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Patients will start immunochemotherapy with one of the approved regimens (R-CHOP, R-Bendamustine, G-CHOP, G-Bendamustine, G-CVP).

Patients randomized to Arm A will receive an induction immunochemotherapy at full doses (standard schedule).

After cycle 4, patients will be assessed for response and will complete their planned therapy if at least a stable disease is confirmed.

At the end of induction responding patients (CR, PR) will be addressed to a standard anti-CD20 maintenance (1 dose every 8 weeks for two years) with the same Monoclonal Antibody (MoAb) given during induction.

Patients will start immunochemotherapy with one of the approved regimens (R-CHOP, R-Bendamustine, G-CHOP, G-Bendamustine, G-CVP).

Patients randomized to Arm B will start their induction treatment with 4 cycles of the immunochemotherapy standard dose chosen by the physician: after cycle 4, patients will be assessed for response and will proceed with subsequent treatment based on the quality of their response. Specifically:

* Patients achieving a CR will receive a shortened treatment: in detail, they won't receive any further chemotherapy but will complete induction with 4 additional cycles of only the Monoclonal Antibody (MoAb) given during the first four cycles;
* In case if response less than CR, (PR,SD), patients will complete treatment as planned for patients in Arm A.

At the end of induction responding patients (CR, PR) will be addressed to a standard anti-CD20 maintenance (1 dose every 8 weeks for two years) with the same Monoclonal Antibody (MoAb) given during induction.

Arm A (Standard arm):

4 cycles of Rituximab-bendamustine Q28 (28-days cycles); Patients will undergo an early restaging after cycle 4: those with at least a stable disease will complete the induction treatment with 2 cycles of R-bendamustine Q28 + 2 cycles Q28 of rituximab;

Both Arms:

Whichever the regimen, in responding patients (Complete Remission CR, Partial Remission PR) at the end of induction a standard maintenance will follows (1 dose every 8 weeks for 2 years) with the same anti-CD20 Monoclonal Antibody (MoAb) used for induction.

Patients in both arms with progressive disease at any time and patients in stable disease (SD) at the End Of Induction (EOI) shall be considered for salvage therapy at clinician discretion.

Immunochemotherapy regimen: Rituximab-bendamustine (Arm A)

Arm B (Experimental arm):

4 cycles of Rituximab-bendamustine Q28 (28-days cycles);

After cycle 4 patients will undergo an early restaging. Induction therapy shall be completed based on the response achieved and on the treatment chosen as below specified:

* if in CR: patients will receive no more chemotherapy but will complete induction with the MoAb only, in this case: 4 cycles of rituximab;
* if less than CR (PR, SD): the immunochemotherapy program will be completed as outlined for Arm A: 2 cycles of R-bendamustine Q28 + 2 cycles Q28 of rituximab;

Both Arms:

Whichever the regimen, in responding patients (CR, PR) at the end of induction a standard maintenance will follows (1 dose every 8 weeks for 2 years) with the same anti-CD20 Monoclonal Antibody (MoAb) used for induction.

Patients in both arms with progressive disease at any time and patients in SD at the End Of Induction (EOI) shall be considered for salvage therapy at clinician discretion.

Immunochemotherapy regimen: Rituximab-bendamustine (Arm B)

Arm A (Standard arm):

4 cycles of R-CHOP Q21 (21-days cycles); R-CHOP = Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone

Patients will undergo an early restaging after cycle 4: those with at least a stable disease will complete the induction treatment with 2 cycles of R-CHOP Q21 + 2 cycles Q21 of rituximab;

Both Arms:

Whichever the regimen, in responding patients (Complete Remission CR, Partial Remission PR) at the end of induction a standard maintenance will follows (1 dose every 8 weeks for 2 years) with the same anti-CD20 Monoclonal Antibody (MoAb) used for induction.

