DA-EPOCH-R Induction Followed by Nivolumab Consolidation in Newly Diagnosed MYC, BCL2 and/or BCL6 Rearranged HGBL

NCT03620578 | Active Not Recruiting Phase 2 DMC

• 2 other identifiers: HO1522017-003631-12
• Study Type: interventional
• Target: 97
• Locations: 2 countries
• Sites: 24

Brief 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.

Conditions

Non Hodgkin Lymphoma; Lymphoma, B-Cell; High-grade B-cell Lymphoma; MYC Translocation; BCL-2 Translocation

Keywords

DLBCL; HGBL; BCL-2; BCL-6; double-hit; triple-hit; R-CHOP; DA-EPOCH-R; Nivolumab; PD1/PDL1 expression

Outcome Measures

Primary Outcomes (1)

• 12 months DFS from Nivolumab consolidation registration

  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)

  12 months

Secondary Outcomes (7)

• Complete metabolic response (CMR) rate on 18F-FDG PET-CT after DA-EPOCH-R

  at 18 weeks

• 18 months Progression-Free Survival (PFS)

  18 months

• 18 months OS

  18 months

• 12 months OSc

  12 months

• Rate of CTCAE grade >=2 toxicities

  During 70 weeks treatment + 100 additional days during follow up

Study Arms (1)

DA-EPOCH-R followed by Nivolumab

EXPERIMENTAL

5 cycles of DA-EPOCH-R protocol induction, followed with one year Nivolumab consolidation for end-of-induction patients who are in complete metabolic response

Drug: DA-EPOCH-R followed by Nivolumab

Interventions

DA-EPOCH-R followed by Nivolumab DRUG

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

Also known as: Opdivo

DA-EPOCH-R followed by Nivolumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• F-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.
• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Stichting Hemato-Oncologie voor Volwassenen Nederland: lead

Study Sites (24)

BE-Antwerpen-ZNASTUIVENBERG

Antwerp, Belgium

Location

BE-Leuven-UZLEUVEN

Leuven, Belgium

Location

NL-Den Bosch-JBZ

's-Hertogenbosch, Netherlands

Location

NL-Almere-FLEVOZIEKENHUIS

Almere Stad, Netherlands

Location

NL-Amersfoort-MEANDERMC

Amersfoort, Netherlands

Location

NL-Amsterdam-AMC

Amsterdam, Netherlands

Location

NL-Amsterdam-VUMC

Amsterdam, Netherlands

Location

NL-Eindhoven-MAXIMAMC

Eindhoven, Netherlands

Location

NL-Enschede-MST

Enschede, Netherlands

Location

NL-Goes-ADRZ

Goes, Netherlands

Location

NL-Groningen-UMCG

Groningen, Netherlands

Location

NL-Hoofddorp-SPAARNEGASTHUIS

Hoofddorp, Netherlands

Location

NL-Hoorn-DIJKLANDERHOORN

Hoorn, Netherlands

Location

NL-Leeuwarden-MCL

Leeuwarden, Netherlands

Location

NL-Leiden-LUMC

Leiden, Netherlands

Location

NL-Maastricht-MUMC

Maastricht, Netherlands

Location

NL-Nijmegen-RADBOUDUMC

Nijmegen, Netherlands

Location

NL-Rotterdam-ERASMUSMC

Rotterdam, Netherlands

Location

NL-Rotterdam-MAASSTADZIEKENHUIS

Rotterdam, Netherlands

Location

NL-Sittard-Geleen-ZUYDERLAND

Sittard, Netherlands

Location

NL-Den Haag-HAGA

The Hague, Netherlands

Location

NL-Tilburg-ETZ

Tilburg, Netherlands

Location

NL-Utrecht-UMCUTRECHT

Utrecht, Netherlands

Location

NL-Zwolle-ISALA

Zwolle, Netherlands

Location

Related Links

• Website of the HOVON organisation

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin; Lymphoma, B-Cell

Interventions

Nivolumab

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• M. ED Chamuleau, MD PhD

  VUmc / HOVON

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The trial is designed as a prospective, multicenter, non-randomized phase II trial. All eligible patients will be registered during or after first R-CHOP, but before start of DA-EPOCH-R treatment and before start of nivolumab treatment.

Study Record Dates

• First Submitted: July 26, 2018
• First Posted: August 8, 2018
• Study Start: August 1, 2018
• Primary Completion: January 30, 2024
• Study Completion (Estimated): October 1, 2026
• Last Updated: February 14, 2024

Record last verified: 2024-02

Locations

NL (22); BE (2)