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NCT05058404

PHASE3

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

Sponsor: Fondazione Italiana Linfomi - ETS

View on ClinicalTrials.gov

Summary

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).

Official title: 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.

Key Details

Gender

All

Age Range

18 Years - Any

Study Type

INTERVENTIONAL

Enrollment

605

Start Date

2021-12-01

Completion Date

2030-07

Last Updated

2025-09-03

Healthy Volunteers

Conditions

Follicular Lymphoma

Interventions

DRUG

Immunochemotherapy regimen: Rituximab-bendamustine (Arm A)

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.

DRUG

Immunochemotherapy regimen: Rituximab-bendamustine (Arm B)

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.

DRUG

Immunochemotherapy regimen: R-CHOP (Arm A)

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.

DRUG

Immunochemotherapy regimen: R-CHOP (Arm B)

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.

DRUG

Immunochemotherapy regimen: G-bendamustine (Arm A)

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.

DRUG

Immunochemotherapy regimen: G-bendamustine (Arm B)

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.

DRUG

Immunochemotherapy regimen: G-CHOP (Arm A)

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.

DRUG

Immunochemotherapy regimen: G-CHOP (Arm B)

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.

DRUG

Immunochemotherapy regimen: G-CVP (Arm A)

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.

DRUG

Immunochemotherapy regimen: G-CVP (Arm B)

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.

Inclusion Criteria: 1. Histologically documented diagnosis of CD20+ Follicular lymphoma grade 1-2 or 3a, as defined in the 2017 edition of the World Health Organization (WHO) classification; 2. Age ≥ 18 years; 3. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Appendix B); 4. No previous immunochemotherapy for the lymphoma (localized radiotherapy or rituximab monotherapy with max of 4 doses are allowed); 5. Ann Arbor stage II-IV (Appendix A); 6. High tumor burden as per Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria defined as the presence of at least one of the following: * systemic symptoms; * Tumor bulk (any nodal or extranodal tumor mass with diameter \> 7 cm); * involvement of ≥ 3 nodal sites, each with a diameter ≥ 3 cm; * splenomegaly; * compressive syndrome (organ compression); * serous effusion; * circulant malignant cells; * cytopenia; * Eastern Cooperative Oncology Group - Performance Status (ECOG-PS) \> 1; * Lactate dehydrogenase (LDH) \> upper limit of normality (ULN); * β2-microglobulin \> 3 mg/L. 7. At least one site of measurable nodal disease at baseline ≥ 1.5 cm in the longest transverse diameter as determined by CT scan (MRI is allowed if CT scan cannot be performed); or evaluable disease at baseline FDG-PET (18F-fluorodeoxyglucose (FDG)-Positron Emission Tomography (PET)) scan (at least one metabolic active site of disease); 8. Adequate hematological counts (unless due to bone marrow involvement by lymphoma) defined as follows: 1. Absolute Neutrophil count (ANC) \> 1.5 x 109/L; 2. Platelet count ≥ 80 x 109/L ; 3. Hemoglobin ≥ 10 g/dL. 9. Adequate renal function defined as creatinine ≤ 2 mg/dL, unless secondary to lymphoma; 10. Adequate hepatic function defined as bilirubin ≤ 2 mg/dL, unless secondary to lymphoma; 11. Left Ventricular Ejection Fraction (LVEF) \> 50% at bidimensional echocardiogram (mandatory only for patients receiving R/G-CHOP); 12. Life expectancy ≥ 6 months; 13. Subject understands and voluntarily signs an informed consent form approved by an Independent Ethics Committee (IEC) prior to the initiation of any screening or study-specific procedures; 14. Subject must be able to adhere to the study visit schedule and other protocol requirements; 15. Women of childbearing potential (WOCBP) and men must agree to use effective contraception if sexually active. This applies for the time period between signing of the informed consent form and 12 months after last rituximab dose or 18 months after last obinutuzumab dose. A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include but are not limited to hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for continuous 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. The investigator or a designated associate is requested to advise the patient how to achieve highly effective birth control (failure rate of less than 1%) e.g., intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner. The use of condoms by male patients is required (even if surgically sterilized, i.e., status post vasectomy) unless the female partner is permanently sterile. Full sexual abstinence is admitted when this is in line with the preferred and usual lifestyle of the subject, for the same time period planned for other methods of birth control (see above). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post ovulation methods for the female partner) and withdrawal are not acceptable methods of contraception). Exclusion Criteria: 1. Histological diagnosis different from FL grade 1-3a WHO 2017 classification; 2. Suspect or clinical evidence of Central Nervous System (CNS) involvement by lymphoma; 3. Contraindication to the use of anti-CD20 monoclonal antibodies; 4. Subject has received any anticancer therapy (chemotherapy, immunotherapy, investigational therapy, including targeted small molecule agents) within 14 days prior to the first dose of study drug; 5. Noteworthy history of neurologic, psychiatric, endocrinological, metabolic, immunologic, or hepatic disease that would preclude participation in the study or compromise ability to give informed consent; 6. Any history of other active malignancies within 3 years prior to study entry, with the exception of: adequately treated in situ carcinoma of the cervix uterine; basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; limited stage surgically removed breast cancer or adequately treated with radiation therapy; limited stage prostate carcinoma surgically removed or adequately treated with radiation therapy; previous malignancy confined and surgically resected with curative intent; 7. Evidence of other clinically significant uncontrolled condition(s) including, but not limited to: * Uncontrolled and/or active systemic infection (viral, bacterial or fungal), including active ongoing infection from SARS-CoV-2; * Chronic or acute hepatitis B (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e., HBsAg negative, HBsAb positive and HBcAb negative) or positive HBcAb from previous infection or intravenous immunoglobulins (IVIG) may participate; inactive carriers (HBsAg positive with undetectable HBV- DNA) are eligible. Patients with presence of HCV antibody are eligible only if Polymerase Chain Reaction (PCR) negative for HCV-RNA; 8. Women who are pregnant or breastfeeding.