Patients in both arms with progressive disease at any time and patients in stable disease (SD) at the End Of Induction (EOI) shall be considered for salvage therapy at clinician discretion: these patients will be included in the analysis planned by the study.

Immunochemotherapy regimen: R-CHOP (Arm A)

Arm B (Experimental arm):

4 cycles of R-CHOP Q21 (21-days cycles); R-CHOP = Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone

After cycle 4 patients will undergo an early restaging: induction therapy shall be completed based on the response achieved and on the treatment chosen:

* if in CR: patients will receive no more chemotherapy but will complete induction with the MoAb only, in this case: 4 cycles of rituximab;
* if less than CR (PR, SD): the immunochemotherapy program will be completed as outlined for Arm A: 2 cycles of R-CHOP Q21+ 2 cycles Q21of rituximab

Both Arms: in responding patients (CR, PR) at the end of induction a standard maintenance will follows (1 dose every 8 weeks for 2 years) with the same anti-CD20 MoAb used for induction.

Patients in both arms with progressive disease at any time and patients in SD at the EOI shall be considered for salvage therapy at clinician discretion: these patients will be included in the analysis.

Immunochemotherapy regimen: R-CHOP (Arm B)

Arm A (Standard arm):

4 cycles of G-bendamustine Q28 (28-days cycles); G-Bendamustine = Obinutuzumab and Bendamustine

Patients will undergo an early restaging after cycle 4: those with at least a stable disease will complete the induction treatment with 2 cycles of G-bendamustine Q28 (28-days cycles);

Both Arms:

Whichever the regimen, in responding patients (Complete Remission CR, Partial Remission) at the end of induction a standard maintenance will follows (1 dose every 8 weeks for 2 years) with the same anti-CD20 Monoclonal Antibody (MoAb) used for induction.

Patients in both arms with progressive disease at any time and patients in Stable Disease SD at the End Of Induction (EOI) shall be considered for salvage therapy at clinician discretion.

Immunochemotherapy regimen: G-bendamustine (Arm A)

Arm B (Experimental arm):

4 cycles of G-bendamustine Q28 (28-days cycles); G-Bendamustine = Obinutuzumab and Bendamustine

After cycle 4 patients will undergo an early restaging. Induction therapy shall be completed based on the response achieved and on the treatment chosen as below specified:

* if in CR: patients will receive no more chemotherapy but will complete induction with the Monoclonal Antibody (MoAb) only, in this case 2 cycles of obinutuzumab;
* if less than CR (PR, SD): the immunochemotherapy program will be completed as outlined for Arm A: 2 cycles of G-bendamustine Q28;

Both Arms: in responding patients (CR, PR) at the end of induction a standard maintenance will follows (1 dose every 8 weeks for 2 years) with the same anti-CD20 (MoAb) used for induction.

Patients in both arms with progressive disease at any time and patients in SD at the End Of Induction (EOI) shall be considered for salvage therapy at clinician discretion.

Immunochemotherapy regimen: G-bendamustine (Arm B)

Arm A (Standard arm):

4 cycles of G-CHOP Q21 (21-days cycles) G-CHOP = Obinutuzumab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone

Patients will undergo an early restaging after cycle 4: those with at least a stable disease will complete the induction treatment with 2 cycles of G-CHOP Q21 + 2 cycles Q21 of obinutuzumab;

Both Arms:

Whichever the regimen, in responding patients (Complete Remission CR, Partial Remission PR) at the end of induction a standard maintenance will follows (1 dose every 8 weeks for 2 years) with the same anti-CD20 Monoclonal Antibody (MoAb) used for induction.

Patients in both arms with progressive disease at any time and patients in stable disease (SD) at the End Of Induction (EOI) shall be considered for salvage therapy at clinician discretion.

