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

Study Overview
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Brief Summary
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The purpose of this phase 1 study is to evaluate the safety and anti-tumor activity of Loncastuximab Tesirine (ADCT-402) and Durvalumab in participants with Advanced Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma, or Follicular Lymphoma

Detailed Description
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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 participants. 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 participants 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).

Official Title
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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

Conditions
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Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma, Follicular Lymphoma

Intervention / Treatment
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* Drug: Loncastuximab Tesirine and Durvalumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participants aged 18 years or older Pathologic diagnosis of DLBCL, MCL, or FL Participants must have relapsed or refractory disease and have failed or been intolerant to standard therapy Participants who have received previous CD19-directed therapy must have a biopsy that shows CD19 expression after completion of the CD19-directed therapy Measurable disease as defined by the 2014 Lugano Classification Participants must be willing to undergo tumor biopsy ECOG performance status 0-1 Screening laboratory values within the following parameters: Absolute neutrophil count (ANC) ≥1.0 × 103/µL (off growth factors at least 72 hours) Platelet count ≥75 × 103/µL without transfusion in the past 7 days Hemoglobin ≥9.0 g/dL (5.59 mmol/L), transfusion allowed Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and GGT ≤2.5 × the upper limit of normal (ULN) Total bilirubin ≤1.5 × ULN (participants with known Gilbert's syndrome may have a total bilirubin up to ≤3 × ULN) Blood creatinine ≤1.5 × ULN or calculated creatinine clearance ≥60 mL/min by the Cockcroft-Gault equation 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 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: Known history of hypersensitivity to or positive serum human ADA to a CD19 antibody. Previous therapy with any checkpoint inhibitor Autologous stem cell transplant within 100 days prior to start of study drug (C1D1) History of allogenic stem cell transplant History of solid organ transplant 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 criterion: Participants with vitiligo or alopecia Participants with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement Any chronic skin condition that does not require systemic therapy Participants without active disease in the last 5 years may be included but only after consultation with the Study Physician Participants with celiac disease controlled by diet alone Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice) Known seropositive and requiring anti-viral therapy for human immunodeficiency (HIV) virus, hepatitis B virus (HBV), or hepatitis C virus (HCV) History of Stevens-Johnson syndrome or toxic epidermal necrolysis Lymphoma with active central nervous system (CNS) involvement at the time of screening, including leptomeningeal disease 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) Breastfeeding or pregnant 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 Radiotherapy, chemotherapy, or other anti-neoplastic therapy within 14 days prior to start of study drug (C1D1), except shorter if approved by the Sponsor. 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. Use of any other experimental medication within 14 days prior to start of study drug (C1D1) Planned live vaccine administration after starting study drug (C1D1) 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. Congenital long QT syndrome or a corrected QTcF interval of >470 ms at screening (unless secondary to pacemaker or bundle branch block) History of another primary malignancy except for: 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 recurrence Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease Adequately treated carcinoma in situ without evidence of disease 21. History of active primary immunodeficiency History of active primary immunodeficiency or 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 participant at risk.