This is a Phase 2, multicenter, open-label, single-arm study of the efficacy and safety of loncastuximab tesirine given as consolidation therapy after salvage immunochemotherapy in BTKi-treated (or BTKi intolerant) R/R MCL patients.~Primary Objective:~- To assess the efficacy of a consolidation with loncastuximab tesirine following salvage immunochemotherapy (2 courses of Rituximab-Bendamustine-Cytarabine, R-BAC) in Bruton Tyrosine Kinase inhibitors (BTKi) treated (or BTKi intolerant) relapsed/refractory (R/R) Mantle Cell Lymphomas (MCL).~Secondary Objectives:~To evaluate the safety profile of loncastuximab tesirine consolidation.~To assess the rate of Minimal Residual Disease (MRD) negativity after loncastuximab tesirine consolidation.~R/R MCL patients after one, two or three lines of treatment including BTKi treatment (or BTKi intolerant), with complete response (CR) or partial response (PR) or with stable disease (SD) after salvage immunochemotherapy (R-BAC x 2, Rituximab - Bendamustine, Cytarabine) will undergo consolidation with loncastuximab tesirine. A patient with CR, PR or SD after one R-BAC course, which is unable to undergo a second course due to toxicity to chemotherapy, can be considered to proceed for consolidation.~After checking inclusion and exclusion criteria and signing written informed consent, patients will be enrolled in the study, and the system will assign them an alphanumeric code that will identify the patient in every study procedure.~Efficacy parameters will be evaluated according to the Lugano 2014 Classification.~Toxicity parameters will be evaluated according to the definitions of the current version of the NCI (National Cancer Institute) CTCAE (Common Terminology Criteria for Adverse Events) criteria.~After treatment discontinuation, both in the case the protocol treatment was fully administered and in the case of an early discontinuation, patients will be followed-up according to clinical practice timeline and procedures, and information on patient status (progression/relapse, alive/dead, lost to follow-up) will be collected till the end of the study (LPLV), planned 36 months after the start of treatment of the last patient enrolled in the study. In case of progression/relapse during follow-up, the patients will be then followed-up for survival till the study end.~56 patients will be enrolled in the study.~The anticipated study dates are:~Total accrual period: 24 months~Last patient last visit (LPLV): 36 months after the start of treatment of the last patient enrolled.~The study will include a period of screening up to 21 days, a period of treatment of up to 22 weeks and a follow-up period with visits every 4-8 weeks for the first year after study entry and then every 8-12 weeks for at least 2 years.~Treatment includes a period of induction with 2 cycles of 28 days with R-BAC (=8 weeks) + two weeks for restaging + 4 doses of loncastuximab tesirine every 21 days (=12 weeks), i.e., a total period of 22 weeks, for patients who achieved CR, PR or SD after salvage immunochemotherapy. A follow-up period with visits every 4-8 weeks for the first year after study entry and then every 8-12 weeks for at least to 2 years.~For the study is also planned an extended follow-up after the end of the study requiring participating sites to provide only information on patient status (alive, dead, lost to follow-up) and to record possible events occurred after the end of the study, including diagnosis of second neoplasia and long-term toxicity for additional 2 years after the end of the study.~Disease evaluation will be performed initially (Baseline Assessment), after the beginning of treatment with R-BAC (End of Induction), at the end of loncastuximab tesirine consolidation phase (End of Treatment) and then every 6 months during the follow-up period.~Non-responder, relapsing or progressive patients will be treated according to best clinical practice.~Treatment schedule:~INDUCTION PHASE (salvage immunochemotherapy):~• 2 courses of R-BAC (every four weeks):~Rituximab 375 mg/m2 IV day 1,~Bendamustine 70 mg/m2 IV days 2 and 3,~Ara-C 500 mg/m2 IV days 2-4 An optional pre-phase with steroid (prednisone 1 mg/kg/day, maximum of 7 days before starting induction phase) and/or single dose of Vincristine (up to 2 mg total) was allowed.~After restaging at the End of Induction (EOI) patients with CR, PR or SD will receive:~CONSOLIDATION PHASE:~2 infusions of loncastuximab tesirine at a dose of 150 micorgram/kg* every three weeks followed by~2 infusions of loncastuximab tesirine at a dose of 75 micorgram/kg* every three weeks~(For patients with BMI> 35 dose will be calculated based on adjusted weight). Patients will undergo initial staging with CT (Computed Tomography) scan, PET (18F-FDG Positron Emission Tomography)/PET-CT scan and bone marrow (BM) biopsy. Patients will be fully restaged after induction (EOI), after loncastuximab tesirine consolidation (EOT) and then every six months only with CT-scan.~Tumour re-biopsy will be performed only if clinically indicated. Bone Marrow (BM) and Peripheral Blood (PB) samples for MRD evaluation purposes will be taken at the same time points when CT-scan is done (to be performed centrally at certified Euro-MRD academic laboratories, according to Euro-MRD guidelines).~Response to treatment will be evaluated according to the Lugano 2014 criteria. Based on published results we considered the expected 12-month PFS with available treatments to be <30%; we hypothesized that, in this setting of patients, a consolidation with loncastuximab tesirine (ADCT-402) may increase the expected 12-month PFS to ≥50% According to one arm non-parametric survival provided by SWOG (Southwest Oncology Group-NCI), with an alpha error (one sided) equal to 0.05, a beta error equal to 0.10, 2-years of accrual and a minimum of 1 year of follow-up, the required sample size consist of 56 patients who start treatment after screening phase. The lower limit of the 90% confidence interval (according to 1-sided alpha error of 0.05) of the 12-month PFS must be higher than the null hypothesis of 0.30 to conclude that the new treatment is promising for a subsequent phase III study.
This is a prospective, phase 2, multicenter, open-label, single-arm study. Primary objective is to assess the efficacy of loncastuximab tesirine given as consolidation therapy after salvage immunochemotherapy in BTKi (Bruton Tyrosine Kinase inhibitors) -treated (or BTKi intolerant) R/R (Relapse or Refractory) MCL (Mantle Cell Lymphoma) patients. The sponsor of this clinical trial is Fondazione Italiana Linfomi (FIL).