Locations (71)

Ospedale "Monsignor Raffaele Dimiccoli" - Ematologia

Barletta, Barletta Andria Trani, Italy

Casa Sollievo della Sofferenza - U.O. Ematologia

San Giovanni Rotondo, Foggia, Italy

IRCCS Istituto Romagnolo per lo studio dei Tumori "Dino Amadori" - IRST S.R.L. - Ematologia

Meldola, Forlì - Cesena, Italy

A.O. C. Panico - U.O.C Ematologia e Trapianto

Tricase, Lecce, Italy

Nuovo Ospedale Civile di Sassuolo - Day Hospital Oncologico

Sassuolo, Modena, Italy

ASST MONZA Ospedale S. Gerardo - Ematologia

Monza, Monza E Brianza, Italy

IRCCS Centro di Riferimento Oncologico di Aviano - Divisione di Oncologia e dei Tumori immuto-correlati

Aviano, Pordenone, Italy

Presidio ospedaliero "A. TORTORA" - U.O. Onco-ematologia

Pagani, Salerno, Italy

Fondazione del Piemonte per l'Oncologia - IRCCS - Ematologia

Candiolo, Torino, Italy

Ospedale di Castelfranco Veneto - Ematologia

Castelfranco Veneto, Treviso, Italy

ASST Valle Olona - Ospedale di Circolo di Busto Arsizio - S.C. Ematologia

Busto Arsizio, Varese, Italy

Ospedale Dell'Angelo - U.O. Ematologia

Mestre, Venezia, Italy

USLL13 - Dipartimento di Scienze Mediche UOC di Oncologia ed Ematologia Oncologica

Mirano, Venezia, Italy

A.O. SS. Antonio e Biagio e Cesare Arrigo - S.C. Ematologia

Alessandria, Italy

AOU Ospedali Riuniti - Clinica di Ematologia

Ancona, Italy

Ospedale C.e G. Mazzoni - U.O.C. di Ematologia

Ascoli Piceno, Italy

Azienda Ospedaliera S.Giuseppe Moscati - S.C. Ematologia e Trapianto emopoietico

Avellino, Italy

AOU Policlinico Consorziale - U.O. Ematologia con Trapianto

Bari, Italy

IRCCS Istituto Tumori Giovanni Paolo II - U.O.C Ematologia

Bari, Italy

Ospedale S. Martino - UOC Oncologia

Belluno, Italy

A.O.R.N. Gaetano Rummo - DH Ematologico

Benevento, Italy

Nuovo Ospedale degli Infermi - SSD Ematologia

Biella, Italy

ASST Spedali Civili di Brescia - Ematologia

Brescia, Italy

Ospedale Antonio Perrino - U.O. Ematologia e Trapianti di Midollo

Brindisi, Italy

Azienda Ospedaliero - Universitaria Policlinico - Vittorio Emanuele Presidio Ospedale Ferrarotto - Ematologia

Catania, Italy

AO Pugliese Ciaccio - SOC Ematologia

Catanzaro, Italy

Azienda Ospedaliera di Cosenza - UOC Ematologia

Cosenza, Italy

A.O. S. Croce e Carle - S.C. di Ematologia e Trapianto di Midollo Osseo

Cuneo, Italy

Azienda Ospedaliero-Universitaria di Ferrara - Arcispedale Sant'Anna - Ematologia e fisiopatologia della coagulazione

