Clinical trial NCT05058404: Shortened vs Standard Chemotherapy Combined With Immunotherapy for the Initial Treatment of Patients With High Tumor Burden Follicular Lymphoma
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.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Follicular Lymphoma
Keywords: High tumor burden Follicular Lymphoma
Shortened vs standard chemotherapy
Immunotherapy
Initial treatment
Lead sponsor: Fondazione Italiana Linfomi - ETS
Sponsor class: OTHER
First posted: 2021-09-27
Enrollment: 602
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: The endpoint will be assessed from the beginning of the study up to 104 months (end of study)
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: The endpoint will be assessed from the beginning of the study up to 104 months (end of study)
measure: Event-Free Survival (EFS)
timeFrame: The endpoint will be assessed from the beginning of the study up to 104 months (end of study)
measure: Overall Response rate (ORR)
timeFrame: The endpoint will be assessed from the beginning of the study up to 104 months (end of study)
measure: Complete response rate (CRR)
timeFrame: The endpoint will be assessed from the beginning of the study up to 104 months (end of study)
measure: Molecular response
timeFrame: The endpoint will be assessed from the beginning of the study up to 104 months (end of study)
measure: Incidence of toxicities (Safety of the treatment)
timeFrame: The endpoint will be assessed from the beginning of the study up to 104 months (end of study)
measure: Patient-Reported Outcomes (PROs)
timeFrame: The endpoint will be assessed from the beginning of the study up to 104 months (end of study)
Other outcomes:
Locations:
city: Barletta
country: Italy
facility: Ospedale "Monsignor Raffaele Dimiccoli" - Ematologia
state: Barletta Andria Trani
city: San Giovanni Rotondo
country: Italy
facility: Casa Sollievo della Sofferenza - U.O. Ematologia
state: Foggia
city: Meldola
country: Italy
facility: IRCCS Istituto Romagnolo per lo studio dei Tumori "Dino Amadori" - IRST S.R.L. - Ematologia
state: Forlì - Cesena
city: Tricase
country: Italy
facility: A.O. C. Panico - U.O.C Ematologia e Trapianto
state: Lecce
city: Sassuolo
country: Italy
facility: Nuovo Ospedale Civile di Sassuolo - Day Hospital Oncologico
state: Modena
city: Monza
country: Italy
facility: ASST MONZA Ospedale S. Gerardo - Ematologia
state: Monza E Brianza
city: Aviano
country: Italy
facility: IRCCS Centro di Riferimento Oncologico di Aviano - Divisione di Oncologia e dei Tumori immuto-correlati
state: Pordenone
city: Pagani
country: Italy
facility: Presidio ospedaliero "A. TORTORA" - U.O. Onco-ematologia
state: Salerno
city: Candiolo
country: Italy
facility: Fondazione del Piemonte per l'Oncologia - IRCCS - Ematologia
state: Torino
city: Castelfranco Veneto
country: Italy
facility: Ospedale di Castelfranco Veneto - Ematologia
state: Treviso
city: Busto Arsizio
country: Italy
facility: ASST Valle Olona - Ospedale di Circolo di Busto Arsizio - S.C. Ematologia
state: Varese
city: Mestre
country: Italy
facility: Ospedale Dell'Angelo - U.O. Ematologia
state: Venezia
city: Mirano
country: Italy
facility: USLL13 - Dipartimento di Scienze Mediche UOC di Oncologia ed Ematologia Oncologica
state: Venezia
city: Alessandria
country: Italy
facility: A.O. SS. Antonio e Biagio e Cesare Arrigo - S.C. Ematologia
city: Ancona
country: Italy
facility: AOU Ospedali Riuniti - Clinica di Ematologia
city: Ascoli Piceno
country: Italy
facility: Ospedale C.e G. Mazzoni - U.O.C. di Ematologia
city: Avellino
country: Italy
facility: Azienda Ospedaliera S.Giuseppe Moscati - S.C. Ematologia e Trapianto emopoietico
city: Bari
country: Italy
facility: AOU Policlinico Consorziale - U.O. Ematologia con Trapianto
city: Bari
country: Italy
facility: IRCCS Istituto Tumori Giovanni Paolo II - U.O.C Ematologia
city: Belluno
country: Italy
facility: Ospedale S. Martino - UOC Oncologia
city: Benevento
country: Italy
facility: A.O.R.N. Gaetano Rummo - DH Ematologico
city: Biella
country: Italy
facility: Nuovo Ospedale degli Infermi - SSD Ematologia
city: Brescia
country: Italy
facility: ASST Spedali Civili di Brescia - Ematologia
city: Brindisi
country: Italy
facility: Ospedale Antonio Perrino - U.O. Ematologia e Trapianti di Midollo
city: Catania
country: Italy
facility: Azienda Ospedaliero - Universitaria Policlinico - Vittorio Emanuele Presidio Ospedale Ferrarotto - Ematologia
city: Catanzaro
country: Italy
facility: AO Pugliese Ciaccio - SOC Ematologia
city: Cosenza
country: Italy
