Clinical trial NCT05929222: Comparison Between Local Radiotherapy Alone or Combined With Obinutuzumab in Early Stage Follicular Lymphoma: the GAZEBO Trial From the Fondazione Italiana Linfomi
Official title: An Open-label, Randomized Phase III Trial Comparing Local Radiotherapy Alone or Combined With Obinutuzumab in Early Stage Follicular Lymphoma: the GAZEBO Trial From the Fondazione Italiana Linfomi
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Follicular Lymphoma
Keywords: Lymphoma
Follicular
Immunotherapy
FL
Radiotherapy
Early
Localized
Obinutuzumab
MRD
Minimal residual disease
PET
Lead sponsor: Fondazione Italiana Linfomi - ETS
Sponsor class: OTHER
Collaborators: name: Roche Pharma AG
First posted: 2023-07-03
Enrollment: 190
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Prospective, multicenter, open label, phase III randomized clinical trial in previously untreated Follicular Lymphoma in early stage. Patients will be randomized to receive Radiotherapy or Radiotherapy plus Obinutuzumab.

Detailed description: Prospective, multicenter, open label, phase III randomized clinical trial in previously untreated Follicular Lymphoma in early stage (I-II non-bulky).

Patients will be randomized to receive:

- Involved-Site Radiation Therapy at standard dose 24Gy - standard arm

OR

- Involved-Site Radiation Therapy at standard dose 24Gy followed by Obinutuzumab 4 infusions weekly + 4 infusions every 3 weeks (8 total doses) - experimental arm

Eligibility criteria: Inclusion Criteria:

1. Histological documented diagnosis of Follicular Lymphoma grade I-IIIA as defined in the 2017 edition of World Health Organization (WHO)
2. Ann Arbor Stage IA or IIA (includible in one radiation field), or IE, non-bulky (\<7 cm). Stage must be determined by PET/CT scan (Appendix 2)
3. Patients performing PET before surgery can also be enrolled without repeating PET after surgery
4. No previous treatment except for steroid pre-treatment
5. FLIPI \< 2, FLIPI2 ≤ 2
6. Age ≥ 18 years
7. Negative bone marrow biopsy
8. Qualitative/quantitative PCR centralized assessment of BCL2/IGH positive cells in peripheral blood (PB), bone marrow (BM).
9. Centralized revision of the lymph node biopsy with FISH for t(14;18)
10. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2
11. At least one site of measurable nodal disease pre-biopsy ≥ 2.0 cm in the longest transverse diameter as determined by CT scan or ultrasonography
12. Adequate renal function defined as follows:

    * Creatinine clearance ≥ 40 mL/min (Cockcroft-Gault formula)
13. Adequate hepatic function per local laboratory reference range as follows:

    * Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x UNL
    * Bilirubin ≤1.5 x UNL (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)
14. Subject understands and voluntarily signs an informed consent form approved by an Independent National Ethics Committee (NEC), prior to the initiation of any screening or study-specific procedures
15. Subject must be able to adhere to the study visit schedule and other protocol requirements
16. Life expectancy ≥ 3 months
17. Fertility and pregnancy prevention criteria

    * Women must be:

      * postmenopausal for at least 1 year (must not have had a natural menses for at least 12 months)
      * surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy),
      * completely abstinent (periodic abstinence from intercourse is not permitted) or if sexually active, be practicing a highly effective method of birth control (e.g., prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double barrier method (e.g.: condoms, diaphragm, or cervical cap, with spermicidal foam, cream, or gel, male partner sterilization) as local regulations permit, before entry, and must agree to continue to use the same method of contraception throughout the study. They must also be pre-pared to continue birth control measures for at least 18 months after terminating treatment.
    * Women of childbearing potential must have a negative pregnancy test at screening
    * Men with female partners of childbearing potential: men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of \< 1% per year during the treatment period and for at least 3 months after the last dose of study treatment. Men must refrain from donating sperm for the same period
    * Male even if surgically sterilized (i.e., status post vasectomy) must agree to 1 of the following

