Early treatment intensification in patients with high risk Mantle Cell Lymphoma using CAR-T-cell treatment after an abbreviated induction therapy with Rituximab and Ibrutinib and 6 months Ibrutinib maintenance (Arm A) as compared to standard of care induction and maintenance (Arm B)
- Trial ID
- 2022-502405-15-01
- Protocol
- CARMAN
Trial statistics
Objectives
The primary objective of this study is to exploratively compare the **efficacy** of a CAR-T-cell treatment strategy using KTE-X19 in patients with previously untreated high-risk **Mantle Cell Lymphoma** (MCL) following an experimental treatment regimen (Arm A) against the standard of care (Arm B). This comparison is clinically relevant as it aims to determine whether the CAR-T-cell approach offers superior outcomes in terms of disease control and patient survival, potentially leading to a paradigm shift in the management of high-risk MCL.
Secondary objectives include evaluating the efficacy, safety, tolerability, and quality of life (QoL) associated with the CAR-T-cell treatment strategy. This will be assessed through additional efficacy endpoints, such as molecular remission after induction and during maintenance in both treatment arms. These secondary objectives are crucial for understanding the broader impact of the treatment on patient well-being and long-term health outcomes.
Participants
The clinical trial focuses on patients diagnosed with **Mantle Cell Lymphoma (MCL)**, specifically targeting those with high-risk features. The study population includes both male and female participants aged between 18 and 75 years. Participants are required to have a histologically confirmed diagnosis of MCL, with specific genetic markers such as overexpression of cyclin D1 or the presence of t(11;14). The trial does not provide information on the total number of participants, as this data was not disclosed by the sponsor. Participants must have an ECOG performance status of 2 or less and meet certain laboratory criteria, including adequate neutrophil and platelet counts, and normal liver and kidney function, unless discrepancies are related to MCL. The trial population was selected based on these criteria, and individuals with prior treatment for MCL or evidence of CNS disease were excluded. Lifestyle considerations include the requirement for sexually active participants to use effective contraception and the willingness to refrain from driving for a specified period post-treatment. The trial is available only in France, and participants must be able to reach the study site within two hours in case of emergencies.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of a **CAR-T-cell** treatment strategy in patients with previously untreated high-risk **Mantle Cell Lymphoma (MCL)**. This study employs a randomized, controlled, and open-label design, comparing the experimental treatment arm with the standard of care. The trial is expected to run until September 2030, with recruitment having commenced in September 2023. Participants will be involved in the study for a maximum of 42 weeks, depending on the treatment arm and response to therapy.
Study visits are structured to ensure comprehensive monitoring and data collection. The initial inclusion visit involves screening to confirm eligibility based on criteria such as histologically confirmed MCL, age between 18-75 years, and specific laboratory values. Following randomization, participants will undergo induction therapy, with subsequent visits scheduled to assess treatment response and manage any adverse events. Follow-up visits will occur at regular intervals to monitor progression-free survival and overall response rates. The end-of-study visit will conclude the participant's involvement, assessing long-term outcomes and any residual effects of the treatment.
Participants may be withdrawn from the study early if they experience stable or progressive disease during induction, any severe adverse events, or if they choose to discontinue participation. The primary endpoint is failure-free survival from randomization, with secondary endpoints including progression-free survival, complete remission rate, and overall survival. Safety assessments will focus on adverse events and toxicities, ensuring participant well-being throughout the trial duration.
Treatment
The clinical trial involves the administration of several **experimental medications** and standard-of-care treatments. **Vincristine sulfate** is administered as an injection with a maximum daily dose of 2 mg and a total dose of 12 mg over a treatment period of 6 weeks. The route of administration is via **IV infusion**. **Cisplatin** is provided as a solution for infusion, with a maximum daily dose of 100 mg/m² and a total dose of 300 mg/m² over 6 weeks, also administered through IV infusion.
**Carmustine** is administered as a powder and solvent for solution for injection/infusion, with a maximum daily and total dose of 300 mg/m² over a 1-week period, delivered via IV infusion. **Doxorubicin** is given as a solution for injection, with a maximum daily dose of 50 mg/m² and a total dose of 300 mg/m² over 6 weeks, administered through IV infusion. **Fludarabine** is provided as a concentrate for solution for infusion, with a maximum daily dose of 30 mg/m² and a total dose of 90 mg/m² over 3 weeks, administered via IV infusion.
**Rituximab** is administered as a solution for infusion, with a maximum daily dose of 375 mg/m² and a total dose of 9000 mg/m² over 42 weeks, delivered through IV infusion. **Bendamustine** is given as a solution for infusion, with a maximum daily dose of 90 mg/m² and a total dose of 1080 mg/m² over 6 weeks, administered via IV infusion. **Prednisolone** is provided in tablet form, with a maximum daily dose of 100 mg and a total dose of 3000 mg over 6 weeks, administered orally and via IV.
