Phase 3 Randomized Trial of Loncastuximab Tesirine and Rituximab Versus Immunochemotherapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma
- Trial ID
- 2023-503916-33-00
- Protocol
- ADCT-402-311
- Sponsor
- ADC Therapeutics SA
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3 randomized study is to evaluate the **efficacy** of **loncastuximab tesirine** combined with **rituximab** compared to standard immunochemotherapy in patients with relapsed or refractory **Diffuse Large B-Cell Lymphoma (DLBCL)**. This evaluation is clinically relevant as it aims to determine the potential of this combination therapy to improve treatment outcomes in a patient population with limited options due to the relapsed or refractory nature of their disease.
Participants
The clinical trial involves a total of **190 participants** diagnosed with **Diffuse Large B-Cell Lymphoma (DLBCL)**, including those with DLBCL transformed from indolent lymphoma or high-grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements. The study population comprises both male and female subjects aged **18 years or older**. Participants were selected based on their relapsed or refractory disease status following at least one multi-agent systemic treatment regimen and are not considered candidates for stem cell transplantation due to performance status, advanced age, or significant medical comorbidities. The trial includes individuals with an **ECOG performance status** of 0-2 and requires adequate organ function as defined by specific laboratory parameters. Lifestyle considerations such as diet and physical activity are not specified. The trial population includes a vulnerable population, and both genders are represented. Participants must have measurable disease as per the 2014 Lugano Classification and provide formalin-fixed paraffin-embedded tumor tissue for analysis. Women of childbearing potential and men with female partners of childbearing potential must adhere to strict contraceptive measures during and after the study period.
Plans and Procedures
The clinical trial is a **randomized**, **controlled**, and **double-blind** study designed to evaluate the efficacy of **loncastuximab tesirine** combined with **rituximab** compared to standard immunochemotherapy in patients with relapsed or refractory **Diffuse Large B-Cell Lymphoma (DLBCL)**. The trial aims to establish the therapeutic value and benefit-risk balance of the investigational treatment. The study is expected to run from April 2021 to February 2026, with participant involvement lasting up to 24 months, depending on individual treatment response and tolerability.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, including age, disease status, and organ function. Following successful screening, participants will be randomized to receive either the investigational treatment or standard immunochemotherapy. The trial includes regular follow-up visits to monitor treatment efficacy and safety, with assessments such as imaging studies and laboratory tests. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
Early termination from the study may occur if a participant experiences unacceptable toxicity, disease progression, or withdraws consent. The primary endpoint of the trial is progression-free survival, defined as the time from randomization to disease recurrence, progression, or death from any cause. The study is conducted under strict ethical guidelines, ensuring the safety and well-being of all participants throughout the trial duration.
Treatment
The clinical trial involves the administration of **Zynlonta**, a 10 mg powder for concentrate for solution for infusion, containing the active substance **loncastuximab tesirine**. This experimental medication is administered intravenously. The dosage is calculated based on the participant's body weight, with a maximum daily dose of 150 µg/kg and a total maximum dose of 750 µg/kg over a treatment period of up to 24 weeks. Compliance with the dosing schedule is monitored throughout the trial.
**Oxaliplatin** is used as a comparator treatment in the study. It is provided as a concentrate for solution for infusion and is administered intravenously. The dosage is determined by the body surface area of the participant, with a maximum daily dose of 100 mg/m² and a total maximum dose of 800 mg/m² over a 16-week treatment period. Participant adherence to the dosing regimen is closely monitored.
**Truxima**, containing the active substance **rituximab**, is another experimental medication used in the trial. It is available as a 100 mg concentrate for solution for infusion and is administered intravenously. The dosage is based on the participant's body surface area, with a maximum daily dose of 375 mg/m² and a total maximum dose of 3000 mg/m² over a 24-week treatment period. Compliance is ensured through regular monitoring.
