Study to Evaluate the Efficacy and Safety of Loncastuximab Tesirine in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Study Overview
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Brief Summary
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The purpose of this Phase 2 study is to evaluate the clinical efficacy and safety of Loncastuximab Tesirine (ADCT-402) in patients with relapsed or refractory Diffuse Large B-Cell Lymphoma.

Detailed Description
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This is a Phase 2, multi-center, open-label, single-arm study of the efficacy and safety of loncastuximab tesirine used as monotherapy in patients with relapsed or refractory DLBCL. The study will enroll approximately 140 patients Loncastuximab Tesirine is an antibody drug conjugate (ADC) composed of a humanized antibody directed against human cluster of differentiation 19 (CD19), stochastically conjugated through a cathepsin-cleavable linker to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxin. Loncastuximab tesirine has been designed to target and kill CD19-expressing malignant B-cells. A 2-stage design will be used in this clinical study, with an interim analysis for futility on the first 52 patients. If ≥10 patients respond (CR+PR), the study will proceed to complete full enrollment. Enrollment will continue during the interim analysis; however, further enrollment will be halted if futility is confirmed. For each patient, the study will include a Screening Period (of up to 28 days), a Treatment Period (cycles of 3 weeks), and a Follow-up Period (approximately every 12 week visits for up to 3 years after treatment discontinuation). Patients may continue treatment until disease progression, unacceptable toxicity, or other discontinuation criteria, whichever occurs first.

Official Title
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A Phase 2 Open-Label Single-Arm Study to Evaluate the Efficacy and Safety of Loncastuximab Tesirine in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL) (LOTIS-2)

Conditions
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Diffuse Large B-Cell Lymphoma Refractory, Diffuse Large B-cell Lymphoma Recurrent

Intervention / Treatment
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* Drug: Loncastuximab tesirine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patient aged 18 years or older. Pathologic diagnosis of DLBCL, as defined by the 2016 WHO classification, to include: DLBCL not otherwise specified; primary mediastinal large B-cell lymphoma; and high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements Relapsed or refractory disease following two or more multi-agent systemic treatment regimens Patients who have received previous CD19-directed therapy must have a biopsy that shows CD19 protein expression after completion of the CD19-directed therapy. Measurable disease as defined by the 2014 Lugano Classification Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block or minimum 10 freshly cut unstained slides if block is not available ECOG performance status 0-2 Adequate organ function Negative beta-human chorionic gonadotropin (β-HCG) pregnancy test within 7 days prior to start of study drug (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 loncastuximab tesirine. 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 loncastuximab tesirine. Exclusion Criteria: Previous treatment with loncastuximab tesirine Known history of hypersensitivity to or positive serum human ADA to a CD19 antibody Pathologic diagnosis of Burkitt lymphoma 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 Autologous stem cell transplant (ASCT) within 30 days prior to start of study drug (C1D1) Allogeneic stem cell transplant (AlloSCT) within 60 days prior to start of study drug (C1D1) Active graft-versus-host disease Post-transplant lymphoproliferative disorders Active autoimmune disease, including motor neuropathy considered of autoimmune origin and other central nervous system (CNS) autoimmune disease 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 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 Major surgery, radiotherapy, chemotherapy or other anti-neoplastic therapy within 14 days prior to start of study drug (C1D1), except shorter if approved by the Sponsor 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 version 4.0 [CTCAE v4.0]) 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 >480 ms at screening (unless secondary to pacemaker or bundle branch block) 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

