Safety and Efficacy of Bendamustine, Gemcitabine, Rituximab, Nivolumab (BeGeRN) in Patients With r/r DLBCL (BeGeRN)

A Phase I/II Clinical Trial to Evaluate the Safety and Efficacy of Bendamustine, Gemcitabine, Rituximab, Nivolumab Combination (BeGeRN) in Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma

Despite the current advances in clinical oncology, the prognosis of patients with resistant diffuse large B cell lymphoma or relapse after high dose chemotherapy is dismal. Therefore there is a need for the introduction of novel treatment regimens. This phase I/II trial evaluates the safety and efficacy of combination bendamustine, gemcitabine, nivolumab and rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma. The safety of combination treatment will be evaluated with the determination of recommended dose schedule prior to expansion of enrollment to evaluate the antitumor activity of bendamustine, gemcitabine, rituximab, and nivolumab.

Study Overview

• Status: Completed
• Conditions: Diffuse Large B Cell Lymphoma
• Intervention / Treatment: Drug: Bendamustine hydrochloride; Drug: Gemcitabine 500 mg; Drug: Nivolumab; Drug: Rituximab; Drug: Gemcitabine 700 mg; Drug: Gemcitabine 1000 mg

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Russian Federation
  • Saint-Petersburg, Russian Federation, 197089
    • First Pavlov State Medical University of St. Petersburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis: Histologically confirmed diffuse large B-cell lymphoma
• Refractory or relapsed after at least two prior lines of treatment (i.e. induction and salvage regimen) for diffuse large B-cell lymphoma.
• Age 18-70 years old
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-2
• Signed informed consent
• No severe concurrent illness

Exclusion Criteria:

• Uncontrolled bacterial or fungal infection at the time of enrollment
• Requirement for vasopressor support at the time of enrollment
• Karnofsky index <30%
• Pregnancy
• Somatic or psychiatric disorder making the patient unable to sign informed consent
• Active or prior documented autoimmune disease requiring systemic treatment.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Gemcitabine 500; Days 1,2 Bendamustine Hydrochloride 70 mg/m2/day iv; Days 1,8,15 Gemcitabine 500 mg/m2/day iv; Days 1,15 Nivolumab 1mg/kg/day iv; Day 0 Rituximab 375mg/kg/day iv. Duration of cycle 28 days	Drug: Bendamustine hydrochloride; 70 mg/m2 by intravenous (IV) infusion for up to 2 cycles; Other Names: Ribomustin; Drug: Gemcitabine 500 mg; 500 mg/m2 by intravenous (IV) infusion on day 1,8,15 for up to 2 cycles; Other Names: Gemzar; Drug: Nivolumab; 1 mg/kg by intravenous (IV) infusion on day 1,15 for up to 2 cycles; Other Names: Opdivo; Drug: Rituximab; 375 mg/m2 by intravenous (IV) infusion on day 0 for up to 2 cycles
Experimental: Gemcitabine 700; Days 1,2 Bendamustine Hydrochloride 70 mg/m2/day iv; Days 1,8,15 Gemcitabine 700 mg/m2/day iv; Days 1,15 Nivolumab 1mg/kg/day iv; Day 0 Rituximab 375mg/kg/day iv. Duration of cycle 28 days	Drug: Bendamustine hydrochloride; 70 mg/m2 by intravenous (IV) infusion for up to 2 cycles; Other Names: Ribomustin; Drug: Nivolumab; 1 mg/kg by intravenous (IV) infusion on day 1,15 for up to 2 cycles; Other Names: Opdivo; Drug: Rituximab; 375 mg/m2 by intravenous (IV) infusion on day 0 for up to 2 cycles; Drug: Gemcitabine 700 mg; 700 mg/m2 by intravenous (IV) infusion on day 1,8,15 for up to 2 cycles; Other Names: Gemzar
Experimental: Gemcitabine 1000; Days 1,2 Bendamustine Hydrochloride 70 mg/m2/day iv; Days 1,8,15 Gemcitabine 1000 mg/m2/day iv; Days 1,15 Nivolumab 1mg/kg/day iv; Day 0 Rituximab 375mg/kg/day iv. Duration of cycle 28 days	Drug: Bendamustine hydrochloride; 70 mg/m2 by intravenous (IV) infusion for up to 2 cycles; Other Names: Ribomustin; Drug: Nivolumab; 1 mg/kg by intravenous (IV) infusion on day 1,15 for up to 2 cycles; Other Names: Opdivo; Drug: Rituximab; 375 mg/m2 by intravenous (IV) infusion on day 0 for up to 2 cycles; Drug: Gemcitabine 1000 mg; 1000 mg/m2 by intravenous (IV) infusion on day 1,8,15 for up to 2 cycles; Other Names: Gemzar

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The recommended phase 2 dose (RP2D)	The recommended phase 2 dose (RP2D) of Bendamustine Hydrochloride and Gemcitabine in combination with Nivolumab and Rituximab in patients with Diffuse Large B-cell Lymphoma	6 months
Overall Response Rate (ORR)	Overall response rate (ORR), defined as the proportion of patients with complete response (CR) or partial response (PR) in measurable lesions as defined by LYRIC criteria and duration of response.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)		12 months
Progression-Free Survival (PFS)		12 months
Duration of Response (DOR)		12 months
Frequency of grade 3 or higher treatment-related adverse events by CTCAE 4.03	Toxicity parameters based on NCI CTCAE 4.03 grades: hematological toxicity (CBC), hepatotoxicity (liver function tests), nephrotoxicity (creatinine), neurotoxicity (attending physician assessment), fatigue (attending physician assessment), rash (attending physician assessment), colitis (attending physician assessment), pneumonitis (attending physician assessment), autoimmune disorders (level of hormones, presence of autoimmune antibodies, attending physician assessment).	12 months

Collaborators and Investigators

• Sponsor: St. Petersburg State Pavlov Medical University

Study record dates

Study Major Dates

• Study Start (Actual): March 27, 2017
• Primary Completion (Actual): January 27, 2020
• Study Completion (Actual): January 27, 2020

Study Registration Dates

• First Submitted: August 22, 2017
• First Submitted That Met QC Criteria: August 22, 2017
• First Posted (Actual): August 23, 2017

Study Record Updates

• Last Update Posted (Actual): June 7, 2021
• Last Update Submitted That Met QC Criteria: June 2, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: Gemcitabine; Nivolumab; Rituximab; Diffuse Large B-cell Lymphoma; Bendamustine Hydrochloride
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Gemcitabine; Nivolumab; Bendamustine Hydrochloride; Rituximab
• Other Study ID Numbers: DLBCL BeGeRN 1/2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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