CAR-T-cell Treatment for Untreated High Risk MANtle Cell Lymphoma

NCT06482684 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: CARMAN2022-502405-15-01
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 2

Brief Summary

First-line CAR-T-cell consolidation after an abbreviated induction with 2 cycles of Rituximab and Ibrutinib prior to CAR-T-cell treatment and followed by 6 months of maintenance with Ibrutinib in patients with high risk MCL.

Conditions

Mantle Cell Lymphoma

Keywords

High Risk MCL; CAR-T-Cells; MCL Firstline Treatment

Outcome Measures

Primary Outcomes (1)

• Failure Free Survival

  Time from randomization to 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 end of induction treatment and death from any cause, whichever occurred first. Stable disease at end of induction is defined as failure event because it represents a regular indication for salvage treatment in MCL.

  From Randomization to any to any discontinuation of the per protocol treatment due to stable or progressive disease

Secondary Outcomes (4)

• Progression-free survival (PFS)

  from the date of response (CR or PR within 6 months from randomization) to progression or death from any cause

• Complete remission (CR) rate

  6 months from randomization until end of trial

• Time to first response

  date of randomization to the date of first response (CR or PR)

• Overall survival

  day 1 after randomization until end of trial

Study Arms (2)

Arm A

EXPERIMENTAL

The abbreviated induction phase consists of 2 cycles of Ibrutinib + Rituximab and 2 cycles of Ibrutinib + R-CHOP for primary tumor reduction followed by CAR-T-cell treatment. In case of good clinical response (PR or CR) after 2 cycles of Ibrutinib + Rituximab, Ibrutinib + R-CHOP can be omitted. In this case, one cycle of Ibrutinib monotherapy will be applied. T cell apheresis will be performed after the initial 2 cycles. Application of KTE-X19 will be performed after lymphodepleting chemotherapy with Fludarabine and Cyclophosphamide (FC). After stable hematopoietic recovery, maintenance with Ibrutinib will be applied for 6 months but not prior to day 60 post CAR. The follow-up period starts after the completion of Ibrutinib maintenance and takes 4.5 up to 7 years.

Drug: KTE-X19; Drug: Ibrutinib

Arm B

ACTIVE COMPARATOR

Younger patients (≤ 65 years) will receive 3 cycles R-CHOP + Ibrutinib/ 3 cycles R-DHAP alternating, followed by autologous stem cell transplantation (ASCT). Elderly patients (≥ 65 years) will receive 6 cycles of Bendamustine and Rituximab + Ibrutinib or R-CHOP + Ibrutinib without ASCT. Independently of age, control patients receive 2 years of maintenance therapy with Ibrutinib and 3 years of Rituximab maintenance if foreseen by national guidelines, in addition to Ibrutinib maintenance.

Drug: Ibrutinib

Interventions

KTE-X19 DRUG

See description of treatment arms

Arm A

Ibrutinib DRUG

See description of treatment arms

Arm A; Arm B

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed diagnosis of MCL according to WHO classification, with documentation of either overexpression of cyclin D1 or presence of t(11;14)
• At least one High Risk MCL - feature as 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-mutation and/or TP53-overexpression by immunohistochemistry (\> 50% of lymphoma cells)
• No prior treatment for MCL
• Stage II-IV (Ann Arbor)
• 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 discrepancies are related to MCL):
• I. Absolute neutrophil count (ANC) ≥ 1000 cells/μL II. 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 6 months after the last dose of KTE-X19 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

You may not qualify if:

• Subjects not able to give consent
• 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 in follow 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 significant cardiovascular disease such as symptomatic 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. Clinical significant pleural effusion (if not lymphoma related) IV. Endocrinological (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.
• Positive test results for chronic HBV infection (defined as positive HBsAg serology) (mandatory testing) Patients with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) may be included if HBV DNA is undetectable
• Positive test results for hepatitis C (mandatory hepatitis C virus \[HCV\] antibody serology testing). Patients positive for 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 immunosuppression / systemic medication within the last 2 years

Sponsors & Collaborators

• Christian Schmidt, MD: lead
• Johannes Gutenberg University Mainz: collaborator

Study Sites (2)

University Hospital of Mainz

Mainz, Germany

RECRUITING

Klinikum der Universität München

Munich, 81377, Germany

RECRUITING

Related Publications (1)

• Silkenstedt E, Dreyling M. First Line Therapy in Mantle Cell Lymphoma-The Role of BTKi in the Initial Treatment of Transplant-Eligible and -Ineligible Patients. Hematol Oncol. 2025 Jun;43 Suppl 2(Suppl 2):e70073. doi: 10.1002/hon.70073.

  PMID: 40517546 DERIVED

MeSH Terms

Conditions

Lymphoma, Mantle-Cell

Interventions

brexucabtagene autoleucel; ibrutinib

Condition Hierarchy (Ancestors)

Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Study Officials

• Georg Hess, MD

  Johannes Gutenberg University Mainz

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Martin Dreyling, MD

CONTACT

+4989440074900; Martin.Dreyling@med.uni-muenchen.de

Christian Schmidt, MD

CONTACT

+4989440077907; christian_schmidt@med.uni-muenchen.de

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Head of Study Center

Study Record Dates

• First Submitted: June 26, 2024
• First Posted: July 1, 2024
• Study Start: February 15, 2024
• Primary Completion (Estimated): June 15, 2031
• Study Completion (Estimated): December 31, 2031
• Last Updated: July 1, 2024

Record last verified: 2024-06

Locations

DE (2)