**Dexamethasone** is administered in tablet form, with a maximum daily dose of 40 mg and a total dose of 480 mg over 6 weeks, delivered orally and via IV. **Brexucabtagene autoleucel** is provided as a dispersion for infusion, with a maximum daily and total dose of 20 million organisms over 1 week, administered intravenously. **Etoposide** is given as a solution for infusion, with a maximum daily dose of 200 mg/m² and a total dose of 800 mg/m² over 4 weeks, administered via IV infusion.
**Filgrastim** is administered as a solution for injection, with a maximum daily dose of 10 µg/kg and a total dose of 740 µg/kg over 6 weeks, delivered subcutaneously. **Oxaliplatin** is provided as an infusion, with a maximum daily dose of 130 mg/m² and a total dose of 390 mg/m² over 6 weeks, administered via IV infusion. **Cyclophosphamide** is given as a powder for solution for injection or infusion, with a maximum daily dose of 750 mg/m² and a total dose of 4500 mg/m² over 6 weeks, administered via IV infusion.
**Cytarabine** is administered as a solution for infusion, with a maximum daily dose of 4000 mg/m² and a total dose of 18000 mg/m² over 6 weeks, delivered via IV infusion. **Ibrutinib** is provided as hard capsules, with a maximum daily dose of 560 mg and a total dose of 504000 mg over 30 weeks, administered orally. **Thiotepa** is given as a powder for concentrate for solution for injection/infusion, with a maximum daily and total dose of 10 mg/kg over 1 week, administered via IV infusion.
**Tocilizumab** is administered as a solution for infusion, with a maximum daily dose of 800 mg and a total dose of 3200 mg over 1 week, delivered via IV infusion. **Pegfilgrastim** is provided as a solution for injection, with a maximum daily dose of 6 mg and a total dose of 36 mg over 6 weeks, administered subcutaneously. **Melphalan** is given as a powder and solvent for solution for infusion, with a maximum daily and total dose of 140 mg/m² over 1 week, administered via IV infusion.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is **Failure-free survival (FFS)** from randomization, which includes failure events such as any discontinuation of the per protocol treatment due to stable or progressive disease during induction, stable disease at the end of induction, progressive disease at any time after the end of induction treatment, and death from any cause at any time.
Secondary endpoints include several measures: **Progression-free survival (PFS)** from randomization, **Complete remission rate (CR)** and **Overall response rate (ORR)**, which includes CR and partial response (PR) six months from randomization after completion of CAR-T-treatment or high-dose therapy (HDT). The rate of PET negative CR, defined as complete metabolic response rate according to Lugano criteria, will also be evaluated six months from randomization. Additional secondary endpoints include PFS in responders six months from the end of cytoreductive treatment, best response during two years from randomization, time to best response, time to first response from randomization, and **Overall survival (OS)** from randomization. Safety will be monitored through adverse events, serious adverse events, and toxicities as per the Common Terminology Criteria for Adverse Events (CTCAE).
Inclusion and Exclusion Criteria
Inclusion Criteria
- Histologically confirmed diagnosis of MCL according to WHO classification, with documentation of either overexpression of cyclin D1 or presence of t(11;14)
- 18-75 years
- At least 1 measurable lesion according to the Lugano Response Criteria (>1,5 cm nodal lesion or > 1cm extranodal lesion); in case of bone marrow infiltration only, bone marrow aspiration and biopsy is mandatory for all staging evaluations.
- ECOG performance status ≤ 2
- The following laboratory values at screening (unless related to MCL): I. Absolute neutrophil count (ANC) ≥ 1000 cells/μLII. Platelets ≥75,000 cells/μL III. Creatinine <2 mg/dL or calculated creatinine clearance ≥60 mL/min IV. Transaminases (AST and ALT) < 2.5 x ULN V. Total bilirubin <= 2 x ULN unless other reason known (e.g. Gilbert-Meulengracht-Syndrome, or due to lymphoma involvement)
- No evidence of CNS-disease
- Written informed consent form according to ICH/EU GCP and national regulations, ability to follow study instructions and likely to attend and complete all required visits
- Sexually active men and women of child-bearing potential must agree to use one of the highly effective contraceptive methods (combined oral contraceptives using two hormones, contraceptive implants, injectables, intrauterine devices, sterilized partner) together with one of the barrier methods (latex condoms, diaphragms, contraceptive caps) while on study; this should be maintained for 12 months after the last dose of brexu-cel or for 3 months after last dose of Ibrutinib, whichever is longer
- Negative serum or urine pregnancy test (Females of childbearing potential only. Females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential)
- Willingness not to drive a motor vehicle for 8 weeks post CAR T cell treatment
- Possibility to reach the site within 2 hours in case of toxicity / emergency
- At least one high-risk MCL – feature defined as I. MIPI-c high intermediate (HI) or high (H) risk (i.e. high-risk MIPI irrespective of Ki-67 or intermediate risk MIPI) and Ki-67> 30% (Ki-67 based on local pathology)) and/or II. TP53 deletion and /or mutation and/or TP53 overexpression by immunohistochemistry (> 50% of lymphoma cells), sequencing (mutations and deletions) and FISH
- No prior systemic treatment for MCL, except pre-phase treatment as outlined in this trial protocol
- Stage II-IV (according to Lugano 2014 criteria)
Exclusion Criteria
- Subjects not able to give consent
- Positive test results for chronic HBV infection (defined as positive HBsAg serology, mandatory testing) Note: patients with occult or prior HBV infection (defined as negative HBs-Ag and positive total antiHBc-Ab) may be included if HBV DNA is undetectable and patient can receive antiviral prophylaxis.
