E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Diffuse large B-cell Lymphoma |
|
E.1.1.1 | Medical condition in easily understood language |
Diffuse large B-cell Lymphoma |
|
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 |
•To evaluate the 2-year DFS for patients in complete metabolic remission after R-CHOP induction. |
|
E.2.2 | Secondary objectives of the trial |
•To evaluate toxicity and assess the relation of adverse events in time to recovery of the T-cell repertoire •To evaluate the 2-year OS. •To evaluate MRD status at the end of induction therapy, during consolidation treatment and at the end of consolidation. •To evaluate the recovery of the T-cell and NK cell repertoire after induction therapy and during consolidation treatment in relation to toxicity and efficacy.
• To explore the PDL1/HLA expression, mutational load, gene expression immune profile, soluble PDL1, microbiome and T-cell clonality of patients in relation to MRD status and MRD conversion. •To explore the tumor characteristics and mutational dynamics in patients who relapse. •To assess the crossing of the blood-brain barrier of atezolizumab by measuring atezolizumab concentrations in het cerebrospinal fluid.
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Age 18-75 (inclusive) years • Patients with a confirmed histologic diagnosis of diffuse large B-cell lymphoma (DLBCL-NOS) based upon a representative histology specimen according to the WHO classification, revision 2016 • Ann Arbor stages II-IV • WHO performance status 0 – 1 • IPI >=3 at diagnosis • Complete metabolic remission (Deauville 1-3) after 6-8 cycles of R-CHOP according to the Lugano criteria • Negative pregnancy test at study entry • Patient is willing and able use adequate contraception during and until 6 months after the last protocol treatment. • Written informed consent • Patient is capable of giving a written informed consent
|
|
E.4 | Principal exclusion criteria |
Diagnosis • All histopathological diagnoses other than DLBCL-NOS according to the WHO classification, revision 2016,including: -High-grade B-cell lymphoma with a double/triple translocation with MYC, BCL2 and/or BCL6. Please note that patients with an isolated MYC translocation or an isolated BCL2 translocation or an isolated BCL-6 translocation are eligible (single hit translocation). -Testicular large B-cell lymphoma -Primary mediastinal B cell lymphoma -Transformed indolent lymphoma -Post-transplant lymphoproliferative disorder
Organ dysfunction • Clinical signs of severe pulmonary dysfunction. • Clinical signs of heart failure (NYHA classification II-IV). • Symptomatic coronary artery disease or cardiac arrhythmias not well controlled with medication. • Myocardial infarction during the last 6 months. •Significant renal dysfunction (serum creatinine ≥ 150 umol/l or clearance ≤ 30ml/min Creatinine clearance may be calculated by Cockcroft –Gault formula. •Inadequate hematological function: hemoglobin < 5.5 mmol/L , ANC < 1.0x109/L or platelets < 75x109 /L •Signs or known history of bleeding disorder •Spontaneous INR > 1.5, aPTT >33 •Significant hepatic dysfunction (total bilirubin ≥ 1.5x upper limit of normal (ULN) or transaminases ≥ 2.5 x ULN), unless related to Gilberts syndrome. •Clinical signs of severe cerebral dysfunction •Patients with a history of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant and adversely affecting compliance to study drugs •Major surgery within the last 4 weeks
Known or suspected infection • Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection or any major episode of infection requiring treatment with IV antibiotics or hospitalization within 4 before date of registration. Suspected active or latent tuberculosis needs to be confirmed by positive interferon gamma (IFN-γ) release assay • Patients known to be HIV-positive • Active chronic hepatitis B or C infection • Administration of a live, attenuated vaccine within 4 weeks before date of registration or anticipation that such a live attenuated vaccine will be required during the study and for a period of 5 months after discontinuation of atezolizumab.
Auto-immune • Any active or history of documented autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. The following exceptions are allowed: Patients with autoimmune-related hypothyroidism or type 1 diabetes mellitus who are on stable treatment. • History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis per chest CT scan at screening. • Patients with uncontrolled asthma or allergy, requiring systemic steroid treatment • Regular treatment with corticosteroids within the 4 weeks prior to date of registration, unless administered for indications other than NHL at a dose equivalent to < 30 mg/day prednisone/prednisolone.
General • Serious underlying medical conditions, which could impair the ability of the patient to participate in the trial (e.g. ongoing infection, uncontrolled diabetes mellitus, gastric ulcers, active autoimmune disease) • Current participation in another clinical trial interfering with this trial • History of active cancer during the past 5 years, except basal cell carcinoma of the skin or stage 0 cervical carcinoma or carcinoma in situ (for which no systemic treatment was indicated) • Life expectancy < 6 months • Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule
Prior treatment • Prior treatment with atezolizumab, or anti PD-1 or PDL-1 antibodies. • Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA4 therapeutic antibodies. • Treatment with systemic immunostimulatory agents (including but not limited to IFN, interleukin [IL]-2) within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to date of registration. • Treatment with systemic immunosuppressive medications, including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (anti-TNF) agents within 2 weeks prior to date of registration; inhaled corticosteroids and mineralocorticoids are allowed.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
• Disease free survival measured from the date of registration to relapse or death from any cause whichever comes first. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
The endpoint will be evaluated when applicable data for all patients are available |
|
E.5.2 | Secondary end point(s) |
• (Severe) Adverse Events and the relation of adverse events in time to the recovery of the T-cell repertoire • Overall survival, calculated from registration until death from any cause. Patients still alive or lost to follow up are censored at the last date known to be alive. • The relationship between MRD status at the end-of-induction and end-of-consolidation therapy. • The relation between MRD conversion and 2-years DFS and OS • The relationship between T-cell repertoire, PDL1/HLA expression, mutational load, gene immune signature, microbiome and effect of atezolizumab on MRD conversion. • The relation between the T-cell and NK cell repertoire and adverse events.
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
The endpoint will be evaluated when applicable data for all patients are available |
|
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 | 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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 32 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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 | 6 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
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 |
E.8.9.2 | In all countries concerned by the trial days | 0 |