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

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)

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.

Study Overview

• Status: Terminated
• Conditions: Diffuse Large B-cell Lymphoma
• Intervention / Treatment: Drug: Loncastuximab Tesirine; Drug: Rituximab

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
• Enrollment (Actual): 41
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Alessandria, Italy, 15121
    • Ospedaliera Santi Antonio E Biagio E Cesare Arrigo-SC Ematologia
  • Brescia, Italy, 25123
    • Azienda Socio Sanitaria Territoriale (ASST) degli Spedali Civili di Brescia
  • Milano, Italy, 20122
    • Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico
• Puerto Rico
  • San Juan, Puerto Rico, 00919-1227
    • Hospital Español Auxilio Mutuo
• Spain
  • Barcelona, Spain, 08003
    • Hospital del Mar - Parc de Salut Mar
  • Barcelona, Spain, 08908
    • Institut Català d'Oncologia - Hospital Duran i Reynals (ICO L'Hospitalet)
  • Cáceres, Spain, 10003
    • Hospital San Pedro de Alcantara
  • Madrid, Spain, 28034
    • Hospital Universitario Ramón y Cajal
  • Madrid, Spain, 28040
    • Hospital Universitario Fundacion Jimenez Diaz
  • València, Spain, 46015
    • Hospital Arnau de Vilanova
  • Cantabria
    • Santander, Cantabria, Spain, 39008
      • Hospital Universitario Marqués de Valdecilla
  • Navarre
    • Pamplona, Navarre, Spain, 31008
      • Clinica Universidad de Navarra - Pamplona
• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona Cancer Center
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Winthrop P. Rockefeller Cancer Institute
  • Colorado
    • Aurora, Colorado, United States, 80012
      • Rocky Mountain Cancer Centers - Aurora
  • Illinois
    • Niles, Illinois, United States, 60714
      • USOR - Illinois Cancer Specialists - Niles
  • Kentucky
    • Pikeville, Kentucky, United States, 41501
      • Leonard Lawson Cancer Center
  • Nevada
    • Reno, Nevada, United States, 89511
      • Cancer Care Specialists - Nevada
  • New York
    • Babylon, New York, United States, 11702
      • New York Cancer & Blood Specialists - New Hyde Park
    • Port Jefferson, New York, United States, 11776
      • New York Cancer & Blood Specialists - Babylon Medical Oncology
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Novant Health Cancer Specialists - Charlotte
  • Ohio
    • Cincinnati, Ohio, United States, 45236
      • USOR - Oncology Hematology Care - Kenwood
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center
    • Columbus, Ohio, United States, 43210
      • Ohio Health - Research and Innovation Institute
  • Oregon
    • Eugene, Oregon, United States, 97401
      • Willamette Valley Cancer Institute and Research Center - Eugene
  • Pennsylvania
    • Reading, Pennsylvania, United States, 19611
      • Reading Hospital - Tower Health
  • South Carolina
    • Greenville, South Carolina, United States, 29605
      • Prisma Health Cancer Institute
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57105
      • Avera Cancer Institute
  • Texas
    • Austin, Texas, United States, 78705
      • Texas Oncology - Austin Midtown
    • Dallas, Texas, United States, 75230
      • Texas Oncology - Medical City Dallas
    • Dallas, Texas, United States, 75231
      • USOR - Texas Oncology - Presbyterian Cancer Center Dallas
    • Dallas, Texas, United States, 75246
      • USOR - Texas Oncology - Baylor Charles A. Sammons Cancer Center
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center
    • San Antonio, Texas, United States, 78240
      • USOR - Texas Oncology - San Antonio
    • Tyler, Texas, United States, 75702
      • Texas Oncology Northeast Texas - Tyler
  • Virginia
    • Blacksburg, Virginia, United States, 24060
      • Blue Ridge Cancer Care - Blacksburg
    • Gainesville, Virginia, United States, 20155
      • USOR - Virginia Cancer Specialists - Gainesville Office
    • Richmond, Virginia, United States, 23229
      • Virginia Cancer Institute - West End
    • Virginia Beach, Virginia, United States, 23456
      • USOR - Virginia Oncology Associates
  • Washington
    • Richland, Washington, United States, 99352
      • Kadlec Clinic - Hematology and Oncology
    • Vancouver, Washington, United States, 98684
      • USOR - Northwest Cancer Specialists, P.C. dba Compass Oncology - Vancouver Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 80 years and older (Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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	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.
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	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CR Rate	Defined as percentage of participants with a best overall response (BOR) of CR as determined by the Investigator according to the 2014 Lugano Classification criteria. CR was defined as achieving: Complete metabolic response for positron emission tomography (PET)-computed tomography (CT) OR; Complete radiologic response (target node regress to <1.5 cm, no non-measured lesions, no organ enlargement, no new lesions and normal bone marrow morphology) for CT if disease was not fluorodeoxyglucose (FDG)-avid at baseline.	Up to a maximum of 17.1 months
Cohort B: Percentage of Participants Who Completed 4 Cycles of Treatment	Defined by the number of participants who completed a total of 4 cycles of therapy divided by the total number of participants * 100.	Up to 12 weeks (3 week cycle length)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR)	Defined as the percentage of participants who achieved either CR or PR as BOR as determined by Investigator according to the 2014 Lugano Classification criteria. CR was defined as achieving: Complete metabolic response for PET-CT OR; Complete radiologic response (target node regress to <1.5 cm, no non-measured lesions, no organ enlargement, no new lesions and normal bone marrow morphology) for CT if disease was not FDG-avid at baseline. PR was defined as achieving: Partial metabolic response (findings indicate residual disease) for PET-CT OR; Partial remission (>50% decrease in target measurable nodes, regression/ absence/ no increase of non-measured lesions, spleen regressed by >50% in length and no new lesions) for CT if disease was not FDG-avid at baseline.	Up to a maximum of 17.1 months
