A Study to Evaluate the Pharmacokinetics and Safety of Loncastuximab Tesirine in Participants With Relapsed or Refractory Diffuse Large B-cell Lymphoma or High-grade B-cell Lymphoma With Hepatic Impairment (LOTIS-10)

Study Overview
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Brief Summary
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The primary objective of this study is to determine the recommended dosing regimen of loncastuximab tesirine in diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBCL) participants with moderate and severe hepatic impairment.

Official Title
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A Phase 1b Open-Label Study to Evaluate the Pharmacokinetics and Safety of Loncastuximab Tesirine in Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma or High-grade B-cell Lymphoma With Hepatic Impairment (LOTIS-10)

Conditions
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Diffuse Large B-Cell Lymphoma, High-grade B-cell Lymphoma

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 participants aged 18 years or older Pathologic diagnosis of relapsed (disease that has recurred following a response) or refractory (disease that failed to respond to prior therapy) DLBCL not otherwise specified, DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma (2016 World Health Organization classification) who have received at least one systemic treatment regimen Measurable disease as defined by the 2014 Lugano Classification Normal hepatic function or hepatic impairment as defined by the National Cancer Institute Organ Dysfunction Working Group hepatic impairment classification: Arm A Normal hepatic function: bilirubin and aspartate aminotransferase (AST) ≤ upper limit of normal (ULN) Arm B Moderate hepatic impairment: bilirubin > 1.5 × to 3 × ULN (any AST) Arm C Severe hepatic impairment: bilirubin > 3 × ULN (any AST) ECOG performance status 0 to 2 for participants with normal hepatic function. ECOG 0 to 3 for participants with moderate or severe hepatic impairment Adequate organ function Women of childbearing potential (WOCBP)* must agree to use a highly effective method of contraception from the time of giving informed consent until at least 10 months after the last dose of study drug. Men with female partners who are of childbearing potential must agree to use a condom when sexually active or practice total abstinence from the time of the first dose until at least 7 months after the last dose of study drug. Exclusion Criteria: Previous therapy with loncastuximab tesirine Allogenic or autologous stem cell transplant within 60 days prior to start of study drug (C1D1) Human immunodeficiency virus (HIV) seropositive Serologic evidence of chronic hepatitis B virus (HBV) infection and unable or unwilling to receive standard prophylactic antiviral therapy or with detectable HBV viral load Serologic evidence of hepatitis C virus (HCV) infection without completion of curative treatment or with detectable HCV viral load History of Stevens-Johnson syndrome or toxic epidermal necrolysis Lymphoma with active central nervous system involvement at the time of screening, including leptomeningeal disease 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

