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Non Hodgkin LymphomaPhase 2HO152NCT03620578

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

A Phase 2 study testing DA-EPOCH-R followed by Nivolumab in people with Non Hodgkin Lymphoma and Lymphoma, B-Cell, run by Stichting Hemato-Oncologie voor Volwassenen Nederland at 24 sites in 2 countries.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
Search all trials

Trial 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)… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
DA-EPOCH-R followed by Nivolumab
Could I receive a placebo?
No, everyone receives an active treatment
How many people
97 participants
Where
24 sitesin 2 countries
Study dates
1 Aug 2018to Oct 2026
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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

Who cannot join

  • 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.
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  • 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.

Trial locations and contacts

24 sites in 2 countries.

24 sites in 2 countries

Netherlands22 sites

  • NL-Den Bosch-JBZ

    's-Hertogenbosch

  • NL-Almere-FLEVOZIEKENHUIS

    Almere Stad

  • NL-Amersfoort-MEANDERMC

    Amersfoort

  • NL-Amsterdam-AMC

    Amsterdam

  • NL-Amsterdam-VUMC

    Amsterdam

  • NL-Eindhoven-MAXIMAMC

    Eindhoven

  • NL-Enschede-MST

    Enschede

  • NL-Goes-ADRZ

    Goes

  • NL-Groningen-UMCG

    Groningen

  • NL-Hoofddorp-SPAARNEGASTHUIS

    Hoofddorp

  • NL-Hoorn-DIJKLANDERHOORN

    Hoorn

  • NL-Leeuwarden-MCL

    Leeuwarden

  • NL-Leiden-LUMC

    Leiden

  • NL-Maastricht-MUMC

    Maastricht

  • NL-Nijmegen-RADBOUDUMC

    Nijmegen

  • NL-Rotterdam-ERASMUSMC

    Rotterdam

  • NL-Rotterdam-MAASSTADZIEKENHUIS

    Rotterdam

  • NL-Sittard-Geleen-ZUYDERLAND

    Sittard

  • NL-Den Haag-HAGA

    The Hague

  • NL-Tilburg-ETZ

    Tilburg

  • NL-Utrecht-UMCUTRECHT

    Utrecht

  • NL-Zwolle-ISALA

    Zwolle

Other trials in Netherlands

Belgium2 sites

  • BE-Antwerpen-ZNASTUIVENBERG

    Antwerp

  • BE-Leuven-UZLEUVEN

    Leuven

Other trials in Belgium

About this study

Official title: A Phase II Study Evaluating the Effect of DA-EPOCH-R Induction Followed by Nivolumab Consolidation in Patients With Newly Diagnosed High Grade B Cell Lymphoma (HGBL) With MYC and BCL2 and/or BCL6 Rearrangements

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.

Read the 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.

Being tested
DA-EPOCH-R followed by Nivolumab
Keywords
DLBCL, HGBL, BCL-2, BCL-6, double-hit, triple-hit, R-CHOP, DA-EPOCH-R, Nivolumab, PD1/PDL1 expression
Medical subject headings
Lymphoma, Non-Hodgkin, Lymphoma, B-Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • DA-EPOCH-R followed by NivolumabDrug

    Also called Opdivo

    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 groups in NCT03620578
Study groupRoleWhat they receive
DA-EPOCH-R followed by NivolumabExperimental5 cycles of DA-EPOCH-R protocol induction, followed with one year Nivolumab consolidation for end-of-induction patients who are in complete metabolic response
Receives: Drug: DA-EPOCH-R followed by Nivolumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  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)

    Measured: 12 months

Secondary outcomes (7)

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

    CMR rate on 18F-FDG PET-CT after DA-EPOCH-R

    Measured: at 18 weeks

  2. 18 months Progression-Free Survival (PFS)

    18 months PFS (defined as time from registration to disease progression, relapse or death, whichever comes first)

    Measured: 18 months

  3. 18 months OS

    18 months OS (defined as time from registration until death from any cause; patients still alive or lost to follow up are censored at the date they were last known to be alive) of all patients

    Measured: 18 months

  4. 12 months OSc

    12 months overall survival under consolidation (OSc), defined as time from registration for consolidation until death from any cause. Patients still alive or lost to follow up are censored at the date they were last known to be alive

    Measured: 12 months

  5. Rate of CTCAE grade >=2 toxicities

    Rate of CTCAE grade >=2 toxicities

    Measured: During 70 weeks treatment + 100 additional days during follow up

  6. consolidation MRD conversion

    Rate of conversion to MRD negativity during consolidation

    Measured: 12 months

  7. predictive value of mid-treatment 18F-FDG PET-CT

    Assessment of the predictive value of mid-treatment 18F-FDG PET-CT with respect to CMR at the end of DA-EPOCH-R therapy

    Measured: 2 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted8 Aug 2018
  2. Study start1 Aug 2018
  3. Primary completion30 Jan 2024
  4. Study completionOct 2026 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Model description
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.
Masking
None (open label)
Enrolment
97 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03620578
Sponsor's protocol ID
HO152
Other IDs
2017-003631-12, 2017
Acronym
HO152
Status last verified
Feb 2024
First submitted
26 Jul 2018
Last updated
14 Feb 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing DA-EPOCH-R followed by Nivolumab in people with Non Hodgkin Lymphoma and Lymphoma, B-Cell, run by Stichting Hemato-Oncologie voor Volwassenen Nederland at 24 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 14 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 24 sites in Netherlands, Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

12 months DFS from Nivolumab consolidation registration (time frame: 12 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03620578.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Feb 2024.

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