Clinical trial NCT05045664: Early Stage Follicular LymphOma and RadioTherapy PLUS Anti-CD20 Antibody
Official title: Early Stage Follicular LymphOma and RadioTherapy PLUS Anti-CD20 Antibody
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Early Stage Follicular Lymphoma WHO Grade 1/2 or 3a
Lead sponsor: Heidelberg University
Sponsor class: OTHER
First posted: 2021-09-16
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Controlled, open, randomised, 2 parallel groups, multi-centre, national, treatment phase III trial
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Morphologic complete response
timeFrame: Week 18
Secondary outcomes:
measure: Metabolic complete response
timeFrame: week 18
measure: Morphologic response
timeFrame: Month 6
measure: PFS
timeFrame: 2 years
measure: Frequency and extent of Toxicity
timeFrame: until month 30
measure: Overall survival
timeFrame: 2 years
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Vivantes Klinikum Berlin
city: Essen
country: Germany
facility: University of Essen
city: Göttingen
country: Germany
facility: University of Göttingen
city: Heidelberg
country: Germany
facility: University Hospital Heidelberg
city: Munich
country: Germany
facility: LMU München
city: Munich
country: Germany
facility: Technische Universität München
city: Mönchengladbach
country: Germany
facility: Strahlentherapie KH Maria Hilf
city: Regensburg
country: Germany
facility: Krankenhaus Barmherzige Brüder
city: Rostock
country: Germany
facility: University of Rostock
city: Stuttgart
country: Germany
facility: Katharinen Hospital Stuttgart
city: Tübingen
country: Germany
facility: University of Tübingen
city: Ulm
country: Germany
facility: University of Ulm
Study officials:
affiliation: Heidelberg University
name: Klaus Herfarth, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Konig L, Dreyling M, Durig J, Engelhard M, Hohloch K, Viardot A, Witzens-Harig M, Kieser M, Klapper W, Pott C, Herfarth K. 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. Trials. 2019 Aug 30;20(1):544. doi: 10.1186/s13063-019-3614-y.
citation: Hoskin PJ, Kirkwood AA, Popova B, Smith P, Robinson M, Gallop-Evans E, Coltart S, Illidge T, Madhavan K, Brammer C, Diez P, Jack A, Syndikus I. 4 Gy versus 24 Gy radiotherapy for patients with indolent lymphoma (FORT): a randomised phase 3 non-inferiority trial. Lancet Oncol. 2014 Apr;15(4):457-63. doi: 10.1016/S1470-2045(14)70036-1. Epub 2014 Feb 24.
citation: Herfarth K, Borchmann P, Schnaidt S, Hohloch K, Budach V, Engelhard M, Viardot A, Engenhart-Cabillic R, Keller U, Reinartz G, Eich HT, Witzens-Harig M, Hess CF, Dorken B, Durig J, Wiegel T, Hiddemann W, Hoster E, Pott C, Dreyling M. Rituximab With Involved Field Irradiation for Early-stage Nodal Follicular Lymphoma: Results of the MIR Study. Hemasphere. 2018 Nov 30;2(6):e160. doi: 10.1097/HS9.0000000000000160. eCollection 2018 Dec.
citation: Hoskin P, Popova B, Schofield O, Brammer C, Robinson M, Brunt AM, Madhavan K, Illidge T, Gallop-Evans E, Syndikus I, Clifton-Hadley L, Kirkwood AA. 4 Gy versus 24 Gy radiotherapy for follicular and marginal zone lymphoma (FoRT): long-term follow-up of a multicentre, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2021 Mar;22(3):332-340. doi: 10.1016/S1470-2045(20)30686-0. Epub 2021 Feb 1.