- Positive test results for hepatitis C (mandatory hepatitis C virus [HCV] antibody serology testing). Patients positive for anti-HCV antibody are eligible only if PCR is negative for HCV RNA
- Patients with known HIV infection (mandatory test)
- History or presence of CNS disorder, such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, cerebral edema, posterior reversible encephalopathy syndrome, or any autoimmune disease with CNS involvement
- History of or active autoimmune disease (e.g. Crohn’s disease, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immuno-suppression / systemic medication within the last 2 years
- History of deep vein thrombosis or pulmonary embolism requiring therapeutic anticoagulation within 6 months of enrollment
- Known severe primary immunodeficiency
- Any medical condition likely to interfere with safety or efficacy of study treatment
- Live vaccine ≤ 6 weeks prior to planned start of study treatment
- Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow up schedule
- Subjects without legal capacity, unable to understand the nature, scope, significance and consequences of this clinical study
- Known history of hypersensitivity to the investigational drug, to drugs with a similar chemical structure or to aminoglycosides
- Simultaneously active participation in another clinical study involving an investigational medicinal product within 30 days prior to enrollment. Patients included infollow up periods of other clinical trials without ongoing trial medication are allowed
- Subjects with a physical or psychiatric condition which at the investigator’s discretion may put the subject at risk, may confound the study results, or may interfere with the subject’s participation in this clinical study
- Known or persistent abuse of medication, drugs or alcohol
- Serious concomitant disease interfering with a regular therapy according to the study protocol: I. Clinically symptomatic cardiovascular disease such as arrhythmias, congestive heart failure, higher grade AV-block, unstable angina, myocardial infarction, cardiac angioplasty or stenting within 12 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association. Functional Classification or LVEF below 50% II. Baseline oxygen saturation ≤ 92% on room air III. Endocrinological, e.g. severe, not sufficiently controlled diabetes mellitus
- Current or planned pregnancy or nursing women. History of or active malignancy other than MCL, non-melanoma skin cancer, carcinoma in situ (e.g. cervix, bladder, breast) or prostate cancer unless disease-free for at least 3 years (and PSA within normal range in case of prostate cancer).
- Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous (IV) antimicrobials for management.
- History of or active malignancy other than MCL unless disease-free for at least 3 years, except nonmelanoma skin cancer, carcinoma in situ (e.g., cervix, bladder, breast) or treated prostate cancer with PSA within normal range.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Recruiting | 01 Sept 2023 | 7 |
 France | Recruiting | 01 Sept 2023 | 42 |
 Germany | Recruiting | 01 Sept 2023 | 64 |
 The Netherlands | Recruiting | 01 Sept 2023 | — |
 Spain | Recruiting | 01 Sept 2023 | 27 |
| Netherlands | — | — | 10 |
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 |
|---|---|---|---|---|---|---|
DOXORUBICIN | Other | — | IV INFUSION | 50 | 6 | SUB06391MIG |
RITUXIMAB | Other | — | IV INFUSION | 375 | 42 | SUB12570MIG |
FILGRASTIM | Other | — | SUBCUTANEOUS | 10 | 6 | SUB07627MIG |
CYCLOPHOSPHAMIDE | Other | — | IV INFUSION | 750 | 6 | SUB06859MIG |
THIOTEPA | Other | — | IV INFUSION | 10 | 1 | SUB10985MIG |
TOCILIZUMAB | Other | — | IV INFUSION | 800 | 1 | SUB20313 |
DEXAMETHASONE | Other | — | ORAL AND IV | 40 | 6 | SUB07017MIG |
VINCRISTINE SULFATE | Other | — | IV INFUSION | 2 | 6 | SUB05101MIG |
OXALIPLATIN | Other | — | IV INFUSION | 130 | 6 | SUB09490MIG |
BENDAMUSTINE | Other | — | IV INFUSION | 90 | 6 | SUB05707MIG |