Clinical Trials /

Gazyvaro and Low Dose Radiotherapy in Early Stage Follicular Lymphoma

NCT03341520

Description:

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.

Related Conditions:
  • Follicular Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: 2016-002059-89
  • NCT ID: NCT03341520

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

Interventions

DrugSynonymsArms
Obinutuzumab Injection [Gazyva]Gazyvarointerventional arm

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
interventional armExperimentalObinutuzumab 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
  • Obinutuzumab Injection [Gazyva]

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Rate of metabolic response
Time Frame:week 18
Safety Issue:
Description: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

Measure:Rate of morphologic response
Time Frame:week 7, week 18, month 6
Safety Issue:
Description:rate of morphologic complete remission (CR) after low-dose involved site radiotherapy in combination with Obinutuzumab in patients with initially remaining lymphoma
Measure:Progression free survival (PFS)
Time Frame:2 years
Safety Issue:
Description:PFS of all patients
Measure:Toxicity
Time Frame:Start until month 30
Safety Issue:
Description:Common Toxicity Criteria (CTC) Toxicity
Measure:Overall survival (OS)
Time Frame:2 years
Safety Issue:
Description:OS of all patients
Measure:Relapse rate
Time Frame:start until month 30
Safety Issue:
Description:Relapse rate of all patients
Measure:Quality of life (QoL) EORTC QLQ-C30
Time Frame:Initially, week 18, month 12, month 24
Safety Issue:
Description:QoL according EORTC QLQ-C30
Measure:Minimal residual disease (MRD) response
Time Frame:initially, week 18, month 6, month 12, month 18, month 24
Safety Issue:
Description:Minimal residual disease
Measure:Relapse pattern
Time Frame:start until month 30
Safety Issue:
Description:Relapse pattern (e.g. out-field or in-field) of all relapses
Measure:Quality of life (QoL) FACT-Lymph25
Time Frame:Initially, week 18, month 12, month 24
Safety Issue:
Description:QoL according FACT-Lymph25 questionnaires

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Heidelberg University

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