Open-label of Loncastuximab Tesirine (ADCT-402) in Relapsed/Refractory Marginal Zone Lymphoma

Inclusion Criteria:

1. Men and women, aged 18 years or older.

2. Histologically confirmed MZL, including extranodal, nodal, and splenic subtypes.

3. Previously received 1 or more lines of systemic therapy, including at least 1anti-CD20 antibody (cluster of differentiation antigen 20) (either as monotherapy orin combination as chemoimmunotherapy), with documented progression or documentedfailure to achieve CR or PR after the most recent systemic treatment regimen.Subjects with H. pylori-positive gastric extranodal MZL who received an initialtreatment with currently accepted antibiotics may be considered eligible if, afterantibiotic regimen, subject has histologically confirmed MZL and was subsequentlytreated with at least 1 line of systemic therapy.

4. Radiographically measurable lymphadenopathy or extranodal lymphoid malignancy (defined as the presence of ≥ 1 lesion that measures > 1.5 cm in the LDi and ≥ 1.0cm in the longest perpendicular diameter as assessed by CT or MRI per responsecriteria for lymphomas.68 Imaging must be conducted within 6 weeks prior to thestart of therapy.

5. Subjects with splenic MZL who do not meet the radiographically measurabledisease criteria described herein are eligible for participation provided thatbone marrow infiltration of MZL is histologically confirmed.

6. Subjects with skin EMZL (extranodal marginal zone lymphoma) who do not meet theradiographically measurable disease criteria described herein are eligible forparticipation provided that skin lesion measures ≥ 1.5 cm in diameter by tapemeasure and is documented by photo or there are multiple skin lesions measuring >1cm in diameter on the body that cannot be incorporated in one radiation fieldand at least one of them is histologically confirmed as MZL.

7. Subjects with gastric extranodal MZL histologically confirmed and need therapybut do not have measurable disease and in which response to treatment can beassess by multiple random gastric biopsies.

8. Subjects with conjunctival EMZL who do not meet the radiographically measurabledisease criteria described herein are eligible for participation provided thatconjunctival lesion measures ≥ 1 cm in diameter by tape measure and isdocumented by photo or there are multiple conjunctival lesions measuringtogether >1 5cm that cannot be treated by radiation because of previousradiation therapy, contraindications to radiation and patient refusal toreceive radiation therapy. At least one of these lesions needs behistologically confirmed as MZL.

9. Subjects must be willing to provide a lymph node or tissue biopsy from the mostrecent available archival tissue or undergo an incisional or excisional lymph nodeor tissue biopsy. a. Subjects with splenic MZL who do not have a tumor to biopsy or an archival tumortissue sample are eligible for participation provided subject is willing to undergoa bone marrow biopsy or provide an archival bone marrow biopsy that was obtainedbefore the date of the first dose of study treatment; bone marrow sample must showhistologically confirmed infiltration of MZL.

10. Patient should have at least one of the following criteria for treatmentinitiation):

• Involvement of ≥3 nodal sites, each with diameter of ≥3 cm

• Any nodal or extranodal tumor mass with a diameter of ≥5 cm

• B symptoms (fever ≥ 38 degrees Celsius of unclear etiology, night sweats,weight loss > 10% within the prior 6 months) or other symptoms attributed todisease or specific organ involvement associated with the relapse.

• Risk of local compressive symptoms that may result in organ compromise

• Splenomegaly or splenic lesion without splenomegaly

• Leukopenia attributed to MZL (leukocytes < 1000/mm3)

• Leukemia (> 5.000 lymphoma cells/mm3)

• Threatened organ function, especially for extranodal MZL

• Requirement for transfusion or growth factor support attributed to lymphoma

• Involvement of 2 or more extranodal sites, with tumor/lesion in each extranodalsite ≥1 cm

• Progression or relapsed within 24 months after MZL diagnosis in patientspreviously treated with ≥1 line of systemic therapy

7. Life expectancy > 3 months.

8. ECOG (Eastern Cooperative Oncology Group ) performance status 0 to 2 (Refer toAppendix A).69

9. Adequate hematologic, hepatic, and renal function tested within 6 weeks prior to thestart of therapy (values must not be achieved with growth factors):

10. ANC (absolute neutrophil count ) ≥ 1.0 × 109/L.

11. Hemoglobin ≥ 8.0 g/dL.

12. Platelet count ≥ 50 × 109/L.

13. Total bilirubin ≤ 1.5 × ULN (upper limit of normal ). Subjects with documentedhistory of Gilbert's syndrome and in whom total bilirubin elevations areaccompanied by elevated indirect bilirubin are eligible.

