HOVON 152 DLBCL. 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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Stichting Hemato-Oncologie voor Volwassenen Nederland (Hovon), Stichting Hemato-Oncologie voor Volwassenen Nederland (Hovon)

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

26 Jul 2018 → ongoing

Decision date (initial)

2023-06-01

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

BMS

External identifiers

EU CT number

2022-501038-48-00

EudraCT number

2017-003631-12

ClinicalTrials.gov

NCT03620578

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

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 8

1. To evaluate CMR rate after completion of DA-EPOCH-R
2. To evaluate 18 months PFS and OS of all patients
3. To evaluate 12 months overall survival under consolidation (OSc) of patients registered for consolidation
4. To evaluate safety of nivolumab treatment
5. To explore the accuracy of mid-treatment 18F-FDG PET-CT to predict CMR end-of-treatment.
6. To explore the efficacy of nivolumab with regard to induction of MRD negativity by circulating tumor DNA and extracellular vesicle associated microRNA
7. To explore PD1/PDL1 expression in relation to NGS, GEP and to outcome
8. To explore T cell subsets and clonality during treatment and in relation to MRD

Conditions and MedDRA coding

Diffuse Large B-Cell Lymphoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. 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 including high-grade B-cell lymphoma with MYC and BCL2 rearrangements, transformed from previously untreated FL.
2. Age ≥ 18 year.
3. Patient started with or has received one course of full dose R-CHOP or DA-EPOCH-R (cycle 1).Starting with DA-EPOCH-R in cycle 1 is only allowed when FISH results (confirming DH/TH diagnosis) are directly available at diagnosis. [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].
4. WHO performance status 0-3 during or after induction cycle 1
5. Ann Arbor stage II-IV at diagnosis
6. 18F-FDG PET scan and contrast enhanced CT-scan performed preferably within 28 days before start first induction cycle
7. 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
8. Negative pregnancy test at study entry
9. Patient is willing and able to use adequate contraception until 6 months post last treatment administration
10. Written informed consent
11. Patient is capable of giving informed consent

Exclusion criteria 20

1. 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.
2. Known history of indolent lymphoma previously treated with immunochemotherapy
3. Inadequate renal function or creatinine clearance < 30 mL/min (after rehydration)
4. Inadequate hepatic function: bilirubin > 3 times ULN (total) except patients with Gilbert's syndrome as defined by > 80% unconjugated bilirubin.
5. Inadequate hematological function: ANC < 1.0x109/L or platelets < 75x109 /L before induction cycle 1 unless lymphoma related.
6. CNS localization of the lymphoma. CSF analysis before start of treatment is only necessary in case of suspicion of CNS localization.
7. Female subject pregnant or breast-feeding.
8. History of active malignancy during the past 5 years with the exception of basal carcinoma of the skin or stage 0 cervical carcinoma
9. 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.
10. 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.
11. HIV positivity.
12. Active Hepatitis B or C infection as defined by positive serology and transaminitis. Non-active Hepatitis B carriers may be included if protected
13. Severe pulmonary dysfunction (CTCAE grade III-IV)
14. 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.
15. 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.
16. 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.
17. Severe neurological or psychiatric disease.
18. Current participation in another clinical trial interfering with this trial.
19. Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
20. Claustrophobia precluding PET-CT.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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-FDG PET-CT.

Secondary endpoints 10

1. CMR rate on 18F-FDG PET-CT after DA-EPOCH-R
2. 18 months PFS (defined as time from registration to disease progression, relapse or death, whichever comes first)
3. 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
4. 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
5. Rate of CTCAE grade >=2 toxicities
6. Rate of conversion to MRD negativity during consolidation
7. Assessment of the predictive value of mid-treatment 18F-FDG PET-CT with respect to CMR at the end of DA-EPOCH-R therapy
8. Association of PD1/PDL1 expression in relation NGS, GEP and to outcome
9. Association of MRD measurements by circulating tumor DNA and microRNA
10. Association of T cell subsets and clonality during nivolumab treatment and to MRD

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Stichting Hemato-Oncologie voor Volwassenen Nederland (Hovon)

Sponsor organisation

Stichting Hemato-Oncologie voor Volwassenen Nederland (Hovon)

Address

Dr. Molewaterplein 40

City

Rotterdam

Postcode

3015 GD

Country

Netherlands

Scientific contact point

Organisation

Haemato Oncology Foundation For Adults Netherlands (HOVON)

Contact name

M. Chamuleau

Public contact point

Organisation

Haemato Oncology Foundation For Adults Netherlands (HOVON)

Contact name

HOVON Data Center

Third parties 1

Stichting Hemato-Oncologie voor Volwassenen Nederland (Hovon)

Sponsor organisation

Stichting Hemato-Oncologie voor Volwassenen Nederland (Hovon)

Address

Dr. Molewaterplein 40

City

Rotterdam

Postcode

3015 GD

Country

Netherlands

Scientific contact point

Organisation

Haemato Oncology Foundation For Adults Netherlands (HOVON)

Contact name

M. Chamuleau

Public contact point

Organisation

Haemato Oncology Foundation For Adults Netherlands (HOVON)

Contact name

HOVON Data Center

Third parties 1

Locations

2 EU/EEA countries · 24 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

2 submissions — initial application plus substantial / non-substantial modifications