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
- Trial ID
- 2022-501038-48-00
- Protocol
- HO152
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this phase II study is to increase the 12-month **disease-free survival** (DFS) rate in patients with double-hit/triple-hit high-grade B-cell lymphoma (DH/TH-HGBL) who achieve complete metabolic response (CMR) after DA-EPOCH-R induction therapy, from 70% to 85% through the use of nivolumab consolidation treatment. This objective is clinically relevant as it aims to improve long-term outcomes in a patient population with aggressive lymphoma subtypes characterized by MYC and BCL2 and/or BCL6 rearrangements.
Secondary objectives include:
- Evaluating the CMR rate after completion of DA-EPOCH-R.
- Assessing 18-month progression-free survival (PFS) and overall survival (OS) of all patients.
- Evaluating 12-month overall survival under consolidation (OSc) for patients registered for consolidation.
- Assessing the safety of nivolumab treatment.
- Exploring the accuracy of mid-treatment 18F-FDG PET-CT in predicting end-of-treatment CMR.
- Exploring the efficacy of nivolumab in inducing minimal residual disease (MRD) negativity through circulating tumor DNA and extracellular vesicle-associated microRNA.
- Exploring PD1/PDL1 expression in relation to next-generation sequencing (NGS), gene expression profiling (GEP), and outcomes.
- Exploring T cell subsets and clonality during treatment and in relation to MRD.
Participants
The clinical trial involves participants diagnosed with **Diffuse Large B-Cell Lymphoma**, specifically targeting those with high-grade B-cell lymphoma characterized by MYC in combination with BCL2 and/or BCL6 rearrangements. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a WHO performance status of 0-3 during or after the first induction cycle and must have measurable disease as determined by a contrast-enhanced CT scan. The trial includes individuals who have started or received one course of full-dose R-CHOP or DA-EPOCH-R, with specific conditions regarding the availability of FISH results. The study population is selected based on their ability to provide informed consent and their willingness to use adequate contraception until six months post-treatment. The sponsor has not provided information regarding the total number of participants. The trial does include a vulnerable population, and lifestyle considerations such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of a treatment regimen for patients with **Diffuse Large B-Cell Lymphoma** (DLBCL), specifically those with high-grade B-cell lymphoma characterized by MYC and BCL2 and/or BCL6 rearrangements. This is a Phase II, randomized, double-blind, controlled trial. The trial aims to assess the impact of DA-EPOCH-R induction therapy followed by nivolumab consolidation on disease-free survival (DFS) at 12 months. The trial is expected to run until March 2027, with recruitment having commenced in July 2022.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and disease characteristics. The inclusion criteria require participants to have measurable disease, a negative pregnancy test at entry, and the ability to provide informed consent. Following the screening, participants will receive the induction therapy, and their response will be monitored through regular follow-up visits. These visits will include assessments such as 18F-FDG PET-CT scans to evaluate complete metabolic response (CMR) and other relevant clinical evaluations.
The trial will involve a maximum treatment period of 52 weeks for nivolumab, with other drugs like rituximab, doxorubicin hydrochloride, prednisolone, vincristine sulfate, etoposide, and cyclophosphamide administered for up to 18 weeks. Participants will be monitored for primary endpoints, including 12-month DFS, and secondary endpoints such as progression-free survival (PFS) and overall survival (OS). The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted to evaluate the long-term effects of the treatment.
Participant involvement is expected to last up to 52 weeks, depending on the treatment regimen. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or disease progression. The trial's methodology ensures rigorous monitoring and data collection to achieve its objectives, with a focus on safety and efficacy outcomes.
Treatment
The clinical trial involves the administration of several **experimental medications** to evaluate their efficacy in patients with high-grade B cell lymphoma. **Rituximab** is administered as a **solution for infusion** with a maximum daily dose of 375 mg/m² and a total dose not exceeding 3000 mg/m². The route of administration is **intravenous**, and the treatment period is up to 18 weeks. **Rituximab** is a protein-based therapeutic agent used in this study.
