Multicenter Study of Safety and Efficacy Nivolumab at the Fixed Dose 40 mg (Nivo40) in Combination With Chemo-Immunotherapy for the Treatment of Newly Diagnosed PMBL

Nivolumab at the Fixed Dose 40 mg (Nivo40) in Combination With Chemo-Immunotherapy for the Treatment of Newly Diagnosed Primary Mediastinal B-Cell Lymphoma

This compares the effects of nivolumab at a fixed dose of 40 mg with chemo-immunotherapy versus chemo-immunotherapy alone in treating patients with newly diagnosed primary mediastinal B-cell lymphoma (PMBCL). Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of cancer cells to grow and spread. Treatment for PMBCL involves chemotherapy combined with an immunotherapy called rituximab. Chemotherapy drugs work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Giving nivolumab with chemo-immunotherapy may help treat patients with PMBCL.

Study Overview

• Status: Recruiting
• Conditions: Primary Mediastinal Lymphoma
• Intervention / Treatment: Drug: Filgrastim; Drug: Cyclophosphamide; Drug: Doxorubicin Hydrochloride; Drug: Etoposide Phosphate; Drug: Prednisolone; Drug: Rituximab; Drug: Vincristine Sulfate; Drug: Pegfilgrastim; Drug: Nivolumab 40 mg in 4 ml Injection

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Yana Mangasarova, MD; Phone Number: +74956122361; Email: v.k.jana@mail.ru
• Study Contact Backup: Name: Euvgena Zvonkov, MD,PhD; Phone Number: +74956122361; Email: dr.zvonkov@mail.ru

Study Locations

• Russian Federation
  • Moscow, Russian Federation, 125167
    • Recruiting
    • National Research Center for Hematology
    • Contact: Yana Mangasarova, MD; Phone Number: +74956122361; Email: v.k.jana@mail.ru

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

- Patient must have histologically confirmed primary mediastinal B-cell lymphoma (PMBCL) as defined by World Health Organization (WHO) criteria Age 18-70 years old Ejection fraction greater than 50% ECOG 0-2 status Signed informed consent No severe concurrent illness measurable disease (at least one lesion that can be accurately measured in at least two dimensions on a CT scan, at least >15 mm in largest diameter

Exclusion Criteria:

• Uncontrolled bacterial or fungal infection at the time of enrollment
• Requirement for vasopressor support at the time of enrollment
• Severe organ failure: creatinine more than 2 norms; ALT, AST more than 5 norms; bilirubin more than 1.5 norms
• Karnofsky index <30%
• Pregnancy
• Somatic or psychiatric disorder making the patient unable to sign an informed consent
• Active or prior documented autoimmune disease requiring systemic treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: A; Active Comparator: Arm A (DA-EPOCH-R) Patients receive prednisone or prednisolone on days 1-5 and rituximab IV or rituximab and hyaluronidase human SC over 5 minutes on day 1 or 5. Patients also receive etoposide phosphate, doxorubicin hydrochloride, and vincristine sulfate IV over 96 hours on days 1-4 and cyclophosphamide IV over 30-60 minutes on day 5. Beginning 24-72 hours after completing cyclophosphamide, patients receive filgrastim or pegylated filgrastim SC daily until ANC is >= 500/uL after the expected nadir. Treatment repeats every 21 days for up to 6 cycles (5 if the patient had 1 prior cycle of treatment) in the absence of disease progression or unacceptable toxicity. Patients also undergo FDG-PET/CT on study. When СR is achieved according to PET / CT after 4 cycles of chemotherapy, 2 randomization is performed, a total of 4 or 6 chemotherapy courses	Drug: Filgrastim; G-CSF; Drug: Cyclophosphamide; Ciclofosfamida; Drug: Doxorubicin Hydrochloride; Adriamycin; Drug: Etoposide Phosphate; Etopophos; Drug: Prednisolone; Prednisolonum; Drug: Rituximab; Chimeric Anti-CD20 Antibody; Drug: Vincristine Sulfate; Oncovin; Drug: Pegfilgrastim; PEG-filgrastim
Experimental: B; (DA-EPOCH-R, nivolumab) Patients receive treatment as in Arm A. Patients also receive nivolumab 40 mg IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 6 cycles (5 if the patient had 1 prior cycle of treatment) in the absence of disease progression or unacceptable toxicity. Patients also undergo FDG-PET/CT on study. When СR is achieved according to PET / CT after 4 cycles of chemotherapy, 2 randomization is performed, a total of 4 or 6 chemotherapy courses.	Drug: Filgrastim; G-CSF; Drug: Cyclophosphamide; Ciclofosfamida; Drug: Doxorubicin Hydrochloride; Adriamycin; Drug: Etoposide Phosphate; Etopophos; Drug: Prednisolone; Prednisolonum; Drug: Rituximab; Chimeric Anti-CD20 Antibody; Drug: Vincristine Sulfate; Oncovin; Drug: Pegfilgrastim; PEG-filgrastim; Drug: Nivolumab 40 mg in 4 ml Injection; Opdivo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	The primary analysis will be a one-sided Log-rank test stratified by choice of backbone and radiation therapy and whether the patient had a cycle of therapy prior to enrolling.	From enrollment on the study to first occurrence of relapse/progression or death, assessed up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy-related event-free survival	Will be analyzed using a one-sided stratified Log-rank test at alpha = 0.05 or 0.025, as appropriate, with events defined as progression, change in therapy due to a finding that led to concern about efficacy, biopsy + disease after 6 cycles of therapy, and death.	Up to 5 years
Therapy-related event-free survival	Will be analyzed using a one-sided stratified Log-rank test at alpha = 0.05 or 0.025, as appropriate, with events defined as progression, change in therapy due to a finding that led to concern about efficacy, biopsy + disease after 6 cycles of therapy, and death.	Up to 5 years
Overall survival	Will be analyzed using a one-sided stratified Log-rank test at alpha = 0.05 or 0.025, as appropriate, with events defined as only death.	Up to 5 years

Collaborators and Investigators

• Sponsor: National Research Center for Hematology, Russia
• Investigators: Study Director: Elena Parovichnikova, MD,PhD, Nathional Medical Research Center for Hematology Moscow Russia 125167

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2022
• Primary Completion (Estimated): April 1, 2029
• Study Completion (Estimated): April 1, 2029

Study Registration Dates

• First Submitted: March 6, 2023
• First Submitted That Met QC Criteria: December 18, 2023
• First Posted (Actual): January 3, 2024

Study Record Updates

• Last Update Posted (Actual): January 3, 2024
• Last Update Submitted That Met QC Criteria: December 18, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: PET-adapted Treatment; Nivolumab at the fixed dose 40 mg; R-DA-EPOCH
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Immune Checkpoint Inhibitors; Prednisolone; Cyclophosphamide; Etoposide; Etoposide phosphate; Nivolumab; Rituximab; Doxorubicin; Liposomal doxorubicin; Vincristine
• Other Study ID Numbers: PMBL-2022

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No