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

Follicular Lymphoma Clinical Trial

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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05058404
• Other study ID #: FIL_FOLL19
• Status: Recruiting
• Phase: Phase 3
• Start date: December 1, 2021
• Est. completion date: July 2030

Study information

• Verified date: December 2023
• Source: Fondazione Italiana Linfomi - ETS
• Contact: Antonella Ferranti
• Phone: 0131033153
• Email: aferranti[@]filinf.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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 information / eligibility

• Status: Recruiting
• Enrollment: 602
• Est. completion date: July 2030
• Est. primary completion date: July 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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);

• ß2-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.

Related Conditions & MeSH terms

• Follicular Lymphoma
• Lymphoma
• Lymphoma, Follicular

Intervention

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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Locations

Country	Name	City	State
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	IRCCS Centro di Riferimento Oncologico di Aviano - Divisione di Oncologia e dei Tumori immuto-correlati	Aviano	Pordenone
Italy	AOU Policlinico Consorziale - U.O. Ematologia con Trapianto	Bari
Italy	IRCCS Istituto Tumori Giovanni Paolo II - U.O.C Ematologia	Bari
Italy	Ospedale "Monsignor Raffaele Dimiccoli" - Ematologia	Barletta	Barletta Andria Trani
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	ASST Valle Olona - Ospedale di Circolo di Busto Arsizio - S.C. Ematologia	Busto Arsizio	Varese
Italy	Fondazione del Piemonte per l'Oncologia - IRCCS - Ematologia	Candiolo	Torino
Italy	Ospedale di Castelfranco Veneto - Ematologia	Castelfranco Veneto	Treviso
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 - Unit? funzionale di Ematologia	Firenze
Italy	Ospedale San Giovanni di Dio - SOS Ematologia clinica e oncoematologia ASL Toscana Centro	Firenze
Italy	Ospedale Policlinico San Martino S.S.R.L. - IRCCS per l Oncologia - Ematologia	Genova
Italy	Ospedale Vito Fazzi - Ematologia	Lecce
Italy	IRCCS Istituto Romagnolo per lo studio dei Tumori "Dino Amadori" - IRST S.R.L. - Ematologia	Meldola	Forlì - Cesena
Italy	Azienda Ospedali Riuniti Papardo-Piemonte - S.C. Ematologia	Messina
Italy	Ospedale Dell'Angelo - U.O. Ematologia	Mestre	Venezia
Italy	ASST Grande Ospedale Metropolitano Niguarda - SC Ematologia	Milano
Italy	ASST Santi Paolo e Carlo - Onco - Ematologia	Milano
Italy	Istituto Scientifico San Raffaele - Unit? Linfomi - Dipartimento Oncoematologia	Milano
Italy	Ospedale Maggiore Policlinico - Fondazione IRCCS Ca Granda - Ematologia	Milano
Italy	USLL13 - Dipartimento di Scienze Mediche UOC di Oncologia ed Ematologia Oncologica	Mirano	Venezia
Italy	ASST MONZA Ospedale S. Gerardo - Ematologia	Monza	Monza E Brianza
Italy	AOU Universit? degli Studi della Campania Luigi Vanvitelli - Oncologia Medica ed Ematologia	Napoli
Italy	AOU Maggiore della Carit? di Novara - SCDU Ematologia	Novara
Italy	AOU di Padova - Ematologia	Padova
Italy	I.R.C.C.S. Istituto Oncologico Veneto - Oncologia 1	Padova
Italy	Presidio ospedaliero "A. TORTORA" - U.O. Onco-ematologia	Pagani	Salerno
Italy	A.O. Ospedali Riuniti Villa Sofia-Cervello - Divisione di Ematologia	Palermo
Italy	AOU Policlinico Giaccone - 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 Unit? Sanitaria Locale-IRCCS - Arcispedale Santa Maria Nuova - Ematologia	Reggio Emilia
Italy	Ospedale degli Infermi di Rimini - U.O. di Ematologia	Rimini
Italy	Ospedale S. Camillo - Ematologia	Roma
Italy	Ospedale S. Eugenio - UOC Ematologia	Roma
Italy	Policlinico Tor Vergata - Ematologia	Roma
Italy	Policlinico Umberto I - Universit? "La Sapienza" - Istituto Ematologia -Dipartimento di Medicina Traslazionale e di Precisione	Roma
Italy	Universit? 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	Casa Sollievo della Sofferenza - U.O. Ematologia	San Giovanni Rotondo	Foggia
Italy	AOU di Sassari - Ematologia	Sassari
Italy	Nuovo Ospedale Civile di Sassuolo - Day Hospital Oncologico	Sassuolo	Modena
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 Citt? di Torino - SSD di Ematologia e Malattie Trombotiche	Torino
Italy	Ospedale Ca Foncello - S.C di Ematologia	Treviso
Italy	A.O. C. Panico - U.O.C Ematologia e Trapianto	Tricase	Lecce
Italy	Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI) - SC Ematologia	Trieste

Sponsors (1)

Lead Sponsor	Collaborator
Fondazione Italiana Linfomi - ETS

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression Free Survival (PFS)	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.	The endpoint will be assessed from the beginning of the study up to 104 months (end of study)
Secondary	Overall Survival (OS)	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 endpoint will be assessed from the beginning of the study up to 104 months (end of study)
Secondary	Event-Free Survival (EFS)	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.	The endpoint will be assessed from the beginning of the study up to 104 months (end of study)
Secondary	Overall Response rate (ORR)	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 endpoint will be assessed from the beginning of the study up to 104 months (end of study)
Secondary	Complete response rate (CRR)	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.	The endpoint will be assessed from the beginning of the study up to 104 months (end of study)
Secondary	Molecular response	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.	The endpoint will be assessed from the beginning of the study up to 104 months (end of study)
Secondary	Incidence of toxicities (Safety of the treatment)	Safety of the treatment according to the current version of the CTCAE. Incidence of toxicities	The endpoint will be assessed from the beginning of the study up to 104 months (end of study)
Secondary	Patient-Reported Outcomes (PROs)	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.	The endpoint will be assessed from the beginning of the study up to 104 months (end of study)