Shortened vs Standard Chemotherapy Combined With Immunotherapy for the Initial Treatment of Patients With High Tumor Burden Follicular Lymphoma
- Conditions
- Follicular Lymphoma
- Registration Number
- NCT05058404
- Lead Sponsor
- Fondazione Italiana Linfomi - ETS
- Brief 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).
- Detailed Description
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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 602
-
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;
-
Age ≥ 18 years;
-
Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Appendix B);
-
No previous immunochemotherapy for the lymphoma (localized radiotherapy or rituximab monotherapy with max of 4 doses are allowed);
-
Ann Arbor stage II-IV (Appendix A);
-
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.
-
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);
-
Adequate hematological counts (unless due to bone marrow involvement by lymphoma) defined as follows:
- Absolute Neutrophil count (ANC) > 1.5 x 109/L;
- Platelet count ≥ 80 x 109/L ;
- Hemoglobin ≥ 10 g/dL.
-
Adequate renal function defined as creatinine ≤ 2 mg/dL, unless secondary to lymphoma;
-
Adequate hepatic function defined as bilirubin ≤ 2 mg/dL, unless secondary to lymphoma;
-
Left Ventricular Ejection Fraction (LVEF) > 50% at bidimensional echocardiogram (mandatory only for patients receiving R/G-CHOP);
-
Life expectancy ≥ 6 months;
-
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;
-
Subject must be able to adhere to the study visit schedule and other protocol requirements;
-
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).
-
Histological diagnosis different from FL grade 1-3a WHO 2017 classification;
-
Suspect or clinical evidence of Central Nervous System (CNS) involvement by lymphoma;
-
Contraindication to the use of anti-CD20 monoclonal antibodies;
-
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;
-
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;
-
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;
-
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;
-
Women who are pregnant or breastfeeding.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Primary Outcome Measures
Name Time Method Progression Free Survival (PFS) The endpoint will be assessed from the beginning of the study up to 104 months (end of study) 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.
- Secondary Outcome Measures
Name Time Method Molecular response The endpoint will be assessed from the beginning of the study up to 104 months (end of study) 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.
Event-Free Survival (EFS) The endpoint will be assessed from the beginning of the study up to 104 months (end of study) 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.
Patient-Reported Outcomes (PROs) The endpoint will be assessed from the beginning of the study up to 104 months (end of study) 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.
Incidence of toxicities (Safety of the treatment) The endpoint will be assessed from the beginning of the study up to 104 months (end of study) Safety of the treatment according to the current version of the CTCAE. Incidence of toxicities
Overall Survival (OS) The endpoint will be assessed from the beginning of the study up to 104 months (end of study) 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.
Overall Response rate (ORR) The endpoint will be assessed from the beginning of the study up to 104 months (end of study) 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.Complete response rate (CRR) The endpoint will be assessed from the beginning of the study up to 104 months (end of study) 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.
