Clinical Trials /

Study to Evaluate the Efficacy of Response-adapted Strategy in Follicular Lymphoma

NCT02063685

Description:

Recently, the availability of R has substantially changed therapeutic approach to FL patients, since its combination with chemotherapy has improved response rates, progression free survival (PFS) and overall survival (OS). Based on the results of recently completed randomized studies the standard treatment for patients with FL should consist of an initial therapy with R-CHOP combination followed by two-year maintenance with R. Although results of randomized trials confirmed that this approach results in an improved patients' outcome and made a step forward in the management of patients with FL, one important question that can be raised is if this approach is really needed for all patients with FL or if some of them could benefit from a reduced intensity treatment achieving the same results in terms of outcome and survival . This question is of particular interest for newly diagnosed patients for whom maintenance does not affect OS. More recent data demonstrated that the outcome of patients with FL can be further predicted by evaluating the quality of response to therapy studying minimal residual disease (MRD). This project addresses the objective of evaluating if combining clinical response assessed on FDG-PET scan and molecular response measured through MRD detection could permit to single out groups of patients at different risk of progression and to consequently modulate maintenance therapies, with the aim to provide clinicians a more rational use of the available diagnostic and therapeutic resources.

Related Conditions:
  • Follicular Lymphoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Study to Evaluate the Efficacy of Response-adapted Strategy in Follicular Lymphoma
  • Official Title: A Multicenter, Phase III, Randomized Study to Evaluate the Efficacy of Response-adapted Strategy to Define Maintenance After Standard Chemoimmunotherapy in Patients With Advanced-stage Follicular Lymphoma.

Clinical Trial IDs

  • ORG STUDY ID: FIL_FOLL12
  • NCT ID: NCT02063685

Conditions

  • Follicular Non-Hodgkin's Lymphoma

Interventions

DrugSynonymsArms
R-CHOP or R-bendamustineRituximab, Cyclophosphamide,, Hydroxydaunorubicin, Oncovin, Prednisone, BendamustineGROUP 1 - STANDARD
ObservationGROUP 1a
Maintenance weekly x4RituximabGROUP 1b
Ibritumomab Tiuxetan + MaintenanceIbritumomab TiuxetanGROUP 2
Standard MaintenanceRituximabGROUP 1 - STANDARD

Purpose

Recently, the availability of R has substantially changed therapeutic approach to FL patients, since its combination with chemotherapy has improved response rates, progression free survival (PFS) and overall survival (OS). Based on the results of recently completed randomized studies the standard treatment for patients with FL should consist of an initial therapy with R-CHOP combination followed by two-year maintenance with R. Although results of randomized trials confirmed that this approach results in an improved patients' outcome and made a step forward in the management of patients with FL, one important question that can be raised is if this approach is really needed for all patients with FL or if some of them could benefit from a reduced intensity treatment achieving the same results in terms of outcome and survival . This question is of particular interest for newly diagnosed patients for whom maintenance does not affect OS. More recent data demonstrated that the outcome of patients with FL can be further predicted by evaluating the quality of response to therapy studying minimal residual disease (MRD). This project addresses the objective of evaluating if combining clinical response assessed on FDG-PET scan and molecular response measured through MRD detection could permit to single out groups of patients at different risk of progression and to consequently modulate maintenance therapies, with the aim to provide clinicians a more rational use of the available diagnostic and therapeutic resources.

Detailed Description

      This is a multicenter, randomized, phase III, superiority study comparing standard vs
      response driven approach to maintenance. Adult patients (age ≥ 18 years) with naïve,
      untreated follicular lymphoma, stage II-IV, Follicular Lymphoma International Prognostic
      Index 2 (FLIPI2) >0 requiring a therapeutic intervention will be recruited and randomly
      assigned in a 1:1 ratio to either standard or experimental arm.

      All patients will receive the same induction therapy with 6 cycles of R-CHOP or
      R-bendamustine and 2 additional doses of Rituximab.

      At baseline patients will be assessed for molecular status and staged by means of CT scan. A
      baselineFluorine-18-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) scan should
      also be performed.

