CAR-T-cell treatment for untreated high risk MANtle Cell Lymphoma

Phase 1

Recruiting

• Conditions: Mantle Cell Lymphoma (MCL); MedDRA version: 21.0Level: PTClassification code: 10026805Term: Mantle cell lymphoma stage IV Class: 100000004864; MedDRA version: 21.0Level: PTClassification code: 10026803Term: Mantle cell lymphoma stage II Class: 100000004864; MedDRA version: 21.0Level: PTClassification code: 10026804Term: Mantle cell lymphoma stage III Class: 100000004864; Therapeutic area: Diseases [C] - Neoplasms [C04]

• Registration Number: CTIS2022-502405-15-01
• Lead Sponsor: Klinikum Der Universitat Munchen AöR

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2023-06-21
• Last Update Posted: 21 August 2024

Recruitment & Eligibility

• Status: Recruiting
• Sex: All
• Target Recruitment: 91

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 discrepancies are 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, only in France available, 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, 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)

Exclusion Criteria

Subjects not able to give consent, 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, History of deep vein thrombosis or pulmonary embolism requiring therapeutic anticoagulation within 6 months of enrolment, Known severe primary immunodeficiency, Any medical condition likely to interfere with assessment of 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 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.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The primary objective is to exploratively compare the efficacy of a CAR-T-cell treatment strategy with KTE- X19 in patients with previously untreated high risk mantle cell lymphoma (MCL) following experimental treatment (Arm A) as compared with standard of care (Arm B).;Secondary Objective: To evaluate the efficacy, safety, tolerability, and quality of life (QoL) associated with a CAR-T-cell treatment strategy in terms of additional efficacy endpoints including molecular remission after induction and during maintenance in both arms.;Primary end point(s): Primary endpoint: Failure-free survival (FFS) from randomization. Failure events: •Any discontinuation of the per protocol treatment due to stable or progressive disease during induction •Stable disease at end of induction •Progressive disease at any time after end of induction treatment •Death from any cause at any time

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s):Progression-free survival (PFS) from randomization;Secondary end point(s):Complete remission rate (CR) and overall response rate (ORR: CR, PR) 6 months from randomization (after completion of CAR-T-treatment or HDT, respectively);Secondary end point(s):Rate of PET negative CR (complete metabolic response rate, Lugano criteria) 6 months from randomization;Secondary end point(s):PFS in responders 6 months from end of cytoreductive treatment;Secondary end point(s):Best response during 2 years from randomization;Secondary end point(s):Time to best response, time to first response from randomization;Secondary end point(s):Overall survival (OS) from randomization;Secondary end point(s):Safety: adverse events, serious adverse events, toxicities (CTCAE)