| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Diffuse Large B-Cell Lymphoma (DLBCL) |
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| E.1.1.1 | Medical condition in easily understood language |
| Diffuse Large B-Cell Lymphoma |
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| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to evaluate whether the addition of epcoritamab to 6 cycles of standard R-CHOP followed by 2 cycles of epcoritamab can prolong progression-free survival (PFS) compared with 6 cycles of standard R-CHOP alone followed by 2 cycles of rituximab in subjects with newly diagnosed DLBCL with an IPI of 2-5. |
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| E.2.2 | Secondary objectives of the trial |
| The first secondary objective is to evaluate and compare PFS between the two treatment arms in subjects with newly diagnosed DLBCL with an IPI of 2-5 (i.e., all-randomized subjects). The other secondary objectives are to evaluate and compare each key secondary endpoint for both the subset of subjects with an IPI of 3-5 and all randomized subjects per the hierarchical order specified in Section 7.7. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Age ≥ 18 years old and < 80 years old, with a life expectancy of ≥ 12 months.
2.Subject is planned to receive treatment with 6 cycles of standard R CHOP per investigator determination.
3.Subject must have newly diagnosed, histologically confirmed CD20+ DLBCL (de novo or histologically transformed from a diagnosis of follicular lymphoma) at most recent representative tumor biopsy based on the pathology report, with a World Health Organization (WHO) 2016 classification and including:
- DLBCL, Not Otherwise Specified (NOS).
- High grade B-cell lymphoma with MYC and BCL-2 and/or BCL-6 rearrangement with DLBCL morphology.
- T-cell/histiocyte-rich large B-cell lymphoma.
- Epstein Barr virus-positive DLBCL, NOS.
- Follicular lymphoma Grade 3b.
4.Availability of archival or freshly collected tumor tissue at Screening. Archival paraffin-embedded tissue must be obtained within 8 weeks prior to Cycle 1 Day 1.
5.Subject must have an IPI score of 2-5. The number of subjects with an IPI of 2 will not exceed approximately 30% of the overall sample size.
6.Subject must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2 prior to initiating R-CHOP treatment. Note that subject with an initial ECOG performance status ≥ 3 may be screened if pre-phase treatment is planned. Subject may be eligible if ECOG performance status were to improve to 0-2 during pre phase treatment.
7.Subject has at least one target lesion defined as:
- ≥ 1 measurable nodal lesion (long axis > 1.5 cm ) or ≥ 1 measurable extra-nodal lesion (long axis > 1 cm) on CT scan or MRI.
AND
- PET-positive on PET-CT scan.
8.Laboratory values meeting the following criteria within the screening period prior to the first dose of study drug:
- Absolute neutrophil count (ANC) ≥ 0.5 × 109/L. (antibacterial prophylaxis per instititutional standard practice should be concidered for subjects with ANC < 1.0 x 109/L)
- Hemoglobin ≥ 8 g/dL.
- Platelet count ≥ 75 × 109/L, or ≥ 25 × 109/L in the presence of bone marrow involvement or splenomegaly
- Serum aspartate aminotransferase or serum alanine aminotransferase ≤ 3.0 × upper limit of normal (ULN) unless due to hepatic involvement of disease or non-hepatic origin.
- Total bilirubin level ≤ 1.5 × ULN, unless the bilirubin rise is due to Gilbert's syndrome or lymphoma hepatobiliary involvement. Subjects with Gilbert´s sydrome must have direct bilirubin < 2 × ULN. subjects with hepatobiliary involvement must have a total bilirubin of < 5 × ULN and without a percutaneous biliary drain.
- Estimated creatinine clearance ≥ 40 mL/min, as calculated by the Cockcroft-Gault formula with considerations for body weight.
- Prothrombin time/international normalized ratio/activated partial thromboplastin time ≤ 1.5 × ULN, unless receiving anticoagulation.
