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Clinical picture: NHL (Non Hodgkin Lymphoma)
Trial: HOVON 151 DLBCL
2. Patient eligibility criteria
3. Registration (& randomization) of patients
4. Participating parties
5. Participating sites
6. Instruction videos
7. Download documentation / forms
The following documents are updated:
12-FEB-2020: Drug order form and pharmacy manual (update)
03-FEB-2020: Labmanual V6 & FAQ document (update)
18-Oct-2019: Newsletter 4.1
17-Sep-2019: Registration form is updated (IPI score clarification)
07-May-2019: Protocol v3 & ICF v4
27-Sept-2018: Toedienlijst version 2
3-Dec-2018: Flowsheet 'verpleegkundige instructies'
18-01-2019: SAE instructies (versienummer aangepast)
In high risk diffuse large B-cell lymphoma (DLBCL), International Prognostic Index (IPI)-score ≥ 3, 21% of patients will relapse within 2-years after completion of R-CHOP induction treatment despite achieving a complete remission. Patient relapsing within a year after R-CHOP treatment have a very poor prognosis, even after second line chemotherapy, with only 15% of patients achieving a long remission. Therefore, additional therapy in first line treatment is required for these patients. The immune checkpoint inhibitor atezolizumab is a monoclonal antibody directed against the program death ligand 1 (PDL1). The PD1 and PDL1 inhibitors have shown excellent results in relapsed Hodgkin lymphoma and promising results in relapsed B-cell non Hodgkin lymphoma. Given the acceptable toxicity profile of atezolizumab, this study examines the efficacy and toxicity of atezolizumab as consolidation treatment after R-CHOP induction in DLBCL patients at high risk of relapse.
Type of study
Prospective Phase II study
Echelon level specification
Type of monitoring for this study
Site evaluation visits
Target number of patients
Date of first EC&CA submission
Date of activation
Change history / amendement
20-MAR-2019 Protocol and ICF amendement
• To evaluate the 2-year disease free survival (DFS)
• To evaluate toxicity and asses the relation of adverse events in time to recovery of the T-cell repertoire.
• To evaluate the 2-year overall survival (OS)
• To evaluate minimal residual disease (MRD) status at the end of induction therapy and at various time points during consolidation treatment.
• To evaluate the recovery of the T-cell and NK cell repertoire after induction therapy and at various time points 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.
2. Patient eligibility 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
1. Rituximab may have been administered either intravenously or subcutaneously. A rituximab biosimilar may have been used when it is approved for the indication of DLBCL.
2. Only dose reductions for vincristine are allowed during R-CHOP. Patients should have received a cumulative dose that equals at least 6 cycles R-CHOP without dose reduction.
3. Central nervous system prophylaxis (MTX) by intrathecal or IV therapy is allowed.
4. 18F-FDG-PET scan should have been made 4-8 weeks after last induction cycle
• Negative pregnancy test at study entry.
• Patient is willing and able use adequate contraception during and until 5 months after the last protocol treatment.
• Written informed consent
• Patient is capable of giving a written informed consent.
• 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.
• 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:
CrCl = [(140 – age [in years]) x weight (kg)] (x [0.85 if Female) / (0.815 x serum creatinine [μmol/L])
• Inadequate hematological function: hemoglobin < 5.5 mmol/L ANC < 1.0x109/L or platelets < 75x109 /L.
• 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 weeks 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.
• 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.
• 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
• Life expectancy < 6 months
• Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule
• 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.
3. Registration (& randomization) of patients
Eligible patients should be registered before start of treatment. Patients need to be registered at the HOVON Data Center by one of the following options:
♦ By ALEA; select the [patient] tab and click the [ Add new patient] button. Complete all items and click the [Submit] button
♦ By faxing the completed registration/randomization CRF +31.10.7041028 Monday through Friday, from 09:00 to 17:00 CET
♦ By phone +31.10.7041560 Monday through Friday, from 09:00 to 17:00
BE-BRUGGE-AZ St. Jan 0
NL-Amersfoort Meander MC 0
NL-Den Bosch-JBZ 5
NL-Den Haag-HAGA 0
NL-Dordrecht-Albert Schweitzer 0
NL-Eindhoven-Catharina ZH 3
NL-Eindhoven-Maxima MC 1
NL-Hilversum-Tergooi ZH 0
NL-Hoofddorp-Spaarne Gasthuis 0
NL-Rotterdam=-Erasmus MC 0
NL-Sittard-Zuyderland MC 0