      * practice effective barrier contraception during the entire study treatment period and through 3 months after the last dose of study drug, or
      * agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (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 of Follicular lymphoma grade IIIb
2. Staging \>II or B symptoms or bulky disease (\> 7 cm)
3. Stage II with distant involved sites, not includible in a single radiation field
4. Primary cutaneous follicular lymphoma
5. Known HIV positivity
6. Positive serology for hepatitis C (HC) defined as a positive test for HCAb, in which case reflexively perform a HC RNA on the same sample to confirm the result, if negative, the patient is eligible.
7. Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a quantitative HBVDNA test will be performed and if positive the subject will be excluded. Patients with HBcAb positivity and negative HBV DNA should be prophylactically treated with oral Lamivudine (100 mg /day). Note: subjects with serologic evidence of prior vaccination to HBV (i.e., hepatitis B surface (HBs) antigen negative, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate
8. Central Nervous System (CNS) involvement with lymphoma
9. Significant history of neurologic, psychiatric, endocrinological, metabolic, immunologic, or hepatic disease that would preclude participation in the study or compromise ability to give informed consent
10. Any history of other active malignancies within 3 years prior to study entry, except for adequately treated in situ carcinoma of the cervix uterine, basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin, previous malignancy confined and surgically resected with curative intent
11. Evidence of other clinically significant uncontrolled condition(s) including, but not limited to:

    * Uncontrolled and/or active systemic infection (viral, bacterial or fungal)
    * Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment.
12. If female, the patient is pregnant or breast-feeding
13. Patients participating in other clinical studies.