facility: Azienda Ospedaliera di Cosenza - UOC Ematologia
city: Cuneo
country: Italy
facility: A.O. S. Croce e Carle - S.C. di Ematologia e Trapianto di Midollo Osseo
city: Ferrara
country: Italy
facility: Azienda Ospedaliero-Universitaria di Ferrara - Arcispedale Sant'Anna - Ematologia e fisiopatologia della coagulazione
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Careggi - Unitа funzionale di Ematologia
city: Firenze
country: Italy
facility: Ospedale San Giovanni di Dio - SOS Ematologia clinica e oncoematologia ASL Toscana Centro
city: Genova
country: Italy
facility: Ospedale Policlinico San Martino S.S.R.L. - IRCCS per l Oncologia - Ematologia
city: Lecce
country: Italy
facility: Ospedale Vito Fazzi - Ematologia
city: Messina
country: Italy
facility: Azienda Ospedali Riuniti Papardo-Piemonte - S.C. Ematologia
city: Milano
country: Italy
facility: Istituto Scientifico San Raffaele - Unitа Linfomi - Dipartimento Oncoematologia
city: Milano
country: Italy
facility: ASST Santi Paolo e Carlo - Onco - Ematologia
city: Milano
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda - SC Ematologia
city: Milano
country: Italy
facility: Ospedale Maggiore Policlinico - Fondazione IRCCS Ca Granda - Ematologia
city: Napoli
country: Italy
facility: AOU Universitа degli Studi della Campania Luigi Vanvitelli - Oncologia Medica ed Ematologia
city: Novara
country: Italy
facility: AOU Maggiore della Caritа di Novara - SCDU Ematologia
city: Padova
country: Italy
facility: I.R.C.C.S. Istituto Oncologico Veneto - Oncologia 1
city: Padova
country: Italy
facility: AOU di Padova - Ematologia
city: Palermo
country: Italy
facility: AOU Policlinico Giaccone - Ematologia
city: Palermo
country: Italy
facility: A.O. Ospedali Riuniti Villa Sofia-Cervello - Divisione di Ematologia
city: Parma
country: Italy
facility: UO Ematologia e CTMO - AOU di Parma
city: Pavia
country: Italy
facility: IRCCS Policlinico S. Matteo di Pavia - Div. di Ematologia
city: Pescara
country: Italy
facility: P.O. Spirito Santo di Pescara - UOS Dipartimentale - Centro di diagnosi e Terapia dei linfomi
city: Piacenza
country: Italy
facility: Ospedale Guglielmo da Saliceto - U.O.Ematologia
city: Pisa
country: Italy
facility: AOU Pisana - U.O. Ematologia
city: Potenza
country: Italy
facility: A.O.R. "San Carlo" - U.O. Ematologia
city: Prato
country: Italy
facility: Ospedale S. Stefano - SOS Oncoematologia, ASL Toscana Centro
city: Ravenna
country: Italy
facility: Ospedale delle Croci - Ematologia
city: Reggio Calabria
country: Italy
facility: Grande Ospedale Metropolitano Bianchi Melacrino Morelli - Ematologia
city: Reggio Emilia
country: Italy
facility: Azienda Unitа Sanitaria Locale-IRCCS - Arcispedale Santa Maria Nuova - Ematologia
city: Rimini
country: Italy
facility: Ospedale degli Infermi di Rimini - U.O. di Ematologia
city: Roma
country: Italy
facility: Policlinico Tor Vergata - Ematologia
city: Roma
country: Italy
facility: Ospedale S. Eugenio - UOC Ematologia
city: Roma
country: Italy
facility: Ospedale S. Camillo - Ematologia
city: Roma
country: Italy
facility: Policlinico Umberto I - Universitа "La Sapienza" - Istituto Ematologia -Dipartimento di Medicina Traslazionale e di Precisione
city: Roma
country: Italy
facility: Universitа Cattolica S. Cuore - Ematologia
city: Rovigo
country: Italy
facility: Ospedale di Rovigo - S.O.S. Oncoematologia
city: Salerno
country: Italy
facility: Ematologia e Trapianti A.O. San Giovanni di Dio e Ruggi D Aragona - U.O. Ematologia
city: Sassari
country: Italy
facility: AOU di Sassari - Ematologia
city: Siena
country: Italy
facility: AOU Senese - U.O.C. Ematologia
city: Sondrio
country: Italy
facility: Azienda Ospedaliera della Valtellina e della Valchiavenna P.O. Sondrio - Medicina Interna - Centro Malattie del Sangue P.O. Sondrio
city: Terni
country: Italy
facility: A.O. S. Maria di Terni - S.C. Oncoematologia
city: Torino
country: Italy
facility: A.O.U. Citta della Salute e della Scienza di Torino - Ematologia Universitaria
city: Torino
country: Italy
facility: A.O.U. Citta della Salute e della Scienza di Torino - S.C.Ematologia
city: Torino
country: Italy
facility: San Giovanni Bosco - ASL Cittа di Torino - SSD di Ematologia e Malattie Trombotiche
city: Treviso
country: Italy
facility: Ospedale Ca Foncello - S.C di Ematologia
city: Trieste
country: Italy
facility: Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI) - SC Ematologia
Study officials:
affiliation: Reggio Emilia - Azienda Unitа Sanitaria Locale-IRCCS - Arcispedale Santa Maria Nuova - Ematologia
name: Stefano Luminari, MD
role: PRINCIPAL_INVESTIGATOR
References: