HOVON HO151 NHL

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Main info

Identificatie:
HO151 NHL
Sponsor:
HOVON
Working group party:
Lymphoma
Age:
18-75
Stadium:
1st lijn
Echelon:
Level C-HIC&C-SCT
Included patients:
101
(of 109)
Active sites:
31
(of 30)
Title:

A phase II study evaluating the feasibility and clinical efficacy of atezolizumab consolidation treatment in high risk diffuse large B-cell lymphoma

Timeline

Scheduled
Actual
2018
11 jan.
Opportunity
2018
15 mrt.
EC Approval
2018
28 aug.
EC Approval
2018
30 aug.
Activated
2018
30 aug.
First Site
2018
07 sep.
First Site
2018
07 sep.
FPI
2019
15 jan.
FPI
2023
30 sep.
Endpoint Analysis

News

18-06-2021: updated ICF_(NL) - non substantial amendment
17-May-2021: Updated labmanual (version 10) is available
10-May-2021: A screening list is active for the registration of the last 12 patients in this study - please contact the HDC trial manager or central datamanagers of this study
19-Apr-2021: Nieuwsbrief 9 & updated PET-CT verzendformulier
24-Feb-2021: Updated Pharmacy Manual and drug order form
01-Feb-2021: Instruction for collecting faeces (NL) is updated
17-Sep-2019: Registration form is updated (IPI score clarification)
07-May-2019: Protocol v3 & ICF v4
27-Sept-2018: 'Toedienlijst' version 2
03-Dec-2018: Flowsheet 'verpleegkundige instructies'
18-01-2019: SAE instructions (updated version number)

Flow

Flow

Details

Phase:
Prospective Phase II study
Monitoring Type:
Site Evaluation Visit
Objectives:

Primary objective

  • To evaluate the 2-year DFS for patients in complete metabolic remission after R-CHOP induction.

Note: The 2-year event free survival, defined as relapse, re-treatment or death, was established as a robust end point for disease related outcome in DLBCL.81 Since in this study re-treatment can only be initiated after relapse, 2-years EFS equals 2-years DFS

Secondary objective

  • To evaluate toxicity and assess the relation of adverse events in time to recovery of the Tcell repertoire.
  • To evaluate the 2-year OS.
  • To evaluate MRD status at the end of induction therapy, at various time points during consolidation treatment and at the end of consolidation (see paragraph 10.5.1).
  • 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 (see paragraph 10.5.3)

Exploratory objectives

  • 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. (see paragraph 10.5.2).
  • To explore the tumor characteristics and mutational dynamics in patients who relapse (see paragraph 10.5.6).
  • To assess the crossing of the blood-brain barrier of atezolizumab by measuring atezolizumab concentrations in het cerebrospinal fluid.

Eligibility

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 (see appendix A).
  • Ann Arbor stages II-IV (see appendix B).
  • WHO performance status 0 – 1 (see appendix E).
  • IPI ≥ 3 at diagnosis (see appendix C).
  • Complete metabolic remission (Deauville 1-3) after 6-8 cycles of R-CHOP according to the Lugano criteria (see appendix D).
  • Of note:
  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. F-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.
Exclusion Criteria:

Diagnosis

  • All histopathological diagnoses other than DLBCL-NOS according to the WHO classification, revision 2016 (see appendix A), 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: CrCl = (140 - age [in years]) x weight [kg] (x 0.85 for females)/ (0.815 x serum creatinine [μmol/L])
  • Inadequate hematological function: hemoglobin < 5.5 mmol/L ANC < 1.0x10^9/L or platelets <75x10^9 /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.

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
  • 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.

Registration Details

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 CET

Interim analysis (Q2/Q3-2020)

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Participating Sites

Ziekenhuizen die deelnemen aan het onderzoek staan benoemd op de HOVON website bij het onderzoek. Het kan zijn dat uw ziekenhuis niet genoemd wordt, maar wel aan het onderzoek deelneemt. Informeer hiernaar bij uw arts.

Site
31 results
Order by
Accrual rate
Activation date
NL-Groningen-UMCG
9
07 sep. 2018
NL-Den Bosch-JBZ
7
14 jan. 2019
NL-Ede-ZGV
6
07 jan. 2019
NL-Rotterdam-MAASSTADZIEKENHUIS
6
04 jul. 2019
NL-Eindhoven-CATHARINA
6
31 jan. 2019
BE-Leuven-UZLEUVEN
5
10 apr. 2019
NL-Nieuwegein-ANTONIUS
5
05 nov. 2018
BE-Roeselare-AZDELTA
5
30 jan. 2019
NL-Amersfoort-MEANDERMC
5
09 jan. 2019
NL-Breda-AMPHIA
4
10 apr. 2019
NL-Delft-RDGG
4
26 nov. 2018
NL-Nijmegen-CWZ
4
04 jan. 2019
NL-Amsterdam-VUMC
3
22 jan. 2019
NL-Eindhoven-MAXIMAMC
3
11 feb. 2019
NL-Leiden-LUMC
3
01 nov. 2019
BE-Antwerpen-ZNASTUIVENBERG
3
07 jun. 2019
NL-Hoofddorp-SPAARNEGASTHUIS
2
10 jul. 2019
NL-Tilburg-ETZ
2
12 dec. 2019
NL-Apeldoorn-GELREAPELDOORN
2
03 apr. 2020
BE-Brugge-AZBRUGGE
2
26 mrt. 2019
NL-Dordrecht-ASZ
2
01 mei 2019
BE-Antwerpen Edegem-UZA
2
18 mrt. 2019
NL-Sittard-Geleen-ZUYDERLAND
2
02 aug. 2019
NL-Maastricht-MUMC
2
15 jan. 2019
NL-Amsterdam-OLVG
2
17 jul. 2019
NL-Leeuwarden-MCL
1
24 dec. 2018
NL-Enschede-MST
1
31 okt. 2019
NL-Hilversum-TERGOOI
1
07 mrt. 2019
NL-Rotterdam-ERASMUSMC
1
03 mei 2019
NL-Zwolle-ISALA
1
20 mei 2019
NL-Den Haag-HAGA
08 jul. 2019
= Active hospitals
= Inactive hospitals

Participating Parties

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