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 - ETS (FIL ETS).

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, three or four 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.

49 patients will be enrolled in the study.

The anticipated study dates are:

• Total accrual period: 48 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/four 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:

Standard Induction phase:

2 courses of R-BAC every 28 days according to the following schedule

• Rituximab 375 mg/m2 i.v. Day 1
• Bendamustine 70 mg/m2, Days 2 and 3
• Cytarabine 500 mg/m2, Day 2-4

Reduced Induction phase:

For patients deemed FRAIL or UNFIT for standard induction therapy (based on protocol dose and as per medical judgment), reduced R-BAC options may be considered. For patients > 80 years old the reduced induction schedule is recommended.

Two different schedules will be allowed

Cycle 1-2

• Rituximab 375 mg/m2 i.v. Day 1
• Bendamustine 70 mg/m2, Days 2 and 3
• Cytarabine 500 mg/m2, Day 2 and 3

or

Cycle 1-2

• Rituximab 375 mg/m2 i.v. Day 1
• Bendamustine 100 mg, Days 2 and 3
• Cytarabine 500 mg, Day 2 and 3

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 microgram/kg* every three weeks followed by

• 2 infusions of loncastuximab tesirine at a dose of 75 microgram/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 <20%; we hypothesized that, in this setting of patients, a consolidation with loncastuximab tesirine (ADCT-402) may increase the expected 12-month PFS to ≥40% 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 3 year of follow-up, the required sample size consist of 49 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 0.20 to conclude that the new treatment is promising for a subsequent phase III study.

Inclusion Criteria:

• Histologically documented diagnosis of MCL as defined in the 2017 edition of the World Health Organization (WHO) classification

• Age ≥ 18 and < 85 years

• Relapsed/Refractory disease after one, two, three or four lines of treatment

• Bendamustine-naive or relapsed after at least one year after the last cycle of a bendamustine-containing regimen

• Previous treatment with BTKi (Bruton Tyrosine Kinase inhibitors) monotherapy or BTKi containing regimens with R/R disease; and/or patients who discontinued BTKi monotherapy or BTKi containing regimens for adverse events and have active disease necessitating treatment.

• Previous treatment with any anti-CD19 agents is allowed (included CAR-T treatment) If previous anti-CD19 treatment has occurred, tissue CD19 expression must be assessed by histology or flow cytometry

• Venetoclax treated patients are allowed.

• Stem cell transplant eligible patients are allowed.

• Measurable nodal or extranodal disease ≥ 1.5 cm in longest diameter, and measurable in 2 perpendicular dimensions. Note: Patients with bone marrow involvement only are eligible. In case of bone marrow infiltration only, bone marrow aspiration and biopsy are mandatory for all staging evaluations

• ECOG (Eastern Cooperative Oncology Group)/WHO (World Health Organization) performance status ≤ 2 (unless MCL-related)

• The following laboratory values at screening (unless due to bone marrow involvement by lymphoma):

  • Absolute Neutrophil count (ANC) > 1.0×109/L
  • Platelet count ≥ 75.000/mm3
  • Creatinine clearance ≥ 40 mL/min (Cockcroft-Gault formula)
  • Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x ULN (upper limit of normal)
  • Bilirubin ≤ 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non- hepatic origin)

• Subject understands and voluntarily signs an informed consent form approved by an Independent Ethics Committee (IEC), prior to the initiation of any screening or study-specific procedures.

• Subject must be able to adhere to the study visit schedule and other protocol requirements.

• Life expectancy ≥ 3 months.

• Women of childbearing potential (WOCBP) and men must agree to use effective contraception if sexually active.This applies for the time period between signing of the informed consent form and at least 10 months after last loncastuximab tesirine (ADCT-402) dose. Men with female partners who are of childbearing potential must agree to use effective contraception if sexually active. This applies for the time period between signing of the informed consent form and at least 7 months after last loncastuximab tesirine (ADCT-402) dose.

Exclusion Criteria:

• Subjects who have received a bendamustine containing regimen and relapsed less than one year after the end of treatment.

• Known history of hypersensitivity to human antibodies.

• Allogenic stem cell transplant within 6 months prior to start of first study drug.

• Allogenic stem cell transplant with active / uncontrolled graft-versus-host disease.

• Previous treatment with CD19 targeting agents.

• More than four lines of previous treatment (autologous stem cell transplant performed as part of consolidation to a previous line of therapy should not be considered as a line of therapy).

• Active second malignancy in the last three years other than non-melanoma skin cancers, non-metastatic prostate cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast, or any other tumor that the Sponsor and Coordinating Investigator agree and document should not be considered preclusive to participate in the study.

• Major surgery or any anticancer therapy including chemotherapy, immunotherapy, radiotherapy, investigational therapy, including targeted small molecule agents within 14 days prior to start of study drug (R-BAC). A shorter interval in special settings must be approved by the Sponsor and/or Investigator.

• Cardiovascular disease (NYHA, New York Heart Association, class ≥2).

• Significant history of neurologic, psychiatric, endocrinological, metabolic, immunologic, or hepatic disease that would preclude participation in the study or compromise ability to give informed consent.

• Evidence of other clinically significant uncontrolled condition(s) including, but not limited to:

  • Uncontrolled and/or active systemic infection (viral including COVID 19, bacterial or fungal);
  • Chronic or acute hepatitis B (HBV) or hepatitis C (HCV) requiring treatment. Note:

subjects with serologic evidence of prior vaccination to HBV (i.e., HBsAg negative, HBsAb positive and HBcAb negative) or positive HBcAb from previous infection or intravenous immunoglobulins (IVIG) may participate; inactive carriers (HBsAg positive with undetectable HBV DNA) are eligible. Patients with presence of HCV antibody are eligible only if PCR results (polimerase chain reaction) negative for HCV RNA.

• HIV seropositivity.
• Lymphoma with active CNS (central nervous system) involvement at the time of screening, including leptomeningeal disease.
• Congenital long QT syndrome or a corrected QTcF interval of >480 msec at screening (unless secondary to pacemaker or bundle branch block).
• Any other significant medical illness, abnormality, or condition that would, in the Investigator's judgment, make the patient inappropriate for study participation or put the patient at risk.
• If female, the patient is pregnant or breast-feeding.