E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Lymphoma of B-cell origin |
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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 | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10012819 |
E.1.2 | Term | Diffuse large B-cell lymphomas |
E.1.2 | System Organ Class | 100000004851 |
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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 |
Compare the clinical efficacy of epcoritamab to standard of care (SOC) (R-GemOx or BR) |
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E.2.2 | Secondary objectives of the trial |
Compare other measures of epcoritamab efficacy to SOC |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Must be at least 18 years of age; 2. ECOG PS score of 0-2; 3. One of the confirmed histologies below wiht CD20 positivity: a. DLBCL, NOS (according to the WHO 2016 classification) and including de novo or histologically transformed from follicular lymphoma (FL). b. “Double-hit” or “triple-hit” DLBCL with MYC and BCL2 and / or BCL6 traslocations c. FL Grade 3B d. T-cell/histiocyte-rich large B-cell lymphoma 4. CD20-positivity at representative tumor biopsy based on the pathology report; 5. Relapsed or refractory disease and previously treated with at least 1 line of systemic antineoplastic therapy including anti-CD20 mAb-containing combination chemotherapy since lymphoma diagnosis (ie, having received R-CHOP or an equivalent regimen that would be considered adequate first-line treatment for DLBCL); 6. Failed previous HDT-ASCT or not eligible for HDT-ASCT at screening. If ineligible for HDT-ASCT, the decision must have been based on age, performance status, comorbidity, and/or insufficient response to prior treatment; 7. Has measurable disease: a. A fluorodeoxyglucose-positron emission tomography (FDG- PET) scan demonstrating positive lesion(s) compatible with computed tomography (CT) or magnetic resoncance imagining (MRI)-defined anatomical tumor sites b. ≥1 measurable nodal lesion (long axis >1.5 cm and short axis >1.0 cm) and/or ≥1 measurable extra-nodal lesion (long axis >1.0 cm) on CT scan or MRI; 8. Absolute neutrophil count ≥1.0 x 10e9/L (growth factor permitted); 9. Platelet count >75 x 10e9/L (or >50 x 10e9/L if bone marrow involvement or splenomegaly); 10. Alanine aminotransferase and aspartate aminotransferase level ≤3 times the upper limit of normal (x ULN), unless enzyme elevation is due to a nonhepatic origin or lymphoma involvement of the liver and ALAT and ASAT levels are ≤5 xULN; 11. Total bilirubin level ≤2 x ULN, unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin or lymphoma involvement of the liver and total bilirubin is ≤5xULN; 12. Estimated glomerular filtration rate (eGFR) ≥50 mL/min/1.73m2 as calculated by Cockcroft-Gault; 13. PT/INR/aPTT ≤1.5 xULN, unless receiving anticoagulation; 14. A female subject with reproductive potential must agree to use adequate contraception during the trial, and for 12 months after the last administration of trial treatment. Adequate contraception is defined as highly effective methods of contraception; 15. A female subject of childbearing potential must have a negative serum (beta-hCG) pregnancy test at screening and a negative serum or urine pregnancy test before treatment administration on Day 1 of Cycle 1; 16. A male subject who is sexually active with a female of reproductive potential and has not had a vasectomy must agree to use a barrier method of birth control and must agree not to donate sperm during the trial and for 12 months after receiving the last administration of trial treatment. 17. Life expectancy >2 months on SOC treatment. 18. Able to provide baseline fresh or archival tumor biopsies. |
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E.4 | Principal exclusion criteria |
1. Primary central nervous system (CNS) tumor or known CNS involvement as assessed by brain MRI at screening or by CT and lumbar puncture (if MRI contraindicated); 2. Any prior therapy with a bispecific antibody targeting CD3 and CD20; 3. History of severe allergic or anaphylactic reactions to anti-CD20 antibody therapy; 4. Contraindication to any component of SOC regimen selected prior to randomization; 5. Major surgery within 4 weeks prior to randomization; 6. Chemotherapy and other non-investigational antineoplastic agents (except CD20 mAbs) within 4 weeks or 5 half-lives (whichever is shorter) prior to randomization; 7. ASCT within 100 days of randomization; 8. Treatment with CAR-T therapy within 100 days prior to randomization; 9. Receiving immunosuppressive therapy, including more than the equivalent of ≥20 mg of prednisolone daily, unless for control of lymphoma or intermittent prophylaxis/treatment of allergic reactions; 10. Seizure disorder requiring anti-epileptic therapy; 11. Vaccination with live vaccines within 28 days prior to randomization. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. Experimental and/or non authorized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinations are not allowed; 12. Clinically significant cardiovascular disease 13. Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) >470 msec; 14. Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results; 15. Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection requiring systemic treatment at time of randomization; 16. Known history of positivity for human immunodeficiency virus (HIV) infection. Note: HIV testing is required at screening only if required per local health authorities or institutional standards. 17. Active hepatitis B virus (HBV) (DNA polymerase chain reaction [PCR]-positive) or hepatitis C (RNA PCR-positive infection). Subjects with evidence of prior HBV but who are PCR-negative are permitted in the trial but should receive prophylactic antiviral therapy. Subjects who received treatment for hepatitis C that was intended to eradicate the virus may participate if hepatitis C RNA levels are undetectable. 18. Has known past or current malignancy other than inclusion diagnosis, except for: a. Cervical carcinoma of Stage 1B or less b. Non-invasive basal cell or squamous cell skin carcinoma c. Non-invasive, superficial bladder cancer d. Prostate cancer with a current PSA level <0.1 ng/mL e. Any curable cancer with a complete response of >2 years duration; 19. Contraindication to all uric acid lowering agents; 20. A woman of childbearing potential with a positive serum or urine pregnancy test at screening. Female subjects must also agree not to breastfeed during the entire trial and until 12 months after the last administration of study drug; 21. Clinically significant liver disease, including active hepatitis, current alcohol abuse, or cirrhosis; 22. Active tuberculosis or history of completed treatment for active tuberculosis within the past 12 months; 23. Receiving immunostimulatory agent; 24. Prior allogeneic hematopoietic stem cell transplantation. |
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- Progression-free survival (PFS) determined by Lugano criteria per independent review committee (IRC) assessment and investigator assessment - Overall response rate (ORR) determined by Lugano criteria per IRC assessment and investigator assessment - Complete response (CR) rate, determined by Lugano criteria per IRC assessment and investigator assessment - Duration of response (DOR) determined by Lugano criteria per IRC assessment and investigator assessment |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.4 | Safety | No |
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 | No |
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 | 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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 103 |
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 |
Singapore |
Taiwan |
Australia |
Canada |
Israel |
Japan |
Korea, Republic of |
Russian Federation |
Turkey |
United Kingdom |
United States |
Austria |
Belgium |
Denmark |
Finland |
France |
Germany |
Hungary |
Italy |
Netherlands |
Norway |
Poland |
Spain |
Sweden |
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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
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The end of trial is considered completed when the last subject dies or withdraws from the trial. However, the maximum trial duration is approximately 5 years after the last subject is randomized |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 6 |