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: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Normal Hepatic Function<br>Participants will receive loncastuximab tesirine 0.15 mg/kg once every 3 weeks (Q3W) for two cycles, then 0.075 mg/kg Q3W for subsequent cycles (1 cycle = 21 days). Participants who have a toxicity meeting the criteria for dose reduction will have subsequent doses reduced by 50%. If the toxicity recurs, subsequent doses must be reduced by an additional 50%. A maximum of 2 dose reductions are allowed. Participants who have a toxicity meeting the criteria for dose reduction following Cycle 2 will receive the protocol-specified dose of 50% of initiate dose for Cycle 3, i.e., they will not have an additional dose reduction for Cycle 3. | Drug: Loncastuximab Tesirine<br>* Intravenous (IV) Infusion<br>* Other names: ADCT-402;|
| Experimental: Arm B: Moderate Hepatic Impairment<br>Participants will receive loncastuximab tesirine in a standard 3+3 dose-escalation design. Initial dose will be 0.09 mg/kg Q3W for two cycles, then 0.045 mg/kg Q3W for subsequent cycles (1 cycle = 21 days). The highest dose possibly administered will be 0.15 mg/kg Q3W. Participants who have a toxicity meeting the criteria for dose reduction will have subsequent doses reduced by 50%. If the toxicity recurs, subsequent doses must be reduced by an additional 50%. A maximum of 2 dose reductions are allowed. Participants who have a toxicity meeting the criteria for dose reduction following Cycle 2 will receive the protocol-specified dose of 50% of initiate dose for Cycle 3, i.e., they will not have an additional dose reduction for Cycle 3. | Drug: Loncastuximab Tesirine<br>* Intravenous (IV) Infusion<br>* Other names: ADCT-402;|
| Experimental: Arm C: Severe Hepatic Impairment<br>Participants will receive loncastuximab tesirine in a standard 3+3 dose-escalation design. Initial dose will be 0.09 mg/kg Q3W for two cycles, then 0.045 mg/kg Q3W for subsequent cycles (1 cycle = 21 days). The highest dose possibly administered will be 0.15 mg/kg Q3W. Participants who have a toxicity meeting the criteria for dose reduction will have subsequent doses reduced by 50%. If the toxicity recurs, subsequent doses must be reduced by an additional 50%. A maximum of 2 dose reductions are allowed. Participants who have a toxicity meeting the criteria for dose reduction following Cycle 2 will receive the protocol-specified dose of 50% of initiate dose for Cycle 3, i.e., they will not have an additional dose reduction for Cycle 3. | Drug: Loncastuximab Tesirine<br>* Intravenous (IV) Infusion<br>* Other names: ADCT-402;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Moderate or Severe Hepatic Impairment Who Experience a Dose-Limiting Toxicity (DLT) |  | Day 1 to Day 21 of Cycle 1, where a cycle is 21 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Concentration (Cmax) of Loncastuximab Tesirine and SG3199 in Serum |  | Day 1 up to 1 year | 
| Time to Cmax (Tmax) of Loncastuximab Tesirine and SG3199 in Serum |  | Day 1 up to 1 year | 
| Area Under the Concentration-time Curve from Time Zero to the Last Quantifiable Concentration (AUClast) of Loncastuximab Tesirine and SG3199 in Serum |  | Day 1 up to 1 year | 
| Area Under the Concentration-time Curve from Time Zero to the End of the Dosing Interval (AUCtau) of Loncastuximab Tesirine and SG3199 in Serum |  | Day 1 up to 1 year | 
| Area Under the Concentration-time Curve from Time Zero to Infinity (AUCinf) of Loncastuximab Tesirine and SG3199 in Serum |  | Day 1 up to 1 year | 
| Apparent Terminal Elimination Half-life (Thalf) of Loncastuximab Tesirine and SG3199 in Serum |  | Day 1 up to 1 year | 
| Apparent Clearance (CL) of Loncastuximab Tesirine and SG3199 in Serum |  | Day 1 up to 1 year | 
| Apparent Steady-state Volume of Distribution (Vss) of Loncastuximab Tesirine and SG3199 in Serum |  | Day 1 up to 1 year | 
| Accumulation Index (AI) of Loncastuximab Tesirine and SG3199 in Serum |  | Day 1 up to 1 year | 
| Number of Participants Who Experience an Adverse Event (AE) |  | Up to approximately 3 years | 
| Number of Participants Who Experience a Treatment-emergent Adverse Event (TEAE) |  | Up to approximately 1 year | 
| Number of Participants Who Experience an Adverse Event (AE) Leading to Dose Delay |  | Up to approximately 1 year | 
| Number of Participants Who Experience an Adverse Event (AE) Leading to Dose Interruption |  | Up to approximately 1 year | 
| Number of Participants Who Experience an Adverse Event (AE) Leading to Dose Reduction |  | Up to approximately 1 year | 
| Number of Participants Who Experience a Clinically Significant Change from Baseline in Safety Laboratory Values |  | Baseline up to approximately 1 year | 
| Number of Participants Who Experience a Clinically Significant Change from Baseline in Vital Signs |  | Baseline up to approximately 1 year | 
| Number of Participants Who Experience a Clinically Significant Change from Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status |  | Baseline up to approximately 1 year | 
| Number of Participants Who Experience a Clinically Significant Change from Baseline in 12-Lead Electrocardiogram (ECG) Measurements |  | Baseline up to approximately 1 year | 
| Overall Response Rate (ORR) |  | Up to approximately 3 years | 
| Duration of Response (DOR) |  | Up to approximately 3 years | 
| Complete Response (CR) Rate |  | Up to approximately 3 years | 
| Progression-Free Survival (PFS) |  | Up to approximately 3 years | 
| Relapse-Free Survival (RFS) |  | Up to approximately 3 years | 
| Overall Survival (OS) |  | Up to approximately 3 years | 
| Number of Participants With Anti-drug Antibody (ADA) Titers to Loncastuximab Tesirine |  | Day 1 up to 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Loncastuximab Tesirine, Lymphoma, DLBCL, HGBCL, Hepatic Impairment