14. ALT(alanine aminotransferase) /AST (aspartate aminotransferase ) ≤ 3.0 ULN or ≤ 5 × ULN in the presence of liver involvement by lymphoma.

15. Calculated creatinine clearance ≥ 45 mL/min by the Cockcroft-Gault Equation70or the estimated glomerular filtration rate ≥ 45 mL/min/1.73 m2 using theModification of Diet in Renal Disease formula.

16. Willingness to avoid pregnancy or fathering children based on the criteria below:

17. Woman of nonchildbearing potential (ie, surgically sterile with a hysterectomyand/or bilateral oophorectomy OR ≥ 12 months of amenorrhea and at least 45years of age).

18. Woman of childbearing potential who has a negative serum pregnancy test atscreening and who agrees to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through safety follow-up at least 9 months after the last dose of loncastuximab tesirine. Permitted methods thatare at least 99% effective in preventing pregnancy should be communicated tothe subject and their understanding confirmed.

19. Man, who agrees to take appropriate precautions to avoid fathering children (with atleast 99% certainty) from screening through at least 6 months after the last dose ofstudy treatment. Permitted methods that are at least 99% effective in preventingpregnancy should be communicated to the subject and their understanding confirmed.

Exclusion Criteria:

1. Evidence of DLBCL transformation. a. Subjects with presumptive evidence oftransformation based on clinical assessment of factors such as, but not limited to,increasing lactate dehydrogenase, rapidly worsening disease, or frequent B-symptoms,must be ruled out for a transformation to a more aggressive disease, such as DLBCL.

2. History of central nervous system lymphoma (either primary or metastatic) orleptomeningeal disease.

3. Concurrent anticancer therapy (eg, chemotherapy, radiation therapy, surgery,immunotherapy, biologic therapy, hormonal therapy, investigational therapy, or tumorembolization).

4. Allogeneic stem cell transplant within the last 6 months, or autologous stem celltransplant within the last 3 months before the date of the first dose of studytreatment.

5. Active graft versus host disease.

6. Receipt of anticancer medications or investigational drugs within the followingintervals before the date of the first dose of study treatment:

7. < 10 weeks from completion of any radio- or toxin-immunoconjugates.

8. < 4 weeks for immunotherapy

9. <. 3 weeks for radiotherapy.

10. < 2 weeks for any investigational agent or other anticancer medications.

11. Steroids that are used for treatment of allergy or other underlying conditionare permittable, but not steroids started to treat lymphoma. Subjects receivingcorticosteroids must be at a dose level ≤ 10 mg/day within 7 days of the studytreatment administration.

12. Inadequate recovery from toxicity and/or complications from a major surgery beforestarting therapy.

13. Prior treatment-related toxicities have not resolved to NCI CTCAE v5.071 ≤ Grade 1before the date of the first dose of study treatment, except for stable chronictoxicities (≤ Grade 2) not expected to resolve (eg, stable Grade 2 peripheralneurotoxicity).

14. Previous treatment with anti CD19 (cluster of differentiation antigen 19 )approaches

15. Current or previous other malignancy within 3 years of study entry, except curedbasal or squamous cell skin cancer, superficial bladder cancer, prostateintraepithelial neoplasm, carcinoma in situ of the cervix, or other noninvasive orindolent malignancy.

16. Significant concurrent, uncontrolled medical condition, including, but not limitedto, renal, hepatic, hematological, GI, endocrine, pulmonary, neurological, cerebral,or psychiatric disease. Patients with pleural effusion, pericardial effusion orascites should not be enrolled in this study, unless effusions are caused bylymphoma.

17. Chronic or current active infectious disease requiring systemic antibiotics,antifungal, or antiviral treatment or exposure to a live vaccine within 30 days ofdosing.

18. Known HIV infection or positivity on immunoassay. Note: HIV screening test isoptional

19. Liver disease: HBV (hepatitis B virus) or HCV (hepatitis C virus) infection:Subjects positive for HBsAg or hepatitis B core antibody will be eligible if theyare negative for HBV-DNA; these subjects should be considered for prophylacticantiviral therapy. Subjects positive for anti-HCV antibody will be eligible if theyare negative for HCV-RNA.

20. Current New York Heart Association Class II to IV congestive heart failure oruncontrolled arrhythmia.

21. Uncontrolled or symptomatic arrhythmia, stroke in last 6 months, liver cirrhosis,and autoimmune disorder requiring immunosuppression or long-term corticosteroids (>10 mg daily prednisone equivalent)

22. Currently pregnant or breastfeeding.

23. Any condition that would, in the investigator's judgment, interfere with fullparticipation in the study, including administration of study treatment andattending required study visits; pose a significant risk to the subject; orinterfere with interpretation of study data.

24. Patients with impaired decision-making capacity