Early Stage Follicular LymphOma and RadioTherapy PLUS Anti-CD20 Antibody (FORTplus)

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.

Study Overview

• Status: Recruiting
• Conditions: Early Stage Follicular Lymphoma WHO Grade 1/2 or 3a
• Intervention / Treatment: Radiation: Standard; Drug: Standard; Radiation: Experimental; Drug: Experimental

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Klaus Herfarth, MD; Phone Number: +496221568202; Email: klaus.herfarth@med.uni-heidelberg.de

Study Locations

• Germany
  • Berlin, Germany, 10967
    • Recruiting
    • Vivantes Klinikum Berlin
    • Contact: Christian Scholz, MD; Email: christianw.scholz@vivantes.de
  • Essen, Germany, 45147
    • Not yet recruiting
    • University of Essen
  • Göttingen, Germany, 37075
    • Recruiting
    • University of Göttingen
    • Contact: Stefan Rieken, MD; Email: stefan.rieken@med.uni-goettingen.de
  • Heidelberg, Germany, 69120
    • Recruiting
    • University Hospital Heidelberg
    • Contact: Klaus Herfarth, MD; Phone Number: +496221568202; Email: klaus.herfarth@med.uni-heidelberg.de
    • Sub-Investigator: Julia Meissner, MD
  • Munich, Germany, 81377
    • Not yet recruiting
    • LMU Munchen
    • Contact: Martin Dreyling, MD; Email: Martin.dreyling@med.uni-muenchen.de
  • Munich, Germany, 81675
    • Recruiting
    • Technische Universität München
    • Contact: Simon Heidegger, MD; Email: Simon.heidegger@tum.de
  • Mönchengladbach, Germany, 41063
    • Recruiting
    • Strahlentherapie KH Maria Hilf
    • Contact: Ursula Nestle, MD; Phone Number: +49-2161-8921801; Email: Ursula.nestle@mariahilf.de
  • Regensburg, Germany, 93049
    • Recruiting
    • Krankenhaus Barmherzige Brüder
    • Contact: Bernhard Heilmeier, MD; Email: Bernhard.Heilmeier@barmherzige-regensburg.de
  • Rostock, Germany, 18057
    • Recruiting
    • University of Rostock
    • Contact: Guido Hildebrandt, MD; Email: guido.hildebrandt@med.uni-rostock.de
  • Stuttgart, Germany
    • Not yet recruiting
    • Katharinen Hospital Stuttgart
  • Tübingen, Germany, 72076
    • Recruiting
    • University of Tubingen
    • Contact: Stefan Wirths, MD; Email: Stefan.Wirths@med.uni-tuebingen.de
  • Ulm, Germany, 89081
    • Recruiting
    • University of Ulm
    • Contact: Christian Buske, MD; Email: Christian.buske@uni-ulm.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Heidelberg University
• Investigators: Principal Investigator: Klaus Herfarth, MD, Heidelberg University

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 6, 2022
• Primary Completion (Anticipated): December 31, 2026
• Study Completion (Anticipated): December 31, 2029

Study Registration Dates

• First Submitted: August 25, 2021
• First Submitted That Met QC Criteria: September 12, 2021
• First Posted (Actual): September 16, 2021

Study Record Updates

• Last Update Posted (Actual): March 13, 2023
• Last Update Submitted That Met QC Criteria: March 10, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, Follicular; Antineoplastic Agents; Antineoplastic Agents, Immunological; Obinutuzumab
• Other Study ID Numbers: 2021-000362-15

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes