A Study of Loncastuximab Tesirine and Rituximab (Lonca-R) in Previously Untreated Unfit/Frail Participants With Diffuse Large B-cell Lymphoma (DLBCL) (LOTIS-9)

• ClinicalTrials.gov Identifier: NCT05144009
• Recruitment Status: Completed
• First Posted: December 3, 2021
• Last Update Posted: January 31, 2024
• Sponsor: ADC Therapeutics S.A.
• Information provided by (Responsible Party): ADC Therapeutics S.A.

Tracking Information

• First Submitted Date: November 22, 2021
• First Posted Date: December 3, 2021
• Last Update Posted Date: January 31, 2024
• Actual Study Start Date: June 21, 2022
• Actual Primary Completion Date: January 22, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 22, 2022)

• CR Rate [ Time Frame: Up to 5.5 years ]
• Cohort B: Percentage of Participants Completing 4 Cycles of Treatment [ Time Frame: Up to 12 weeks ]

Original Primary Outcome Measures (submitted: November 22, 2021)

• CR Rate [ Time Frame: Up to 5.5 years ]
• Cohorts A and B, Part 2: 2-year Progression Free Survival (PFS) [ Time Frame: Up to 2 years ]
• Cohort B, Part 1: Percentage of Participants Completing 4 Cycles of Treatment [ Time Frame: Up to 12 weeks ]

Current Secondary Outcome Measures (submitted: February 22, 2022)

• Overall Response Rate (ORR) [ Time Frame: Up to 22 weeks ]
• 2-year Progression-free Survival (PFS) [ Time Frame: Up to 2 years ]
• 3-year Overall Survival (OS) [ Time Frame: Up to 3 years ]
• Duration of Response (DoR) [ Time Frame: Up to 5.5 years ]
• Number of Participants who Experience a Treatment-emergent Adverse Event [ Time Frame: Up to 5.5 years ]
  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.
• Number of Participants with a Clinically Significant Change from Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status Score [ Time Frame: Baseline up to 22 weeks ]
  ECOG performance status will be assessed on a 6-point scale ranging from 0 (fully active) to 5 (dead).
• Serum Concentration of Loncastuximab Tesirine Pyrrolobenzodiazepine (PBD)-conjugated Antibody [ Time Frame: Up to 2 years ]
• Serum Concentration of SG3199 Unconjugated Warhead [ Time Frame: Up to 2 years ]
• Serum Concentration of Total Antibody [ Time Frame: Up to 2 years ]
• Number of Participants with Confirmed Positive Anti-Drug Antibody (ADA) Responses [ Time Frame: Up to 2 years ]
• Number of Participants with a Change from Baseline in Patient-reported Outcomes [ Time Frame: Baseline up to 22 weeks ]
  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.

Original Secondary Outcome Measures (submitted: November 22, 2021)

• Overall Response Rate (ORR) [ Time Frame: Up to 22 weeks ]
• 3-year Overall Survival (OS) [ Time Frame: Up to 3 years ]
• Duration of Response (DoR) [ Time Frame: Up to 5.5 years ]
• Number of Participants who Experience a Treatment-emergent Adverse Event [ Time Frame: Up to 5.5 years ]
  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.
• Number of Participants with a Clinically Significant Change from Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status Score [ Time Frame: Baseline up to 22 weeks ]
  ECOG performance status will be assessed on a 6-point scale ranging from 0 (fully active) to 5 (dead).
• Number of Participants with a Change from Baseline in Patient-reported Outcomes [ Time Frame: Baseline up to 22 weeks ]
  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.
• Cohort A, Part 1: 2-years PFS [ Time Frame: Up to 2 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Diffuse Large B-cell Lymphoma

Intervention

• Drug: Loncastuximab Tesirine
  Intravenous (IV) Infusion
  Other Names:

  • Zynlonta
  • ADCT-402
• Drug: Rituximab
  Cycle 1 - Intravenous (IV) Infusion. Cycle 2+ - Intravenous (IV) Infusion or Subcutaneous (SC) Administration.

Study Arms

• Experimental: Cohort A : Loncastuximab Tesirine + Rituximab (Lonca-R)

  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

  Interventions:

  • Drug: Loncastuximab Tesirine
  • Drug: Rituximab
• Experimental: Cohort B : Loncastuximab Tesirine + Rituximab (Lonca-R)

  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

  Interventions:

  • Drug: Loncastuximab Tesirine
  • Drug: Rituximab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 2, 2023): 41
• Original Estimated Enrollment (submitted: November 22, 2021): 340
• Actual Study Completion Date: January 22, 2024
• Actual Primary Completion Date: January 22, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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:

  1. Absolute neutrophil count (ANC) ≥1.0 x 10^3/µL (off growth factors at least 72 hours).
  2. Platelet count ≥75 x 10^3/µL without transfusion in the past 7 days.
  3. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transferase (GGT) ≤2.5 x the upper limit of normal (ULN).
  4. Total bilirubin ≤1.5 x ULN (participants with known Gilbert's syndrome may have a total bilirubin up to ≤3 x ULN).
  5. 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:

  1. Aged ≥80 years
  2. ADL score of 6
  3. IADL score of 8
  4. CIRS-G: no score of 3-4 and <5 scores of 2

Inclusion Criteria specific for Cohort B:

• Frail as defined by sGA:

  1. Aged ≥80 years
  2. ADL score of <6 and/or
  3. IADL score of <8 and/or
  4. 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.

  1. Left ventricular ejection fraction (LVEF) ≥30 to <50%
  2. History of myocardial infarction within 6 months prior to screening
  3. Ischemic heart disease
  4. 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:

  1. CD4+ T-cell (CD4+) counts <350 cells/µL
  2. Acquired immunodeficiency syndrome (AIDS) - defining opportunistic infection within 12 months prior to screening
  3. Not on anti-retroviral therapy, or on anti-retroviral therapy for <4 weeks at the time of screening
  4. 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 80 Years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Italy, Puerto Rico, Spain, United States

Administrative Information

• NCT Number: NCT05144009
• Other Study ID Numbers: ADCT-402-203; 2021-005312-57 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: ADC Therapeutics S.A.
• Original Responsible Party: Same as current
• Current Study Sponsor: ADC Therapeutics S.A.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: ADC Therapeutics S.A.
• Verification Date: January 2024