A Study of Loncastuximab Tesirine and Rituximab (Lonca-R) in Previously Untreated Unfit/Frail Participants With Diffuse Large B-cell Lymphoma (DLBCL)

Study Overview
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Brief Summary
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The main objective of the trial is to assess the efficacy and tolerability of Lonca-R in unfit and frail participants with previously untreated DLBCL.

Detailed Description
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The primary objectives of this trial are shown below: Cohort A: To assess the efficacy of a response-adapted treatment of Lonca-R in unfit participants with previously untreated DLBCL, high-grade B cell lymphoma (HGBCL), or Grade 3b follicular lymphoma (FL). Cohort B: To assess the tolerability and efficacy of a response-adapted treatment of Lonca-R in frail participants with previously untreated DLBCL, or HGBCL, or Grade 3b FL who are ineligible for standard R-mini-CHOP. The simplified geriatric assessment (sGA) developed by the Fondazione Italiana Linfomi (FIL) identifies three distinct categories (fit, unfit, and frail) based on age, activities of daily living (ADL), instrumental activities of daily living (IADL) and the Cumulative Illness Rating Scale for Geriatrics (CIRS-G). Participants will be assigned to Cohort A (unfit) or B (frail) using the sGA.

Official Title
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A Phase 2 Open-label Study of Loncastuximab Tesirine in Combination With Rituximab (Lonca-R) in Previously Untreated Unfit/Frail Patients With Diffuse Large B-cell Lymphoma (DLBCL) (LOTIS-9)

Conditions
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Diffuse Large B-cell Lymphoma

Intervention / Treatment
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* Drug: Loncastuximab Tesirine
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologic diagnosis of DLBCL, as defined by the 2016 World Health Organization (WHO) classification (including participants with DLBCL transformed from indolent lymphoma), or HGBCL, or Grade 3b FL. Measurable disease as defined by the 2014 Lugano Classification. Stages I-IV. ECOG PS 0-2; ECOG PS 3 allowed if decline in status is deemed related to lymphoma & felt to be potentially reversible by the treating physician. Adequate organ function as defined by screening laboratory values within the following parameters: Absolute neutrophil count (ANC) ≥1.0 x 10^3/µL (off growth factors at least 72 hours). Platelet count ≥75 x 10^3/µL without transfusion in the past 7 days. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transferase (GGT) ≤2.5 x the upper limit of normal (ULN). Total bilirubin ≤1.5 x ULN (participants with known Gilbert's syndrome may have a total bilirubin up to ≤3 x ULN). Calculated creatinine clearance >30 mL/min by the Cockcroft and Gault equation. Note: A laboratory assessment may be repeated a maximum of two times during the screening period to confirm eligibility. 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 12 months after the last dose of study treatment. 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 participant receives his last dose of study treatment. Inclusion Criteria specific for Cohort A: Unfit as defined by the simplified geriatric assessment (sGA). Includes all of the following: Aged ≥80 years ADL score of 6 IADL score of 8 CIRS-G: no score of 3-4 and <5 scores of 2 Inclusion Criteria specific for Cohort B: Frail as defined by sGA: Aged ≥80 years ADL score of <6 and/or IADL score of <8 and/or CIRS-G: ≥1 score of 3-4 and/or >5 scores of 2 OR Aged ≥65 - <80 with at least one of the following cardiac comorbidities that make anthracycline-containing regimens inadvisable as determined by the investigator. Left ventricular ejection fraction (LVEF) ≥30 to <50% History of myocardial infarction within 6 months prior to screening Ischemic heart disease History of stroke within 12 months prior to screening Exclusion Criteria: Known history of hypersensitivity to or positive serum human anti-drug antibody to a cluster of differentiation 19 (CD19) antibody. Previous therapy for DLBCL, HGBCL, or Grade 3b FL (with exception of corticosteroid course for symptom management of less than 14 days). Previous therapy with loncastuximab tesirine and rituximab for any indication. Known history of hypersensitivity to any component of study treatment (loncastuximab tesirine and rituximab) Human immunodeficiency virus (HIV) seropositive with any of the following: CD4+ T-cell (CD4+) counts <350 cells/µL Acquired immunodeficiency syndrome (AIDS) - defining opportunistic infection within 12 months prior to screening Not on anti-retroviral therapy, or on anti-retroviral therapy for <4 weeks at the time of screening HIV viral load ≥400 copies/mL 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. 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). Major surgery, radiotherapy, chemotherapy, or other anti-neoplastic therapy within 14 days prior to start of study drug (Cycle 1 Day 1 [C1D1]), except shorter if approved by the Sponsor. Use of any other experimental medication within 14 days prior to start of study drug (C1D1). Received live vaccine within 4 weeks of C1D1. Congenital long QT syndrome or a corrected Fridericia correction of the QT measure (QTcF) interval of >480 ms at screening (unless secondary to pacemaker or bundle branch block). 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. Any other significant medical illness, abnormality, or condition that would, in the Investigator's judgment, make the participant inappropriate for study participation or put the participant at risk.

