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Follicular Non-Hodgkin's LymphomaPhase 3NCT02063685

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

A Phase 3 study testing R-CHOP or R-bendamustine, Observation and Maintenance weekly x4 in people with Follicular Non-Hodgkin's Lymphoma, run by Fondazione Italiana Linfomi - ETS at 48 sites in Italy.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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). Read more about this study

Who is it for?
Ages 18 years and olderHealthy volunteers can take part
Conditions the study is for
Follicular Non-Hodgkin's Lymphoma
What is being tested?
R-CHOP or R-bendamustine, Observation and Maintenance weekly x4
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
807 participants
Where
48 sitesItaly
Study dates
Jul 2012to Dec 2021
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • Healthy volunteers accepted
  • Adult, Older adult

Who may be able to join

  • 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
Show all 24Show fewer
  • 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.

Who cannot join

  • 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
Show all 17Show fewer
  • 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.

Trial locations and contacts

48 sites in 1 country.

48 sites in 1 country

Italy48 sites

  • Ospedale Civile Ss. Antonio E Biagio Di Alessandria - Alessandria (Al)

    Alessandria, 15121

  • A.O. Universitaria Ospedali Riuniti - Ospedale Umberto I Di Ancona _

    Ancona, 60126

  • A.O. Universitaria Ospedale Consorziale Policlinico Di Bari

    Bari, 70124

  • A.O. Ospedale Degli Infermi

    Biella, 13900

  • A.O. Universitaria Policlinico S.Orsola-Malpighi Di Bologna

    Bologna, 40138

  • Pres.Ospedal.Spedali Civili Brescia

    Brescia, 25125

  • Stabilimento "Perrino" - Brindisi -

    Brindisi, 72100

  • Ospedale Armando Businco - Cagliari

    Cagliari, 09121

  • Fondazione Del Piemonte Per L'Oncologia Ircc Di Candiolo

    Candiolo, Torino, 10060

  • A.O. Universitaria Ospedale Vittorio Emanuele Di Catania

    Catania, 95124

  • ASUR 8

    Civitanova Marche, Macerata, 62012

  • Azienda Ospedaliera S. Croce E Carle Di Cuneo

    Cuneo, 12100

  • A.O. Universitaria Careggi Di Firenze

    Florence, 50139

  • A.O. Universitaria S. Martino Di Genova

    Genova, 16132

  • Ematologia Ospedale Vito Fazzi

    Lecce

  • Presidio Ospedaliero - Matera -

    Matera, 75100

  • Irst - Istituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori - Sede Di Meldola (Fc)

    Meldola, Forlì Cesena, 47014

  • Azienda Ospedaliera Papardo

    Messina, 98158

  • Fondazione IRCCS Milano INT

    Milan, MI, 20133

  • Irccs Ospedale Maggiore Policlinico Di Milano

    Milan, 20122

  • Ospedale Ca' Granda-Niguarda

    Milan, 20162

  • A.O. Universitaria Policlinico Di Modena

    Modena, 41124

  • Azienda Ospedaliera S. Gerardo Di Monza

    Monza, Monza Brianza, 20900

  • Irccs Istituto Nazionale Tumori Fondazione Pascale

    Naples

  • P.O. Umberto I

    Nocera Inferiore, Salerno, 84014

  • A.O. Universitaria Maggiore Della Carita' Di Novara

    Novara, 28100

  • Ospedale San Francesco

    Nuoro, 08100

  • A.O. Universitaria Policlinico Giaccone Di Palermo

    Palermo, 90127

  • A.O. "V. Cervello"

    Palermo, 90146

  • A O Universitaria di Parma

    Parma

  • IRCCS Policlinico S. Matteo

    Pavia, 27100

  • Azienda Ospedaliera Di Perugia - Ospedale S. Maria Della Misericordia -

    Perugia, 06134

  • Ospedale Civile Spirito Santo

    Pescara, 65124

  • Ausl Di Piacenza

    Piacenza, 29121

  • A.O. Universitaria Pisana

    Pisa, 56126

  • Ospedale Bianchi - Melacrino - Morelli

    Reggio Calabria, 89123

  • Ausl Di Rimini

    Rimini, 47924

  • Irccs Centro Di Riferimento Oncologico Di Basilicata (Crob)

