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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Diffuse Large B Cell Lymphoma

Intervention / Treatment
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* Drug: Bendamustine hydrochloride
* Drug: Gemcitabine 500 mg
* Drug: Gemcitabine 700 mg
* Drug: Gemcitabine 1000 mg
* Drug: Nivolumab
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: There will be 2 parts in this study. In Part 1, the safety of combination treatment will be evaluated prior to expansion of enrollment to evaluate treatment effect in Part 2. The arms in Part 1 include 3 different dosage regimens of gemcitabine (500 / 700 / 1000). Part 2 of the study will further characterize the safety and evaluate the antitumor activity of drug combination by enrolling patients at the recommended dose schedule determined in Part 1.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gemcitabine 500<br>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<br>* 70 mg/m2 by intravenous (IV) infusion for up to 2 cycles<br>* Other names: Ribomustin;Drug: Gemcitabine 500 mg<br>* 500 mg/m2 by intravenous (IV) infusion on day 1,8,15 for up to 2 cycles<br>* Other names: Gemzar;Drug: Nivolumab<br>* 1 mg/kg by intravenous (IV) infusion on day 1,15 for up to 2 cycles<br>* Other names: Opdivo;Drug: Rituximab<br>* 375 mg/m2 by intravenous (IV) infusion on day 0 for up to 2 cycles<br>|
| Experimental: Gemcitabine 700<br>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<br>* 70 mg/m2 by intravenous (IV) infusion for up to 2 cycles<br>* Other names: Ribomustin;Drug: Gemcitabine 700 mg<br>* 700 mg/m2 by intravenous (IV) infusion on day 1,8,15 for up to 2 cycles<br>* Other names: Gemzar;Drug: Nivolumab<br>* 1 mg/kg by intravenous (IV) infusion on day 1,15 for up to 2 cycles<br>* Other names: Opdivo;Drug: Rituximab<br>* 375 mg/m2 by intravenous (IV) infusion on day 0 for up to 2 cycles<br>|
| Experimental: Gemcitabine 1000<br>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<br>* 70 mg/m2 by intravenous (IV) infusion for up to 2 cycles<br>* Other names: Ribomustin;Drug: Gemcitabine 1000 mg<br>* 1000 mg/m2 by intravenous (IV) infusion on day 1,8,15 for up to 2 cycles<br>* Other names: Gemzar;Drug: Nivolumab<br>* 1 mg/kg by intravenous (IV) infusion on day 1,15 for up to 2 cycles<br>* Other names: Opdivo;Drug: Rituximab<br>* 375 mg/m2 by intravenous (IV) infusion on day 0 for up to 2 cycles<br>|

What is the study measuring?
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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 |
| --- | --- | --- |
| 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 | 
| Duration of Response (DOR) |  | 12 months | 
| Progression-Free Survival (PFS) |  | 12 months | 
| Overall Survival (OS) |  | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diffuse Large B-cell Lymphoma, Nivolumab, Bendamustine Hydrochloride, Gemcitabine, Rituximab