Gazyvaro and Low Dose Radiotherapy in Early Stage Follicular Lymphoma

Study Overview
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Brief Summary
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Combined modality approach using Obitunuzumab and involved site low dose irradiation in early stage nodal follicular lymphoma. Radiation dose will be adapted for low-responders. Primary Objective: Evaluation of the rate of metabolic CR after low-dose involved site radiotherapy in combination with Gazyvaro (Obinutuzumab) in early stage nodal follicular lymphoma in order to avoid conventional full dose IF radiotherapy. Secondary Objective: Efficacy and safety of a response adapted radiation dose treatment schedule.

Detailed Description
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Extended field or total nodal irradiation had been the gold standard for early stage follicular lymphoma for a long time in Germany. An involved field (IF) irradiation has been favored due to the toxicity of large field irradiation in other countries (e.g. USA). However, smaller irradiation fields have been accompanied with an increased risk of recurrence. A combination of involved field irradiation with the anti-CD20 antibody Rituximab (MIR trial) has led to similar efficacy results compared to the large field irradiation but with markedly reduced side effects. Haas et al. showed in a prospective trial, that a low dose radiation therapy (LDRT) can lead to a complete remission in up to 60% in follicular lymphoma. This is presumed to result from immune modulatory effects induced by LDRT. The effectiveness of LDRT could also be demonstrated in another prospective, randomized British trial (FORT trial: 2 x2 Gy vs. 12 x 2 Gy) with a CR rate of 40% after 2 x 2 Gy (60% after 12 x 2 Gy). Currently, it is unknown, which patients need a higher radiation dose and which not. A metabolic complete remission (CR) is an important prognostic marker for progression-free survival. According to the results of the PRIMA trial, CR is a very strong predictive parameter if the CR is established using FDG-PET. In the present GAZAI trial, patients with early stage nodular follicular lymphoma will be treated in a combined approach of immunotherapy with an anti-CD20 antibody and small field (involved site) irradiation as in the MIR trial. In GAZAI, the fully humanized anti-CD20 antibody Obinutuzumab (GAZYVARO) will be used, which showed a high efficacy in combination with bendamustin in patients with follicular lymphoma refractory to Rituximab (GADOLIN trial). In addition, the radiation dose will be limited to 2 x2 Gy in responding patients. A dose build-up to a total of 40 Gy (dose in the MIR trial) will be performed in case of failure to achieve a complete CR based on a FDG-PET in week 18. Primary endpoint of the trial is the rate of CR (based on FDG-PET/CT) after Obinutuzumab and 2x2 Gy IS radiotherapy in week 18. Secondary endpoints are the morphological CR rate in week 7, week 18 and month 6, the PFS, the toxicity, the recurrence rate, the recurrence pattern, overall survival and quality of life.

Official Title
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Therapy of Nodal Follicular Lymphoma (WHO Grade 1/2) in Clinical Stage I/II Using Response Adapted Involved Site Radiotherapy in Combination With Gazyvaro

Conditions
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Stage II Grade 1 Follicular Lymphoma, Stage II Grade 2 Follicular Lymphoma, Stage I Follicular Lymphoma Grade 1, Stage II Follicular Lymphoma Grade 2

Intervention / Treatment
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* Drug: Obinutuzumab Injection [Gazyva]
* Radiation: Low dose radiation Therapy (LDRT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Centrally reviewed CD20-positive follicular lymphoma grade 1/2 based on WHO classification (2016) Untreated (radiation-, chemo- or immunotherapy) nodal lymphoma (including involvement of Waldeyer´s ring) Age: ≥18 years ECOG: 0-2 Stage: clinical stage I or II (Ann Arbor classification) Risk profile: Largest diameter of the lymphoma * 7 cm (sectional images) Written informed consent and willingness to cooperate during the course of the trial Adequate hematologic function (unless abnormalities are related to NHL), defined as follows: Hemoglobin ≥ 9.0 g/dL; absolute neutrophil count ≥ 1.5 × 109/L, Platelet count ≥ 75 × 109/L Capability to understand the intention and the consequences of the clinical trial Adequate contraception for men and women of child-bearing age during therapy and 18 months thereafter Patients with non-active hepatitis B infection (HBsAg neg/HBcAB pos/HBV DNA neg) under 1-year require prophylactic anti-viral therapy (e.g. Entecavir®) possible (see also 5.6. Prior and Concomitant Disease) Exclusion Criteria: Extra nodal manifestation Secondary cancer in the patient's medical history (exclusion: basalioma, spinalioma, melanoma in situ, bladder cancer T1a, non-metastasized solid tumor in constant remission, which was diagnosed >3 years ago Concomitant diseases: congenital or acquired immune-deficiency syndromes, active infections including viral hepatitis (serology positive for HBsAg or HBcAb in combination positive HBV DNA), uncontrolled concomitant diseases including significant cardiovascular or pulmonary disease (see also 5.6. Prior and Concomitant Disease) Severe psychiatric disease Pregnancy / lactation Known hypersensitivity against Gazyvaro (Obinutuzumab) or drugs with similar chemical structure or any other additive of the pharmaceutical formula of the study drug Participation in another interventional trial or follow-up period of a competing trial which can influence the results of this current trial Creatinine > 1.5 times the upper limit of normal (ULN) (unless creatinine clearance normal), or calculated creatinine clearance < 40 mL/min AST or ALT > 2.5 × ULN Total bilirubin ≥ 1.5 × ULN INR > 1.5 × ULN PTT or aPTT > 1.5 × the ULN

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Interventional Model Description: Open, non-controlled, national multi-center phase II trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: interventional arm<br>Obinutuzumab Injection [Gazyva] 1000mg flat i.v. on week 1, 2, 3, 4, 8, 12, 16; Low dose radiation Therapy (LDRT) involved site 2 x 2 Gy in week 9 | Drug: Obinutuzumab Injection [Gazyva]<br>* 7x 1000mg flat dose<br>* Other names: Gazyvaro;Radiation: Low dose radiation Therapy (LDRT)<br>* 2 x 2 Gy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of metabolic complete remission (CR) | rate of metabolic complete remission (CR) after low-dose involved site radiotherapy in combination with Obinutuzumab in patients with initially remaining PET positive lymphoma | week 18 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of morphologic complete remission (CR) | rate of morphologic complete remission (CR) after low-dose involved site radiotherapy in combination with Obinutuzumab in patients with initially remaining lymphoma | week 7, week 18, month 6 | 
| Progression free survival (PFS) | PFS of all patients | 2 years | 
| Toxicity | Common Toxicity Criteria (CTC) Toxicity | Start until month 30 | 
| Overall survival (OS) | OS of all patients | 2 years | 
| Relapse rate | Relapse rate of all patients | start until month 30 | 
| Quality of life (QoL) EORTC QLQ-C30 | QoL according EORTC QLQ-C30 | Initially, week 18, month 12, month 24 | 
| Minimal residual disease (MRD) response | Minimal residual disease | initially, week 18, month 6, month 12, month 18, month 24 | 
| Relapse pattern | Relapse pattern (e.g. out-field or in-field) of all relapses | start until month 30 | 
| Quality of life (QoL) FACT-Lymph25 | QoL according FACT-Lymph25 questionnaires | Initially, week 18, month 12, month 24 |