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ADCT-402<br>Dose escalation phase: Ascending doses of Loncastuximab tesirine will be administered using a traditional 3+3 design. Dose level 1: 90 µg/kg, every 3 weeks (Q3W). Dose level 2: 120 µg/kg, Q3W. Dose level 3: 150 µg/kg, Q3W. Loncastuximab tesirine will be given for 2 doses, 3 weeks apart. Dose expansion phase: Loncastuximab tesirine will be administered at the recommended dose determined in the dose escalation phase. Durvalumab will also be administered at a dose of 1500 mg once every 4 weeks (Q4W) throughout the dose escalation phase and dose expansion phase. | Drug: Loncastuximab Tesirine and Durvalumab<br>* intravenous infusion<br>* Other names: Zynlonta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Treatment-emergent Adverse Event (TEAE) | A TEAE was defined as an adverse event (AE) that occurred or worsened in the period extending from the first dose of study drugs to 30 days after the last dose of study drugs or initiation of new anti-cancer therapy (whichever occurred earlier). Evaluation of TEAEs included the number of participants with at least one: TEAE, serious TEAE and grade ≥3 TEAE as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 CTCAE grading scale: Grade 3 = Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4 = Life-threatening consequences; urgent intervention indicated. Grade 5 = Death related to AE. Clinically significant changes from baseline for safety laboratory values, vital sign measurements and electrocardiograms (ECGs) were recorded as TEAEs. | Day 1 to 30 days after the last dose of study drugs (maximum treatment duration at study termination was 336 days) | 
| Number of Participants With a Dose-limiting Toxicity | DLTs were defined as specific events which occurred in the 21-day DLT evaluation period of the dose escalation part, except any events that were clearly due to underlying disease or extraneous causes. The grading and severity of events were based on the guidelines provided in the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. | 21 days after first dose of durvalumab (Day 8 to Day 29) | 
| Number of Participants With a Treatment-emergent Adverse Event Leading to Dose Interruption or Reduction |  | Day 1 to end of treatment (maximum treatment duration at study termination was 336 days) | 
| Number of Participants With Changes From Baseline on the Eastern Cooperative Oncology Group (ECOG) Performance Status | Eastern Cooperative Oncology Group (ECOG) performance status was scored on a 6-point scale where higher scores indicate a worse outcome. ECOG scores included the following: 0 = fully active, able to carry on all pre-disease performance without restriction 1 = restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work 2 = ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking hours 3 = capable of only limited self-care; confined to bed or chair more than 50% of waking hours 4 = completely disabled; cannot carry on any self-care; totally confined to bed or chair 5 = dead | Day 1 to end of treatment (maximum treatment duration at study termination was 336 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR according to the 2014 Lugano classification as determined by the investigator. Overall response rate was the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR). CR was defined as achieving each of the following: Complete metabolic response. Complete radiologic response (target node regress to <1.5 cm, no non-measured lesions, no organ enlargement, no new lesions and normal bone marrow morphology). PR was defined as achieving each of the following: Partial metabolic response (findings indicate residual disease). Partial remission (>50% decrease in target measurable nodes, regression/ absence/ no increase of non-measured lesions, spleen regressed by >50% in length and no new lesions). | Up to 1.5 years | 
| Duration of Response (DOR) | DOR was defined as the time from the documentation of first tumor response (CR or PR) to disease progression or death. CR was defined as achieving each of the following: Complete metabolic response. Complete radiologic response (target node regress to <1.5 cm, no non-measured lesions, no organ enlargement, no new lesions and normal bone marrow morphology). PR was defined as achieving each of the following: Partial metabolic response (findings indicate residual disease). Partial remission (>50% decrease in target measurable nodes, regression/ absence/ no increase of non-measured lesions, spleen regressed by >50% in length and no new lesions). | Up to 1.5 years | 
| Complete Response Rate (CRR) | CRR was defined as the percentage of participants with a BOR of CR, according to the 2014 Lugano classification, as determined by the investigator. CR was defined as achieving each of the following: Complete metabolic response. Complete radiologic response (target node regress to <1.5 cm, no non-measured lesions, no organ enlargement, no new lesions and normal bone marrow morphology). | Up to 1.5 years | 
