Brief Summary:
The purpose of this study is to evaluate the efficacy of loncastuximab tesirine (ADCT-402)
combined with rituximab compared to standard immunochemotherapy.
Inclusion Criteria:
- Male or female participant aged 18 years or older
- Pathologic diagnosis of DLBCL, as defined by the 2016 World Health Organization
classification (including participants with DLBCL transformed from indolent lymphoma),
or high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements
- Relapsed (disease that has recurred following a response) or refractory (disease that
failed to respond to prior therapy) disease following at least one multi-agent
systemic treatment regimen [For China only: Adequate first line anti-DLBCL therapy is
defined as having received at least 4 cycles of multiagent systemic treatment regimen
containing rituximab and anthracycline, unless the participants are intolerant to the
regimen, or had disease progression during the treatment. If disease progression
occurred during the treatment period, then the disease is considered refractory where
the number of treatment cycles will not be specified. For participants who are
ineligible for anthracycline, anthracycline is not required.]
- Not considered by the investigator to be a candidate for stem cell transplantation
based on performance status, advanced age, and/or significant medical comorbidities
such as organ dysfunction
- Measurable disease as defined by the 2014 Lugano Classification as assessed by
positron-emission tomography (PET)- computed tomography (CT) or by CT or magnetic
resonance imaging (MRI) if tumor is not fluorodeoxyglucose (FDG)-avid on screening
PET-CT
- Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block (or minimum
10 freshly cut unstained slides if block is not available) Note: Any biopsy since
initial diagnosis is acceptable, but if several samples are available, the most recent
sample is preferred [For China only: This inclusion criterion is not applicable]
- ECOG performance status 0-2
- Adequate organ function as defined by screening laboratory values within the following
parameters:
1. Absolute neutrophil count ≥1000/μL (off growth factors for at least 72 hours)
2. Platelet count ≥100000/μL without transfusion within the past 2 weeks
3. ALT, AST, and GGT ≤2.5 × the upper limit of normal (ULN)
4. Total bilirubin ≤1.5 × ULN (participants with known Gilbert's syndrome may have a
total bilirubin up to ≤3 × 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.
- Negative beta-human chorionic gonadotropin (β-hCG) pregnancy test within 7 days prior
to start of study drug (Cycle 1 Day 1) for women of childbearing potential
- Women of childbearing potential 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 giving informed consent until at least 7 months after the participant
receives his last dose of study treatment.
Exclusion Criteria:
- Previous treatment with loncastuximab tesirine
- Previous treatment with R-GemOx
- Known history of hypersensitivity to a CD19 antibody, loncastumiximab tesirine
(including SG3249) or any of its excipients, or history of positive serum human ADA to
a CD19 antibody
- Pathologic diagnosis of Burkitt lymphoma
- 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
- Autologous transplant within 30 days prior to start of study drug (Cycle 1 Day 1)
- Allogeneic transplant within 60 days prior to start of study drug (Cycle 1 Day 1)
- Active graft-versus-host disease
- Post-transplantation lymphoproliferative disorders
- Active autoimmune disease, including motor neuropathy considered of autoimmune origin
and other central nervous system (CNS) autoimmune disease
- Human immunodeficiency virus (HIV) seropositive with any of the following:
1. CD4+ T-cell (CD4+) counts <350 cells/μL
2. Acquired immunodeficiency syndrome-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 CNS involvement, 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)
- Breastfeeding or pregnant
- Uncontrolled hypertension (blood pressure ≥160/100 mm Hg repeatedly), unstable angina,
congestive heart failure (greater than New York Heart Association class II),
electrocardiographic evidence of acute ischemia, coronary angioplasty or myocardial
infarction within 6 months prior to screening, uncontrolled atrial or ventricular
cardiac arrhythmia, poorly controlled diabetes, severe chronic pulmonary disease, or
other serious medical condition which is likely to significantly impair the
participant's ability to tolerate the study treatment
- Major surgery within 4 weeks prior to start of study drug (Cycle 1 Day 1);
radiotherapy, chemotherapy or other antineoplastic therapy within 14 days prior to
start of study drug (Cycle 1 Day 1), except shorter if approved by the Sponsor
- Use of any other experimental medication within 14 days or 5 half-lives prior to start
of study drug (Cycle 1 Day 1)
