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

This is a Phase 1b, open-label, single-arm combination study with a dose escalation phase
(Part 1) followed by a dose expansion phase (Part 2). The study will enroll approximately 60
patients.

A standard 3+3 dose escalation design will be used for Part 1. The DLT period will be the 21
days following the first dose of ibrutinib. The initial 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. Depending on the safety and tolerability of
loncastuximab tesirine given concurrently with ibrutinib in the initial cohort, subsequent
cohorts may receive either loncastuximab tesirine with concurrent ibrutinib or loncastuximab
tesirine followed by ibrutinib (sequential therapy).

Patients who have a response of PR or stable disease (SD) at the 14-week assessment may
receive two additional doses of loncastuximab tesirine given 4 weeks apart.

Part 2 will consist of up to two expansion cohorts, one for DLBCL and one for MCL. Each
cohort will be 20 patients treated at the dose determined in Part 1.

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 patient aged 18 years or older

2. Pathologic diagnosis of DLBCL, non-GCB subtype; or MCL

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

4. Patients with MCL must have relapsed or refractory disease and have received at least
one prior line of therapy

5. Patients 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 upper limit of normal (ULN); ≤5 × ULN if
there is liver involvement

5. Total bilirubin ≤1.5 × ULN (patients 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 16 weeks after
the last dose of study therapy. 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 16 weeks after the patient
receives his last dose of study therapy

Exclusion Criteria:

1. Known history of hypersensitivity to or positive serum human 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). Note: Testing is not
mandatory to be eligible

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 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

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 with warfarin or equivalent vitamin K antagonists

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 judgment, make the patient inappropriate for study participation or put
the patient at risk