Gazyvaro and Low Dose Radiotherapy in Early Stage Follicular Lymphoma
- Conditions
- Stage II Grade 2 Follicular LymphomaStage I Follicular Lymphoma Grade 1Stage II Follicular Lymphoma Grade 2Stage II Grade 1 Follicular Lymphoma
- Interventions
- Radiation: Low dose radiation Therapy (LDRT)
- Registration Number
- NCT03341520
- Lead Sponsor
- Heidelberg University
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 89
- 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)
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description interventional arm Obinutuzumab Injection [Gazyva] 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 interventional arm Low dose radiation Therapy (LDRT) 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
- Primary Outcome Measures
Name Time Method Rate of metabolic complete remission (CR) week 18 rate of metabolic complete remission (CR) after low-dose involved site radiotherapy in combination with Obinutuzumab in patients with initially remaining PET positive lymphoma
- Secondary Outcome Measures
Name Time Method Toxicity Start until month 30 Common Toxicity Criteria (CTC) Toxicity
Rate of morphologic complete remission (CR) week 7, week 18, month 6 rate of morphologic complete remission (CR) after low-dose involved site radiotherapy in combination with Obinutuzumab in patients with initially remaining lymphoma
Progression free survival (PFS) 2 years PFS of all patients
Quality of life (QoL) EORTC QLQ-C30 Initially, week 18, month 12, month 24 QoL according EORTC QLQ-C30
Minimal residual disease (MRD) response initially, week 18, month 6, month 12, month 18, month 24 Minimal residual disease
Relapse pattern start until month 30 Relapse pattern (e.g. out-field or in-field) of all relapses
Quality of life (QoL) FACT-Lymph25 Initially, week 18, month 12, month 24 QoL according FACT-Lymph25 questionnaires
Overall survival (OS) 2 years OS of all patients
Relapse rate start until month 30 Relapse rate of all patients
Trial Locations
- Locations (12)
University of Tuebingen
🇩🇪Tuebingen, Baden-Wuerttemberg, Germany
Vivantes Klinikum
🇩🇪Berlin, Germany
University of Cologne
🇩🇪Cologne, Germany
University of Essen
🇩🇪Essen, Germany
University of Frankfurt
🇩🇪Frankfurt, Germany
University of Heidelberg
🇩🇪Heidelberg, Germany
Site Marburg
🇩🇪Marburg, Germany
Klinikum Kempten
🇩🇪Kempten, Germany
LMU
🇩🇪Munich, Germany
TU
🇩🇪Munich, Germany
University of Ulm
🇩🇪Ulm, Germany
University of Muenster
🇩🇪Münster, Germany