Safety and Efficacy Study of Loncastuximab Tesirine + Ibrutinib in Diffuse Large B-Cell or Mantle Cell Lymphoma

A Phase 1/2 Open-Label Study to Evaluate the Safety and Efficacy of Loncastuximab Tesirine and Ibrutinib in Patients With Advanced Diffuse Large B-Cell Lymphoma or Mantle Cell Lymphoma (LOTIS-3)

The purpose of this Phase 1/2 study is to evaluate the safety and efficacy of Loncastuximab Tesirine (ADCT-402) in combination with Ibrutinib in participants with Advanced Diffuse Large B-Cell Lymphoma or Mantle Cell Lymphoma.

The Phase 1 portion of the study will cover the dose escalation portion of the study. This will then be followed by the Phase 2 portion of the study, which will treat participants with the dose of loncastuximab tesirine determined in the Phase 1 portion of the study. The ibrutinib dose of 560 mg daily, will remain the same throughout both phases of the study.

A standard 3+3 dose escalation design will be used for the Phase 1 portion of the study. The dose-limiting toxicity (DLT) period will be the 21 days following the first dose of ibrutinib. The dose escalation cohort will receive loncastuximab tesirine for 2 cycles with concurrent ibrutinib (concomitant therapy) and may then continue ibrutinib therapy up to one year.

The Phase 2 portion of the study will involve 3 cohorts:

• Non-germinal center B-cell diffuse large B-cell lymphoma (Non-GCB DLBCL) cohort
• Germinal center B-cell diffuse large B-cell lymphoma (GCB DLBCL) cohort
• Mantle cell lymphoma (MCL) cohort

Each of the cohorts will be treated with the recommended dose of loncastuximab tesirine determined in the Phase 1 portion of the study.

The study will include a Screening Period (of up to 28 days), a Treatment Period (cycles of 3 to 4 weeks), and a Follow-up Period (approximately every 12 week visits for up to 2 years after treatment discontinuation).

Inclusion Criteria:

1. Male or female participant aged 18 years or older

2. Pathologic diagnosis of DLBCL or MCL (For Italy Sites Only: MCL patients are excluded.)

3. Participants with DLBCL must have relapsed or refractory disease and have failed or been intolerant to available standard therapy

4. Participants with MCL must have relapsed or refractory disease and have received at least one prior line of therapy (For Italy Sites Only: This exclusion criterion is not applicable)

5. Participants who have received previous CD19-directed therapy must have a biopsy which shows CD19 expression after completion of the CD19-directed therapy

6. Measurable disease as defined by the 2014 Lugano Classification

7. Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block (or minimum 10 freshly cut unstained slides if block is not available)

8. ECOG performance status 0 to 2

9. Screening laboratory values within the following parameters:

   1. Absolute neutrophil count (ANC) ≥1.0 × 103/µL (off growth factors at least 72 hours)
   2. Platelet count ≥75 × 103/µL without transfusion in the past 7 days
   3. Hemoglobin ≥8 g/dL (4.96 mmol/L), transfusion allowed
   4. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transferase (GGT) ≤2.5 × the ULN
   5. Total bilirubin ≤1.5 × ULN (participants with known Gilbert's syndrome may have a total bilirubin up to ≤3 × ULN)
   6. Blood creatinine ≤1.5 × ULN or calculated creatinine clearance ≥60 mL/min by the Cockcroft and Gault equation

10. Negative beta-human chorionic gonadotropin (β-HCG) pregnancy test within 7 days prior to start of study drugs on C1D1 for women of childbearing potential

11. Women of childbearing potential must agree to use a highly effective method of contraception from the time of giving informed consent until at least 9 months after the last dose of loncastuximab tesirine or 1 month after last dose of ibrutinib, whichever comes last. Men with female partners who are of childbearing potential must agree that they will use a highly effective method of contraception from the time of giving informed consent until at least 6 months after the participant receives his last dose of loncastuximab tesirine or 3 months after last dose of ibrutinib, whichever comes last

Exclusion Criteria:

1. Known history of hypersensitivity to or positive serum human anti-drug antibody (ADA) to a CD19 antibody
2. Known history of hypersensitivity to ibrutinib
3. Previous therapy with ibrutinib or other BTK inhibitors
4. Previous therapy with loncastuximab tesirine
5. Requires treatment or prophylaxis with a moderate or strong cytochrome P450 (CYP) 3A inhibitor
6. Allogenic or autologous transplant within 60 days prior to start of study drugs (C1D1)
7. Active graft-versus-host disease
8. Post-transplantation lymphoproliferative disorder
9. Active autoimmune disease, including motor neuropathy considered of autoimmune origin and other central nervous system (CNS) autoimmune disease
10. Known seropositive and requiring anti-viral therapy for human immunodeficiency (HIV) virus, hepatitis B virus (HBV), or hepatitis C virus (HCV).
11. History of Stevens-Johnson syndrome or toxic epidermal necrolysis
12. Lymphoma with active CNS involvement at the time of screening, including leptomeningeal disease
13. Clinically significant third space fluid accumulation (i.e., ascites requiring drainage or pleural effusion that is either requiring drainage or associated with shortness of breath)
14. Breastfeeding or pregnant
15. Significant medical comorbidities, including but not limited to, uncontrolled hypertension (blood pressure [BP] ≥160/100 millimeters of mercury (mmHg) repeatedly), unstable angina, congestive heart failure (greater than New York Heart Association class II), electrocardiographic evidence of acute ischemia, coronary angioplasty or myocardial infarction within 6 months prior to screening, uncontrolled atrial or ventricular cardiac arrhythmia, poorly controlled diabetes mellitus, or severe chronic pulmonary disease, or tuberculosis infection (tuberculosis screening based on local standards).
16. Major surgery, radiotherapy, chemotherapy, or other anti-neoplastic therapy within 14 days prior to start of study drugs (C1D1), except shorter if approved by the Sponsor
17. Use of any other experimental medication within 14 days prior to start of study drugs (C1D1)
18. Planned live vaccine administration after starting study drugs (C1D1)
19. Any condition that could interfere with the absorption or metabolism of ibrutinib including malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel
20. Inherited or acquired bleeding disorders
21. Ongoing anticoagulation treatment, except for low-dose heparinisation or equivalent
22. Failure to recover to Grade ≤1 (Common Terminology Criteria for Adverse Events [CTCAE] version 4.0) from acute non-hematologic toxicity (Grade ≤2 neuropathy or alopecia) due to previous therapy prior to screening
23. Congenital long QT syndrome or a corrected QTcF interval of >480 ms at screening (unless secondary to pacemaker or bundle branch block)
24. Active second primary malignancy other than non-melanoma skin cancers, non metastatic prostate cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast, or other malignancy that the Sponsor's medical monitor and Investigator agree, and document should not be exclusionary
25. Any other significant medical illness, abnormality, or condition that would, in the Investigator's judgement, make the participant inappropriate for study participation or put the participant at risk