Clinical trial NCT03341520: Gazyvaro and Low Dose Radiotherapy in Early Stage Follicular Lymphoma
Official title: Therapy of Nodal Follicular Lymphoma (WHO Grade 1/2) in Clinical Stage I/II Using Response Adapted Involved Site Radiotherapy in Combination With Gazyvaro
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Stage II Grade 1 Follicular Lymphoma
Stage II Grade 2 Follicular Lymphoma
Stage I Follicular Lymphoma Grade 1
Stage II Follicular Lymphoma Grade 2
Lead sponsor: Heidelberg University
Sponsor class: OTHER
Collaborators: name: Roche Pharma AG
First posted: 2017-11-14
Enrollment: 89
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Open, non-controlled, national multi-center phase II trial
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

* 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)

Exclusion Criteria:

* 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

Primary outcomes:
measure: Rate of metabolic complete remission (CR)
timeFrame: week 18
Secondary outcomes:
measure: Rate of morphologic complete remission (CR)
timeFrame: week 7, week 18, month 6
measure: Progression free survival (PFS)
timeFrame: 2 years
measure: Toxicity
timeFrame: Start until month 30
measure: Overall survival (OS)
timeFrame: 2 years
measure: Relapse rate
timeFrame: start until month 30
measure: Quality of life (QoL) EORTC QLQ-C30
timeFrame: Initially, week 18, month 12, month 24
measure: Minimal residual disease (MRD) response
timeFrame: initially, week 18, month 6, month 12, month 18, month 24
measure: Relapse pattern
timeFrame: start until month 30
measure: Quality of life (QoL) FACT-Lymph25
timeFrame: Initially, week 18, month 12, month 24
Other outcomes:
Locations:
city: Tuebingen
country: Germany
facility: University of Tuebingen
state: Baden-Wuerttemberg
city: Berlin
country: Germany
facility: Vivantes Klinikum
city: Cologne
country: Germany
facility: University of Cologne
city: Essen
country: Germany
facility: University of Essen
city: Frankfurt
country: Germany
facility: University of Frankfurt
city: Heidelberg
country: Germany
facility: University of Heidelberg
city: Kempten
country: Germany
facility: Klinikum Kempten
city: Marburg
country: Germany
facility: Site Marburg
city: Munich
country: Germany
facility: LMU
city: Munich
country: Germany
facility: TU
city: Münster
country: Germany
facility: University of Muenster
city: Ulm
country: Germany
facility: University of Ulm
Study officials:
affiliation: Radiation Therapy, University Hospital of Heidelberg ,Germany
name: Klaus Herfarth, MD
role: STUDY_CHAIR
References:
citation: Mac Manus MP, Hoppe RT. Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University. J Clin Oncol. 1996 Apr;14(4):1282-90. doi: 10.1200/JCO.1996.14.4.1282.
citation: Haas RL, Poortmans P, de Jong D, Aleman BM, Dewit LG, Verheij M, Hart AA, van Oers MH, van der Hulst M, Baars JW, Bartelink H. High response rates and lasting remissions after low-dose involved field radiotherapy in indolent lymphomas. J Clin Oncol. 2003 Jul 1;21(13):2474-80. doi: 10.1200/JCO.2003.09.542.
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: Trotman J, Fournier M, Lamy T, Seymour JF, Sonet A, Janikova A, Shpilberg O, Gyan E, Tilly H, Estell J, Forsyth C, Decaudin D, Fabiani B, Gabarre J, Salles B, Van Den Neste E, Canioni D, Garin E, Fulham M, Vander Borght T, Salles G. Positron emission tomography-computed tomography (PET-CT) after induction therapy is highly predictive of patient outcome in follicular lymphoma: analysis of PET-CT in a subset of PRIMA trial participants. J Clin Oncol. 2011 Aug 10;29(23):3194-200. doi: 10.1200/JCO.2011.35.0736. Epub 2011 Jul 11.
citation: Sehn LH, Chua N, Mayer J, Dueck G, Trneny M, Bouabdallah K, Fowler N, Delwail V, Press O, Salles G, Gribben J, Lennard A, Lugtenburg PJ, Dimier N, Wassner-Fritsch E, Fingerle-Rowson G, Cheson BD. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 2016 Aug;17(8):1081-1093. doi: 10.1016/S1470-2045(16)30097-3. Epub 2016 Jun 23.
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.