Skip to content
TriangleGet started
← Study library

NCT02063685 · CITED IN SOURCE DOCUMENTS

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

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase
PHASE3
Status at capture
COMPLETED
Registry last update
2022-06-21

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.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

No posted result sections were captured. Registered plans do not establish that a treatment works.

Who could take part
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.
healthy Volunteers
true
minimum Age
18 Years
sex
ALL
std Ages
  1. ADULT
  2. OLDER_ADULT
Treatment arms and interventions
arm Groups
  1. description
    R-CHOP or R-bendamustine + Standard Maintenance
    intervention Names
    1. Drug: R-CHOP or R-bendamustine
    2. Drug: Standard Maintenance
    label
    GROUP 1 - STANDARD
    type
    OTHER
  2. description
    FDG-PET POSITIVE (score 4-5) patients (High risk) R-CHOP or R-bendamustine + Ibritumomab Tiuxetan + Maintenance
    intervention Names
    1. Drug: R-CHOP or R-bendamustine
    2. Drug: Ibritumomab Tiuxetan + Maintenance
    label
    GROUP 2
    type
    EXPERIMENTAL
  3. description
    FDG-PET NEGATIVE (score 1-3) AND MRD NEGATIVE R-CHOP or R-bendamustine + Observation
    intervention Names
    1. Drug: R-CHOP or R-bendamustine
    2. Drug: Observation
    label
    GROUP 1a
    type
    EXPERIMENTAL
  4. description
    FDG-PET NEGATIVE (score 1-3) AND MRD POSITIVE R-CHOP or R-bendamustine + Maintenance weekly x4
    intervention Names
    1. Drug: R-CHOP or R-bendamustine
    2. Drug: Maintenance weekly x4
    label
    GROUP 1b
    type
    EXPERIMENTAL
interventions
  1. arm Group Labels
    1. GROUP 1 - STANDARD
    2. GROUP 1a
    3. GROUP 1b
    4. GROUP 2
    description
    As induction therapy all patients will receive 6 courses of: Rituximab: 375 mg/m² day 1 iv Cyclophosphamide: 750 mg/m² day 1 iv Doxorubicin: 50 mg/m² day 1 iv Vincristine: 1.4 mg/m² day 1 iv (max dose 2mg) Prednisone: 100 mg day 1-5 os To allow administration of all drugs on the same day, Rituximab rapid infusion is permitted starting from cycle 2. Cycles are to be repeated every 21 days. or 6 courses of: Rituximab: 375 mg/m² day 1 iv Bendamustine: 90 mg/m² day 1 and 2 iv. To allow administration of all drugs on the same day, Rituximab rapid infusion is permitted starting from cycle 2. Cycles are to be repeated every 28 days.
    name
    R-CHOP or R-bendamustine
    other Names
    1. Rituximab
    2. Cyclophosphamide,
    3. Hydroxydaunorubicin
    4. Oncovin
    5. Prednisone
    6. Bendamustine
    type
    DRUG
  2. arm Group Labels
    1. GROUP 1a
    description
    not maintenance therapy and followed-up with MRD monitoring.
    name
    Observation
    type
    DRUG
  3. arm Group Labels
    1. GROUP 1b
    description
    Four weekly doses of Rituximab (375 mg/m²). Rituximab could be repeated for MRD positive for a maximum of three courses
    name
    Maintenance weekly x4
    other Names
    1. Rituximab
    type
    DRUG
  4. arm Group Labels
    1. GROUP 2
    description
    single dose of (90)Y Ibritumomab Tiuxetan (0.4 mCi/kg). Following RIT patients will continue maintenance with Rituximab (375 mg/m² every 2 months) for a total of 11 infusions.
    name
    Ibritumomab Tiuxetan + Maintenance
    other Names
    1. Ibritumomab Tiuxetan
    type
    DRUG
  5. arm Group Labels
    1. GROUP 1 - STANDARD
    description
    Rituximab 375 mg/m² every 2 months for 2 years. Maintenance will have to be started no more than 12 weeks after the last induction chemoimmunotherapy infusion.
    name
    Standard Maintenance
    other Names
    1. Rituximab
    type
    DRUG
Study design
allocation
RANDOMIZED
intervention Model
SINGLE_GROUP
masking Info
masking
NONE
primary Purpose
TREATMENT
Enrollment
count
807
type
ACTUAL
Registered outcome plans (not posted results)
primary Outcomes
  1. 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.
    measure
    PFS
    time Frame
    12/31/2019
secondary Outcomes
  1. 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
    CRR
    time Frame
    12/31/2019
  2. 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
    ORR
    time Frame
    12/31/2019
  3. 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
    DR
