DA-EPOCH-R followed by Nivolumab: 5 induction cycles of DA-EPOCH-R protocol, for patient with Deauville imaging response criteria proven complete metabolic response followed with one year Nivolumab consolidation therapy
Study summary
The prognosis of patients with "high-grade B cell lymphoma with cellular myelocytomatosis (MYC) and B cell lymphoma 2 (BCL2) and/or B cell lymphoma 6 (BCL6) rearrangements" (double hit (DH)/triple hit (TH)-HGBL) with rituximab-CHOP (R-CHOP) is dismal as compared to patients with diffuse large B cell lymphoma (DLBCL) without MYC, BCL2 and/or BCL6 rearrangements. Currently, there is no other standard first line treatment for these patients. Dose Adjusted - Etoposide Prednisone Vincristine Cyclophosphamide Doxorubicin - Rituximab (DA-EPOCH-R) and nivolumab are both feasible treatments. Nivolumab may induce auto-immune reactions. DA-EPOCH-R may induce more hematological toxicity than R-CHOP. The hypothesis is that addition of nivolumab to DA-EPOCH-R will contribute to increased survival.
Eligibility
Sex
ALL
Min age
18 Years
Max age
—
Healthy volunteers
No
Inclusion Criteria:
Inclusion Criteria for DA-EPOCH-R induction:
* High-grade B-cell lymphoma, with MYC in combination with BCL2 and/or BCL6 rearrangements as assessed by fluorescence in situ hybridization (FISH) according to the WHO 2016 classification including high-grade B-cell lymphoma with MYC and BCL2 rearrangements, transformed from previously untreated FL.
* Age ≥ 18 year.
* Patient started with or has received one course of full dose R-CHOP. \[Reversed R-CHOP (cyclophosphamide, vincristine and doxorubicin on day 5) is allowed; local radiation or short course (max 7 days) of steroids (max 100 mg/day) before R-CHOP is allowed. Mini-R-CHOP is not allowed\].
* World Health Organization (WHO) performance status 0-3 during or after the first R-CHOP cycle.
* Ann Arbor stage II-IV at diagnosis.
* 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 criteria for Nivolumab consolidation:
* Complete metabolic response on end of induction 18F-FDG PET-CT assessed with the Deauville response criteria
* Patient has completed at least R-CHOP plus four cycles of DA-EPOCH-R induction treatment
Exclusion Criteria:
Exclusion Criteria 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 previously treated with immunochemotherapy.
* Inadequate renal function or creatinine clearance \< 30 mL/min (after rehydration). Creatinine clearance (CrCl) 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 upper limit of normal (ULN) (total) except patients with Gilbert's syndrome as defined by \> 80% unconjugated bilirubin.
* Inadequate hematological function: absolute neutrophil count (ANC) \< 1.0x109/L or platelets \< 75x109 /L before R-CHOP unless lymphoma related.
* Central nervous system (CNS) localization of the lymphoma. Cerebrospinal fluid (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 multigated acquisition (MUGA) should be obtained and left ventricular ejection fraction (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
* Severe pulmonary dysfunction (CTCAE grade III-IV).
* 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.
Exclusion criteria 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.
Primary outcome measure(s)
12 months DFS from Nivolumab consolidation registration — 12 months 12 months DFS (defined as time from registration for consolidation to disease relapse or death, whichever comes first) of patients in CMR as assessed by end of DA-EPOCH-R treatment 18F-Fludeoxyglucose Positron Emission Tomography- Computed Tomography (18F-FDG PET-CT)
Trial sites (24)
Facility
City
Region
Status
BE-Antwerpen-ZNASTUIVENBERG
Antwerp
Belgium
BE-Leuven-UZLEUVEN
Leuven
Belgium
NL-Den Bosch-JBZ
's-Hertogenbosch
Netherlands
NL-Almere-FLEVOZIEKENHUIS
Almere Stad
Netherlands
NL-Amersfoort-MEANDERMC
Amersfoort
Netherlands
NL-Amsterdam-AMC
Amsterdam
Netherlands
NL-Amsterdam-VUMC
Amsterdam
Netherlands
NL-Eindhoven-MAXIMAMC
Eindhoven
Netherlands
NL-Enschede-MST
Enschede
Netherlands
NL-Goes-ADRZ
Goes
Netherlands
NL-Groningen-UMCG
Groningen
Netherlands
NL-Hoofddorp-SPAARNEGASTHUIS
Hoofddorp
Netherlands
NL-Hoorn-DIJKLANDERHOORN
Hoorn
Netherlands
NL-Leeuwarden-MCL
Leeuwarden
Netherlands
NL-Leiden-LUMC
Leiden
Netherlands
NL-Maastricht-MUMC
Maastricht
Netherlands
NL-Nijmegen-RADBOUDUMC
Nijmegen
Netherlands
NL-Rotterdam-ERASMUSMC
Rotterdam
Netherlands
NL-Rotterdam-MAASSTADZIEKENHUIS
Rotterdam
Netherlands
NL-Sittard-Geleen-ZUYDERLAND
Sittard
Netherlands
NL-Den Haag-HAGA
The Hague
Netherlands
NL-Tilburg-ETZ
Tilburg
Netherlands
NL-Utrecht-UMCUTRECHT
Utrecht
Netherlands
NL-Zwolle-ISALA
Zwolle
Netherlands
More Stichting Hemato-Oncologie voor Volwassenen Nederland trials in Belgium
This page summarises publicly available registry data for informational purposes — not medical advice. Eligibility is determined by each study team; patients should discuss participation with their clinician.
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