**Doxorubicin Hydrochloride** is provided as a **concentrate for solution for infusion**. The maximum daily dose is 50 mg/m², with a total dose limit of 414 mg/m². It is administered **intravenously** over a period of 18 weeks. This agent is part of the chemotherapy regimen in the trial.
**Prednisolone** is administered in **tablet form** with a maximum daily dose of 120 mg/m² and a total dose of 3600 mg/m². The route of administration is **oral**, and the treatment duration is 18 weeks. Prednisolone serves as a corticosteroid in the study protocol.
**Vincristine Sulfate** is delivered as a **solution for injection/infusion** with a maximum daily dose of 2 mg and a total dose of 12 mg. The administration is **intravenous**, and the treatment period is 18 weeks. This agent is included in the chemotherapy regimen.
**Nivolumab**, marketed as **Opdivo**, is provided as a **solution for infusion** with a maximum daily and total dose of 480 mg. It is administered **intravenously** over a period of 52 weeks. Nivolumab is a protein-based therapeutic agent used for consolidation treatment in the trial.
**Etoposide** is administered as a **concentrate for solution for infusion** with a maximum daily dose of 103.7 mg/m² and a total dose of 2074 mg/m². The route of administration is **intravenous**, and the treatment duration is 18 weeks. Etoposide is part of the chemotherapy regimen.
**Cyclophosphamide** is provided as a **powder for solution for injection** with a maximum daily dose of 1555 mg/m² and a total dose of 9330 mg/m². It is administered **intravenously** over a period of 18 weeks. Cyclophosphamide is included in the chemotherapy regimen.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The study aims to assess the impact of these treatments on disease-free survival in patients with high-grade B cell lymphoma.
Efficacy
Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the 12-month **disease-free survival (DFS)**, defined as the time from registration for consolidation to disease relapse or death, whichever occurs first, in patients achieving complete metabolic response (CMR) as evaluated by 18F-FDG PET-CT at the end of DA-EPOCH-R treatment. Secondary endpoints include the CMR rate on 18F-FDG PET-CT after DA-EPOCH-R, 18-month progression-free survival (PFS), 18-month overall survival (OS), and 12-month overall survival under consolidation (OSc). Additional secondary endpoints involve the rate of CTCAE grade ≥2 toxicities, conversion to minimal residual disease (MRD) negativity during consolidation, and various associations such as PD1/PDL1 expression with next-generation sequencing (NGS) and gene expression profiling (GEP), MRD measurements by circulating tumor DNA and microRNA, and T cell subsets and clonality during nivolumab treatment in relation to MRD.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.
- Age ≥ 18 year.
- 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].
- WHO performance status 0-3 during or after induction cycle 1
- Ann Arbor stage II-IV at diagnosis
- 18F-FDG PET scan and contrast enhanced CT-scan performed preferably within 28 days before start first induction cycle
- 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
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)
- Inadequate hepatic function: bilirubin > 3 times ULN (total) except patients with Gilbert's syndrome as defined by > 80% unconjugated bilirubin.
- Inadequate hematological function: ANC < 1.0x109/L or platelets < 75x109 /L before induction cycle 1 unless lymphoma related.
- CNS localization of the lymphoma. 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 MUGA should be obtained and 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 01 Jul 2022 | 4 |
 The Netherlands | Not Recruiting | 01 Jul 2022 | — |
| Netherlands | — | — | 93 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
RITUXIMAB | Test | — | INTRAVENOUS USE | 375 | 18 | SUB12570MIG |
DOXORUBICIN HYDROCHLORIDE | Test | — | INTRAVENOUS USE | 50 | 18 | SUB01827MIG |
PREDNISOLONE | Test | — | ORAL USE | 120 | 18 | SUB10018MIG |
VINCRISTINE SULFATE | Test | — | INTRAVENOUS USE | 2 | 18 | SUB05101MIG |
OPDIVO 10 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 480 | 52 | PRD2941375 |
ETOPOSIDE | Test | — | INTRAVENOUS USE | 103.7 | 18 | SUB07337MIG |
CYCLOPHOSPHAMIDE | Test | — | INTRAVENOUS | 1555 | 18 | SUB06859MIG |