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Loncastuximab tesirine<br>Participants will receive loncastuximab tesirine as an IV infusion over 30 minutes on Day 1 of each cycle (every 3 weeks) at a dose of 150 μg/kg Q3W for 2 cycles, then 75 μg/kg Q3W for subsequent cycles for up to one year or until disease progression, unacceptable toxicity, or other discontinuation criteria, whichever occurs first. | Drug: Loncastuximab tesirine<br>* intravenous infusion<br>* Other names: ADCT-402;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR, as determined by central review according to the 2014 Lugano classification, defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR). | Up to 21.5 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) | DOR defined as the time from the first documentation of tumor response to disease progression or death. | Up to 39 months | 
| Complete Response (CR) Rate | CR rate defined as the percentage of treated participants with a best overall response (BOR) of CR. | Up to 39 months | 
| Relapse-free Survival (RFS) | RFS was defined as the time from the documentation of CR to disease progression or death. | Up to 39 months | 
| Progression-free Survival (PFS) | PFS was defined as the time between start of treatment and the first documentation of recurrence, progression, or death. | Up to 40 months | 
| Overall Survival (OS) | OS was defined as the time between the start of treatment and death from any cause. | Up to 43 months | 
| Number of Participants Who Experience Treatment-emergent Adverse Events (TEAEs) | An adverse event (AE) was defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product that did not necessarily have to have a causal relationship with treatment. A TEAE was an adverse event with an onset that began or worsened on or after the first dose date and until 30 days after the last dose date, or start of a new anticancer therapy/procedure, whichever came earlier. TEAE assessments also included those per the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Grade ≥3 AEs and serious TEAEs. AEs were graded using CTCAE version 4 and according to the following: Grade 1 = mild AE, Grade 2 = Moderate AE, Grade 3 = a severe AE, Grade 4 = life-threatening AE, and Grade 5 = death due to AE. For events not listed in the CTCAE criteria, the same grading was used. | Up to 599 days | 
| Number of Participants With Clinically Significant Changes From Baseline in Clinical Laboratory Tests | Clinical laboratory tests included hematology and chemistry. Clinically significant changes were determined by the Investigator. | Baseline up to 599 days | 
| Number of Participants With Clinically Significant Change From Baseline in Vital Signs | Vital sign measurements included arterial blood pressure, heart rate, respiratory rate, and body temperature. Clinical significance was determined by the investigator. | Baseline up to 599 days | 
| Eastern Cooperative Oncology Group (ECOG) Performance Status at Baseline and End of Treatment | ECOG (Eastern Cooperative Oncology Group) Performance Status is scored on a 6-point scale where higher scores indicate a worse outcome. ECOG scores include 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 | Baseline and end of treatment (up to 599 days) | 
| Number of Participants With Clinically Significant Change From Baseline in 12-lead Electrocardiograms (ECGs) | Clinically significant changes from baseline for 12-lead ECGs were measured as abnormal QT interval corrected by Fridericia formula (QTcF) and QT interval corrected by Bazett formula (QTcB) values. | Baseline up to 599 days | 
| Maximum Concentration (Cmax) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199 |  | Cycles 1 and 2: Day 1 pre-dose, and at 0, 4, 168 and 336 hours post-dose; Cycle 3: Day 1 pre-dose and end of infusion | 
| 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 |  | Cycles 1 and 2: Day 1 pre-dose, and at 0, 4, 168 and 336 hours post-dose; Cycle 3: Day 1 pre-dose | 
| Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-∞) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199 |  | Cycles 1 and 2: Day 1 pre-dose, and at 0, 4, 168 and 336 hours post-dose; Cycle 3: Day 1 pre-dose | 
| Apparent Terminal Half-life (Thalf) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199 |  | Cycles 1 and 2: Day 1 pre-dose, and at 0, 4, 168 and 336 hours post-dose; Cycle 3: Day 1 pre-dose | 
| Apparent Clearance (CL) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199 |  | Cycles 1 and 2: Day 1 pre-dose, and at 0, 4, 168 and 336 hours post-dose; Cycle 3: Day 1 pre-dose | 
| Apparent Volume of Distribution at Steady State (Vss) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199 |  | Cycles 1 and 2: Day 1 pre-dose, and at 0, 4, 168 and 336 hours post-dose; Cycle 3: Day 1 pre-dose | 
| Accumulation Index (AI) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199 | AI is the ratio of AUC0-last for each cycle divided by AUC0-last of the previous cycle. | Cycles 1 and 2: Day 1 pre-dose, and at 0, 4, 168 and 336 hours post-dose; Cycle 3: Day 1 pre-dose | 
| Number of Participants With an Anti-drug Antibody (ADA) Response to Loncastuximab Tesirine |  | Up to 599 days | 
| Change From Baseline Score in the EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) | EQ-5D-5L is designed as an international, standardized, instrument for describing and evaluating quality of life (QoL). In the EQ-5D-5L VAS participants are asked to indicate their health state today on a VAS with the endpoints labeled 'the best health you can imagine' (score 100) and 'the worst health you can imagine' (score 0). A higher score on the VAS indicates better health related QoL. A positive change from baseline indicates an improvement in health related QoL. | Baseline, Day 1 of Cycles 2 to 26 (cycle duration of 3 weeks), and end of treatment (up to 599 days) | 
| Change From Baseline Score in the Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) - Lymphoma Subscale (LymS) | Composed of the Functional Assessment of Cancer Therapy - General (FACT-G) plus the 15-item LymS. The FACT-G questionnaire contains 27 items covering 4 core health related quality of life (QoL) subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing (6), and Functional Wellbeing (7). The LymS addresses issues including pain, itching, night sweats, trouble sleeping, fatigue and trouble concentrating. Score range for the LymS was 0 - 60, where a higher score indicates less symptoms. The LymS score is reported. A positive change from baseline indicates an improvement in health related QoL. | Baseline, Day 1 of Cycles 2 to 25 (cycle duration of 3 weeks), and end of treatment (up to 599 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Loncastuximab tesirine