**Dexamethason 4 mg GALEN®** is included as a non-experimental treatment. It is provided in tablet form and administered orally. The maximum daily dose is 4 mg, with a total maximum dose of 96 mg over a 12-week treatment period. Participant adherence to the oral dosing schedule is monitored to ensure compliance.
**Gemcitabine** is used as an additional comparator treatment. It is supplied as a powder for solution for infusion and administered intravenously. The dosage is calculated based on the participant's body surface area, with a maximum daily dose of 1000 mg/m² and a total maximum dose of 8000 mg/m² over a 16-week treatment period. Compliance with the dosing schedule is monitored throughout the trial.
Efficacy
The efficacy of the investigational treatment in the clinical trial will be assessed using the primary endpoint of **Progression-free survival (PFS)**. PFS is defined as the time between randomization and the first documentation of recurrence or progression of the disease, as determined by independent central review, or death from any cause. This endpoint is critical in evaluating the effectiveness of the treatment regimen involving **loncastuximab tesirine** combined with **rituximab** compared to standard immunochemotherapy in patients with relapsed or refractory **Diffuse Large B-Cell Lymphoma (DLBCL)**.
The measurement and analysis of PFS will be conducted at specified intervals throughout the trial duration, ensuring a comprehensive assessment of the treatment's impact on disease progression. The trial is designed as a Phase 3 randomized study, serving as a confirmatory trial to establish the therapeutic value and benefit-risk balance of the investigational treatment. The trial's methodology and endpoints are aligned with regulatory requirements to support the conditional marketing authorization in the EU.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female patient aged 18 years or older
- Pathologic diagnosis of DLBCL, as defined by the 2016 World Health Organization classification (including patients 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
- 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.
- ECOG performance status 0-2
- Adequate organ function as defined by screening laboratory values within the following parameters: a. Absolute neutrophil count ≥1000/µL (off growth factors at least 72 hours) b. Platelet count ≥100000/µL without transfusion within the past 2 weeks c. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transferase (GGT) ≤2.5 × the upper limit of normal (ULN) d. Total bilirubin ≤1.5 × ULN (patients with known Gilbert's syndrome may have a total bilirubin up to ≤3 × ULN) e. 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 patient 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, loncastuximab tesirine (including SG3249) or any of its excipients, or history of or 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: a. CD4+ T-cell (CD4+) counts <350 cells/µL b. Acquired immunodeficiency syndrome-defining opportunistic infection within 12 months prior to screening c. Not on anti-retroviral therapy, or on anti-retroviral therapy for <4 weeks at the time of screening d. 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 patient'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 patient inappropriate for study participation or put the patient at risk
- Known history of hypersensitivity to oxaliplatin or other platinum- based drugs, or gemcitabine, or rituximab, or any of their excipients
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 21 Apr 2021 | 15 |
 Czechia | Not Recruiting | 21 Apr 2021 | 23 |
 France | Not Recruiting | 21 Apr 2021 | 42 |
 Hungary | Not Recruiting | 21 Apr 2021 | 8 |
 Italy | Not Recruiting | 21 Apr 2021 | 55 |
 The Netherlands | Not Recruiting | 21 Apr 2021 | — |
 Poland | Not Recruiting | 21 Apr 2021 | 45 |
 Spain | Not Recruiting | 21 Apr 2021 | 30 |
| Netherlands | — | — | 10 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
GEMCITABINE | Comparator | — | INTRAVENOUS USE | 1000 | 16 | SUB07892MIG |
Truxima 100 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 375.00 | 24 | PRD5065908 |
Truxima 100 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 375.00 | 24 | PRD5065910 |
Zynlonta 10 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 150.00 | 24 | PRD10278221 |
Dexamethason 4 mg GALEN® | Other | TABLETTEN | ORAL USE | 4.00 | 12 | PRD808393 |
Truxima 100 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 375.00 | 24 | PRD5065907 |
OXALIPLATIN | Comparator | — | INTRAVENOUS USE | 100.00 | 16 | SUB09490MIG |
Truxima 100 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 375.00 | 24 | PRD5065909 |