Safety and Antitumor Activity Study of Loncastuximab Tesirine and Durvalumab in Diffuse Large B-Cell, Mantle Cell, or Follicular Lymphoma

Therapuetic Areas:Oncology
Age Range:18 - Any
Start Date:December 6, 2018
End Date:July 6, 2022
Contact:ADC Therapeutics

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A Phase 1 Open-Label Study to Evaluate the Safety and Antitumor Activity of Loncastuximab Tesirine and Durvalumab in Patients With Advanced Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma, or Follicular Lymphoma

The purpose of this Phase 1 study is to evaluate the safety and antitumor activity of
Loncastuximab Tesirine (ADCT-402) and Durvalumab in Patients with Advanced Diffuse Large
B-Cell Lymphoma, Mantle Cell Lymphoma, or Follicular 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 75

A standard 3+3 dose escalation design will be used for Part 1. The DLT period will be the 21
days after the first durvalumab dose.

Part 2 will consist of up to 3 expansion cohorts, one for DLBCL, one for MCL, and one for FL.
Each cohort will be approximately 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, 6' and 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, MCL, or FL

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

4. Patients who have received previous CD19-directed therapy must have a biopsy that
shows CD19 expression after completion of the CD19-directed therapy

5. Measurable disease as defined by the 2014 Lugano Classification

6. Patients must be willing to undergo tumor biopsy

7. ECOG performance status 0-1

8. Screening laboratory values within the following parameters:

1. Absolute neutrophil count (ANC) ≥1.0 × 103/µL (off growth factors at least 72

2. Platelet count ≥75 × 103/µL without transfusion in the past 7 days

3. Hemoglobin ≥9.0 g/dL (5.59 mmol/L), transfusion allowed

4. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and 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-Gault equation

9. Negative beta-human chorionic gonadotropin (β-HCG) pregnancy test within 3 days prior
to start of study drug on C1D1 for women of childbearing potential

10. 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. Previous therapy with any checkpoint inhibitor

3. Autologous stem cell transplant within 100 days prior to start of study drug (C1D1)

4. History of allogenic stem cell transplant

5. History of solid organ transplant

6. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,
or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this

1. Patients with vitiligo or alopecia

2. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
hormone replacement

3. Any chronic skin condition that does not require systemic therapy

4. Patients without active disease in the last 5 years may be included but only
after consultation with the Study Physician

5. Patients with celiac disease controlled by diet alone

7. Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and tuberculosis testing in
line with local practice)

8. Known seropositive and requiring anti-viral therapy for human immunodeficiency (HIV)
virus, hepatitis B virus (HBV), or hepatitis C virus (HCV)

9. History of Stevens-Johnson syndrome or toxic epidermal necrolysis

10. Lymphoma with active central nervous system (CNS) involvement at the time of
screening, including leptomeningeal disease

11. 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)

12. Breastfeeding or pregnant

13. 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, or severe chronic pulmonary disease

14. Radiotherapy, chemotherapy, or other anti-neoplastic therapy within 14 days prior to
start of study drug (C1D1), except shorter if approved by the Sponsor.

15. Major surgery within 28 days prior to start of study drug (C1D1), except shorter if
approved by the Sponsor. Note: Local surgery of isolated lesions for palliative intent
is acceptable.

16. Use of any other experimental medication within 14 days prior to start of study drug

17. Planned live vaccine administration after starting study drug (C1D1)

18. Failure to recover to Grade ≤1 (Common Terminology Criteria for Adverse Events [CTCAE]
version 4.0) from acute nonhematologic toxicity (Grade ≤2 neuropathy or alopecia) due
to previous therapy prior to screening. Patients with an endocrine AE of Grade ≤2 from
prior anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapy are permitted to enroll if they
are stably maintained on appropriate replacement therapy and are asymptomatic.

19. Congenital long QT syndrome or a corrected QTcF interval of >470 ms at screening
(unless secondary to pacemaker or bundle branch block)

20. History of another primary malignancy except for:

1. Malignancy treated with curative intent and with no known active disease ≥5 years
before the first dose of investigational product and of low potential risk for

2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease

3. Adequately treated carcinoma in situ without evidence of disease 21. History of
active primary immunodeficiency

21. Any other significant medical illness, abnormality, or condition that would, in the
Investigator's judgement, make the patient inappropriate for study participation or
put the patient at risk.
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