| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or refractory diffuse large B-cell lymphoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells, a type of lymphocyte that is responsible for producing antibodies |
|
| 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 | HLGT |
| E.1.2 | Classification code | 10025320 |
| E.1.2 | Term | Lymphomas non-Hodgkin's B-cell |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| 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 |
| •To evaluate the efficacy of glofitamab (Glofit)- gemcitabine plus oxaliplatin (GemOx) compared with rituximab in combination with gemcitabine and oxaliplatin (R-GemOx) on the basis of overall survival |
|
| E.2.2 | Secondary objectives of the trial |
•To evaluate the efficacy of Glofit-GemOx compared with R-GemOx on the basis of progression-free survival, complete response rate, objective response rate, duration of objective response, duration of complete response, time to deterioration in physical functioning and fatigue
•To evaluate the safety and tolerability of Glofit-GemOx compared with R-GemOx
•To evaluate the pharmacokinetics of Glofit when administered as a component of Glofit-GemOx
•To evaluate the pharmacokinetics of obinutuzumab
•To evaluate the immune response to Glofit-GemOx |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
•Age >= 18 years
•Life expectancy >= 12 weeks
•Histologically confirmed diffuse large B-cell lymphoma, not otherwise specified (NOS)
•Relapsed or refractory disease
•At least one line of prior systemic therapy
•Patients who have failed only one prior line of therapy must not be a candidate for high-dose chemotherapy followed by autologous stem cell transplant
•Confirmed availability of tumor tissue, unless unobtainable per investigator assessment. Freshly collected biopsy is preferred. Archival tissue is acceptable
•At least one bi-dimensionally measurable nodal lesion, or one bi-dimensionally measurable extranodal lesion, as measured on CT scan
•Eastern Cooperative Oncology Group Performance Status of 0, 1, or 2
•Negative SARS-CoV-2 antigen or PCR test within 7 days prior to enrollment
•Adequate hematologic function; adequate renal function
•For women of childbearing potential: agreement to remain abstinent or use contraceptive measures with a failure rate of <1% per year, and agreement to refrain from donating eggs, during the treatment period and for at least 18 months after the final dose of obinutuzumab, 12 months after the final dose of rituximab, 6 months after the final dose of gemcitabine, 9 months after the final dose of oxaliplatin, 4 months after the final dose of tocilizumab, and 4 months after the final dose of glofitamab.
•For men: with a female partner of childbearing potential or a pregnant female partner, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of <1% per year, and men must agree to refrain from donating sperm, during the treatment period and for at least 6 months after the final dose of oxaliplatin or gemcitabine, 4 months after final dose of rituximab, obinutuzumab, glofitamab or tocilizumab to avoid exposing the embryo |
|
| E.4 | Principal exclusion criteria |
•Patient has failed only one prior line of therapy and is a candidate for stem cell transplantation
•History of transformation of indolent disease to DLBCL
•High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, and high-grade B-cell lymphoma NOS, as defined by 2016 WHO guidelines
•Primary mediastinal B-cell lymphoma
•History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products
•Contraindication to obinutuzumab, rituximab, gemcitabine or oxaliplatin, or tocilizumab
•Prior treatment with glofitamab or other bispecific antibodies targeting both CD20 and CD3
•Prior treatment with R-GemOx or GemOx
•Peripheral neuropathy assessed to be Grade >1 according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) at enrollment
•Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive therapy, or any investigational agent for the purposes of treating cancer within 2 weeks prior to first study treatment
•Treatment with monoclonal antibodies for the purposes of treating cancer within 4 weeks prior to first study treatment
•Primary or secondary central nervous system (CNS) lymphoma at the time of recruitment or history of CNS lymphoma
•Current or history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease
•History of other malignancy that could affect compliance with the protocol or interpretation of results
•Significant or extensive cardiovascular disease or significant pulmonary disease
•Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection at study enrollment or any major episode of infection within 4 weeks prior to the first study treatment
•Diagnosis with SARS-CoV-2 infection within 30 days prior to the first study treatment, including asymptomatic SARS-CoV-2 infection
•Documented SARS-CoV-2 infection within 6 months of first study treatment
•Positive test results for hepatitis B virus infection and hepatitis C virus antibody
•Known history of human immunodeficiency virus (HIV) seropositive status, known or suspected chronic active Epstein-Barr viral infection, hemophagocytic lymphohistiocytosis, history of progressive multifocal leukoencephalopathy
•Adverse events from prior anti-cancer therapy that have not resolved to Grade 1 or better
•Administration of a live, attenuated vaccine within 4 weeks before first study treatment administration or anticipation that such a live, attenuated vaccine will be required during the study
•Prior solid organ transplantation; prior allogeneic stem cell transplant
•Active autoimmune disease requiring treatment
•Prior treatment with systemic immunosuppressive medications, within 4 weeks prior to first dose of study treatment
•Ongoing corticosteroid use >30 mg/day of prednisone or equivalent
•Recent major surgery other than for diagnosis
•Clinically significant history of cirrhotic liver disease
•Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the patient at high risk from treatment complications
•Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 18 months after the final dose of study treatment |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1.Progression-Free Survival
2.Complete response rate
3.Objective response rate
4.Duration of objective response
5.Duration of complete response
6.Time to deterioration in physical functioning and fatigue, as measured by the European Organisation for Research and Treatment of Cancer Quality of Life−Core 30 Questionnaire (EORTC QLQ-C30) and in lymphoma symptoms, as measured by the Functional Assessment of Cancer Therapy−Lymphoma subscale (FACT-Lym LymS)
7.Incidence and severity of adverse events, with severity determined according to NCI CTCAE v5.0, including cytokine-release syndrome (CRS), with severity determined according to the American Society for Transplantation and Cellular Therapy (ASTCT) CRS grading criteria
8.Change from baseline in targeted vital signs
9.Change from baseline in targeted clinical laboratory test results
10.Tolerability, as assessed by dose interruptions, dose reductions, and dose intensity, and study treatment discontinuation because of adverse events
11.Minimum serum concentration of glofitamab
12.Maximum serum concentration of glofitamab
13.AUC for serum concentration−time profile of glofitamab estimated using a population-PK model
14.Minimum serum concentration of obinutuzumab
15.Maximum serum concentration of obinutuzumab
16.Prevalence of anti-drug antibodies (ADAs) against glofitamab at baseline and incidence of ADAs during the study |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-5.Up to 3.5 years
6.Day 1 of Cycle 1- 3, Day 1 of Cycles 5, 7, 9 and 11 and at treatment discontinuation and at the long-term follow up visit
7.Up to 3.5 years
8-9.From baseline (Day -1) to 3.5 years
10.Up to 3.5 year
11-13.Day 1 and 8 of Cycle 1; Day 1,2 of Cycle 2; Day 1 of Cycle 3-6, 8-10, 12, at treatment discontinuation, long-term follow-up and disease progression
14-15.Day 1 and 8 of Cycle 1
16.Day 1, 8 and 15 of Cycle 1, Day 1 of Cycle 2-4; Day 1 of Cycle 6, 8, 10 and 12 at treatment discontinuation, long-term follow-up and disease progression
|
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| 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 | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 37 |
| 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 |
| Australia |
| China |
| Korea, Republic of |
| United States |
| France |
| Poland |
| Spain |
| Switzerland |
| Germany |
| Belgium |
| Denmark |
| United Kingdom |
|
| 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
|
|
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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