PIRTOBRUTINIB for Mantle cell lymphoma

Inclusion criteria

• {"criterion_text":"- Adult patients (≥18 years of age).\n- Stable disease without evidence of clinical progression for at least 3 months. Patients in prolonged observation may be included (over 3 months).\n- 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\n- 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.\n- 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\n- Not included in other clinical trial or treated with an experimental drug unrelated to MCL within the past 2 years.\n- Written informed consent must be obtained before any study-specific assessment is performed.\n- 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.\n- Naïve patients for MCL management (no prior therapies, excluding diagnostic splenectomy)\n- Asymptomatic patients\n- Eastern Cooperative Oncology Group (ECOG) performance status <2 (0 -1)\n- Clinical stage I-IV according to the Ann Arbor classification with no symptoms attributable to MCL\n- 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%)\n- 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."}

Exclusion criteria

• {"criterion_text":"- Subjects with aggressive histological variants: blastoid and pleomorphic variants of MCL\n- History of bleeding diathesis\n- Past medical history of stroke or intracranial haemorrhage within 6 months prior to inclusion.\n- 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.\n- 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\n- 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.\n- 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.\n- 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.\n- Known active cytomegalovirus (CMV) infection. Unknown or negative status are eligible.\n- Concomitant or previous malignancies the last 2 years other than basal skin cancer or in situ uterine cervix cancer.\n- Major surgery within 4 weeks of inclusion.\n- B-cell monoclonal lymphocytosis with MCL phenotype\n- Vaccinated with live, attenuated vaccines within 4 weeks of inclusion.\n- 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.\n- 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).\n- Known hypersensitivity to any of the excipients of Pirtobrutinib or Rituximab or any intended study medications.\n- 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.\n- 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.\n- Presence of B symptoms or any relevant symptoms related to the MCL.\n- Nodal clinical forms with lymph node enlargement > 3 cm (largest diameter).\n- Organ dysfunction related to MCL including creatinine level > 2 mg/dl or altered liver biochemistry (> 3x ULN).\n- Serum LDH over ULN\n- Known central nervous system (CNS) infiltration.\n- Expected MCL therapy requirement in a short time (< 3 months)\n- Anticoagulation requirement with vitamin K antagonists"}

Primary endpoints

• {"endpoint_text":"- Primary objective point will be assessed by the complete remission rate (CRR), defined as the percentage of patients who achieve a complete response (CR) at the end of Cycle 6 of the P-R combination according to the Lugano Classification (Appendix 3)","definition_or_measurement_approach":"Defined as the percentage of patients who achieve a complete response (CR) at the end of Cycle 6 of the P-R combination according to the Lugano Classification (Appendix 3)."}

Secondary endpoints

• {"endpoint_text":"- The activity of P-R combination will be assessed in the overall population according to the Lugano Classification","definition_or_measurement_approach":"Assessed according to the Lugano Classification in the overall population."}
• {"endpoint_text":"- The sensitivity, specificity, false positive and negative rates of MRD assays: Allele-specific oligonucleotide real-time quantitative Polymerase chain reaction (ASO-qPCR) and New Generation Sequencing (NGS) based assays.","definition_or_measurement_approach":"Performance metrics (sensitivity, specificity, false positive and false negative rates) of MRD assays (ASO-qPCR and NGS-based assays)."}
• {"endpoint_text":"- The safety of P-R combination will be assessed by terms of Adverse Events (AEs), Severe Adverse Events (SAEs), Suspected Unexpected Adverse Reactions (SUSARs) during the P-R treatment. All AEs will be classified according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.","definition_or_measurement_approach":"Safety assessed by AE/SAE/SUSAR reporting during treatment, classified per CTCAE v5.0."}
• {"endpoint_text":"- The changes in the total score between baseline and 6, 12, and 24 months and End of Study (EoS) respectively in patient HRQoL measured by patient reported outcomes (PROs): • The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 items (EORTC-QLQ-C30), and • The Functional Assessment of Cancer Therapy-Lymphoma (FACT)-Lym questionnaire.","definition_or_measurement_approach":"Change in HRQoL scores (EORTC-QLQ-C30 and FACT-Lym) between baseline and months 6, 12, 24 and End of Study."}
• {"endpoint_text":"- Longitudinal characterization of tumor samples prior to onset of P-R and at relapse or progression (peripheral blood, plasma, bone marrow and lymph node or other tissues involved) in addition to the study of sequential semestral peripheral blood and plasma samples. The biological characterization will include bulk and single-cell level multi-omics techniques.","definition_or_measurement_approach":"Longitudinal multi-omic characterization (bulk and single-cell) of tumor and sequential peripheral blood/plasma samples before treatment and at relapse/progression."}

Portugal

Earliest CTIS Part Ii Submission Date

17-03-2025

Latest Decision Or Authorization Date

24-06-2025

Processing Time Days

99

Number Of Sites

2

Number Of Participants

6

Spain

Earliest CTIS Part Ii Submission Date

17-03-2025

Latest Decision Or Authorization Date

10-02-2026

Processing Time Days

330

Number Of Sites

14

Number Of Participants

44

Primary sponsor

Full Name

Fundacion Geltamo

Organisation Type

Patient organisation/association

Country Of Registered Address

Spain

Third parties

• {"country":"Spain","full_name":"Evidenze Health Espana S.L.","duties_or_roles":"codes: 1,10,11,12,5,6,8","organisation_type":"Pharmaceutical company"}