Diffuse Large B-cell Lymphoma
Conditions
Keywords
Lymphoma, Loncastuximab Tesirine, Rituximab, Non-Hodgkin's lymphoma, Elderly, R-mini-CHOP, Geriatric Assessment, FIL Tool, Unfit, Frail
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.
Interventions
DRUGLoncastuximab Tesirine
Intravenous (IV) Infusion
DRUGRituximab
Cycle 1 - Intravenous (IV) Infusion. Cycle 2+ - Intravenous (IV) Infusion or Subcutaneous (SC) Administration.
Sponsors
ADC Therapeutics S.A.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Italy, Puerto Rico, Spain, United States
Participant flow
Recruitment details
A total of 41 participants were enrolled in the Unites States and Spain between June 2022 and January 2024.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) Unfit participants (per sGA) received Lonca-R for 3 cycles (each treatment cycle was 3 weeks). A response-adapted approach was implemented, where participants achieving CR after 3 cycles received 1 additional cycle (4 cycles total), and those with PR after 3 cycles received additional cycles based on their cohort assignment (6 cycles total).
Loncastuximab tesirine was administered as an IV infusion on Day 2 of Cycle 1 and Day 1 (prior to rituximab administration) of subsequent cycles. Participants received 150 μg/kg loncastuximab tesirine for 2 cycles, followed by 75 μg/kg loncastuximab tesirine for subsequent cycles. Rituximab was administered as an IV infusion on Day 1 of each cycle at a dose of 375 mg/m\^2. | 17 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) Frail participants (per sGA) or participants with cardiac comorbidities received Lonca-R for 3 cycles (each treatment cycle was 3 weeks). A response-adapted approach was implemented, where participants achieving CR after 3 cycles received 1 additional cycle (4 cycles total), and those with PR or SD (Cohort B only) after 3 cycles received additional cycles based on their cohort assignment (6 cycles total).
Loncastuximab tesirine was administered as an IV infusion on Day 2 of Cycle 1 and Day 1 (prior to rituximab administration) of subsequent cycles. Participants received 150 μg/kg loncastuximab tesirine for 2 cycles, followed by 75 μg/kg loncastuximab tesirine for subsequent cycles. Rituximab was administered as an IV infusion on Day 1 of each cycle at a dose of 375 mg/m\^2. | 24 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 5 | 10 |
| Overall Study | Disease Progression | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Participant Decision | 0 | 2 |
| Overall Study | Study Termination by the Sponsor | 11 | 11 |
Baseline characteristics
| Characteristic | Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Total | Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) |
|---|---|---|---|
| Age, Continuous | 80.0 years STANDARD_DEVIATION 7.07 | 81.7 years STANDARD_DEVIATION 6.16 | 84.1 years STANDARD_DEVIATION 3.48 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 34 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 22 Participants | 38 Participants | 16 Participants |
| Sex: Female, Male Female | 9 Participants | 12 Participants | 3 Participants |
| Sex: Female, Male Male | 15 Participants | 29 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 17 | 10 / 24 |
| other Total, other adverse events | 17 / 17 | 22 / 24 |
| serious Total, serious adverse events | 13 / 17 | 16 / 24 |
Outcome results
Primary
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.
Time frame: Up to 12 weeks (3 week cycle length)
Population: All-Treated Population: All participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Cohort B: Percentage of Participants Who Completed 4 Cycles of Treatment | 33.3 percentage of participants |
Primary
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.
Time frame: Up to a maximum of 17.1 months
Population: All-Treated Population: All participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | CR Rate | 52.9 percentage of participants |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | CR Rate | 41.7 percentage of participants |
Secondary
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.
Time frame: 2 years
Population: All-Treated Population: All participants who received at least 1 dose of study drug. No data was collected for this endpoint due to study early termination.
Secondary
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.
Time frame: 3 years
Population: All-Treated Population: All participants who received at least 1 dose of study drug. No data was collected for this endpoint due to study early termination.
Secondary
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.
