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

Phase 2

Terminated

Conditions: Diffuse Large B-cell Lymphoma

Interventions: Drug: Loncastuximab Tesirine
Drug: Rituximab

Registration Number: NCT05144009

Lead Sponsor: ADC Therapeutics S.A.

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 41

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 & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Cohort A : Loncastuximab Tesirine + Rituximab (Lonca-R)	Loncastuximab Tesirine	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
Cohort A : Loncastuximab Tesirine + Rituximab (Lonca-R)	Rituximab	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
Cohort B : Loncastuximab Tesirine + Rituximab (Lonca-R)	Rituximab	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
Cohort B : Loncastuximab Tesirine + Rituximab (Lonca-R)	Loncastuximab Tesirine	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

Primary Outcome Measures

Name	Time	Method
CR Rate	Up to a maximum of 17.1 months	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.
Cohort B: Percentage of Participants Who Completed 4 Cycles of Treatment	Up to 12 weeks (3 week cycle length)	Defined by the number of participants who completed a total of 4 cycles of therapy divided by the total number of participants \* 100.

Secondary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR)	Up to a maximum of 17.1 months	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.
2-year Progression-free Survival (PFS)	2 years	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.
3-year Overall Survival (OS)	3 years	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.
Duration of Response (DoR)	Up to a maximum of 17.1 months	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.
Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)	Up to approximately 8 months	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.
Maximum Observed Concentration (Cmax) of Conjugated Antibody	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)	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.
Cmax of Total Antibody	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)	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.
Trough Concentration (Ctrough) of Conjugated Antibody	Cycle 1 Day 2: predose (preferably within 2 h prior to start of infusion); Cycles 2-6 Day 1 predose (3 week cycle length)	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.
Ctrough of Total Antibody	Cycle 1 Day 2: predose (preferably within 2 h prior to start of infusion); Cycles 2-6 Day 1 predose (3 week cycle length)	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.
Number of Participants With Confirmed Positive Anti-Drug Antibody (ADA) Response	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)	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.
Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Subscale and Composite Scores	Baseline and End of Treatment Visit (a maximum of 19 weeks)	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.

Trial Locations

Locations (41): University of Texas MD Anderson Cancer Center
🇺🇸
Houston, Texas, United States
Hospital Español Auxilio Mutuo
🇵🇷
San Juan, Puerto Rico
New York Cancer & Blood Specialists - New Hyde Park
🇺🇸
Babylon, New York, United States
Cancer Care Specialists - Nevada
🇺🇸
Reno, Nevada, United States
Novant Health Cancer Specialists - Charlotte
🇺🇸
Charlotte, North Carolina, United States
University Hospitals Cleveland Medical Center
🇺🇸
Cleveland, Ohio, United States
Ohio Health - Research and Innovation Institute
🇺🇸
Columbus, Ohio, United States
USOR - Texas Oncology - Presbyterian Cancer Center Dallas
🇺🇸
Dallas, Texas, United States
USOR - Texas Oncology - San Antonio
🇺🇸
San Antonio, Texas, United States
Ospedaliera Santi Antonio E Biagio E Cesare Arrigo-SC Ematologia
🇮🇹
Alessandria, Italy
USOR - Virginia Cancer Specialists - Gainesville Office
🇺🇸
Gainesville, Virginia, United States
Hospital San Pedro de Alcantara
🇪🇸
Cáceres, Spain
Texas Oncology Northeast Texas - Tyler
🇺🇸
Tyler, Texas, United States
Blue Ridge Cancer Care - Blacksburg
🇺🇸
Blacksburg, Virginia, United States
Reading Hospital - Tower Health
🇺🇸
Reading, Pennsylvania, United States
Texas Oncology - Medical City Dallas
🇺🇸
Dallas, Texas, United States
Texas Oncology - Austin Midtown
🇺🇸
Austin, Texas, United States
Virginia Cancer Institute - West End
🇺🇸
Richmond, Virginia, United States
Willamette Valley Cancer Institute and Research Center - Eugene
🇺🇸
Eugene, Oregon, United States
Kadlec Clinic - Hematology and Oncology
🇺🇸
Richland, Washington, United States
Prisma Health Cancer Institute
🇺🇸
Greenville, South Carolina, United States
Avera Cancer Institute
🇺🇸
Sioux Falls, South Dakota, United States
Hospital del Mar - Parc de Salut Mar
🇪🇸
Barcelona, Spain
Hospital Universitario Marqués de Valdecilla
🇪🇸
Santander, Cantabria, Spain
Clinica Universidad de Navarra - Pamplona
🇪🇸
Pamplona, Navarre, Spain
Azienda Socio Sanitaria Territoriale (ASST) degli Spedali Civili di Brescia
🇮🇹
Brescia, Italy
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
🇮🇹
Milano, Italy
Hospital Arnau de Vilanova
🇪🇸
València, Spain
Institut Català d'Oncologia - Hospital Duran i Reynals (ICO L'Hospitalet)
🇪🇸
Barcelona, Spain
Hospital Universitario Ramón y Cajal
🇪🇸
Madrid, Spain
New York Cancer & Blood Specialists - Babylon Medical Oncology
🇺🇸
Port Jefferson, New York, United States
University of Arizona Cancer Center
🇺🇸
Tucson, Arizona, United States
Rocky Mountain Cancer Centers - Aurora
🇺🇸
Aurora, Colorado, United States
Winthrop P. Rockefeller Cancer Institute
🇺🇸
Little Rock, Arkansas, United States
Leonard Lawson Cancer Center
🇺🇸
Pikeville, Kentucky, United States
USOR - Illinois Cancer Specialists - Niles
🇺🇸
Niles, Illinois, United States
USOR - Oncology Hematology Care - Kenwood
🇺🇸
Cincinnati, Ohio, United States
USOR - Texas Oncology - Baylor Charles A. Sammons Cancer Center
🇺🇸
Dallas, Texas, United States
USOR - Northwest Cancer Specialists, P.C. dba Compass Oncology - Vancouver Cancer Center
🇺🇸
Vancouver, Washington, United States
USOR - Virginia Oncology Associates
🇺🇸
Virginia Beach, Virginia, United States
Hospital Universitario Fundación Jiménez Díaz
🇪🇸
Madrid, Spain