| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Diffuse Large B-Cell Lymphoma (DLBCL) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10012818 |
| E.1.2 | Term | Diffuse large B-cell lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Evaluate the efficacy of loncastuximab tesirine combined with rituximab compared to standard immunochemotherapy |
|
| E.2.2 | Secondary objectives of the trial |
Characterize the safety profile of loncastuximab tesirine combined with rituximab
Characterize the pharmacokinetic (PK) profile of loncastuximab tesirine combined with rituximab
Evaluate the immunogenicity of loncastuximab tesirine combined with rituximab
Evaluate the impact of loncastuximab tesirine combined with rituximab treatment on treatment-related and disease-related symptoms, patient-reported functions, and overall health status |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female patient aged 18 years or older
2. 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
3. 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
4. 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
5. Patients who have received previous CD19-directed therapy must have a biopsy which shows CD19 expression after completion of the CD19-directed therapy
6. 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
7. 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.
8. ECOG performance status 0-2
9. 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 ≥75000/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.
10. 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
11. Women of childbearing potential must agree to use a highly effective method of contraception from the time of giving informed consent until at least 9 months after the last dose of loncastuximab tesirine. Men with female partners who are of childbearing potential must agree that they will use a highly effective method of contraception from the time of giving informed consent until at least 6 months after the patient receives his last dose of loncastuximab tesirine. |
|
| E.4 | Principal exclusion criteria |
1. Previous treatment with loncastuximab tesirine
2. Previous treatment with R-GemOx
3. Known history of hypersensitivity to or positive serum human ADA to a CD19 antibody
4. Pathologic diagnosis of Burkitt lymphoma
5. 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
6. Autologous transplant within 30 days prior to start of study drug (Cycle 1 Day 1)
7. Allogeneic transplant within 60 days prior to start of study drug (Cycle 1 Day 1)
8. Active graft-versus-host disease
9. Post-transplantation lymphoproliferative disorders
10. Active autoimmune disease, including motor neuropathy considered of autoimmune origin and other central nervous system (CNS) autoimmune disease
11. 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
12. 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
13. Serologic evidence of hepatitis C virus (HCV) infection without completion of curative treatment or with detectable HCV viral load
14. History of Stevens-Johnson syndrome or toxic epidermal necrolysis
15. Lymphoma with active CNS involvement, including leptomeningeal disease
16. 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)
17. Breastfeeding or pregnant
18. 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
19. Major surgery, 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
20. Use of any other experimental medication within 14 days or 5 half-lives prior to start of study drug (Cycle 1 Day 1)
21. Received live vaccine within 4 weeks of Cycle 1 Day 1
22. 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
23. Congenital long QT syndrome or a corrected QTcF interval of ≥480 ms at screening (unless secondary to pacemaker or bundle branch block)
24. 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
25. Known history of hypersensitivity to oxaliplatin or any of its excipients |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (PFS) defined as the time between randomization and the first documentation of recurrence or progression by independent central review, or death from any cause |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From baseline (screening), 6 weeks post-dose,12 weeks post-dose, then every 12 weeks until EOT. If no progression at EOT and no initiation of a new anti-cancer therapy, then every 12 weeks for 1 year post-EOT, then every 6 months until disease progression for up to 4 years from EOT |
|
| E.5.2 | Secondary end point(s) |
• Overall survival (OS) defined as the time between randomization and death from any cause
• Overall response rate (ORR) by independent central review according to the 2014 Lugano classification. Overall response rate is defined as the proportion of patients with a best overall response (BOR) of complete response (CR) or partial response (PR)
• CR rate by independent central review defined as the proportion of patients with a BOR of CR
• Duration of Response (DOR) defined as the time from first documentation of response to recurrence or progression by independent central review, or death from any cause
• Frequency and severity of adverse events (AEs)
• Changes from baseline of safety laboratory variables, vital signs, physical examinations, eastern cooperative oncology group (ECOG) performance status, and electrocardiograms (ECGs)
• Concentrations and PK parameters of loncastuximab tesirine pyrrolobenzodiazepine (PBD)-conjugated antibody, total antibody and SG3199 unconjugated warhead
• Anti-drug antibody (ADA) titers to loncastuximab tesirine after treatment with loncastuximab tesirine
• Changes in patient-reported outcomes (PROs) (e.g., symptoms, functions, and overall health status) from baseline as evaluated by EORTC QLQ-C30, Lymphoma subscale (LymS) of FACT-Lym, GP5 item of FACT-Lym, and EQ-5D-5L |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| There are different timepoints for the evaluation of the secondary endpoints |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 31 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Israel |
| Russian Federation |
| Ukraine |
| United States |
| Belgium |
| France |
| Italy |
| Poland |
| Spain |
| Switzerland |
| United Kingdom |
| Czechia |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last visit or last scheduled procedure for the last patient |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
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