to the International Consensus Classification, (ICC) 2022\] or World Health Organization (WHO) Classification 2022. Classical, small-cell variants and marginal-zone variants can be included.
4. Naïve patients for MCL management (no prior therapies, excluding diagnostic splenectomy)
5. Asymptomatic patients
6. Eastern Cooperative Oncology Group (ECOG) performance status \<2 (0-1)
7. Clinical stage I-IV according to the Ann Arbor classification with no symptoms attributable to MCL
8. Patients with a leukemic non-nodal presentation with mainly bone marrow or peripheral blood involvement are eligible. Other asymptomatic clinical presentations are acceptable in case of low tumour burden, including MCL with lymph node enlargement ≤ 3 cm in the largest diameter and with low proliferation index (Ki67 \< 30%)
9. The following laboratory values at screening:

   * Neutrophil count ≥ 1×109/L, Haemoglobin level ≥ 100 g/L and platelet count ≥100×109/L
   * Transaminases (AST and ALT) ≤ 3 x ULN
   * Total bilirubin ≤1.5 x ULN unless bilirubin rise is due to Gilbert's disease
   * 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 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.
10. Stable disease without evidence of clinical progression for at least 3 months. Patients in prolonged observation may be included (over 3 months).
11. Female patients of child-bearing potential must have a negative serum pregnancy test at screening and agree to use highly effective contraception from the start of study treatment (See Appendix 4), during the treatment period and for at least 1 month following the last dose of pirtobrutinib and for 12 months following treatment with Rituximab.
12. Male patients must use highly effective contraception (if sexually active with a female of child-bearing potential) according to the recommendations provided by the Clinical Trial Facilitation and Coordination Group (CTFG), from start of study treatment, during the treatment period, and for at least 1 month following the last dose of pirtobrutinib and for 12 months following treatment with rituximab.
13. Willing and capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol.
14. Not included in other clinical trial or treated with an experimental drug unrelated to MCL within the past 2 years

Exclusion Criteria:

1. Subjects with aggressive histological variants: blastoid and pleomorphic variants of MCL
2. B-cell monoclonal lymphocytosis with MCL phenotype
3. Presence of B symptoms or any relevant symptoms related to the MCL.
4. Nodal clinical forms with lymph node enlargement \> 3 cm (largest diameter).
5. Organ dysfunction related to MCL including creatinine level \> 2 mg/dl or altered liver biochemistry (\> 3x ULN).
6. Serum LDH over ULN
7. Known central nervous system (CNS) infiltration.
8. Expected MCL therapy requirement in a short time (\< 3 months)
9. Anticoagulation requirement with vitamin K antagonists
10. History of bleeding diathesis
11. Past medical history of stroke or intracranial haemorrhage within 6 months prior to inclusion.
12. Significant cardiovascular disease defined as: i) unstable angina or acute coronary syndrome within the past 2 months prior to randomization; ii) history of myocardial infarction within 3 months prior to randomization or documented LVEF by any method of ≤ 40% in the 12 months prior to inclusion; iii) ≥ Grade 3 NYHA functional classification system of heart failure; iv) Uncontrolled or symptomatic arrhythmias.
13. Prolongation of the QT interval corrected for heart rate (QTcF) \> 470 msec. QTcF is calculated using Fridericia's Formula (QTcF): QTcF = QT/(RR0.33). 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. 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
14. Patients who have tested positive for Human Immunodeficiency Virus (HIV) are excluded due to risk of opportunistic infections with both HIV and BTK inhibitors. For patients with unknown HIV status, HIV testing will be performed at Screening and result must be negative for enrolment.
15. Known active hepatitis B virus (HBV) infection based on criteria below: Patients with positive hepatitis B surface antigen (HBsAg) are excluded. Patients with positive hepatitis B core antibody (anti-HBc) and negative HBsAg require a negative hepatitis B polymerase chain reaction (PCR) evaluation before inclusion. Patients who are HBV DNA PCR positive will be excluded. Prophylactic antiviral treatment will be required in the patients with positive anti-HBc finally eligible.
16. Hepatitis C virus (HCV): positive hepatitis C antibody. If positive hepatitis C antibody result, patient will need to have a negative result for hepatitis C ribonucleic acid (RNA) before inclusion. Patients who are hepatitis C RNA positive will be excluded.
17. Known active cytomegalovirus (CMV) infection. Unknown or negative status are eligible.
18. Concomitant or previous malignancies the last 2 years other than basal skin cancer or in situ uterine cervix cancer.
19. Major surgery within 4 weeks of inclusion.
20. Vaccinated with live, attenuated vaccines within 4 weeks of inclusion.
21. Active uncontrolled auto-immune cytopenia (e.g., autoimmune haemolytic anaemia \[AIHA\], idiopathic thrombocytopenic purpura \[ITP\]) for which new therapy was introduced or existing therapy was escalated within the 4 weeks prior to study enrolment to maintain adequate blood counts.
22. 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 any other clinically significant active disease process which in the opinion of the investigator may pose a risk for patient participation (screening for chronic conditions is not required).
23. Known hypersensitivity to any of the excipients of Pirtobrutinib or Rituximab or any intended study medications.
24. Females who are pregnant or breastfeeding or plan to become pregnant or initiate breastfeeding during the study or within 1 month of the last dose of pirtobrutinib or 12 months of the last dose of rituximab.
25. Patients unable to take oral medication or with clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the study drug.