Time frame: Baseline and End of Treatment Visit (a maximum of 19 weeks)
Population: Patient-reported Outcomes Population: All participants who received at least one dose of study treatment and completed at least one questionnaire at Baseline and at one post Baseline visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Subscale and Composite Scores | Physical Well-being Subscale | -5.70 score on a scale | Standard Deviation 4.811 |
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Subscale and Composite Scores | Social/family Well-being Subscale | 0.52 score on a scale | Standard Deviation 1.895 |
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Subscale and Composite Scores | Emotional Well-being Subscale | 2.10 score on a scale | Standard Deviation 4.28 |
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Subscale and Composite Scores | Functional Well-being Subscale | -3.63 score on a scale | Standard Deviation 3.86 |
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Subscale and Composite Scores | Lymphoma Subscale | -4.29 score on a scale | Standard Deviation 10.577 |
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Subscale and Composite Scores | FACT-Lymphoma Trial Outcome Index | -11.99 score on a scale | Standard Deviation 16.188 |
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Subscale and Composite Scores | FACT-G | -6.71 score on a scale | Standard Deviation 11.889 |
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Subscale and Composite Scores | FACT-Lymphoma | -8.71 score on a scale | Standard Deviation 18.267 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Subscale and Composite Scores | FACT-Lymphoma | -2.81 score on a scale | Standard Deviation 14.953 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Subscale and Composite Scores | Physical Well-being Subscale | -1.55 score on a scale | Standard Deviation 4.793 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Subscale and Composite Scores | Lymphoma Subscale | -0.08 score on a scale | Standard Deviation 8.385 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Subscale and Composite Scores | Social/family Well-being Subscale | 1.22 score on a scale | Standard Deviation 5.675 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Subscale and Composite Scores | FACT-G | -2.72 score on a scale | Standard Deviation 10.649 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Subscale and Composite Scores | Emotional Well-being Subscale | -0.95 score on a scale | Standard Deviation 2.396 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Subscale and Composite Scores | FACT-Lymphoma Trial Outcome Index | -3.08 score on a scale | Standard Deviation 12.452 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Subscale and Composite Scores | Functional Well-being Subscale | -1.44 score on a scale | Standard Deviation 6.675 |
Secondary
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.
Time frame: 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)
Population: PK Population: All participants who received study drug and have at least 1 pre-(Cycle 1 Day 1) and 1 post-dose valid PK assessment. Inclusive of only participants with available data at each timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Cmax of Total Antibody | Cycle 1 | 2751 ng/mL | Geometric Coefficient of Variation 59.4 |
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Cmax of Total Antibody | Cycle 2 | 3270 ng/mL | Geometric Coefficient of Variation 68.6 |
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Cmax of Total Antibody | Cycle 3 | 2010 ng/mL | Geometric Coefficient of Variation 49 |
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Cmax of Total Antibody | Cycle 4 | 2044 ng/mL | Geometric Coefficient of Variation 44.8 |
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Cmax of Total Antibody | Cycle 5 | 1874 ng/mL | Geometric Coefficient of Variation 36 |
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Cmax of Total Antibody | Cycle 6 | 1466 ng/mL | Geometric Coefficient of Variation 19.1 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Cmax of Total Antibody | Cycle 5 | 1799 ng/mL | Geometric Coefficient of Variation 25.9 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Cmax of Total Antibody | Cycle 1 | 1971 ng/mL | Geometric Coefficient of Variation 115 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Cmax of Total Antibody | Cycle 4 | 1362 ng/mL | Geometric Coefficient of Variation 56.8 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Cmax of Total Antibody | Cycle 2 | 2746 ng/mL | Geometric Coefficient of Variation 33.5 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Cmax of Total Antibody | Cycle 6 | 1175 ng/mL | Geometric Coefficient of Variation 110 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Cmax of Total Antibody | Cycle 3 | 1834 ng/mL | Geometric Coefficient of Variation 32.6 |
Secondary
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.
Time frame: Cycle 1 Day 2: predose (preferably within 2 h prior to start of infusion); Cycles 2-6 Day 1 predose (3 week cycle length)
Population: PK Population: All participants who received study drug and have at least 1 pre-(Cycle 1 Day 1) and 1 post-dose valid PK assessment. Inclusive of only participants with available data at each timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Ctrough of Total Antibody | Cycle 2 | 805 ng/mL | Geometric Coefficient of Variation 68.5 |
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Ctrough of Total Antibody | Cycle 4 | 633 ng/mL | Geometric Coefficient of Variation 69.1 |
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Ctrough of Total Antibody | Cycle 3 | 619 ng/mL | Geometric Coefficient of Variation 75.9 |
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Ctrough of Total Antibody | Cycle 5 | 509 ng/mL | Geometric Coefficient of Variation 31.8 |
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Ctrough of Total Antibody | Cycle 1 | 503 ng/mL | Geometric Coefficient of Variation 75.1 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Ctrough of Total Antibody | Cycle 5 | 658 ng/mL | Geometric Coefficient of Variation 40.2 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Ctrough of Total Antibody | Cycle 1 | 413 ng/mL | Geometric Coefficient of Variation 56.9 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Ctrough of Total Antibody | Cycle 2 | 650 ng/mL | Geometric Coefficient of Variation 70.2 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Ctrough of Total Antibody | Cycle 3 | 645 ng/mL | Geometric Coefficient of Variation 31.5 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Ctrough of Total Antibody | Cycle 4 | 627 ng/mL | Geometric Coefficient of Variation 26.9 |
Secondary
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.
Time frame: Up to a maximum of 17.1 months
Population: All-Treated Population: All participants who received at least 1 dose of study drug. Inclusive of participants who were censored.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Duration of Response (DoR) | 5.49 months |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Duration of Response (DoR) | NA months |
Secondary
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.
