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

NCT ID: NCT07285590

Last Updated: 2025-12-16

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE2

Total Enrollment

50 participants

Study Classification

INTERVENTIONAL

Study Start Date

2025-09-30

Study Completion Date

2032-12-31

Brief Summary

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This is a multicenter, international, open-label, single-arm phase II clinical trial designed to evaluate the activity and safety of a combination therapy with pirtobrutinib and rituximab (P-R) in treatment-naïve adult patients diagnosed with indolent clinical forms of Mantle Cell Lymphoma (MCL). The study applies a Simon's two-stage design, with an interim analysis after the first 16 patients to determine continuation based on complete remission rate (CRR) after 6 cycles.

Detailed Description

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The current evidence obtained from clinical trials exploring the incorporation of BTK inhibitors in first-line treatment of MCL points toward a clear significant improvement in both patient responses and progression-free survival. Until new data from randomized clinical trials become available, the inclusion of new combinations of BTK inhibitors with chemoimmunotherapy or with new targeted combinations alone, remains a matter of debate. In addition, there is some concern regarding the additional toxicity associated with some of these combinations, which could be ameliorated by a fixed duration of treatment or by the use of newer generation BTK inhibitors, associated with significantly better tolerability. The new non-covalent BTK inhibitor pirtobrutinib has recently shown more promising activity in MCL relapsed/refractory to prior covalent BTK inhibitors therapy, and also with very favourable safety profile (3% of discontinuations due to drug-induced adverse events). Pirtobrutinib could be a very interesting drug to be tested in the upfront setting to try to sort out the significant toxicity more frequently observed with covalent BTK inhibitors. Indeed, indolent clinical forms of MCL that represent around 20% of new MCL diagnosis could be particularly suitable to receive pirtobrutinib as a first-line treatment in combination with rituximab in order to maximize responses and the rate of undetectable molecular minimal residual disease while improving the treatment tolerance. This combination could also limit treatment duration, except for MRD detectable and TP53 mutated cases, according to the data shown in the IMCL-2015 trial. By testing pirtobrutinib in combination with rituximab in a population of indolent MCL patients, the investigators aim to improve and refine the potential new standard treatment for this particular subset of MCL patients. Moreover, the Sponsor plan to conduct a clinical study that will allow not only a deep molecular MRD analysis but also a thorough biological study with different bulk and single-cell level multi-omic platforms in order to gain insight into pirtobrutinib performance in indolent clinical forms of MCL. For this purpose, the Sponsor have designed a multicenter, international, open-label, phase II clinical to assess the efficacy of pirtobrutinib in combination with rituximab in patients with indolent MCL.

Conditions

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Mantle Cell Lymphoma (MCL)

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Pirtobrutinib with rituximab

Patients will receive a P-R combination for at least 24 cycles (C24). The first cycle of P-R will be administered at day 1 (baseline) . Pirtobrutinib discontinuation will be decided after C24, according to the MRD response and the TP53 mutational status. Rituximab treatment will end up at C23.

Group Type EXPERIMENTAL

Pirtobrutinib and rituximab

Intervention Type DRUG

Patients will receive the study treatment (P-R combination) at day 1 (baseline) and during the treatment period (C24). Pirtobrutinib discontinuation per protocol will be decided after C24, according to the MRD response and the TP53 mutational status. Rituximab treatment will end up at C23.

Interventions

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Pirtobrutinib and rituximab

Patients will receive the study treatment (P-R combination) at day 1 (baseline) and during the treatment period (C24). Pirtobrutinib discontinuation per protocol will be decided after C24, according to the MRD response and the TP53 mutational status. Rituximab treatment will end up at C23.

Intervention Type DRUG

Eligibility Criteria

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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.
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Evidenze Health España (CRO)

UNKNOWN

Sponsor Role collaborator

Eli Lilly and Company

INDUSTRY

Sponsor Role collaborator

Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Eva Giné Soca

Role: PRINCIPAL_INVESTIGATOR

Hospital Clinic of Barcelona

Locations

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Instituto Português de Oncologia de Lisboa Francisco Gentil

Lisbon, Lisbon District, Portugal

Site Status RECRUITING

Unidade Local De Saude De Santa Maria E.P.E.

Lisbon, Lisbon District, Portugal

Site Status NOT_YET_RECRUITING

INSTITUT CATALÀ D'ONCOLOGIA (ICO). Hospital Germans Trias I Pujol.

Badalona, Barcelona, Spain

Site Status NOT_YET_RECRUITING

Hospital Universitari Vall d'Hebron

Barcelona, Barcelona, Spain

Site Status RECRUITING

Hospital Clinic de Barcelona

Barcelona, Barcelona, Spain

Site Status RECRUITING

Institut Català d'oncologia de L'Hospitalet (ICO-L'Hospitalet)

L'Hospitalet de Llobregat, Barcelona, Spain

Site Status NOT_YET_RECRUITING

Hospital General Universitario Gregorio Marañón

Madrid, Madrid, Spain

Site Status RECRUITING

Clínica Universidad Navarra

Madrid, Madrid, Spain

Site Status RECRUITING

Hospital Ramon y Cajal

Madrid, Madrid, Spain

Site Status RECRUITING

Hospital Universitario 12 de Octubre

Madrid, Madrid, Spain

Site Status RECRUITING

Hospital Clínico Universitario Virgen de la Arrixaca

El Palmar, Murcia, Spain

Site Status RECRUITING

Hospital Costa del Sol

Marbella, Málaga, Spain

Site Status RECRUITING

Clínica Universidad Navarra

Pamplona, Pamplona, Spain

Site Status RECRUITING

Hospital Universitario de Salamanca

Salamanca, Salamanca, Spain

Site Status RECRUITING

Hospital Clínico de Valencia

Valencia, Valencia, Spain

Site Status RECRUITING

Hospital Universitario y Politécnico La Fe

Valencia, Valencia, Spain

Site Status NOT_YET_RECRUITING

Countries

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Portugal Spain

Central Contacts

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Auxi Moreno

Role: CONTACT

+34 683 636 850

Ana María Méndez

Role: CONTACT

+34 942 203 450

Facility Contacts

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Maria Gomes Silva

Role: primary

+351217229867

Daniela Alves

Role: primary

+351217850000

Juan Manuel Sancho

Role: primary

Ana Marín Niebla

Role: primary

Eva Giné Soca

Role: primary

Eva González-Barca

Role: primary

Mariana Bastos Oreiro

Role: primary

Carlos Grande García

Role: primary

Javier López Jiménez

Role: primary

Ana Jiménez Ubieto

Role: primary

Almudena Cascales Hernández

Role: primary

María Casanova Espinosa

Role: primary

Carlos Grande García

Role: primary

Alejandro Martín García-Sancho

Role: primary

Blanca Ferrer Lores

Role: primary

Rafael Andreu Lapiedra

Role: primary

Related Links

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Other Identifiers

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2024-511983-97-00

Identifier Type: CTIS

Identifier Source: secondary_id

IMCL-2023

Identifier Type: -

Identifier Source: org_study_id