Phase II Multicentric Trial Evaluating Ibrutinib and Rituximab Efficacy and Safety in Indolent Mantle Cell Lymphoma
- Trial ID
- 2024-512370-94-00
- Protocol
- GELTAMO-IMCL-2015
- Sponsor
- Fundacion Geltamo
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this multicentric phase II trial is to explore the **efficacy** of the combination of ibrutinib and rituximab as a therapeutic alternative to the R-CHOP regimen in patients with indolent forms of **Mantle Cell Lymphoma** (MCL). This will be assessed by evaluating the rate of complete responses achieved at 12 months of treatment. The clinical relevance of this objective lies in potentially offering a less toxic and more targeted treatment option for patients with indolent MCL, which could improve patient outcomes and quality of life.
Secondary objectives include:
- Evaluating the efficacy of the ibrutinib and rituximab combination over time in terms of secondary endpoints such as overall response rate (ORR) at 12 months, progression-free survival (PFS), duration of response, overall survival (OS), and minimal residual disease (MRD) analysis.
- Determining the safety and tolerability of ibrutinib in combination with rituximab, including an evaluation of health-related quality of life (QOL).
- Conducting a biological characterization of indolent forms of MCL and their response to the ibrutinib and rituximab combination through genomic studies.
Participants
The clinical trial involves participants diagnosed with **Mantle Cell Lymphoma** (MCL), as classified by the World Health Organization in 2008. The study population includes both male and female subjects aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status of less than 2. Participants are required to have stable disease without evidence of clinical progression for at least three months and must not have received any prior therapies, except for diagnostic splenectomy. The trial includes individuals with asymptomatic presentations, including non-nodal MCL with bone marrow or peripheral blood involvement, and nodal MCL with low tumor burden. The study population was selected based on specific laboratory values at screening, such as a neutrophil count of at least 1x10^9/L and a hemoglobin level of at least 100 g/L. Both genders are included, and participants must adhere to effective birth control methods during and after the study. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is a multicentric, phase II study designed to evaluate the efficacy and safety of a combination therapy involving **ibrutinib** and **rituximab** in patients with indolent clinical forms of **Mantle Cell Lymphoma**. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial is from May 30, 2016, to December 28, 2029, with the primary objective being to assess the rate of complete responses achieved at 12 months of treatment.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as a confirmed diagnosis of Mantle Cell Lymphoma and stable disease without evidence of clinical progression for at least three months. The trial includes follow-up visits to monitor the participants' response to the treatment and any adverse events. The end-of-study visit will evaluate the overall response rate, progression-free survival, duration of response, and overall survival, as well as the rate of negative minimal residual disease and health-related quality of life.
The expected length of participant involvement is up to 87 weeks, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, disease progression, or withdrawal of consent by the participant. The trial aims to provide a therapeutic alternative to the R-CHOP regimen by exploring the efficacy of the I+R combination in achieving complete remission and improving patient outcomes in indolent forms of Mantle Cell Lymphoma.
Treatment
The clinical trial involves the administration of **Ibrutinib**, marketed under the name IMBRUVICA, which is provided in the form of 140 mg **hard capsules**. The pharmaceutical form is a capsule, hard, and the active substance is of chemical origin. The maximum daily dose of Ibrutinib is 560 mg, administered orally. The treatment period is set for a maximum of 87 days. The administration schedule requires monitoring to ensure participant compliance with the dosing regimen. The product is manufactured by Janssen-Cilag International NV and holds the marketing authorization number EU/1/14/945/001.
In addition to Ibrutinib, the trial also includes the administration of **Rituximab**, marketed as MabThera, which is provided as a 100 mg concentrate for solution for infusion. The pharmaceutical form is a solution for infusion, and the active substance is of protein origin. Rituximab is administered intravenously with a maximum daily dose of 375 mg/m². The treatment period for Rituximab is also set for a maximum of 87 days. The product is manufactured by Roche Registration GmbH and holds the marketing authorization number EU/1/98/067/001. Compliance with the dosing schedule is monitored to ensure adherence to the treatment protocol.
Efficacy
The efficacy of the combination of **Ibrutinib** and **Rituximab** in patients with indolent clinical forms of Mantle Cell Lymphoma will be assessed primarily by evaluating the rate of complete remission (CR) achieved at 12 months of treatment. Secondary endpoints include determining the overall response rate (ORR) at 12 months, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Additionally, the study will assess the rate of negative minimal residual disease (MRD), the time to obtain a molecular response, and the median duration of the molecular response in patients responding to the I+R combination.
