Clinical trial NCT02063685: 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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Follicular Non-Hodgkin's Lymphoma
Lead sponsor: Fondazione Italiana Linfomi - ETS
Sponsor class: OTHER
First posted: 2014-02-14
Enrollment: 807
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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 )

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.

Primary outcomes:
measure: PFS
timeFrame: 12/31/2019
Secondary outcomes:
measure: CRR
timeFrame: 12/31/2019
measure: ORR
timeFrame: 12/31/2019
measure: DR
timeFrame: 12/31/2019
measure: EFS
timeFrame: 12/31/2019
measure: OS
timeFrame: 12/31/2019
measure: Molecular response analysis
timeFrame: 12/31/2019
Other outcomes:
Locations:
city: Meldola
country: Italy
facility: Irst - Istituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori - Sede Di Meldola (Fc)
state: Forlì Cesena
city: Civitanova Marche
country: Italy
facility: ASUR 8
state: Macerata
city: Rozzano
country: Italy
facility: Irccs Istituto Clinico Humanitas
state: Milano
city: Milano
country: Italy
facility: Fondazione IRCCS Milano INT
state: MI
city: Monza
country: Italy
facility: Azienda Ospedaliera S. Gerardo Di Monza
state: Monza Brianza
city: Rionero in Vulture
country: Italy
facility: Irccs Centro Di Riferimento Oncologico Di Basilicata (Crob)
state: Potenza
city: Nocera Inferiore
country: Italy
facility: P.O. Umberto I
state: Salerno
city: Candiolo
country: Italy
facility: Fondazione Del Piemonte Per L'Oncologia Ircc Di Candiolo
state: Torino
city: Terni
country: Italy
facility: A.O. S. Maria di Terni
state: TR
city: Alessandria
country: Italy
facility: Ospedale Civile Ss. Antonio E Biagio Di Alessandria - Alessandria (Al)
city: Ancona
country: Italy
facility: A.O. Universitaria Ospedali Riuniti - Ospedale Umberto I Di Ancona _
city: Bari
country: Italy
facility: A.O. Universitaria Ospedale Consorziale Policlinico Di Bari
city: Biella
country: Italy
facility: A.O. Ospedale Degli Infermi
city: Bologna
country: Italy
facility: A.O. Universitaria Policlinico S.Orsola-Malpighi Di Bologna
city: Brescia
country: Italy
facility: Pres.Ospedal.Spedali Civili Brescia
city: Brindisi
country: Italy
facility: Stabilimento "Perrino" - Brindisi -
city: Cagliari
country: Italy
facility: Ospedale Armando Businco - Cagliari
city: Catania
country: Italy
facility: A.O. Universitaria Ospedale Vittorio Emanuele Di Catania
city: Cuneo
country: Italy
facility: Azienda Ospedaliera S. Croce E Carle Di Cuneo
city: Firenze
country: Italy
facility: A.O. Universitaria Careggi Di Firenze
city: Genova
country: Italy
facility: A.O. Universitaria S. Martino Di Genova
city: Lecce
country: Italy
facility: Ematologia Ospedale Vito Fazzi
city: Matera
country: Italy
facility: Presidio Ospedaliero - Matera -
city: Messina
country: Italy
facility: Azienda Ospedaliera Papardo
city: Milano
country: Italy
facility: Irccs Ospedale Maggiore Policlinico Di Milano
city: Milano
country: Italy
facility: Ospedale Ca' Granda-Niguarda
city: Modena
country: Italy
facility: A.O. Universitaria Policlinico Di Modena
city: Napoli
country: Italy
facility: Irccs Istituto Nazionale Tumori Fondazione Pascale
city: Novara
country: Italy
facility: A.O. Universitaria Maggiore Della Carita' Di Novara
city: Nuoro
country: Italy
facility: Ospedale San Francesco
city: Palermo
country: Italy
facility: A.O. Universitaria Policlinico Giaccone Di Palermo
city: Palermo
country: Italy
facility: A.O. "V. Cervello"
city: Parma
country: Italy
facility: A O Universitaria di Parma
city: Pavia
country: Italy
facility: IRCCS Policlinico S. Matteo
city: Perugia
country: Italy
facility: Azienda Ospedaliera Di Perugia - Ospedale S. Maria Della Misericordia -
city: Pescara
country: Italy
facility: Ospedale Civile Spirito Santo
city: Piacenza
country: Italy
facility: Ausl Di Piacenza
city: Pisa
country: Italy
facility: A.O. Universitaria Pisana
city: Reggio Calabria
country: Italy
facility: Ospedale Bianchi - Melacrino - Morelli
city: Rimini
country: Italy
facility: Ausl Di Rimini
city: Roma
country: Italy
facility: Universita' Degli Studi Di Roma 'La Sapienza'
city: San Giovanni Rotondo
country: Italy
facility: Casa sollievo della Sofferenza
city: Siena
country: Italy
facility: A.O. Universitaria Senese
city: Torino
country: Italy
facility: A.O. Universitaria S. Giovanni Battista-Molinette Di Torino
city: Treviso
country: Italy
facility: Ospedale Ca Foncello
city: Tricase (LE)
country: Italy
facility: A.O.Cardinale Panico Ematologia e centro trapianti
city: Udine
country: Italy
facility: A.O. Universitaria S. Maria Della Misericordia Di Udine
city: Varese
country: Italy
facility: Ospedale Di Circolo E Fondazione Macchi
Study officials:
affiliation: Hematology, Azienda Ospedali Riuniti Papardo-Piemonte, Messina, Italy.
name: Donato Mannina, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Diagnostic Medicine, Clinical Medicine and Public Health, University of Modena and Reggio Emilia, Modena , Italy
name: Massimo Federico, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.