9. Left ventricular ejection fraction must be ≥ 50% by multi gated acquisition or transthoracic echocardiography at Screening.
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| E.4 | Principal exclusion criteria |
1. Subject with history of prior systemic anti-lymphoma therapy for DLBCL (including any definitive radiotherapy with curative intent) other than corticosteroids with or without vincristine during pre-phase treatment, or non-curative intent palliative radiotherapy with the stipulation that radiated lesions cannot be selected as target lesion for response assessment.
2. Subject has clinically significant cardiovascular disease, including:
• Myocardial infarction or stroke within 6 months prior to enrollment.
OR
• The following conditions within 3 months prior to enrollment: unstable or uncontrolled disease/condition related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III IV), uncontrolled cardiac arrhythmia
OR
• Screening 12-lead electrocardiogram (ECG) showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) > 470 msec (male) or > 480 sec (female)
OR
• Other clinically significant electrocardiogram abnormalities within 6 months prior to enrollment unless deemed stable and appropriately treated .
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is PFS defined as the duration from the date of randomization to the date of any of the following (whichever occurs first). The primary analysis population is the subset of subjects with an IPI of 3-5.
• Disease progression based on the independent review committee (IRC) assessment per Lugano criteria.
• Death due to any causes.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Throughout the study. Survival follow-up will continue until death, withdrawal of the subject, lost to follow up, study discontinuation, study termination by the Sponsor or the study meets the specified OS event goal (estimated to be approximately 6.5 years after first subject first dose), whichever comes first. |
|
| E.5.2 | Secondary end point(s) |
Key secondary efficacy endpoints include the following:
• PFS in all randomized subjects
• The subsequent key secondary endpoints specified below will be analyzed for both the subset of subjects with an IPI of 3-5 and all randomized subjects per the hierarchical order specified in protocol Section 7.7:
• Event-free survival, defined as the duration from randomization to the date of any of the following (whichever occurs first):
- Disease progression based on IRC assessment per Lugano criteria
- IRC-assessed response of partial response or stable disease followed by non-protocol-specified new antilymphoma therapy (NALT), unless the primary reasons for discontinuing every component of study treatment are not efficacy related
- A positive biopsy on or after the end-of-treatment (EOT) ( i.e., completion of 8 cycles of treatment), regardless of whether NALT is initiated.
-Death due to any causes
• CR on or after treatment completion (i.e., at the EOT scan [Week 28 or 6 (+2) weeks from Cycle 8 Day 1, whichever is later]) by fluorodeoxyglucose positron emission tomography, based on IRC assessment per Lugano criteria
• Overall survival, defined as time from randomization until death due to any causes
• Minimal residual disease (MRD) negativity
Additional efficacy endpoints are included in the protocol body. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Event-free Survival/ Overall Survival: Throughout the study until death, withdrawal of the subject, lost to follow up, study discontinuation, study termination by the Sponsor or the study meets the specified OS event goal (estimated to be approximately 6.5 years after first subject first dose), whichever comes first
- CR: Throughout the study.
- MRD: Throughout study and Post-Treatment Follow-up visits until subject discontinuation.
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| 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 | Yes |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | No |
| 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 | 17 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 200 |
| 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 |
| Argentina |
| Australia |
| Brazil |
| Canada |
| China |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| Puerto Rico |
| South Africa |
| Taiwan |
| United States |
| Switzerland |
| Turkey |
| Serbia |
| Austria |
| Belgium |
| Bulgaria |
| Croatia |
| Czechia |
| Denmark |
| France |
| Germany |
| Greece |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Slovakia |
| Slovenia |
| Spain |
| Sweden |
| United Kingdom |
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| 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
|
The global end of this study shall be defined as the point at which all enrolled subjects have completed all study-specified follow-up (last subject last visit) or the last subject dies or withdraws from the study in the last country where the study was conducted. However, the estimated maximum study duration is 6.5 years after the first subject first dose, although this is dependent on actual enrollment rate and patient response to treatment.
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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