Immunochemotherapy regimen: G-CHOP (Arm A)

4 cycles of G-CHOP Q21 (21-days cycles) G-CHOP = Obinutuzumab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone

After cycle 4 patients will undergo an early restaging. Induction therapy shall be completed based on the response achieved and on the treatment chosen as below specified:

* if in CR: patients will receive no more chemotherapy but will complete induction with the Monoclonal Antibody (MoAb) only, in this case: 4 cycles of obinutuzumab;
* if less than CR (PR, SD): the immunochemotherapy program will be completed as outlined for Arm A: 2 cycles of G-CHOP Q21 + 2 cycles Q21 of obinutuzumab;

Both Arms: in responding patients (CR, PR) at the end of induction a standard maintenance will follows (1 dose every 8 weeks for 2 years) with the same anti-CD20 MoAb used for induction.

Patients in both arms with progressive disease at any time and patients in SD at the EOI shall be considered for salvage therapy at clinician discretion.

Immunochemotherapy regimen: G-CHOP (Arm B)

Arm A (Standard arm):

4 cycles of G-CVP Q21 (21-days cycles) G-CVP = Obinutuzumab, Cyclophosphamide, Vincristine, Prednisone.

Patients will undergo an early restaging after cycle 4: those with at least a stable disease will complete the induction treatment with 4 cycles of G-CVP Q21;

Both Arms:

Whichever the regimen, in responding patients (Complete Remission CR, Partial Remission PR) at the end of induction a standard maintenance will follows (1 dose every 8 weeks for 2 years) with the same anti-CD20 Monoclonal Antibody (MoAb) used for induction.

Patients in both arms with progressive disease at any time and patients in stable disease SD at the End Of Induction (EOI) shall be considered for salvage therapy at clinician discretion.

Immunochemotherapy regimen: G-CVP (Arm A)

Arm B (Experimental arm):

4 cycles of G-CVP Q21 (21-days cycles) G-CVP = Obinutuzumab, Cyclophosphamide, Vincristine, Prednisone.

After cycle 4 patients will undergo an early restaging. Induction therapy shall be completed based on the response achieved and on the treatment chosen as below specified:

* if in CR: patients will receive no more chemotherapy but will complete induction with the Monoclonal Antibody (MoAb) only, in this case: 4 cycles of obinutuzumab;
* if less than CR (PR, SD): the immunochemotherapy program will be completed as outlined for Arm A: 4 cycles of G-CVP Q21

Both Arms: in responding patients (CR, PR) at the end of induction a standard maintenance will follows (1 dose every 8 weeks for 2 years) with the same anti-CD20 MoAb used for induction.

Patients in both arms with progressive disease at any time and patients in SD at the End Of Induction (EOI) shall be considered for salvage therapy at clinician discretion.

Immunochemotherapy regimen: G-CVP (Arm B)

