Beschreibung

Rekrutierung gestartet

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)

Studientherapie

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.
Arm B (control): Younger patients (d 65 years) will receive 3 cycles R-CHOP + Ibrutinib/ 3 cycles R-DHAP alternating, followed by autologous stem cell transplantation (ASCT). Elderly patients (e 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.

Studienstatus

Rekrutierung gestartet/nimmt Patienten auf

Allgemeine Infos zum Antrag

Herr Univ. Prof. Dr. med. Georg Heß
georg.hess@unimedizin-mainz.de

Universitätsmedizin der Johannes Gutenberg-Universität Mainz - Mainz (Prüfzentrum (CAR-T), 11520)
III. Medizinische Klinik und Poliklinik
Langenbeckstr. 1
55131 Mainz

Primary Objective:
To exploratively compare the efficacy of the experimental treatment (Arm A) with standard of care (Arm B)

Secondary Objectives:
To further assess efficacy, safety, and tolerability of CAR-T-cell treatment by means of secondary and exploratory endpoints in comparison to standard of care

adult patients, suitable for CAR-T-cell treatment, untreated for MCL: key selection criterion

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)

150 patients in total, each arm 75

Primary estimand attributes: population: previously untreated high-risk MCL as defined by inclusion and exclusion criteria; variable: FFS, population level summary: FFS hazard ratio (HR) Arm A vs. Arm B, strategies for handling intercurrent events: treatment policy (ineligibility ascertained after registration, failure to receive IMP, new lymphoma treatment before treatment failure); while on treatment (loss to follow-up); composite endpoint (death from any cause).
Statistical design: two-sided log-rank test with significance level of 10% using the following hypotheses:
Null hypothesis H0: FFSA = FFSB for all time points
Alternative hypothesis H1: FFSA ` FFSB for at least one time point.
Sample size estimation: Based on the pooled European MCL Younger (Hermine et al., Lancet 2016) and MCL Elderly (Kluin-Nelemans et al., JCO 2020) trial data, we estimated a median FFS of 27 months for the control group B in the high-risk trial population (own unpublished calculation). With 150 patients randomized 1:1 between Arm A and B within 2 years of recruitment and at least 4.5 years of additional follow-up, allowing for 10% dropouts at 5 years, a power of 90% is achieved to decide against the null hypothesis in case of a true FFS-HR of 0.558 (median FFS in Arm A: 48 months). To detect this difference, 102 FFS events need to be observed. One interim analysis is planned after the observation of 51 FFS events to allow an early stop for superiority (O’Brien-Fleming boundaries) or inferiority (Pocock boundaries). The probability to stop early for superiority is 72% with a HR of 0.42 (median 65 months) and 32% with a HR of 0.56 (median 48 months). The probability to stop early for inferiority is 63% with a HR of 1.85 (median 15 months) and 22% with a HR of 1.36 (median 20 months). In case the FFS of the outcome is substantially better than projected (HR 0.75, median FFS in Arm B 36 months), 90% power is achieved to detect a true FFS-HR of 0.512 (median FFS in Arm A: 70 months).
Test of primary question: In the interim analysis, the standardized logrank statistic will be calculated and compared with the boundaries corresponding to the observed event number according to the pre-specified alpha-spending design. If Z exceeds the superiority or inferiority margin, superiority or inferiority of Arm A vs. Arm B is concluded, respectively. Otherwise the statistical test continues until the final evaluation in which the standardized logrank statistic is compared with the boundaries corresponding to the observed number of events according to the pre-specified alpha-spending design.
Analysis methods: ITT (primary) and PP (sensitivity) evaluations, Kaplan-Meier curves with estimates provided at yearly intervals and two-sided 95% confidence intervals for time to event outcomes, estimation of remission rates along with two-sided 95% confidence intervals, explorative comparison of all secondary and explorative outcomes between treatment groups, exploratory subgroup analyses according to age (=65 years), sex and MIPI group

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

Exploratory endpoints:
• Molecular remission rate 6 months from randomization and during follow-up
• Mutation profile at baseline and at relapse
• Immunophenotype at relapse (e.g. CD19 expression)
• Quality of life: physical functioning (assessed with the EORTC QLQ-C30), physical condition/fatigue (assessed with the EORTC QLQ-NHL-HG29)
• Hematotoxicity associated with the CAR-T-cell therapy
• Diversity and composition of the microbiome

Spezifische Infos zum Antrag

1. Histologically confirmed diagnosis of MCL according to WHO classification, with documentation of either overexpression of cyclin D1 or presence of t(11;14)
2. 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)
3. No prior treatment for MCL
4. Stage II-IV (Ann Arbor)
5. 18-75 years
6. 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.
7. ECOG performance status d 2
8. The following laboratory values at screening (unless discrepancies are related to MCL):
I. Absolute neutrophil count (ANC) e 1000 cells/¼L
II. Platelets e75,000 cells/¼L
III. Creatinine <2 mg/dL or calculated creatinine clearance e60 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)
9. No evidence of CNS-disease
10. 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
11. 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
12. 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)
13. Willingness not to drive a motor vehicle for 8 weeks post CAR T cell treatment
14. Possibility to reach the site within 2 hours in case of toxicity / emergency

1. Subjects not able to give consent
2. Subjects without legal capacity, unable to understand the nature, scope, significance and consequences of this clinical study
3. Known history of hypersensitivity to the investigational drug, to drugs with a similar chemical structure or to aminoglycosides
4. 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
5. 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
6. Known or persistent abuse of medication, drugs or alcohol
7. 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 d 92% on room air
III. Clinical significant pleural effusion (if not lymphoma related)
IV. Endocrinological (severe, not sufficiently controlled diabetes mellitus)
8. 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).
9. Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous (IV) antimicrobials for management.
10. 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
11. 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
12. Patients with known HIV infection (mandatory test)
13. 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
14. 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
15. History of deep vein thrombosis or pulmonary embolism requiring therapeutic anticoagulation within 6 months of enrolment
16. Known severe primary immunodeficiency
17. Any medical condition likely to interfere with assessment of safety or efficacy of study treatment
18. Live vaccine d 6 weeks prior to planned start of study treatment
19. Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow up schedule

Study set up: Q4/2022
First subject in: Q1/2023
Last subject in: Q1/2025
Last subject last treatment: Q2/2025 (latest)
Last subject out: Q3/2029
All sites closed: Q3/2030
Duration of the study approx. 84 months

5 countries
40 sites
15-18 sites in Germany

Gilead / Kite
Janssen

not for public disclosure

15

nach Arm 4-6 TE plus LP und Diagnostik

Ja

• CARMAN_Kurz-Synopse_V2.2