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Pirtobrutinib plus rituximab for adults with newly diagnosed indolent mantle cell lymphoma

International Multicentric Phase II Trial to Evaluate the Efficacy and Safety of Pirtobrutinib in Combination With Rituximab in Patients With Indolent Clinical Forms of Mantle Cell Lymphoma

Phase 2 Interventional Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea · NCT07285590

This trial will test whether combining pirtobrutinib with rituximab is effective and safe for adults newly diagnosed with indolent mantle cell lymphoma.

Quick facts

PhasePhase 2
Study typeInterventional
Enrollment50 (estimated)
Ages18 Years and up
SexAll
SponsorGrupo Español de Linfomas y Transplante Autólogo de Médula Ósea Academic / other
Drugs / interventionsRituximab, pirtobrutinib
Locations16 sites (Lisbon, Lisbon District and 15 other locations)
Trial IDNCT07285590 on ClinicalTrials.gov

What this trial studies

This is an international, multicenter, open‑label, single‑arm Phase II trial of the non‑covalent BTK inhibitor pirtobrutinib given with rituximab in treatment‑naïve adults with indolent mantle cell lymphoma. The study uses a Simon two‑stage design with an interim analysis after the first 16 patients to decide whether to continue based on complete remission rate after six cycles. Primary outcomes focus on activity (complete remission rate) and safety, with secondary assessments including molecular minimal residual disease and tolerability. Eligible patients are asymptomatic with low tumor burden and ECOG performance status 0–1.

Who should consider this trial

Good fit: Ideal candidates are adults (≥18) with treatment‑naïve, asymptomatic indolent mantle cell lymphoma, ECOG 0–1, low tumor burden (e.g., lymph nodes ≤3 cm or leukemic non‑nodal presentation), and no prior systemic MCL therapy.

Not a fit: Patients with symptomatic or aggressive MCL, prior MCL therapy, high tumor burden, or poor performance status (ECOG ≥2) are unlikely to be eligible or to benefit from this approach.

Why it matters

Potential benefit: If successful, the combination could achieve deeper remissions with fewer treatment‑related toxicities and offer a tolerable, fixed‑duration frontline option for patients with indolent MCL.

How similar studies have performed: Other first‑line combinations including BTK inhibitors have shown improved responses and progression‑free survival, and pirtobrutinib has shown promising activity and favorable tolerability in relapsed/refractory MCL, but frontline use with rituximab remains relatively novel.

Eligibility criteria

Show full inclusion / exclusion criteria 
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.

Where this trial is running

Lisbon, Lisbon District and 15 other locations

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Mantle Cell LymphomalymphomaGeltamoRituximabPirtobrutinibMantle cell lymphomaMCL
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.