Ferrara, Italy

Azienda Ospedaliera Universitaria Careggi - Unitа funzionale di Ematologia

Florence, Italy

Ospedale San Giovanni di Dio - SOS Ematologia clinica e oncoematologia ASL Toscana Centro

Florence, Italy

Ospedale Policlinico San Martino S.S.R.L. - IRCCS per l Oncologia - Ematologia

Genova, Italy

Ospedale Vito Fazzi - Ematologia

Lecce, Italy

Azienda Ospedali Riuniti Papardo-Piemonte - S.C. Ematologia

Messina, Italy

Istituto Scientifico San Raffaele - Unitа Linfomi - Dipartimento Oncoematologia

Milan, Italy

ASST Santi Paolo e Carlo - Onco - Ematologia

Milan, Italy

ASST Grande Ospedale Metropolitano Niguarda - SC Ematologia

Milan, Italy

Ospedale Maggiore Policlinico - Fondazione IRCCS Ca Granda - Ematologia

Milan, Italy

AOU Universitа degli Studi della Campania Luigi Vanvitelli - Oncologia Medica ed Ematologia

Naples, Italy

AOU Maggiore della Caritа di Novara - SCDU Ematologia

Novara, Italy

I.R.C.C.S. Istituto Oncologico Veneto - Oncologia 1

Padova, Italy

AOU di Padova - Ematologia

Padova, Italy

AOU Policlinico Giaccone - Ematologia

Palermo, Italy

A.O. Ospedali Riuniti Villa Sofia-Cervello - Divisione di Ematologia

Palermo, Italy

UO Ematologia e CTMO - AOU di Parma

Parma, Italy

IRCCS Policlinico S. Matteo di Pavia - Div. di Ematologia

Pavia, Italy

P.O. Spirito Santo di Pescara - UOS Dipartimentale - Centro di diagnosi e Terapia dei linfomi

Pescara, Italy

Ospedale Guglielmo da Saliceto - U.O.Ematologia

Piacenza, Italy

AOU Pisana - U.O. Ematologia

Pisa, Italy

A.O.R. "San Carlo" - U.O. Ematologia

Potenza, Italy

Ospedale S. Stefano - SOS Oncoematologia, ASL Toscana Centro

Prato, Italy

Ospedale delle Croci - Ematologia

Ravenna, Italy

Grande Ospedale Metropolitano Bianchi Melacrino Morelli - Ematologia

Reggio Calabria, Italy

Azienda Unitа Sanitaria Locale-IRCCS - Arcispedale Santa Maria Nuova - Ematologia

Reggio Emilia, Italy

Ospedale degli Infermi di Rimini - U.O. di Ematologia

Rimini, Italy

Policlinico Tor Vergata - Ematologia

Roma, Italy

Ospedale S. Eugenio - UOC Ematologia

Roma, Italy

Ospedale S. Camillo - Ematologia

Roma, Italy

Policlinico Umberto I - Universitа "La Sapienza" - Istituto Ematologia -Dipartimento di Medicina Traslazionale e di Precisione

Roma, Italy

Universitа Cattolica S. Cuore - Ematologia

Roma, Italy

Ospedale di Rovigo - S.O.S. Oncoematologia

Rovigo, Italy

Ematologia e Trapianti A.O. San Giovanni di Dio e Ruggi D Aragona - U.O. Ematologia

Salerno, Italy

AOU di Sassari - Ematologia

Sassari, Italy

AOU Senese - U.O.C. Ematologia

Siena, Italy

Azienda Ospedaliera della Valtellina e della Valchiavenna P.O. Sondrio - Medicina Interna - Centro Malattie del Sangue P.O. Sondrio

Sondrio, Italy

A.O. S. Maria di Terni - S.C. Oncoematologia

Terni, Italy

A.O.U. Citta della Salute e della Scienza di Torino - Ematologia Universitaria

Torino, Italy

A.O.U. Citta della Salute e della Scienza di Torino - S.C.Ematologia

Torino, Italy

San Giovanni Bosco - ASL Cittа di Torino - SSD di Ematologia e Malattie Trombotiche

Torino, Italy

Ospedale Ca Foncello - S.C di Ematologia

Treviso, Italy

Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI) - SC Ematologia

Trieste, Italy

Clinical Research Directory

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

Summary

Key Details

Conditions

Interventions

Eligibility Criteria

Locations (71)