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Clinical picture: NHL (Non Hodgkin Lymphoma)

Trial: HOVON 152 DLBCL


News
1. Overview
Study details
2. Patient eligibility criteria
3. Registration (& randomization) of patients
4. Participating parties
5. Participating sites
6. Instruction videos
7. Download documentation / forms


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News


HO 152 News

Study has been approved by the EC and CA

1. Overview



Summary

Patients with high grade B cell lymphoma th at harbor a MYC combined with a BCL2 and/or a BCL6 rearrangement (double-hit or triple-hit high-grade B cell lymphoma, DH/TH HGBL) have a dismal prognosis following standard treatment with R-CHOP. Intensified treatment with DA-EPOCH-R induces higher complete metabolic remission (CMR) rates and prolongs disease free survival (DFS) as compared to R-CHOP and other intensified chemotherapy regimens, but relapses do often occur and improved overall survival (OS) has not been achieved.
Check-point inhibitors like nivolumab show promising results in relapsed Non-Hodgkin lymphoma. We expect to induce deeper remissions with DA-EPOCH-R than with R-CHOP, providing a good platform for immune checkpoint inhibition to consolidate complete remission or to induce remission in minimal residual disease (MRD) positive patients, resulting in better DFS.


Status

open


Members

HOVON


 Patienten informatie


Study details



Type of study

Prospective Phase II study


Echelon level

Level D


Echelon level specification

Limited nr of sites


Type of monitoring for this study

Site evaluation visits


Target number of patients

102


Date of activation

31-Jul-2018


Study objectives

Primary objective:
To increase 12 months DFS of DH/TH-HGBL patients in CMR after DA-EPOCH-R from 70% to 85% with nivolumab consolidation treatment

Secondary objectives:
To evaluate CMR rate after DA-EPOCH-R
To evaluate 18 months event free survival (EFS) and overall survival (OS) of all patients
To evaluate 12 months overall survival under consolidation (OSc) of patients registered for consolidation
To evaluate safety of nivolumab treatment
To explore the accuracy of mid-treatment 18F-FDG PET-CT to predict metabolic response end-of-treatment.
To explore the efficacy of nivolumab with regard to induction of MRD negativity by circulating tumor DNA and extracellular vesicle microRNA
To explore PD1/PDL1 expression in relation to NGS, GEP and to outcome
To explore T cell subsets and clonality during treatment and in relation to MRD


2. Patient eligibility criteria



Inclusion criteria

PLEASE NOTE: The inclusion criteria for consolidation are different from the criteria for induction!

Inclusion for DA-EPOCH-R induction:
• High-grade B-cell lymphoma, with MYC in combination with BCL2 and/or BCL6 rearrangements as assessed by FISH according to the WHO 2016 classification.
• Age ≥ 18 year.
• Patient started with or has received one course of full dose R-CHOP. [Reversed R-CHOP (cyclophosphamide, vincristine and doxorubicin on day 5) is allowed; local radiation or short course (max 7 days) of steroids (max 100 mg/day) before R-CHOP is allowed. Mini-R-CHOP is not allowed].
• WHO performance status 0-3 during or after the first R-CHOP cycle (see appendix C).
• Ann Arbor stage II-IV at diagnosis (see appendix A).
• 18F-FDG PET scan and contrast enhanced CT-scan performed within 21 days before start first cycle of R-CHOP.
• Measurable disease: on contrast enhanced CT-scan at least 1 lesion/node with a long axis of >1.5 cm and at least one 18F-FDG avid lesion.
• Negative pregnancy test at study entry.
• Patient is willing and able to use adequate contraception until 6 months post last treatment administration.
• Written informed consent.
• Patient is capable of giving informed consent.

Inclusion for Nivolumab consolidation:
• Complete metabolic response on end of induction 18F-FDG PET-CT assessed with the Deauville response criteria (see 10.3)
• Patient has completed at least R-CHOP plus four cycles of DA-EPOCH-R induction treatment


Exclusion criteria

PLEASE NOTE: The exclusion criteria for consolidation are different from the criteria for induction!

Exclusion for DA-EPOCH-R induction:
• All histopathological diagnoses other than DH/TH-HGBL (like testicular large B-cell lymphoma or primary mediastinal B-cell lymphoma) according to WHO 2016 classification.
• Known history of indolent lymphoma with the execption of localization of an indolent lymphoma component in the bone marrow detected during pre-treatment screening procedures.
• Inadequate renal function or creatinine clearance < 30 mL/min (after rehydration). 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 hepatic function: bilirubin > 3 times ULN (total) except patients with Gilbert's syndrome as defined by > 80% unconjugated bilirubin.
• Inadequate hematological function: ANC < 1.0x109/L or platelets < 75x109 /L before R-CHOP unless lymphoma related.
• CNS localization of the lymphoma. CSF analysis before start of treatment is only necessary in case of suspicion of CNS localization.
• Female subject pregnant or breast-feeding.
• History of active malignancy during the past 5 years with the exception of basal carcinoma of the skin or stage 0 cervical carcinoma.
• Active symptomatic ischemic heart disease, myocardial infarction, or congestive heart failure within the past year. In case of cardiac history, an echo or MUGA should be obtained and LVEF should exceed 40% to be eligible.
• Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, cancer, etc.) that would jeopardize the patient's ability to receive the regimen with reasonable safety.
• HIV positivity.
• Active Hepatitis B or C infection as defined by positive serology and transaminitis. Non-active Hepatitis B carriers may be included if protected (see 9.2.3).
• Severe pulmonary dysfunction (CTCAE grade III-IV, see appendix D).
• Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Prior treatment with an anti-PD1, anti-PDL1, anti-PDL2, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways.
• Severe neurological or psychiatric disease.
• Current participation in another clinical trial interfering with this trial.
• Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
• Claustrophobia precluding PET-CT.

Inclusion for Nivolumab consolidation:
• Inadequate renal function or creatinine clearance < 30 mL/min (after rehydration).
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 hepatic function: bilirubin > 3 times ULN (total) except patients with Gilbert's syndrome as defined by > 80% unconjugated bilirubin.
• Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.


3. Registration (& randomization) of patients



Registration

Registratie via TOP (https://www.hdc.hovon.nl/top). In de toekomst wordt dit ALEA.

Registratie in TOP voor start van de DA-EPOCH-R inductie behandeling. Naast inclusie en exclusie criteria worden ook labwaarden voor eligibility opgevraagd.
LET OP: Tweede registratie in TOP voor start van de Nivolumab consolidatie behandeling. Belangrijk om te controleren of een patiënt eligible is voor inclusie van de consolidatie fase.


4. Participating parties



5. Participating sites



Site
Included patients *
NL-Amsterdam-VUMC
4

* Please note that if TOP is not used to register patients for a study, the number of patients shown is zero.

6. Instruction videos



7. Download documentation / forms


 Protocol

 Patient Information & IC form (NL)



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