    time Frame
    12/31/2019
  4. 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
    EFS
    time Frame
    12/31/2019
  5. 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
    OS
    time Frame
    12/31/2019
  6. 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.
    measure
    Molecular response analysis
    time Frame
    12/31/2019
Full study description
brief Summary
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 )
Source references
references
  1. citation
    Durmo R, Chauvie S, Fallanca F, Bergesio F, Pinto A, Del Giudice I, Coscia M, Corradini P, Angelucci E, Tosi P, Freilone R, Ballerini F, Bari A, Pastore D, Zinzani PL, Bolis S, Flenghi L, Liso A, Olivieri J, Marcheselli L, Merli M, Versari A, Guerra L, Luminari S. Prognostic role of interim PET in follicular lymphoma: a post hoc study of FOLL12 trial by Fondazione Italiana Linfomi. Blood Adv. 2025 Jun 24;9(12):2927-2934. doi: 10.1182/bloodadvances.2024014790.
    pmid
    40106688
    type
    DERIVED
  2. citation
    Luminari S, Manni M, Galimberti S, Versari A, Tucci A, Boccomini C, Farina L, Olivieri J, Marcheselli L, Guerra L, Ferrero S, Arcaini L, Cavallo F, Kovalchuk S, Skrypets T, Del Giudice I, Chauvie S, Patti C, Stelitano C, Ricci F, Pinto A, Margiotta Casaluci G, Zilioli VR, Merli A, Ladetto M, Bolis S, Pavone V, Chiarenza A, Arcari A, Anastasia A, Dondi A, Mannina D, Federico M; Fondazione Italiana Linfomi. Response-Adapted Postinduction Strategy in Patients With Advanced-Stage Follicular Lymphoma: The FOLL12 Study. J Clin Oncol. 2022 Mar 1;40(7):729-739. doi: 10.1200/JCO.21.01234. Epub 2021 Oct 28.
    pmid
    34709880
    type
    DERIVED
Source notices and limitations
    Discovery and provenance
    1. release id
      ctgov-registry-7ad944f6deaf1f5cd6122126
      edge id
      nct-edge-d4d9c2c996f9ad5a8b99
      requested nct id
      NCT02063685
      primary nct id
      NCT02063685
      source kind
      nci_explicit_reference_or_link
      source record id
      Source null
      source file sha256
      fac27ab868761312e338cd8f54adc7127cc23ca36a0da8e2b6602af150db8ee1
      payload sha256
      b94e8efc5985f6692210ecde8046ae3092daea6311c857a68ee03861d9791e2b
      payload
      clinical indication matching status
      not_inferred
      end exclusive
      true
      id
      nct-edge-d4d9c2c996f9ad5a8b99
      link basis
      explicit_NCT_identifier_in_acquired_source
      nct id
      NCT02063685
      occurrences
      1. context exact
        fbyid','CDR0000810017&amp;version=HealthProfessional&amp;language=English'); return(false);">Level of evidence A1</a>]</p></li><li>The <a href="/clinicaltrials/NCT02063685">FOLL12</a> study (NCT02063685) included 807 patients with previously untreated high-tumor burden follicular lymphoma. Patients received rituximab plus chemot
        end
        236635
        exact text
        NCT02063685
        start
        236624
      2. context exact
        on=HealthProfessional&amp;language=English'); return(false);">Level of evidence A1</a>]</p></li><li>The <a href="/clinicaltrials/NCT02063685">FOLL12</a> study (NCT02063685) included 807 patients with previously untreated high-tumor burden follicular lymphoma. Patients received rituximab plus chemotherapy induction and were rando
        end
        236666
        exact text
        NCT02063685
        start
        236655
      offset unit
      unicode_code_points
      source file
      /tmp/cancer-full-research/nci/raw/5301169da6885e1905.html
      source file sha256
      fac27ab868761312e338cd8f54adc7127cc23ca36a0da8e2b6602af150db8ee1
      source json pointer
      Source null
      source kind
      nci_explicit_reference_or_link
      source record id
      Source null
      source retrieved at
      2026-09-09T23:22:02.877411+00:00
      source string basis
      UTF-8_text_with_universal_newline_translation
      source string sha256
      047fe9b01d453b31f39642c6f8ce6a5b55b9a51535081307cd23fe3f476ba79f
      source title
      Indolent B-Cell Non-Hodgkin Lymphoma Treatment (PDQ®)–Health Professional Version
      source update dates
      1. context
        Updated: May 14, 2025
        datetime
        2025-05-14T12:00:00Z
        display
        May 14, 2025

    Preserved source evidence · Independent clinical review pending · Not medical advice