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)

Sponsor

ADC Therapeutics S.A. (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05660395

Collaborator

(none)

Enrollment

Arms

51.5

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Diffuse Large B-Cell Lymphoma High-grade B-cell Lymphoma	Drug: Loncastuximab Tesirine	Phase 1

Study Design

Study Type:

Interventional

Anticipated Enrollment :

56 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

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)

Anticipated Study Start Date :

Dec 19, 2022

Anticipated Primary Completion Date :

Dec 1, 2026

Anticipated Study Completion Date :

Apr 5, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A: Normal Hepatic Function 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 Intravenous (IV) Infusion Other Names: Zynlonta ADCT-402
Experimental: Arm B: Moderate Hepatic Impairment 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 Intravenous (IV) Infusion Other Names: Zynlonta ADCT-402
Experimental: Arm C: Severe Hepatic Impairment 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 Intravenous (IV) Infusion Other Names: Zynlonta ADCT-402

Arm

Intervention/Treatment

Experimental: Arm A: Normal Hepatic Function

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

Intravenous (IV) Infusion

Other Names:

Zynlonta

ADCT-402

Experimental: Arm B: Moderate Hepatic Impairment

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

Intravenous (IV) Infusion

Other Names:

Zynlonta

ADCT-402

Experimental: Arm C: Severe Hepatic Impairment

Drug: Loncastuximab Tesirine

Intravenous (IV) Infusion

Other Names:

Zynlonta

ADCT-402

Outcome Measures

Primary Outcome Measures

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

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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