    Rionero in Vulture, Potenza, 85028

  • Universita' Degli Studi Di Roma 'La Sapienza'

    Roma, 00185

  • Irccs Istituto Clinico Humanitas

    Rozzano, Milano, 20089

  • Casa sollievo della Sofferenza

    San Giovanni Rotondo

  • A.O. Universitaria Senese

    Siena, 53100

  • A.O. S. Maria di Terni

    Terni, TR, 05100

  • A.O. Universitaria S. Giovanni Battista-Molinette Di Torino

    Torino, 10126

  • Ospedale Ca Foncello

    Treviso

  • A.O.Cardinale Panico Ematologia e centro trapianti

    Tricase (LE)

  • A.O. Universitaria S. Maria Della Misericordia Di Udine

    Udine, 33100

  • Ospedale Di Circolo E Fondazione Macchi

    Varese, 21100

Other trials in Italy

About this study

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.

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.

Read the 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 )
Being tested
R-CHOP or R-bendamustine, Observation, Maintenance weekly x4, Ibritumomab Tiuxetan + Maintenance, Standard Maintenance
Medical subject headings
Lymphoma, Follicular

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • R-CHOP or R-bendamustineDrug

    Also called Rituximab, Cyclophosphamide,, Hydroxydaunorubicin, Oncovin

    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.

  • ObservationDrug

    not maintenance therapy and followed-up with MRD monitoring.

  • Maintenance weekly x4Drug

    Also called Rituximab

    Four weekly doses of Rituximab (375 mg/m²). Rituximab could be repeated for MRD positive for a maximum of three courses

  • Ibritumomab Tiuxetan + MaintenanceDrug

    Also called Ibritumomab Tiuxetan

    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.

  • Standard MaintenanceDrug

    Also called Rituximab

    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.

Study groups in NCT02063685
Study groupRoleWhat they receive
GROUP 1 - STANDARDOtherR-CHOP or R-bendamustine + Standard Maintenance
Receives: Drug: R-CHOP or R-bendamustine; Drug: Standard Maintenance
GROUP 2ExperimentalFDG-PET POSITIVE (score 4-5) patients (High risk) R-CHOP or R-bendamustine + Ibritumomab Tiuxetan + Maintenance
Receives: Drug: R-CHOP or R-bendamustine; Drug: Ibritumomab Tiuxetan + Maintenance
GROUP 1aExperimentalFDG-PET NEGATIVE (score 1-3) AND MRD NEGATIVE R-CHOP or R-bendamustine + Observation
Receives: Drug: R-CHOP or R-bendamustine; Drug: Observation
GROUP 1bExperimentalFDG-PET NEGATIVE (score 1-3) AND MRD POSITIVE R-CHOP or R-bendamustine + Maintenance weekly x4
Receives: Drug: R-CHOP or R-bendamustine; Drug: Maintenance weekly x4

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. PFS

    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.

    Measured: 12/31/2019

Secondary outcomes (6)

  1. CRR

    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.

    Measured: 12/31/2019

  2. ORR

    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.

    Measured: 12/31/2019

  3. DR

    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.

    Measured: 12/31/2019

  4. EFS

    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).

    Measured: 12/31/2019

  5. OS

    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.

    Measured: 12/31/2019

  6. Molecular response analysis

    • 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.

    Measured: 12/31/2019

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Feb 2014 (estimated)
  2. Study startJul 2012
  3. Primary completionDec 2021
  4. Study completionDec 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
807 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02063685
Sponsor's protocol ID
FIL_FOLL12
Status last verified
Jun 2022
First submitted
21 Nov 2013
Last updated
21 Jun 2022
Results posted
No
Data monitoring committee
No

Publications

  • 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.

    PubMed 40106688

  • 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.

    PubMed 34709880

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing R-CHOP or R-bendamustine, Observation and Maintenance weekly x4 in people with Follicular Non-Hodgkin's Lymphoma, run by Fondazione Italiana Linfomi - ETS at 48 sites in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 24 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 21 Jun 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 48 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

PFS (time frame: 12/31/2019). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02063685, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Jun 2022.

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