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Gazyvaro and Low Dose Radiotherapy in Early Stage Follicular Lymphoma (GAZAI)

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ClinicalTrials.gov Identifier: NCT03341520
Recruitment Status : Recruiting
First Posted : November 14, 2017
Last Update Posted : August 26, 2021
Sponsor:
Collaborator:
Roche Pharma AG
Information provided by (Responsible Party):
Klaus Herfarth, MD, Heidelberg University

Study Description
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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.


Condition or disease Intervention/treatment Phase
Stage II Grade 1 Follicular Lymphoma Stage II Grade 2 Follicular Lymphoma Stage I Follicular Lymphoma Grade 1 Stage II Follicular Lymphoma Grade 2 Drug: Obinutuzumab Injection [Gazyva] Radiation: Low dose radiation Therapy (LDRT) Phase 2

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 93 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Open, non-controlled, national multi-center phase II trial
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : April 24, 2018
Estimated Primary Completion Date : November 2021
Estimated Study Completion Date : May 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arms and Interventions
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Arm Intervention/treatment
Experimental: interventional arm
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
 Drug: Obinutuzumab Injection [Gazyva]
7x 1000mg flat dose
Other Name: Gazyvaro

Radiation: Low dose radiation Therapy (LDRT)
2 x 2 Gy


Outcome Measures
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Primary Outcome Measures :
  1. Rate of metabolic complete remission (CR) [ Time Frame: 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 :
  1. Rate of morphologic complete remission (CR) [ Time Frame: 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

  2. Progression free survival (PFS) [ Time Frame: 2 years ]
    PFS of all patients

  3. Toxicity [ Time Frame: Start until month 30 ]
    Common Toxicity Criteria (CTC) Toxicity

  4. Overall survival (OS) [ Time Frame: 2 years ]
    OS of all patients

  5. Relapse rate [ Time Frame: start until month 30 ]
    Relapse rate of all patients

  6. Quality of life (QoL) EORTC QLQ-C30 [ Time Frame: Initially, week 18, month 12, month 24 ]
    QoL according EORTC QLQ-C30

  7. Minimal residual disease (MRD) response [ Time Frame: initially, week 18, month 6, month 12, month 18, month 24 ]
    Minimal residual disease

  8. Relapse pattern [ Time Frame: start until month 30 ]
    Relapse pattern (e.g. out-field or in-field) of all relapses

  9. Quality of life (QoL) FACT-Lymph25 [ Time Frame: Initially, week 18, month 12, month 24 ]
    QoL according FACT-Lymph25 questionnaires


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03341520


Contacts
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Contact: Klaus Herfarth, MD +49 6221 568202 klaus.herfarth@med.uni-heidelberg.de

Locations
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Germany
University of Tuebingen Recruiting
Tuebingen, Baden-Wuerttemberg, Germany
Contact: Martin Soekler, MD       martin.soekler@med.uni-tuebingen.de   
Vivantes Klinikum Recruiting
Berlin, Germany
Contact: Christian Scholz, MD       Christiane.scholz@vivantes.de   
University of Cologne Recruiting
Cologne, Germany, 50924
Contact: Kai Hübel, MD       kai.huebel@uk-koeln.de   
University of Essen Recruiting
Essen, Germany, 45122
Contact: Jan Duerig, MD       jan.duerig@uk-essen.de   
University of Frankfurt Recruiting
Frankfurt, Germany, 60590
Contact: Uta Brunnberg, MD       Uta.brunnberg@kgu.de   
University of Heidelberg Recruiting
Heidelberg, Germany, 69120
Contact: Klaus Herfarth, MD       klaus.herfarth@med.uni-heidelberg.de   
Contact: Johann Schmier, MD       johann.schmier@med.uni-heidelberg.de   
Klinikum Kempten Recruiting
Kempten, Germany
Contact: Christian Langer, MD       Christian.langer@klinikum-Kempten.de   
Contact: Florian Sterzing, MD       F.sterzing@strahlentherapie-Kempten.de   
Site Marburg Recruiting
Marburg, Germany
Contact: Rita Engenhart-Cabillic, MD       engenhart@med.uni-marburg.de   
Contact: Ch. Basler, MD       OnkoNet-Marburg@web.de   
LMU Recruiting
Munich, Germany, 81377
Contact: Martin Dreyling, MD       martin.dreyling@med.uni-muenchen.de   
TU Recruiting
Munich, Germany, 81675
Contact: Simon Heidegger, MD       simon.heidegger@mri.tum.de   
University of Muenster Recruiting
Münster, Germany
Contact: Georg Lenz, MD       Georg.lenz@ukmuenster.de   
Contact: Hans Eich, MD       Hans.eich@ukmuenster.de   
University of Ulm Recruiting
Ulm, Germany, 89081
Contact: Christian Buske, MD       christian.buske@uni-ulm.de   
Contact: Andreas Viardot, MD       andreas.viardot@medizin.uni-ulm.de   
Sponsors and Collaborators
Heidelberg University
Roche Pharma AG
Investigators
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Study Chair: Klaus Herfarth, MD Radiation Therapy, University Hospital of Heidelberg ,Germany
  Study Documents (Full-Text)

Documents provided by Klaus Herfarth, MD, Heidelberg University:
Study Protocol and Statistical Analysis Plan  [PDF] October 6, 2017

More Information
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Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Klaus Herfarth, MD, Principal investigator, Heidelberg University
ClinicalTrials.gov Identifier: NCT03341520    
Other Study ID Numbers: 2016-002059-89
First Posted: November 14, 2017    Key Record Dates
Last Update Posted: August 26, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Follicular
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
 Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Obinutuzumab
Antineoplastic Agents, Immunological
Antineoplastic Agents