Antonella Ferranti

Alessandra Dondi

Giuseppe Tarantini, MD

Nicola Cascavilla, MD

Eliana Valentina Liardo, MD

Vincenzo Pavone, MD

Sara Bigliardi, MD

Bolis Silvia, MD

Silvia Bolis, MD

Michele Spina, MD

Catello Califano, MD

Delia Rota Scalabrini, MD

Roberto Sartori, MD

Fabrizio Ciambelli, MD

Renato Bassan, MD

Giovanni Bertoldero, MD

Manuela Zanni, MD

Attilio Olivieri, MD

Piero Galieni, MD

Sonya De Lorenzo, MD

Pellegrino Musto, MD

Carla Minoia, MD

Fable Zustovich, MD

Roberto Vallone, MD

Annarita Conconi, MD

Alessandra Tucci, MD

Domenico Pastore, MD

Francesco Di Raimondo, MD

Marco Rossi, MD

Massimo Gentile, MD

Claudia Castellino, MD

Antonio Cuneo, MD

Benedetta Puccini, MD

Sabrina Moretti, MD

Chiara Ghiggi, MD

Nicola Di Renzo, MD

Donato Mannina, MD

Andres Ferreri, MD

Vittorio Montefusco, MD

Vittorio Ruggero Zilioli, MD

Alessandro Noto, MD

Antonello Sica, MD

Gloria Margiotta, MD

Silvia Finotto, MD

Francesco Piazza, MD

Salvatrice Mancuso, MD

Caterina Patti, MD

Francesca Re, MD

Luca Arcaini, MD

Elsa Pennese, MD

Annalisa Arcari, MD

Sara Galimberti, MD

Michele Cimminiello, MD

Simone Santini, MD

Monica Tani, MD

Caterina Stelitano, MD

Stefano Luminari, MD

Anna Merli, MD

Maria Cantonetti, MD

Elisabetta Abruzzese, MD

Roberta Battistini, MD

Alessandro Pulsoni, MD

Stefan Hohaus, MD

Rossella Paolini, MD

Carmine Selleri, MD

Claudio Fozza, MD

Emanuele Cencini, MD

Andrea Maria Soccodato, MD

Anna Marina Liberati, MD

Federica Cavallo, MD

Carola Boccomini, MD

Maria Pagliaro, MD

Elisabetta Scarpa, MD

Francesco Zaja, MD

FIL_FOLL19 is an open-label, multicenter, randomized phase III trial. The sponsor of this clinical trial is Fondazione Italiana Linfomi (FIL).

The Primary Objective of the study is to demonstrate that, in patients with newly diagnosed, advanced stage Follicular Lymphoma (FL) with high tumor burden according to the Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria, a treatment strategy that reduces the number of chemotherapy cycles in case of early response to immunochemotherapy is not inferior compared to standard therapy at full dose in terms of Progression-Free Survival (PFS).

This is an open-label, multicenter, randomized phase III trial. The study plans to randomize patients with a 1:1 ratio to Arm A (Standard arm) or Arm B (Experimental arm).

Once randomized, each patient will start immunochemotherapy with one of the approved regimens (R-CHOP, R-Bendamustine, G-CHOP, G-Bendamustine, G-CVP) chosen by the physician on a patient basis before randomization.

Patients randomized to Arm A will receive an induction immunochemotherapy at full doses (standard schedule).

After cycle 4, patients will be assessed for response and will complete their planned therapy if at least a stable disease is confirmed.

Patients randomized to Arm B will start their induction treatment with 4 cycles of the immunochemotherapy standard dose chosen by the physician: after cycle 4, patients will be assessed for response and will proceed with subsequent treatment based on the quality of their response.

Specifically:

* Patients achieving a Complete Remission (CR) will receive a shortened treatment: in detail, they won't receive any further chemotherapy but will complete induction with 4 additional cycles of only the Monoclonal Antibody (MoAb) given during the first four cycles (in case of G-bendamustine, 2 additional cycles of obinutuzumab);
* In case if response less than Complete Remission (CR), Partial Remission (PR) or Stable Disease (SD), patients will complete treatment as planned for patients in Arm A.

In both arms, at the end of induction responding patients (CR, PR) will be addressed to a standard anti-CD20 maintenance (1 dose every 8 weeks for two years) with the same Monoclonal Antibody (MoAb) given during induction.

Patients with progressive disease at any time (regardless of treatment arm) will be addressed to salvage therapy.

The study plans the evaluation of quality of life by collecting the Patient-Reported Outcome(s) (PROs) through the Functional Assessment of Cancer Treatment-Lymphoma (FACT-Lym questionnaire) at predetermined timepoints during the study.

This is a prospective, multicenter, phase III, two arms randomized trial with a non-inferiority design with Progression-Free Survival (PFS) as primary endpoint. Patients who meet all eligibility criteria will be centrally randomized to one of the two treatment arms in a 1:1 ratio, using random sequences blocks of variable size. The web-based allocation process, completely concealed to researchers, will be stratified according Follicular Lymphoma International Prognostic Index 2 (FLIPI2) score (0-2, 3-5), chemotherapy regimen (CHOP, Bendamustine, CVP) and anti-CD20 Monoclonal Antibody (MoAb) (rituximab, obinutuzumab). A non-inferiority design has been adopted to demonstrate that a shortened exposure to chemotherapy in patients responding to the first four cycles of immunochemotherapy is not detrimental in terms of PFS compared to full dose standard treatment. The primary comparison will be done as an Intention To Treat (ITT) analysis including all randomized patients.