Ages Eligible for Study
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Minimum Age: 80 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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A : Loncastuximab Tesirine + Rituximab (Lonca-R)<br>Participants who are unfit (per sGA) will receive Lonca-R for 3 cycles. Participants who achieve a complete response (CR) will receive Lonca-R for 1 additional cycle. Participants who achieve a partial response (PR) will receive Lonca-R for 3 additional cycles. Lonca-R will be administered as rituximab 375 mg/m^2 on Day 1 of Cycle 1 and loncastuximab tesirine 150 µg/kg on Day 2 of Cycle 1. During Cycle 2, Lonca-R will be administered as rituximab* 375 mg/m^2 and loncastuximab tesirine 150 µg/kg on Day 1. For cycles 3 and beyond, Lonca-R will be administered as rituximab 375 mg/m^2 and loncastuximab tesirine 75 µg/kg on Day 1. *subcutaneous rituximab 1400mg/dose may be used during Cycle 2 and beyond | Drug: Loncastuximab Tesirine<br>* Intravenous (IV) Infusion<br>* Other names: ADCT-402;Drug: Rituximab<br>* Cycle 1 - Intravenous (IV) Infusion. Cycle 2+ - Intravenous (IV) Infusion or Subcutaneous (SC) Administration.<br>|
| Experimental: Cohort B : Loncastuximab Tesirine + Rituximab (Lonca-R)<br>Participants who are frail (per sGA) or participants with cardiac comorbidities will receive Lonca-R for 3 cycles. Participants who achieve a CR will receive Lonca-R for 1 additional cycle. Participants who achieve a PR will receive Lonca-R for 3 additional cycles for a total of up to 6 cycles. Only participants enrolled in Cohort B, who achieve stable disease (SD) and deriving clinical benefit per the treating physician, may also receive Lonca-R for an additional 3 cycles. Lonca-R will be administered as rituximab 375 mg/m^2 on Day 1 of Cycle 1 and loncastuximab tesirine 150 µg/kg on Day 2 of Cycle 1. During Cycle 2, Lonca-R will be administered as rituximab* 375 mg/m^2 and loncastuximab tesirine 150 µg/kg on Day 1. For cycles 3 and beyond, Lonca-R will be administered as rituximab 375 mg/m^2 and loncastuximab tesirine 75 µg/kg on Day 1. *subcutaneous rituximab 1400mg/dose may be used during Cycle 2 and beyond | Drug: Loncastuximab Tesirine<br>* Intravenous (IV) Infusion<br>* Other names: ADCT-402;Drug: Rituximab<br>* Cycle 1 - Intravenous (IV) Infusion. Cycle 2+ - Intravenous (IV) Infusion or Subcutaneous (SC) Administration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CR Rate |  | Up to 5.5 years | 
| Cohort B: Percentage of Participants Completing 4 Cycles of Treatment |  | Up to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) |  | Up to 22 weeks | 
| 2-year Progression-free Survival (PFS) |  | Up to 2 years | 
| 3-year Overall Survival (OS) |  | Up to 3 years | 
| Duration of Response (DoR) |  | Up to 5.5 years | 
| Number of Participants who Experience a Treatment-emergent Adverse Event | Includes frequency and severity of adverse events (AEs) and serious AEs (SAEs) that occur after study treatment administration. Clinically significant changes from baseline in safety laboratory variables, vital signs and physical examinations will also be recorded as TEAEs/SAEs. | Up to 5.5 years | 
| Number of Participants with a Clinically Significant Change from Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status Score | ECOG performance status will be assessed on a 6-point scale ranging from 0 (fully active) to 5 (dead). | Baseline up to 22 weeks | 
| Serum Concentration of Loncastuximab Tesirine Pyrrolobenzodiazepine (PBD)-conjugated Antibody |  | Up to 2 years | 
| Serum Concentration of SG3199 Unconjugated Warhead |  | Up to 2 years | 
| Serum Concentration of Total Antibody |  | Up to 2 years | 
| Number of Participants with Confirmed Positive Anti-Drug Antibody (ADA) Responses |  | Up to 2 years | 
| Number of Participants with a Change from Baseline in Patient-reported Outcomes | Includes changes in symptoms, functions and overall health status as measured by the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym). The FACT-Lym is scored from 0-168 where a higher score indicates a worse outcome. | Baseline up to 22 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lymphoma, Loncastuximab Tesirine, Rituximab, Non-Hodgkin's lymphoma, Elderly, R-mini-CHOP, Geriatric Assessment, FIL Tool, Unfit, Frail