Early Stage Follicular LymphOma and RadioTherapy PLUS Anti-CD20 Antibody

Study Overview
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Brief Summary
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The MIR study proved the effect of Rituximab in combination with a localized irradiation given in a standard dose. Together with the TROG 99.03 trial, this led to the recommendation of using this combined approach in early stage nodal follicular lymphoma. The GAZAI study is currently looking for the effect of a low dose radiotherapy of 2x2 Gy in combination with Obinutuzumab. The combination seems to show a high CR rate based on the 50% of the patients. This is in contrast to the FORT trial, which showed an inferiority of the 4 Gy dose compared to the standard dose (24 Gy) in terms of response and progression free survival. The goal of the FORTplus trial is to prove (1) the non-inferiority of LDRT (4Gy) in a combined approach with an anti-CD20-antibody. In case of non-inferiority, a possible (2) superiority of the Obinutuzumab + LDRT should be tested against Rituximab + standard dose using the same test set. The radiation dose can significantly be reduced to 16% of the standard dose if (1) is confirmed. Knowing the data of the FORT trial, this would have a significant influence on the treatment of the disease worldwide even if the difference in the CR rate at week 18 is not as high as currently in the historical comparison expected.

Official Title
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Early Stage Follicular LymphOma and RadioTherapy PLUS Anti-CD20 Antibody

Conditions
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Early Stage Follicular Lymphoma WHO Grade 1/2 or 3a

Intervention / Treatment
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* Radiation: Standard
* Radiation: Experimental
* Drug: Standard
* Drug: Experimental


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: • Centrally reviewed CD20-positive follicular lymphoma grade 1/2 or 3a based on WHO classification (2008) Untreated (radiation-, chemo- or immunotherapy) nodal follicular lymphoma (including involvement of Waldeyer´s ring) Age: ≥18 years ECOG: 0-2 Stage: clinical stage I or II (Ann Arbor classification) based on FDG-PET Staging 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 bone marrow capacity: ANC ≥ 1.5 x 103/ml, thrombocytes ≥ 100000 x 10 3/ml, hemoglobin ≥ 10 g/dL 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 Exclusion Criteria: Extra nodal manifestation of follicular lymphoma 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) Serious disease interfering with a regular therapy according to the study protocol, e.g: congenital or acquired immune-deficiency syndromes, active infections including viral hepatitis, uncontrolled concomitant diseases including significant cardiovascular or pulmonary disease Severe psychiatric disease Pregnancy / lactation Known hypersensitivity against Obinutuzumab or Rituximab drugs with similar chemical structure or any other additive of the pharmaceutical formula of the study drug Active hepatitis B infection (inactive hepatitis B infections require additional prophylactic anti-viral medication for 1 year (e.g. Lamivudin, Entecavir, Tenofovir) 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Controlled, open, randomised, 2 parallel groups, multi-centre, national, treatment phase III trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard<br>Standard dose (24 Gy) involved site radiotherapy plus Rituximab | Radiation: Standard<br>* 12 x 2 Gy involved site radiotherapy plus Rituximab<br>Drug: Standard<br>* Rituximab with 12 x 2 Gy involved site radiotherapy<br>* Other names: Rituximab;|
| Experimental: Experimental<br>ow-dose (4 Gy) involved site radiotherapy in combination with Obinutuzumab | Radiation: Experimental<br>* 2 x2 Gy involved site radiotherapy plus Obinutuzumab<br>Drug: Experimental<br>* Obinutuzumab with 2 x2 Gy involved site radiotherapy<br>* Other names: Obinutuzumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Morphologic complete response | Rate of morphologic complete response based on CT scan in patients with initially remaining lymphoma | Week 18 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolic complete response | Rate of metabolic complete response based on FDG PET in patients with initially remaining lymphoma | week 18 | 
| Morphologic response | Morphologic CR in patients with initially remaining lymphoma | Month 6 | 
| PFS | Progression-free survival (PFS) of each treatment arm | 2 years | 
| Frequency and extent of Toxicity | Toxicity (NCI-CTC criteria, version 5) of all patients | until month 30 | 
| Overall survival | Overall survival (OS) of each treatment arm | 2 years |