Health-related quality of life (QOL) during treatment will also be evaluated, alongside rates of adverse events (AEs), serious adverse events (SAEs), and suspected unexpected serious adverse reactions (SUSARs) categorized by CTC grade (Version 4.03). Genomic studies will be conducted to explore IGHV mutational status, DNA copy-number, and whole exome sequencing in indolent clinical forms of Mantle Cell Lymphoma. The efficacy parameters will be measured and collected at specified timepoints, with the primary endpoint assessed at the 12-month mark.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Subjects with confirmed diagnosis of Mantle Cell Lymphoma (World Health Organization Classification, WHO 2008). Classical, small-cell variants and marginal-zone variants can be included.
- Age 18 years or older.
- Subjects must not have received any prior therapies (excluding diagnostic splenectomy).
- Asymptomatic patients.
- Ann Arbor clinical stages I-IV.
- Eastern Cooperative Oncology Group (ECOG) performance status <2 (0-1).
- Subjects with a non-nodal MCL presentation with mainly bone marrow or peripheral blood involvement.
- Other asymptomatic clinical presentations are acceptable in case of low tumor burden, including nodal MCL with lymph node enlargement ≤ 3 cm in the maximum diameter and with low proliferation index (Ki-67 ≤ 30%).
- The following laboratory values at screening: ● ● Neutrophil count ≥ 1×10e9/L, Hemoglobin level ≥ 100 g/L or platelet count ≥ 100×10e9/L Transaminases (AST and ALT) ≤ 3 x ULN ●Total bilirubin ≤ 1.5 x ULN unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin ●Creatinine ≤ 2 x ULN or calculated creatinine clearance ≥ 40 mL/min/1.73m2
- Stable disease without evidence of clinical progression criteria for at least 3 months. Patients in prolonged therapeutic abstention may be included.
- Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. Men must agree to not donate sperm during and after the study. For females, these restrictions apply for 1 month after the last dose of study drug. For males, these restrictions apply for 3 months after the last dose of study drug.
- Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [ß-hCG]) or urine pregnancy test at Screening. Women who are pregnant or breastfeeding are ineligible for this study.
- Sign (or their legally-acceptable representatives must sign) an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study.
Exclusion Criteria
- Aggressive histological variants: blastic and pleomorphic variants (blastoid).
- Proliferation index measured by Ki-67 > 30%.
- B-cell monoclonal lymphocytosis with MCL phenotype.
- Eastern Cooperative Oncology Group (ECOG) performance status ≥2.
- Presence of B symptoms or any relevant symptoms related to the MCL.
- Nodal clinical forms with lymph node enlargement > 3 cm (maximum diameter).
- Cytopenias attributable to MCL: Neutrophil count < 1×10e9/L, Hemoglobin level < 100 g/L or platelet count < 100×10e9/L.
- Organ dysfunction related to MCL including creatinine level > 2 ULN or altered liver biochemistry (> 3x ULN).
- Gradual increase in different determinations of serum LDH attributable to MCL that exceeds 20% of the ULN.
- Known CNS infiltration.
- Subjects with expected therapy requirement for MCL in a short time (< 3 months).
- Patients with active hepatitis B or C infection or HIV infection. Positive test results for chronic HBV infection (defined as positive HBsAg serology) or positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology testing) will be excluded with the following exceptions. Patients with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) may be included if HBV DNA is undetectable, provided that they are willing to undergo monthly DNA testing or antiviral prophylaxis. Patients who have protective titers of hepatitis B surface antibody (HBsAb) after vaccination or prior but cured hepatitis B are eligible. Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA.
- Anticoagulation requirement with vitamin K antagonists.
- Past medical history of stroke or intracranial haemorrhage within 6 months prior to inclusion
- Required medication with strong CYP3A4/5 inhibitors.
- Any serious comorbidity that makes the patient unacceptable for receiving the treatment
- Concomitant or previous malignancies the last 2 years other than basal skin cancer or in situ uterine cervix cancer.
- Pregnancy or lactation.
- Major surgery within 4 weeks of inclusion.
- Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification.
- Vaccinated with live, attenuated vaccines within 4 weeks of randomization.
- Uncontrolled systemic infection requiring intravenous (IV) antibiotics.
- Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator’s opinion, could compromise the subject’s safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Not Recruiting | 30 May 2016 | 50 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
MabThera 100 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 375 | 87 | PRD2154041 |
IMBRUVICA 140 mg hard capsules | Test | HARD CAPSULES | ORAL | 560 | 87 | PRD1729387 |