- Received live vaccine within 4 weeks of Cycle 1 Day 1
- Failure to recover to ≤Grade 1 (Common Terminology Criteria for Adverse Events [CTCAE]
version 5.0) from acute non-hematologic toxicity (except alopecia) due to previous
therapy prior to screening
- Congenital long QT syndrome or a corrected QTcF interval of ≥480 ms at screening
(unless secondary to pacemaker or bundle branch block)
- 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
- Known history of hypersensitivity to oxaliplatin or other platinum-based drugs, or
gemcitabine, or rituximab, or any of their excipients
Primary outcome:
1. Progression-free Survival (PFS) (Time Frame - Up to 4 years)
Secondary outcome:
1. Overall Survival (OS) (Time Frame - Up to 4 years)
2. Overall Response Rate (ORR) (Time Frame - Up to 4 years)
3. Complete Response Rate (CRR) (Time Frame - Up to 4 years)
4. Duration of Response (DOR) (Time Frame - Up to 4 years)
5. Number of Participants Who Experience At Least One Treatment-Emergent Adverse Event (TEAE) (Time Frame - Day 1 up to a maximum of Week 39)
6. Number of Participants Who Experience At Least One Serious Adverse Event (SAE) (Time Frame - Up to 4 years)
7. Number of Participants Who Experience a Clinically Significant Change From Baseline in Clinical Laboratory Results (Time Frame - Day 1 up to a maximum of Week 25)
8. Number of Participants Who Experience a Clinically Significant Change From Baseline in Vital Sign Measurements (Time Frame - Day 1 up to a maximum of Week 25)
9. Number of Participants Who Experience a Clinically Significant Change From Baseline in Physical Examinations (Time Frame - Day 1 up to a maximum of Week 25)
10. Number of Participants Who Experience a Clinically Significant Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status (Time Frame - Day 1 up to a maximum of Week 25)
11. Number of Participants Who Experience a Clinically Significant Change From Baseline in Electrocardiogram (ECG) Results (Time Frame - Day 1 up to a maximum of Week 25)
12. Average Concentration of Loncastuximab Tesirine at the End of Infusion (Time Frame - Day 1 of Cycles 1 through 6 (each cycle is 3 weeks))
13. Average Concentration of Loncastuximab Tesirine Before Infusion (Time Frame - Day 1 of Cycles 1 through 6 (each cycle is 3 weeks))
14. Number of Participants With Anti-Drug Antibody (ADA) Titers to Loncastuximab Tesirine (Time Frame - Day 1 up to a maximum of Week 25)
15. Part 2: Change from Baseline in Health-Related Quality of Life (HRQoL) as Measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire -Core 30 (EORTC QLQ-C30) (Time Frame - Baseline up to a maximum of Week 25)
16. Part 2: Change from Baseline in Health-Related Quality of Life (HRQoL) as Measured by the Lymphoma Subscale of Functional Assessment of Cancer Therapy- Lymphoma (LymS of FACT-Lym) (Time Frame - Baseline up to a maximum of Week 25)
17. Part 2: Change from Baseline in Health-Related Quality of Life (HRQoL) as Measured by GP5 Item of the Functional Assessment of Cancer Therapy- Lymphoma (FACT-Lym) (Time Frame - Baseline up to a maximum of Week 25)
18. Part 2: Change from Baseline in Health-Related Quality of Life (HRQoL) as Measured by EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) (Time Frame - Baseline to up to 4 years)
- Experimental: Part 1: Loncastuximab Tesirine + Rituximab (Lonca-R)
Part 1 consists of a non-randomized safety run-in period evaluating the study drug for the first 20 participants.
Participants will receive Lonca-R on Day 1 of each cycle for up to 8 cycles, where 1 cycle is 3 weeks. Lonca-R will be administered via an intravenous infusion of loncastuximab tesirine 150 µg/kg + rituximab 375 mg/m^2 Q3W for 2 cycles, then loncastuximab tesirine 75 µg/kg + rituximab 375 mg/m^2 Q3W for up to 6 additional cycles. - Experimental: Part 2: Loncastuximab Tesirine + Rituximab (Lonca-R)
Randomized participants will receive Lonca-R on Day 1 of each cycle for up to 8 cycles, where 1 cycle is 3 weeks. Lonca-R will be administered via an intravenous infusion of loncastuximab tesirine 150 µg/kg + rituximab 375 mg/m^2 every Q3W for 2 cycles, then loncastuximab tesirine 75 µg/kg + rituximab 375 mg/m^2 Q3W for up to 6 additional cycles. - Active Comparator: Part 2: Standard Immunochemotherapy (R-GemOx)
Randomized participants will receive R-GemOx consisting of rituximab, gemcitabine and oxaliplatin as a standard immunochemotherapy treatment on Day 1 or Day 2 of each cycle for up to 8 cycles, where 1 Cycle is 2 weeks. R-GemOx will be administered via an intravenous infusion of rituximab 375 mg/m^2 + gemcitabine 1000 mg/m^2 + oxaliplatin 100 mg/m^2 every 2 weeks (Q2W) for up to 8 cycles.
- Loncastuximab Tesirine (Zynlonta / ADCT-402 / ):
Intravenous Infusion - Rituximab:
Intravenous Infusion - Gemcitabine:
Intravenous Infusion - Oxaliplatin:
Intravenous Infusion
Quelle: ClinicalTrials.gov