Shortened vs Standard Chemotherapy Combined With Immunotherapy for the Initial Treatment of Patients With High Tumor Burden Follicular Lymphoma

Shortened vs Standard Chemotherapy Combined With Immunotherapy for the Initial Treatment of Patients With High Tumor Burden Follicular Lymphoma. A Randomized, Open Label, Phase III Study by Fondazione Italiana Linfomi.

The length of time during and after the treatment that patients live with the disease, but it does not get worse. Progression-Free Survival (PFS) will be measured from the time of study entry to documented progression or to the patient's death as a result of any causes. Subjects with incomplete follow-up or with no disease evaluation will be censored at the date of last available documented status of freedom from failure.

Overall Survival, the percentage of patients alive, will be measured from the time of study entry to death from any cause. Patients who have not died at the time of the final analysis will be censored at the date of the last contact.

The measure of time after treatment that patients have not have cancer come back or get worse. It will be measured from the time of study entry to any treatment failure, including disease progression, or discontinuation of treatment for any reason (e.g., disease progression, toxicity, patient preference, initiation of a new treatment without documented progression) or death from any cause.

Overall response rate (ORR) is defined as the proportion of patients who have a partial or complete response to therapy; It will be defined according to Response Criteria for Non-Hodgkin Lymphoma (NHL) with Positron Emission Tomography (PET) (Lugano 2014). ORR will include the sum of patients in Complete Remission and Partial Remission (CR + PR). It will be evaluated on assessed patients and on all treated patients, considering patients without a response assessment (due to any reason) as non-responders.

The best overall response will be defined as the best response between the date of beginning of therapy and the last restaging.

The Complete Response Rate is defined as the percentage of patient in Complete Remission. It will be defined according to Response Criteria for Non-Hodgkin Lymphoma (NHL) with Positron Emission Tomography (PET) (Lugano 2014). CRR will include only patients in Complete Remission (CR). It will be evaluated on assessed patients and on all treated patients, considering patients without a response assessment (due to any reason) as non-responders.

Molecular response assessed by means of the evaluation of the Bcl2/IgH rearrangement at baseline and of the Minimal Residual Disease (MRD) at subsequent defined timepoints.

Safety of the treatment according to the current version of the CTCAE. Incidence of toxicities

Health Related Quality of Life (HR-QoL) will be evaluated by means of Patient-Reported Outcome(s) PROs. Patients will be asked to complete the Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) questionnaire at prespecified points during the study. The questionnaire results will be analyzed according to recommendations of the instrument scoring procedures.

Fondazione Italiana Linfomi - ETS

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Shortened vs Standard Chemotherapy Combined With Immunotherapy for the Initial Treatment of Patients With High Tumor Burden Follicular Lymphoma	NCT05058404	Follicular Lymp...	Immunochemother... Immunochemother... Immunochemother... Immunochemother... Immunochemother... Immunochemother... Immunochemother... Immunochemother... Immunochemother... Immunochemother...	18 Years -	Fondazione Italiana Linfomi - ETS
Shortened vs Standard Chemotherapy Combined With Immunotherapy for the Initial Treatment of Patients With High Tumor Burden Follicular Lymphoma	NCT05058404	Follicular Lymp...	Immunochemother... Immunochemother... Immunochemother... Immunochemother... Immunochemother... Immunochemother... Immunochemother... Immunochemother... Immunochemother... Immunochemother...	18 Years -	Fondazione Italiana Linfomi - ETS

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