Beschreibung

Rekrutierung gestartet

Early Stage Follicular LymphOma and RadioTherapy PLUS Anti-CD20 Antibody

Studientherapie

Patients with PET positive remaining lymphoma after diagnostic surgery will be randomized in one of two arms using the strata stage (I / II) and remaining lymphoma <11mm (yes/no) (see also figure below):


Arm 1 (Standard arm): 8x Rituximab (375mg/m2) in weeks 1,2,3,4,9,10,11,12. Radiation therapy of the involved sites 12 x 2 Gy (week 9-11)
Arm 2 (Experimental Arm): 7x Obinutuzumab (1000mg) in weeks 1,2,3,4,8,12,16. Radiation therapy of the involved sites 2 x 2 Gy (week 9)
All patients receive restating FDG-PET for response evaluation in week 18. Patients of the experimental arm, who don't show a metabolic CR will receive a salvage RT as in the GAZAI study.


Patients, who do not show remaining PET positive lymphoma after diagnostic surgery (about 25-30% according to GAZAI study) should receive the treatment of the experimental arm without restaging FDG-PET/CT in week 18 and should be evaluated for secondary endpoints.

Studienstatus

Rekrutierung gestartet/nimmt Patienten auf

Allgemeine Infos zum Antrag

Herr Prof. Dr. med. Klaus Herfarth
klaus.herfarth@med.uni-heidelberg.de

Universitätsklinikum Heidelberg - Heidelberg (Institution, 12043)
Klinik für RadioOnkologie und Strahlentherapie
Im Neuenheimer Feld 400
69120 Heidelberg

Evaluation of the rate of morphologic CR after low-dose involved site radiotherapy in combination with Obinutuzumab in early stage nodal follicular lymphoma compared to standard dose radiotherapy in combination with Rituximab

Efficacy and safety of these 2 approaches

Patients with early stage nodal FL (grade 1/2/3a)

The primary objective of this trial is to demonstrate noninferiority of GAZAI concept (experimental treatment E) as compared to the MIR concept (control treatment C) with respect to the primary end point "morphologic complete response (CR/CRu)". For this purpose, the following test problems will be assessed:

Null hypothesis H0: pE (metabolic CR rate for E)  pRF (metabolic CR rate for C) d -´ versus alternative hypothesis H1: pE - pC > -´, where ´ = 0.05 defines the noninferiority margin that is deemed to be acceptable in view of the advantages of the low-dose radiotherapy intervention with respect to aspects other than the primary end point. This test problem will be analyzed applying the noninferiority test for rates according to Farrington and Manning (Farrington and Manning 1990) at a one-sided significance level of ± = 2.5%. If the null hypothesis can be rejected, the null hypotheses of H0_³ are tested at one-sided level of ± = 2.5% for margins ³ < ´ as long as H0_³ has to be accepted for a value ³_stop. Then, noninferiority of E as compared to C has been shown for all noninferiority margins ³ larger than ³_stop. This multiple test procedure controls the overall type I error rate ± (Bauer and Kieser 1996).

Sample size calculation is based on the following considerations. In view of the advantages of the low-dose radiotherapy intervention E as compared to C in dimensions other than the primary end points, an inferiority by a difference in CR rates of 0.05 for E as compared to C is deemed to be acceptable. Therefore, the noninferiority range was set equal to ´ = 0.05.

Based on the above mentioned data, CR rates of pE=0.80 and pC = 0.60 are assumed for sample size calculation using a conservative approach. Under these assumptions, the sample size required to achieve a power of 1  ² = 80% for the one-sided Farrington-Manning test at level ± = 2.5% amounts to 2 × 53 = 106 patients.

For the same rate difference but with assumed overall rates of 0.75 (CR rates of 65%(C) and 85%(E)) and 0.80(CR rates of 70%(C) and 90%(E)), respectively, instead of 0.70, sample sizes of 2 × 47 = 94 and 2 × 41 = 82 are required.

To cope with the uncertainty about the assumed overall rate of 0.70, a blinded sample size review is performed after the outcome of the primary variable is available for 50 patients. No significance test is performed then, and hence, there is no option for early stopping with rejection of the null hypothesis. Instead, the overall rate for the primary variable is estimated based on the pooled available data and the sample size is recalculated and adjusted using this value and leaving the values for ±, 1  ², difference between CR rates = 0.20, and ´ = 0.05 as above. It was shown that this procedure does not affect the type I error rate of the analysis (Friede, Mitchell et al. 2007). Therefore, the analysis can be performed at the (unadjusted) one-sided level ± = 2.5%.

25-30% of the patients will have no remaiing PET positive lymphoma after diagnostic surgery. Those should be treated according to th eGAZAi arm to enlarge the number of treated patients using this regime to receive more robust data for the secondary enpoints

Morphologic complete response (CR) in week 18 in patients with remaining macroscopic lymphoma after initial diagnostic biopsy judged by CT.

Metabolic CR rate in week 18 in patients with initially remaining lymphoma judged by FDG-PET
Progression-free survival (PFS) (2 years after individual treatment start)
Toxicity (NCI-CTC criteria, version 5)
Relapse rate and pattern of recurrence
Overall survival (OS) (2 years)
Quality of life according EORTC QLQ C30 and FACT-Lym questionnaires at inclusion and in week 18, month 12, and 24

Spezifische Infos zum Antrag

Centrally reviewed CD20-positive follicular lymphoma grade 1/2 and 3a based on WHO classification (2017)
Untreated (radiation-, chemo- or immunotherapy) nodal lymphoma (including involvement of Waldeyer
s ring)
Age: e18 years
ECOG: 0-2
Stage: clinical stage I or II (Ann Arbor classification), verified by FDG-PET/CT
Risk profile: Largest diameter of the lymphoma d 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 e 9.0 g/dL; absolute neutrophil count e 1.5 × 10ÿ9/L, Platelet count e 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

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
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 e 1.5 × ULN
INR>1.5×ULN
PTT or aPTT>1.5 × ULN

4.5 yrs recruitment
2.5 years f/u

Germany only: 15 sites

Financial and drug support by Roche Pharma Germany (Roche international pending)

2,4 Mio

18

3600 €

Nein

• trial chart
   
• FORTplus_Synopse deutsch