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

NCT ID: NCT03620578

Last Updated: 2024-02-14

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 97 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-08-01
• Study Completion Date: 2026-10-31

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.

Detailed Description

The dismal prognosis of DH-DLBCL patients following standard therapy with R-CHOP (overall survival at 2 years 35% for MYC+ vs 61% for MYC- patients) justifies upfront new treatment approaches.

Attempts have been made to improve prognosis of DH-DLBCL patients with intensified chemotherapy schemes like DA-EPOCH-R, standard treatment of Burkitt lymphoma with high dose multi-agent chemotherapy (R-CODOX-M/R-IVAC) and autologous stem cell transplantation. These treatment schedules seem to prolong disease-free survival (DFS), but relapses do often occur and improved OS has not been achieved. The investigators hypothesize to increase the number of patients in complete remission with DA-EPOCH-R to 65% as compared to 50% for R-CHOP. DA-EPOCH-R is a well-known scheme for the treatment of patients with Burkitt Lymphoma, and is one of the treatment arms of the Hemato-Oncologie voor Volwassenen Nederland (HOVON) 127 protocol. For DH-DLBCL patients the investigators expect that it will improve the complete remission (CR) rate and prolong DFS as compared to R-CHOP as has been shown in several retrospective studies. It is also clear from these studies that relapses still occur and that OS is not improved by chemotherapy only.

The investigators expect to induce deeper remission with DA-EPOCH-R providing the opportunity for nivolumab to consolidate complete remission, prolong DFS, or to induce conversion of minimal residual disease (MRD) positivity to MRD negativity.

A new approach underlying this proposal is to enhance anti-tumor immune responses. Malignancies with MYC aberrations were long thought to be independent of immune responses. However, recently it was shown that MYC expressing lymphoma and leukaemia mouse and human cell lines upregulate programmed death-ligand 1 (PDL1) ("don't find me" signal) and CD47 ("don't eat me" signal) expression. Inactivation of MYC enhanced tumour immune responses in vivo in mice. Moreover, a subset of DLBCL does express PDL1.

No correlation with MYC rearrangements or protein expression has been described in these studies; however, these data suggest that tumours with MYC overexpression may be especially vulnerable to treatment with immune check point inhibitors, providing the rationale for treatment with nivolumab.

Conditions

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

DA-EPOCH-R followed by Nivolumab

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

Group Type: EXPERIMENTAL

DA-EPOCH-R followed by Nivolumab

Intervention Type: 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

Interventions

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

Intervention Type: DRUG

Other Intervention Names

Opdivo

Eligibility Criteria

Inclusion Criteria

• 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.

• 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

• 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.

• 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Stichting Hemato-Oncologie voor Volwassenen Nederland

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

M. ED Chamuleau, MD PhD

Role: PRINCIPAL_INVESTIGATOR

VUmc / HOVON

Locations

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

Countries

Belgium; Netherlands

Related Links

http://www.hovon.nl

Website of the HOVON organisation

Other Identifiers

2017-003631-12

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

HO152

Identifier Type: -

Identifier Source: org_study_id