Therapy of nodal Follicular Lymphoma (WHO grade 1/2) in clinical stage I/II using response adapted Involved Site Radiotherapy in combination with Obinutuzumab (Gazyvaro) - GAZAI Trial (GAZyvaro and response adapted Involved-site Radiotherapy): a study protocol for a single-arm, non-randomized, open, national, multi-center phase II trial

Abstract

Background: Large field irradiation had been standard for early-stage follicular lymphoma (FL) for a long time. Although involved field radiotherapy (IF-RT) was recently favored because of the toxicity of large field irradiation, smaller irradiation fields have been accompanied with an increased risk of out-of-field recurrence. The MIR (MabThera® and Involved field Radiation) trial has shown that the combination of IF-RT at a dose of 30-40 Gy with the anti-CD20 antibody rituximab has led to similar efficacy compared with large field irradiation but with markedly reduced side effects. Immune modulating radiation therapy alone using low-dose radiotherapy (LDRT) of 2 × 2 Gy has been shown to be effective in FL. The GAZAI (GAZyvaro and response Adapted Involved-site Radiotherapy) trial aims to prove the efficacy of LDRT in combination with a novel anti-CD20 therapy.

Methods/design: The GAZAI trial is a non-randomized, open, non-controlled, German, multi-center phase II trial that includes patients with early-stage (I and II) nodular FL (grades 1 and 2) confirmed by central histological review. A maximum of 93 patients will be included in the trial. Patients will receive a combined approach of immunotherapy with the fully humanized anti-CD20 antibody obinutuzumab (Gazyvaro®) and involved site radiotherapy (IS-RT) with 2 × 2 Gy. The primary endpoint of the trial is the rate of metabolic complete response (CR), based on fludeoxyglucose positron emission tomography/computed tomography, after obinutuzumab and 2 × 2 Gy IS-RT in week 18. Secondary endpoints are morphologic CR rate in weeks 7 and 18 and month 6, progression-free survival, toxicity, recurrence patterns, overall survival, and quality of life. Additionally, minimal residual disease response is assessed. The risk for a potentially higher recurrence rate after LDRT will be minimized by additional salvage radiation up to the "full dose" of 40 Gy for patients who have less than a metabolic CR and morphologic partial response/CR, which will be evaluated in week 18, offering a response-adapted approach.

Discussion: The goal of this trial is a further reduction of the radiation dose in patients with nodal early-stage FL showing a good response to a combination of LDRT and anti-CD20 immunotherapy and a comparison with the currently published MIR trial.

Trial registration: EudraCT number: 2016-002059-89. ClinicalTrials.gov identifier: NCT03341520 .

Keywords: Anti-CD20 antibody; Follicular lymphoma; Involved site radiotherapy; Low-dose radiotherapy; Obinutuzumab; PET/CT.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1

The study flow chart shows the two stage screening with 1) centrally approved histology and CT or MRI staging and 2) FDG-PET/CT as well as the further stratification and follow up

Fig. 2

Intervention and assessment schedule for the GAZAI (GAZyvaro and response Adapted Involved-site Radiotherapy) trial. Abbreviations: AE adverse event, aPTT activated partial thromboplastin time, CR complete response, CT computed tomography, CTCAE Common Terminology Criteria for Adverse Events, ECOG Eastern Cooperative Oncology Group, EORTC European Organization for Research and Treatment of Cancer, FACT Lym Functional Assessment of Cancer Therapy - Lymphoma, FDG-PET/CT fludeoxyglucose positron emission tomography/computed tomography, INR international normalized ratio, IS involved site, LDH lactate dehydrogenase, MRD minimal residual disease, MRI magnetic resonance imaging, PTT partial thromboplastin time, QLQ Quality of Life Questionnaire, RT radiotherapy