      At the end of chemoimmunotherapy all patients will be assessed for disease response by common
      clinical and laboratory examination, CT scan and FDG-PET. An intermediate assessment of
      response with CT scan and FDG-PET (optional) will also be performed after the first four
      courses of R-chemoimmunotherapy.

      At the end of induction therapy the status of minimal residual disease will be also
      evaluated.

      After induction treatment all responding patients in the standard arm will receive standard
      maintenance therapy with Rituximab (every 2 months for 2 years), while patients in the
      experimental arm will be subdivided into two risk groups and assigned to different post
      induction treatments based on FDG-PET and MRD results. In both arms, patients with stable or
      progressive disease (PET positive and less than PR on CT scan) will be addressed to salvage
      treatment chosen at physician discretion.

      In the experimental arm, risk group allocation will be performed primarily on the basis of
      FDG-PET results:

        -  Group 1 (low risk): negative FDG-PET

        -  Group 2 (high risk): positive FDG-PET

      Patients at low risk (FDG-PET negative) will received maintenance therapy according to their
      MRD status,particularly:

        -  Group 1a (MRD negative): observation

        -  Group 1b (MRD positive): pre-emptive Rituximab therapy

      Patient at high risk (FDG-PET positive) will receive maintenance regardless of their MRD
      status:

      · Group 2: intensified maintenance ((90)Y Ibritumomab Tiuxetan + Rituximab maintenance )
    

Trial Arms

NameTypeDescriptionInterventions
GROUP 1 - STANDARDOtherR-CHOP or R-bendamustine + Standard Maintenance
  • R-CHOP or R-bendamustine
  • Standard Maintenance
GROUP 2ExperimentalFDG-PET POSITIVE (score 4-5) patients (High risk) R-CHOP or R-bendamustine + Ibritumomab Tiuxetan + Maintenance
  • R-CHOP or R-bendamustine
  • Ibritumomab Tiuxetan + Maintenance
GROUP 1aExperimentalFDG-PET NEGATIVE (score 1-3) AND MRD NEGATIVE R-CHOP or R-bendamustine + Observation
  • R-CHOP or R-bendamustine
  • Observation
GROUP 1bExperimentalFDG-PET NEGATIVE (score 1-3) AND MRD POSITIVE R-CHOP or R-bendamustine + Maintenance weekly x4
  • R-CHOP or R-bendamustine
  • Maintenance weekly x4

Eligibility Criteria

        Inclusion Criteria:

          -  Histological diagnosis of B-Cell CD20+ Follicular Lymphoma (FL), grade I, II, IIIa
             according to the WHO 2008 classification

          -  ECOG performance status 0-2

          -  Age ≥ 18 years

          -  Ann Arbor stage II-IV

          -  FLIPI2>0

          -  Presence of evaluable/measurable disease after diagnostic biopsy

          -  At least one of the following criteria for defining active disease:

               -  systemic symptoms

               -  cytopenia due to bone marrow involvement

               -  LDH> upper normal value

               -  any nodal or extranodal tumor mass with a diameter >7cm

               -  involvement of ≥ 3 nodal sites, each with a diameter of ≥ 3cm

               -  extranodal disease

               -  rapidly progressive disease

          -  Life expectancy > 6 months

          -  Left ventricular ejection fraction (LVEF) ³ 50%

          -  Serum negativity for HIV

          -  Serum negativity for HBsAg; HBcAb positive but HBV-DNA negative patients are allowed
             with mandatory Lamivudine prophylaxis.

          -  Serum negativity for HCV, except for those patients without signs of active viral
             replication assessed by HCV-RNA copies

          -  Serum creatinine < 2mg/dl , serum bilirubin < 1.5mg/dl, aspartate amino-transferase
             (AST/GOT) £ 2.5xUNV, alanine amino-transferase (ALT/GPT) £ 2.5xUNV, and alkaline
             phosphatase £ 4 times the upper limit of normal (unless the increase is attributed
             directly to the presence of tumour by the Investigator)

          -  Patients with no previous treatment for the lymphoma with the exception of
             locoregional radiotherapy (IFRT)

          -  Adequate measure adoption to avoid pregnancy

          -  Written informed consent given at time of registration

          -  Patient must be accessible for treatment and follow up.

