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

NCT ID: NCT02063685

Last Updated: 2022-06-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 807 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-07-31
• Study Completion Date: 2021-12-31

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 )

Conditions

Follicular Non-Hodgkin's Lymphoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

GROUP 1 - STANDARD

R-CHOP or R-bendamustine + Standard Maintenance

Group Type: OTHER

R-CHOP or R-bendamustine

Intervention Type: DRUG

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.

Standard Maintenance

Intervention Type: DRUG

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.

GROUP 2

FDG-PET POSITIVE (score 4-5) patients (High risk) R-CHOP or R-bendamustine + Ibritumomab Tiuxetan + Maintenance

Group Type: EXPERIMENTAL

R-CHOP or R-bendamustine

Intervention Type: DRUG

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.

Ibritumomab Tiuxetan + Maintenance

Intervention Type: DRUG

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.

GROUP 1a

FDG-PET NEGATIVE (score 1-3) AND MRD NEGATIVE R-CHOP or R-bendamustine + Observation

Group Type: EXPERIMENTAL

R-CHOP or R-bendamustine

Intervention Type: DRUG

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.

Observation

Intervention Type: DRUG

not maintenance therapy and followed-up with MRD monitoring.

GROUP 1b

FDG-PET NEGATIVE (score 1-3) AND MRD POSITIVE R-CHOP or R-bendamustine + Maintenance weekly x4

Group Type: EXPERIMENTAL

R-CHOP or R-bendamustine

Intervention Type: DRUG

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.

Maintenance weekly x4

Intervention Type: DRUG

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

Interventions

R-CHOP or R-bendamustine

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.

Intervention Type: DRUG

Observation

not maintenance therapy and followed-up with MRD monitoring.

Intervention Type: DRUG

Maintenance weekly x4

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

Intervention Type: DRUG

Ibritumomab Tiuxetan + Maintenance

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.

Intervention Type: DRUG

Standard Maintenance

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.

Intervention Type: DRUG

Other Intervention Names

Rituximab; Cyclophosphamide,; Hydroxydaunorubicin; Oncovin; Prednisone; Bendamustine; Rituximab; Ibritumomab Tiuxetan; Rituximab

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Fondazione Italiana Linfomi - ETS

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Donato Mannina, MD

Role: PRINCIPAL_INVESTIGATOR

Hematology, Azienda Ospedali Riuniti Papardo-Piemonte, Messina, Italy.

Massimo Federico, MD

Role: PRINCIPAL_INVESTIGATOR

Department of Diagnostic Medicine, Clinical Medicine and Public Health, University of Modena and Reggio Emilia, Modena , Italy

Locations

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

Meldola, Forlì Cesena, Italy

ASUR 8

Civitanova Marche, Macerata, Italy

Irccs Istituto Clinico Humanitas

Rozzano, Milano, Italy

Fondazione IRCCS Milano INT

Milan, MI, Italy

Azienda Ospedaliera S. Gerardo Di Monza

Monza, Monza Brianza, Italy

Irccs Centro Di Riferimento Oncologico Di Basilicata (Crob)

Rionero in Vulture, Potenza, Italy

P.O. Umberto I

Nocera Inferiore, Salerno, Italy

Fondazione Del Piemonte Per L'Oncologia Ircc Di Candiolo

Candiolo, Torino, Italy

A.O. S. Maria di Terni

Terni, TR, Italy

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

Alessandria, , Italy

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

Ancona, , Italy

A.O. Universitaria Ospedale Consorziale Policlinico Di Bari

Bari, , Italy

A.O. Ospedale Degli Infermi

Biella, , Italy

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

Bologna, , Italy

Pres.Ospedal.Spedali Civili Brescia

Brescia, , Italy

Stabilimento "Perrino" - Brindisi -

Brindisi, , Italy

Ospedale Armando Businco - Cagliari

Cagliari, , Italy

A.O. Universitaria Ospedale Vittorio Emanuele Di Catania

Catania, , Italy

Azienda Ospedaliera S. Croce E Carle Di Cuneo

Cuneo, , Italy

A.O. Universitaria Careggi Di Firenze

Florence, , Italy

A.O. Universitaria S. Martino Di Genova

Genova, , Italy

Ematologia Ospedale Vito Fazzi

Lecce, , Italy

Presidio Ospedaliero - Matera -

Matera, , Italy

Azienda Ospedaliera Papardo

Messina, , Italy

Irccs Ospedale Maggiore Policlinico Di Milano

Milan, , Italy

Ospedale Ca' Granda-Niguarda

Milan, , Italy

A.O. Universitaria Policlinico Di Modena

Modena, , Italy

Irccs Istituto Nazionale Tumori Fondazione Pascale

Napoli, , Italy

A.O. Universitaria Maggiore Della Carita' Di Novara

Novara, , Italy

Ospedale San Francesco

Nuoro, , Italy

A.O. Universitaria Policlinico Giaccone Di Palermo

Palermo, , Italy

A.O. "V. Cervello"

Palermo, , Italy

A O Universitaria di Parma

Parma, , Italy

IRCCS Policlinico S. Matteo

Pavia, , Italy

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

Perugia, , Italy

Ospedale Civile Spirito Santo

Pescara, , Italy

Ausl Di Piacenza

Piacenza, , Italy

A.O. Universitaria Pisana

Pisa, , Italy

Ospedale Bianchi - Melacrino - Morelli

Reggio Calabria, , Italy

Ausl Di Rimini

Rimini, , Italy

Universita' Degli Studi Di Roma 'La Sapienza'

Roma, , Italy

Casa sollievo della Sofferenza

San Giovanni Rotondo, , Italy

A.O. Universitaria Senese

Siena, , Italy

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

Torino, , Italy

Ospedale Ca Foncello

Treviso, , Italy

A.O.Cardinale Panico Ematologia e centro trapianti

Tricase (LE), , Italy

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

Udine, , Italy

Ospedale Di Circolo E Fondazione Macchi

Varese, , Italy

Countries

Italy

References

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.

Reference Type: DERIVED

PMID: 40106688 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34709880 (View on PubMed)

Other Identifiers

FIL_FOLL12

Identifier Type: -

Identifier Source: org_study_id