A Phase 2 interventional study of Pirtobrutinib and rituximab in Mantle Cell Lymphoma (MCL), sponsored by Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea. Recruiting at 16 sites in 2 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-12-16.
Sponsored by Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea · Phase 2, Interventional, and Treatment
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.
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.
The following laboratory values at screening:
Exclusion Criteria:
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
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.
Drug: 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.
Efficacy of Pirtobrutinib in combination with rituximab after 6 cycles
To assess the activity of Pirtobrutinib in combination with rituximab (P-R) as a therapeutic alternative to immunochemotherapy (R-Bendamustine or R-CHOP regimen) in patients with an indolent clinical presentation of MCL. The primary objective 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.
Time frame: At the end of Cycle 6 (each cycle is 28 days)
To evaluate the activity of Pirtobrutinib-Rituximab combination along time in terms of ORR
The activity of P-R combination will be assessed in the overall population according to the Lugano Classification in terms of: • overall response rate (ORR), defined as the percentage of patients who achieved partial response (PR) or complete response (CR) according to the Lugano Classification criteria.
Time frame: At month 6, month 12 and month 24.
Evaluation of MRD
To evaluate and compare the MRD detection ability of different MRD assays. 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.
Time frame: After cycle 6, cycle 12, cycle 30, cycle 36, cycle 42, cycle 48 (each cycle is 28 days), and End of treatment (28 days after las administration of Study drug).
To determine the safety and tolerability of P-R combination
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, and second neoplasms and other serious events G≥3 occurring after treatment discontinuation. All AEs will be classified according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Time frame: Baseline, during all the cycles day 1 visit (each cycle is 28 days) and at EoT (28 days afert las administration of Study drug).
To assess the patient Health-related Quality of Life (HRQoL)
This objective will be evaluated descriptively. The changes in the total score in patient HRQoL measured by patient reported outcomes (PRO): The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core (EORT-QLQ-C30): This questionnaire is a self-administered tool specifically developed to assess the quality of life in treated cancer patients participating in international clinical trials. It is composed of both multi-item scales and single-item measures. It consists of 30 items grouped into three multi-items measures: i) functional scales (items 1-7, 20-27), ii) symptom scales (items 8-19, 28), and (3) global health status (items 29 and 30). Items from 1 to 27 are ranked from 1 (not at all) to 4 (very much). Items 29 and 30 are ranked from 1 (very poor) to 7 (excellent). All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.
Time frame: Between baseline and month 6, month 12, and month 24 and End of Study (month 48)
To assess the patient Health-related Quality of Life (HRQoL).
This objective will be evaluated descriptively. The changes in the total score in patient HRQoL measured by patient reported outcomes (PRO): The Functional Assessment of Cancer Therapy-Lymphoma (FACT)-Lym questionnaire (version 4): This questionnaire is a self-administered tool that specifically evaluates the Lymphoma therapy in adult patients. It consists of 42 5-points Likert-type items, ranked from 0 (not at all) to 4 (very much).
Time frame: Between baseline and month 6, month 12, and month 24 and End of Study (month 48)
To perform a comprehensive biological characterization of cases with an indolent clinical presentation of MCL
Longitudinal characterization of tumor samples prior onset of Pirtobrutinib-Rituximab and at relapse or progression (peripheral blood, plasma, bone marrow and lymph node or other tissues involved) in addition to sequential follow-up (peripheral blood and plasma samples). The biological characterization will include bulk and single-cell level multi-omic techniques.
Time frame: After cycle 6, cycle 12, cycle 18, cycle 24, cycle 30, cycle 36, cycle 42 and cycle 48 (Each cycle is 28 days)
To evaluate the activity of Pirtobrutinib-Rituximab combination along time in terms of CRR
The activity of P-R combination will be assessed in the overall population according to the Lugano Classification in terms of: • Complete response rate (CRR) at 12 and 24 months in overall population.
Time frame: At months 12 and 24
To evaluate the activity of Pirtobrutinib-Rituximab combination along time in terms of MRD response
The rate of undetectable MRD, defined as the percentage of patients with undetectable MRD, by Allele-specific oligonucleotide real-time quantitative Polymerase chain reaction (ASO-qPCR) and New Generation Sequencing (NGS) based assays according to the response assessment (Lugano Classification criteria) after Cycle 6, Cycle 12 and Cycle 24.
Time frame: At the end of Cycle 6, Cycle 12 and Cycle 24 (each cycle is 28 days)
To evaluate the activity of Pirtobrutinib-Rituximab combination along time in terms of MRD response:
The time to achieve an undetectable MRD and the median duration of the undetectable MRD response in P-R responding patients.
Time frame: At the end of Cycle 6, Cycle 12 and Cycle 24 (each cycle is 28 days)
To evaluate the activity of Pirtobrutinib-Rituximab combination along time in terms of clinical and molecular response duration and survival.
Time-to-event variables, (calculated in the overall population): Duration of response (DoR), defined as the time from the documentation of tumor response to disease progression or death, in the event of no documented recurrence, or start of a new anti - lymphoma treatment because of refractory or persistent disease.
Time frame: From the start of the study treatment with P-R until the date of first documented progression, recurrence or death, whichever came first, assessed up to 48 months
To evaluate the activity of Pirtobrutinib-Rituximab combination along time in terms of clinical and molecular response duration and survival.
Time-to-event variables, (calculated in the overall population): Progression-free survival (PFS), defined as the time between start of study treatment with P-R and the first documentation of recurrence, progression, or death in the event of no documented recurrence, or start of a new anti - lymphoma treatment, due a refractory or persistent disease.
Time frame: From the start of the study treatment with P-R until the date of first documented progression, recurrence or death, whichever came first, assessed up to 48 months
To evaluate the activity of Pirtobrutinib-Rituximab combination along time in terms of clinical and molecular response duration and survival.
Time-to-event variables, (calculated in the overall population): Overall survival (OS), defined as the time between the start of treatment and death from any cause.
Time frame: From the start of the study treatment with P-R until the date of death
Plan to share: Yes — Data obtained through this study may be provided to qualified researchers with academic interest in hematology diseases. All individual data collected during the trial will be available. Data shared will be coded, with no PHI included. Study protocol, statistical analysis plan, informed consent form and clinical study report will be also available. Information will be available beginning 6 months after final publication with no end date established. Approval of the request and execution of all applicable agreements are prerequisites to the sharing of data with the requesting party. Data requests can be submitted starting 6 months after article publication. Access to trial IPD can be requested by qualified researchers and will be provided following review and approval of a research and execution of a Data Sharing Agreement (DSA). For more information or to submit a request, please contact to GELTAMO though the web page: https://www.geltamo.com/contacto
Supporting information: Study protocol, Sap, Icf, Csr
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