        Exclusion Criteria:

          -  Histological diagnosis of :

               -  any lymphoma other than follicular lymphoma and all CD20 negative B-cell
                  lymphomas

               -  grade III b follicular lymphoma

               -  evidence of transformation to high grade lymphoma

          -  Ann Arbor stage I

          -  Suspect or clinical evidence of CNS involvement by lymphoma

          -  History of other malignancies within 5 years prior to study entry except for
             adequately treated carcinoma in situ of the cervix or basal or squamous cell skin
             cancer, low grade, early stage localized prostate cancer treated surgically with
             curative intent, good prognosis DCIS of the breast treated with lumpectomy alone with
             curative intent

          -  Evidence of any severe active acute or chronic infection

          -  Concurrent co-morbid medical condition which might exclude administration of full dose
             chemotherapy

          -  Severe chronic obstructive pulmonary disease with hypoxemia

          -  Severe diabetes mellitus difficult to control with adequate insulin therapy

          -  Myocardial infarction within 6 months before study entry

          -  Clinically significant secondary cardiovascular disease e.g. uncontrolled
             hypertension, (resting diastolic blood pressure >115 mmHg), uncontrolled multifocal
             cardiac arrhythmias, symptomatic angina pectoris or congestive cardiac failure NYHA
             class III-IV

          -  HbsAg-positive, HIV-positive, or HCVAb-positive patients

          -  Known hypersensitivity or anaphylactic reactions to murine antibodies or proteins

          -  Any other co-existing medical or psychological condition that would preclude
             participation in the study or compromise ability to give informed consent

          -  Follicular lymphoma, showing a negative baseline PET scan.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:Accepts Healthy Volunteers

Primary Outcome Measures

Measure:PFS
Time Frame:12/31/2019
Safety Issue:
Description:To evaluate whether a FDG-PET and MRD response-based maintenance therapy is more effective in terms of Progression-Free Survival (PFS) than a standard maintenance therapy with Rituximab in patients with untreated, advanced, follicular lymphoma. Progression Free Survival (PFS) PFS will be measured from the date of randomization to the date of documented first occurrence of disease progression or relapse or to the date of death from any cause. Responding patients and patients who are lost to follow up will be censored at their last assessment date.

Secondary Outcome Measures

Measure:CRR
Time Frame:12/31/2019
Safety Issue:
Description:Complete Response Rate (CRR) is defined as the number of CR after the completion of the study treatment. Patients without a response assessment (due to any reasons) will be considered as non-responders.
Measure:ORR
Time Frame:12/31/2019
Safety Issue:
Description:Overall Response Rate (ORR) after the completion of the treatment, defined as the sum of Complete Response and Partial Response. Patients without a response assessment (due to any reasons) will be considered as non-responders.
Measure:DR
Time Frame:12/31/2019
Safety Issue:
Description:Duration of Response (DR) is from the time when criteria for response (ie, CR or PR) are met, to the first documentation of relapse or progression.
Measure:EFS
Time Frame:12/31/2019
Safety Issue:
Description:Event Free Survival (EFS) is measured from the time from study entry to any treatment failure including disease progression, or discontinuation of treatment for any reason (eg, disease progression, toxicity, patient preference, initiation of new treatment without documented progression, or death).
Measure:OS
Time Frame:12/31/2019
Safety Issue:
Description:Overall survival (OS) is defined as the time from the first day of study treatment until the date of death irrespective of cause. Patients who have not died at the time of end of the whole study , and patients who are lost to follow up , will be censored at the date of the last contact.
Measure:Molecular response analysis
Time Frame:12/31/2019
Safety Issue:
Description:Rate of molecular remission will be defined as the proportion of patients polymerase chain reaction (PCR) negative for Bcl2/IgH at different time-points including those achieving continuous MR in two or more consecutive time-points. Patients without a response assessment (due to any reasons) will be excluded from the analysis. Rate of conversion will be defined as the proportion of patients from baseline PCR-positivity to PCR-negativity. Patients without a response assessment (due to any reasons) will be excluded from the analysis. Rate of molecular relapse will be defined as the proportion of patients from PCR-negativity to PCR-positivity. Patients without a response assessment (due to any reasons) will be excluded from the analysis.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Fondazione Italiana Linfomi ONLUS

Last Updated