Time frame: 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)
Population: PK Population: All participants who received study drug and have at least 1 pre-(Cycle 1 Day 1) and 1 post-dose valid PK assessment. Inclusive of only participants with available data at each timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Maximum Observed Concentration (Cmax) of Conjugated Antibody | Cycle 1 | 1667 ng/mL | Geometric Coefficient of Variation 274 |
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Maximum Observed Concentration (Cmax) of Conjugated Antibody | Cycle 2 | 2461 ng/mL | Geometric Coefficient of Variation 65.2 |
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Maximum Observed Concentration (Cmax) of Conjugated Antibody | Cycle 3 | 1456 ng/mL | Geometric Coefficient of Variation 40.6 |
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Maximum Observed Concentration (Cmax) of Conjugated Antibody | Cycle 4 | 1581 ng/mL | Geometric Coefficient of Variation 28.6 |
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Maximum Observed Concentration (Cmax) of Conjugated Antibody | Cycle 5 | 1377 ng/mL | Geometric Coefficient of Variation 18.2 |
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Maximum Observed Concentration (Cmax) of Conjugated Antibody | Cycle 6 | 1087 ng/mL | Geometric Coefficient of Variation 28.2 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Maximum Observed Concentration (Cmax) of Conjugated Antibody | Cycle 5 | 1700 ng/mL | Geometric Coefficient of Variation 15.2 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Maximum Observed Concentration (Cmax) of Conjugated Antibody | Cycle 1 | 1788 ng/mL | Geometric Coefficient of Variation 52.2 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Maximum Observed Concentration (Cmax) of Conjugated Antibody | Cycle 4 | 1163 ng/mL | Geometric Coefficient of Variation 59.4 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Maximum Observed Concentration (Cmax) of Conjugated Antibody | Cycle 2 | 2353 ng/mL | Geometric Coefficient of Variation 30.5 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Maximum Observed Concentration (Cmax) of Conjugated Antibody | Cycle 6 | 617 ng/mL | Geometric Coefficient of Variation 83.9 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Maximum Observed Concentration (Cmax) of Conjugated Antibody | Cycle 3 | 1407 ng/mL | Geometric Coefficient of Variation 29.6 |
Secondary
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.
Time frame: Up to approximately 8 months
Population: All-Treated Population: All participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Any TEAEs | 17 Participants |
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Any CTCAE Grade 3 or Higher TEAEs | 13 Participants |
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Any Serious TEAEs | 13 Participants |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Any TEAEs | 23 Participants |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Any CTCAE Grade 3 or Higher TEAEs | 18 Participants |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Any Serious TEAEs | 16 Participants |
Secondary
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.
Time frame: 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)
Population: Immunogenicity Population: All participants who received study drug and had at least 1 valid anti-drug antibody assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Number of Participants With Confirmed Positive Anti-Drug Antibody (ADA) Response | 0 Participants |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Number of Participants With Confirmed Positive Anti-Drug Antibody (ADA) Response | 0 Participants |
Secondary
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.
Time frame: Up to a maximum of 17.1 months
Population: All-Treated Population: All participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Overall Response Rate (ORR) | 94.1 percentage of participants |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Overall Response Rate (ORR) | 66.7 percentage of participants |
Secondary
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.
Time frame: Cycle 1 Day 2: predose (preferably within 2 h prior to start of infusion); Cycles 2-6 Day 1 predose (3 week cycle length)
Population: PK Population: All participants who received study drug and have at least 1 pre-(Cycle 1 Day 1) and 1 post-dose valid PK assessment. Inclusive of only participants with available data at each timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Trough Concentration (Ctrough) of Conjugated Antibody | Cycle 2 | 548 ng/mL | Geometric Coefficient of Variation 35.6 |
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Trough Concentration (Ctrough) of Conjugated Antibody | Cycle 4 | 391 ng/mL | Geometric Coefficient of Variation 25.4 |
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Trough Concentration (Ctrough) of Conjugated Antibody | Cycle 3 | 411 ng/mL | Geometric Coefficient of Variation 53.8 |
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Trough Concentration (Ctrough) of Conjugated Antibody | Cycle 5 | 353 ng/mL | Geometric Coefficient of Variation 24 |
| Cohort A: Loncastuximab Tesirine + Rituximab (Lonca-R) | Trough Concentration (Ctrough) of Conjugated Antibody | Cycle 1 | 324 ng/mL | Geometric Coefficient of Variation 30.7 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Trough Concentration (Ctrough) of Conjugated Antibody | Cycle 5 | 453 ng/mL | Geometric Coefficient of Variation 34.8 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Trough Concentration (Ctrough) of Conjugated Antibody | Cycle 1 | 215 ng/mL | Geometric Coefficient of Variation 142 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Trough Concentration (Ctrough) of Conjugated Antibody | Cycle 2 | 449 ng/mL | Geometric Coefficient of Variation 70.3 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Trough Concentration (Ctrough) of Conjugated Antibody | Cycle 3 | 479 ng/mL | Geometric Coefficient of Variation 35.1 |
| Cohort B: Loncastuximab Tesirine + Rituximab (Lonca-R) | Trough Concentration (Ctrough) of Conjugated Antibody | Cycle 4 | 436 ng/mL | Geometric Coefficient of Variation 32.1 |