2-year Progression-free Survival (PFS)	PFS was defined as the time from first dose of study drug until the first date of either disease progression (PD) or death due to any cause. The 2-year PFS was defined as the percentage of participants that were PFS event-free at 2 years per investigator assessment with 95% confidence interval (CI) estimated using Kaplan-Meier method.	2 years
3-year Overall Survival (OS)	OS was defined as the time from randomization date until death due to any cause. The 3-year OS was defined as the percentage of participants that were OS event-free at 3 years with 95% CI estimated using Kaplan-Meier method.	3 years
Duration of Response (DoR)	Defined for participants with CR or PR only as the interval between the date of initial documentation of a response and the date of the first documented progressive disease (based on radiographic or clinical progression at end of study or death due to any cause, whichever occurred first) per investigator assessment with 95% CI estimated using Kaplan-Meier method. CR was defined as achieving: Complete metabolic response for PET-CT OR; Complete radiologic response (target node regress to <1.5 cm, no non-measured lesions, no organ enlargement, no new lesions and normal bone marrow morphology) for CT if disease was not FDG-avid at baseline. PR was defined as achieving: Partial metabolic response (findings indicate residual disease) for PET-CT OR; Partial remission (>50% decrease in target measurable nodes, regression/ absence/ no increase of non-measured lesions, spleen regressed by >50% in length and no new lesions) for CT if disease was not FDG-avid at baseline.	Up to a maximum of 17.1 months
Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)	An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product. A TEAE was defined as an AE that occurred or worsened in the period extending from the first dose of study drug to 15 weeks after the last dose of study drugs in this study or start of a new anticancer therapy, whichever was earlier. A serious AE (SAE) was defined as an AE that resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or an important medical event. A severe AE was defined as Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Grade 3 (severe) or above. Clinically significant changes in safety laboratory variables, vital signs, physical examinations, and Eastern Cooperative Oncology Group performance score were recorded as AEs.	Up to approximately 8 months
Maximum Observed Concentration (Cmax) of Conjugated Antibody	Pharmacokinetic (PK) was assessed by a central laboratory using validated bioanalytical methods. Analysis considered model development for conjugated antibodies and total antibodies only, as pre-specified in protocol section 9.9.	Cycle 1 Day 2: predose (preferably within 2 h prior to start of infusion) and at the end (within -5 to +10 min) of loncastuximab tesirine infusion; Cycles 2-6 Day 1 predose and at the end of loncastuximab tesirine infusion (3 week cycle length)
Cmax of Total Antibody	PK was assessed by a central laboratory using validated bioanalytical methods. Analysis considered model development for conjugated antibodies and total antibodies only, as pre-specified in protocol section 9.9.	Cycle 1 Day 2: predose (preferably within 2 h prior to start of infusion) and at the end (within -5 to +10 min) of loncastuximab tesirine infusion; Cycles 2-6 Day 1 predose and at the end of loncastuximab tesirine infusion (3 week cycle length)
Trough Concentration (Ctrough) of Conjugated Antibody	PK was assessed by a central laboratory using validated bioanalytical methods. Analysis considered model development for conjugated antibodies and total antibodies only, as pre-specified in protocol section 9.9.	Cycle 1 Day 2: predose (preferably within 2 h prior to start of infusion); Cycles 2-6 Day 1 predose (3 week cycle length)
Ctrough of Total Antibody	PK was assessed by a central laboratory using validated bioanalytical methods. Analysis considered model development for conjugated antibodies and total antibodies only, as pre-specified in protocol section 9.9.	Cycle 1 Day 2: predose (preferably within 2 h prior to start of infusion); Cycles 2-6 Day 1 predose (3 week cycle length)
Number of Participants With Confirmed Positive Anti-Drug Antibody (ADA) Response	Detection of ADAs against loncastuximab tesirine was performed by using a screening assay for identification of antibody positive samples/participants and a confirmation assay. A participant was considered to have an ADA response if ADA sample was positive at any pre-specified, post-treatment timepoint.	Cycle 1 Day 2 pre-dose (preferably within 2 h prior to start of infusion) then Day 1 pre-dose of Cycles 2, 4, and 6 (3 week cycle length)
Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Subscale and Composite Scores	The following score ranges were possible for the FACT-Lym subscale and composite scores, with higher scores indicating better quality of life/outcome: 0 to 28 for physical well-being, social/family well-being, and functional well-being; 0 to 24 for emotional well-being; 0 to 60 for lymphoma subscale score; 0 to 116 for FACT-Lym trial outcome index; 0 to 108 for FACT-G total score; and 0 to 168 for FACT-Lym Total. An increase in subscale/composite scores from Baseline indicated better quality of life/outcome.	Baseline and End of Treatment Visit (a maximum of 19 weeks)

Collaborators and Investigators

• Sponsor: ADC Therapeutics S.A.

Study record dates

Study Major Dates

• Study Start (Actual): June 21, 2022
• Primary Completion (Actual): January 22, 2024
• Study Completion (Actual): January 22, 2024

Study Registration Dates

• First Submitted: November 22, 2021
• First Submitted That Met QC Criteria: November 22, 2021
• First Posted (Actual): December 3, 2021

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 7, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Elderly; Lymphoma; Rituximab; Non-Hodgkin's lymphoma; Loncastuximab Tesirine; R-mini-CHOP; Geriatric Assessment; FIL Tool; Unfit; Frail
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Rituximab; Loncastuximab tesirine
• Other Study ID Numbers: ADCT-402-203; 2021-005312-57 (EudraCT Number); 2022-501601-12-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No