| Relapse-free Survival (RFS) | RFS was defined as the time from the documentation of CR to disease progression or death. CR was defined as achieving each of the following: Complete metabolic response. Complete radiologic response (target node regress to <1.5 cm, no non-measured lesions, no organ enlargement, no new lesions and normal bone marrow morphology). Disease progression was defined as progressive metabolic disease and one of the following: Target node progression. An individual extranodal lesion must be abnormal with length > 1.5cm and/or increase of length > 50%. New or clear progression of non-measured lesions. Regrowth of previously resolved lesions or new nodes >1.5 cm in length. New or recurrent bone marrow involvement. | Up to 1.5 years | 
| Progression-free Survival (PFS) | PFS was defined as the time between start of treatment and the first documentation of progression, or death. Disease progression was defined as progressive metabolic disease and one of the following: Target node progression. An individual extranodal lesion must be abnormal with length > 1.5cm and/or increase of length > 50%. New or clear progression of non-measured lesions. Regrowth of previously resolved lesions or new nodes >1.5 cm in length. New or recurrent bone marrow involvement. | Up to 1.5 years | 
| Overall Survival (OS) | OS was defined as the time between the start of treatment and death from any cause. | Up to 1.5 years | 
| Maximum Concentration (Cmax) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199 | Cmax of loncastuximab tesirine conjugated antibody and total antibody was calculated for Cycles 1 and 2. Cmax of warhead SG3199 was only calculated for Cycle 1 as data was not collected for Cycle 2. | Cycles 1 and 2 (where Cycle 1 was 4 weeks long and Cycle 2 was 6 weeks long): Day 1 pre-dose and at 0.5 and 4 hours post-dose, Day 8 and Day 15 | 
| Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199 | AUC0-last of loncastuximab tesirine conjugated antibody and total antibody was calculated for Cycles 1 and 2. AUC0-last of warhead SG3199 was only calculated for Cycle 1 as data was not collected for Cycle 2. | Cycles 1 and 2 (where Cycle 1 was 4 weeks long and Cycle 2 was 6 weeks long): Day 1 pre-dose and at 0.5 and 4 hours post-dose, Day 8 and Day 15 | 
| Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199 | AUCinf of loncastuximab tesirine conjugated antibody and total antibody was calculated for Cycles 1 and 2. AUCinf of warhead SG3199 was only calculated for Cycle 1 as data was not collected for Cycle 2. | Cycles 1 and 2 (where Cycle 1 was 4 weeks long and Cycle 2 was 6 weeks long): Day 1 pre-dose and at 0.5 and 4 hours post-dose, Day 8 and Day 15 | 
| Apparent Terminal Half-life (Thalf) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199 | Thalf of loncastuximab tesirine conjugated antibody and total antibody was calculated for Cycles 1 and 2. Thalf of warhead SG3199 was only calculated for Cycle 1 as data was not collected for Cycle 2. | Cycles 1 and 2 (where Cycle 1 was 4 weeks long and Cycle 2 was 6 weeks long): Day 1 pre-dose and at 0.5 and 4 hours post-dose, Day 8 and Day 15 | 
| Apparent Clearance (CL) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199 | CL for Cycle 2 reflects steady-state clearance. CL of loncastuximab tesirine conjugated antibody and total antibody was calculated for Cycles 1 and 2. | Cycles 1 and 2 (where Cycle 1 was 4 weeks long and Cycle 2 was 6 weeks long): Day 1 pre-dose and at 0.5 and 4 hours post-dose, Day 8 and Day 15 | 
| Apparent Volume of Distribution at Steady State (Vss) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199 | Vss of loncastuximab tesirine conjugated antibody and total antibody was calculated for Cycles 1 and 2. | Cycles 1 and 2 (where Cycle 1 was 4 weeks long and Cycle 2 was 6 weeks long): Day 1 pre-dose and at 0.5 and 4 hours post-dose, Day 8 and Day 15 | 
| Accumulation Index (AI) of Loncastuximab Tesirine Conjugated Antibody and Total Antibody | AI is the ratio of drug accumulation after repeated administration compared to a single dose. AI of loncastuximab tesirine conjugated antibody and total antibody was calculated from Cycles 1 and 2. | Cycles 1 and 2 (where Cycle 1 was 4 weeks long and Cycle 2 was 6 weeks long): Day 1 pre-dose and at 0.5 and 4 hours post-dose, Day 8 and Day 15 | 
| Number of Participants With an Anti-drug Antibody (ADA) Response to Loncastuximab Tesirine | Detection of ADAs were performed by using a screening assay for identification of antibody positive samples/patients, a confirmation assay, and titer assessment, and were performed using the Meso-Scale Discovery Electrochemiluminescence platform. | Cycle 1 (= 3 weeks): Day 1 pre-dose & Day 15; Cycles 2, 3, 5, 6, & 7 (Cycle 2 = 6 weeks, other cycles = 4 weeks): Day 1 pre-dose; 30 days after last dose of study drugs | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Loncastuximab Tesirine in Combination with Durvalumab