Trial Locations
- Locations (71)
IRCCS Istituto Romagnolo per lo studio dei Tumori "Dino Amadori" - IRST S.R.L. - Ematologia
🇮🇹Meldola, Forlì - Cesena, Italy
Nuovo Ospedale Civile di Sassuolo - Day Hospital Oncologico
🇮🇹Sassuolo, Modena, Italy
Ospedale "Monsignor Raffaele Dimiccoli" - Ematologia
🇮🇹Barletta, Barletta Andria Trani, Italy
Casa Sollievo della Sofferenza - U.O. Ematologia
🇮🇹San Giovanni Rotondo, Foggia, Italy
A.O. C. Panico - U.O.C Ematologia e Trapianto
🇮🇹Tricase, Lecce, 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
ASST Valle Olona - Ospedale di Circolo di Busto Arsizio - S.C. Ematologia
🇮🇹Busto Arsizio, Varese, Italy
Ospedale di Castelfranco Veneto - Ematologia
🇮🇹Castelfranco Veneto, Treviso, 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
A.O.R.N. Gaetano Rummo - DH Ematologico
🇮🇹Benevento, Italy
Nuovo Ospedale degli Infermi - SSD Ematologia
🇮🇹Biella, 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
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
🇮🇹Firenze, Italy
Ospedale San Giovanni di Dio - SOS Ematologia clinica e oncoematologia ASL Toscana Centro
🇮🇹Firenze, Italy
Azienda Ospedali Riuniti Papardo-Piemonte - S.C. Ematologia
🇮🇹Messina, Italy
Ospedale Policlinico San Martino S.S.R.L. - IRCCS per l Oncologia - Ematologia
🇮🇹Genova, Italy
Ospedale Vito Fazzi - Ematologia
🇮🇹Lecce, Italy
ASST Santi Paolo e Carlo - Onco - Ematologia
🇮🇹Milano, Italy
ASST Grande Ospedale Metropolitano Niguarda - SC Ematologia
🇮🇹Milano, Italy
Ospedale Maggiore Policlinico - Fondazione IRCCS Ca Granda - Ematologia
🇮🇹Milano, Italy
AOU Universitа degli Studi della Campania Luigi Vanvitelli - Oncologia Medica ed Ematologia
🇮🇹Napoli, Italy
I.R.C.C.S. Istituto Oncologico Veneto - Oncologia 1
🇮🇹Padova, Italy
IRCCS Policlinico S. Matteo di Pavia - Div. di Ematologia
🇮🇹Pavia, Italy
AOU di Padova - Ematologia
🇮🇹Padova, Italy
AOU Policlinico Giaccone - Ematologia
🇮🇹Palermo, Italy
Grande Ospedale Metropolitano Bianchi Melacrino Morelli - Ematologia
🇮🇹Reggio Calabria, Italy
A.O. Ospedali Riuniti Villa Sofia-Cervello - Divisione di Ematologia
🇮🇹Palermo, Italy
UO Ematologia e CTMO - AOU di Parma
🇮🇹Parma, Italy
P.O. Spirito Santo di Pescara - UOS Dipartimentale - Centro di diagnosi e Terapia dei linfomi
🇮🇹Pescara, Italy
Azienda Unitа Sanitaria Locale-IRCCS - Arcispedale Santa Maria Nuova - Ematologia
🇮🇹Reggio Emilia, Italy
Ospedale S. Eugenio - UOC Ematologia
🇮🇹Roma, 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
Policlinico Tor Vergata - Ematologia
🇮🇹Roma, Italy
Ospedale S. Stefano - SOS Oncoematologia, ASL Toscana Centro
🇮🇹Prato, Italy
Ospedale delle Croci - Ematologia
🇮🇹Ravenna, Italy
Ospedale degli Infermi di Rimini - U.O. di Ematologia
🇮🇹Rimini, Italy
Policlinico Umberto I - Universitа "La Sapienza" - Istituto Ematologia -Dipartimento di Medicina Traslazionale e di Precisione
🇮🇹Roma, Italy
AOU Senese - U.O.C. Ematologia
🇮🇹Siena, Italy
Ospedale S. Camillo - 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
Universitа Cattolica S. Cuore - Ematologia
🇮🇹Roma, Italy
AOU di Sassari - Ematologia
🇮🇹Sassari, 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
San Giovanni Bosco - ASL Cittа di Torino - SSD di Ematologia e Malattie Trombotiche
🇮🇹Torino, Italy
Ospedale Ca Foncello - S.C di Ematologia
🇮🇹Treviso, 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
Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI) - SC Ematologia
🇮🇹Trieste, Italy
ASST Spedali Civili di Brescia - Ematologia
🇮🇹Brescia, Italy
ASST MONZA Ospedale S. Gerardo - Ematologia
🇮🇹Monza, Monza E Brianza, Italy
Ospedale Dell'Angelo - U.O. Ematologia
🇮🇹Mestre, Venezia, Italy
Istituto Scientifico San Raffaele - Unitа Linfomi - Dipartimento Oncoematologia
🇮🇹Milano, Italy
AOU Maggiore della Caritа di Novara - SCDU Ematologia
🇮🇹Novara, Italy