Primary outcomes:
measure: Progression-free survival (PFS)
timeFrame: From treatment start up to 33 months (9 months treatment period and 24 months of follow-up)
Secondary outcomes:
measure: Complete response rate (CRR)
timeFrame: From therapy start up to end of treatment (9 months)
measure: Overall response rate (ORR)
timeFrame: From therapy start up to end of treatment (9 months)
measure: Disease Free Survival (DFS)
timeFrame: From post radiotherapy assessment up to 45 months (9 months treatment phase plus 36 months of follow-up)
measure: Event Free Survival (EFS)
timeFrame: From therapy start up to 45 months (9 months treatment phase plus 36 months of follow-up)
measure: Number of patients with Molecular Response at end of treatment
timeFrame: From therapy start up to end of treatment (9 months)
measure: Rate of Adverse Events
timeFrame: From therapy start up to 45 months (9 months treatment phase plus 36 months of follow-up)
measure: Prognostic and predictive impact of presence/abscence of t(14;18) rearrangement measured by FISH
timeFrame: From therapy start up to 45 months (9 months treatment phase plus 36 months of follow-up)
measure: Prognostic role of Minimal Residual Disease by conventional (BCL2/IGH rearrangement by ddPCR) and ctDNA method
timeFrame: From therapy start up to 45 months (9 months treatment phase plus 36 months of follow-up)
measure: Prognostic and predictive value of different threshold of metabolic response expressed as SUVmax, MTV and TLG at baseline (PET-0);
timeFrame: At baseline (before therapy start)
measure: Prognostic and predictive role of liquid biopsy by DNA sequencing for lymphoma mutations
timeFrame: From therapy start up to 45 months (9 months treatment phase plus 36 months of follow-up)
measure: Prognostic and predictive value of radiological markers assessed by Machine Learning tools (pyRadiomics)
timeFrame: From therapy start up to 45 months (9 months treatment phase plus 36 months of follow-up)
measure: Correlation of MRD results with the radiomics results and clinical outcomes
timeFrame: From therapy start up to 45 months (9 months treatment phase plus 36 months of follow-up)
measure: Comparison between genotype at diagnosis and at relapse assessed by RNA sequencing (CIBERSORTx)
timeFrame: From therapy start up to 45 months (9 months treatment phase plus 36 months of follow-up)
measure: Evaluation of liquid biopsy as a tool to identity specific mutations predictive for clonal evolution of lymphoma
timeFrame: From therapy start up to 45 months (9 months treatment phase plus 36 months of follow-up)
Other outcomes:
Locations:
city: Alessandria
country: Italy
facility: Azienda Ospedaliera Nazionale Ss Antonio E Biagio E C Arrigo, SCDU Ematologia
city: Avellino
country: Italy
facility: AORN San Giuseppe Moscati Avellino, U.O.C. Ematologia e Trapianto Emopoietico
city: Aviano
country: Italy
facility: Centro Di Riferimento Oncologico Di Aviano, S.O.C. Oncologia Medica e dei Tumori Immunocorrelati
city: Bari
country: Italy
facility: Istituto Tumori Bari Giovanni Paolo II, U.O. di Ematologia e Terapia Cellulare
city: Biella
country: Italy
facility: Ospedale degli Infermi di Biella, SSD Ematologia
city: Brescia
country: Italy
facility: Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia, U.O. Ematologia
city: Cagliari
country: Italy
facility: ARNAS G. Brotzu, SC Ematologia e CTMO
city: Candiolo
country: Italy
facility: Istituto Di Candiolo Fondazione Del Piemonte Per Loncologia IRCCS, Oncologia Medica
city: Castelfranco Veneto
country: Italy
facility: Istituto Oncologico Veneto, U.O.C. Oncoematologia
city: Catania
country: Italy
facility: Azienda Ospedaliero Universitaria Policlinico G Rodolico San Marco Di Catania, UOC Ematologia
city: Cuneo
country: Italy
facility: Azienda Ospedaliera Santa Croce E Carle, S.C. di Ematologia
city: Firenze
country: Italy
facility: Careggi University Hospital, SOD Ematologia
city: Ivrea
country: Italy
facility: Ssd Ematologia ASLTO4, S.S.D. Ematologia
city: Latina
country: Italy
facility: Ospedale Santa Maria Goretti, SOD Ematologia
city: Meldola
country: Italy
facility: Istituto Romagnolo Per Lo Studio Dei Tumori Dino Amadori IRST S.r.l., Oncoematologia
city: Messina
country: Italy
facility: Azienda Ospedali Riuniti Papardo-Piemonte, U.O. Ematologia
city: Milano
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda, SC Ematologia
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale Dei Tumori, S.C. Ematologia e Trapianto Midollo Osseo Allogenico
city: Milano
country: Italy
facility: Ospedale San Raffaele S.r.l., Unitа Linfomi - Dipartimento Oncoematologia
city: Modena
country: Italy
facility: Azienda Ospedaliero Universitaria Di Modena, S.C. Ematologia
city: Monza
country: Italy
facility: Azienda Ospedaliera S Gerardo Di Monza, Ematologia
city: Napoli
country: Italy
facility: Azienda Ospedaliera Universitaria Federico II Di Napoli, U.O.C. di Ematologia e Trapianti di Midollo
city: Novara
country: Italy
facility: Azienda Ospedaliero-Universitaria Maggiore Della Carita, SCDU Ematologia
city: Padova
country: Italy
facility: Istituto Oncologico Veneto, UOC Oncologia 1
city: Palermo
country: Italy
facility: Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello, Oncoematologia
city: Palermo
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone, U.O.C. Ematologia
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo, U.O.C. Ematologia I
city: Perugia
country: Italy
facility: Hospital Santa Maria Della Misericordia, S.C. di Ematologia con TMO
city: Piacenza
country: Italy
facility: Azienda Unità Sanitaria Locale Di Piacenza, U.O.Ematologia
city: Pisa
country: Italy
facility: Azienda Ospedaliero Universitaria Pisana, U.O. Ematologia
city: Ravenna
country: Italy
facility: Azienda Unita Sanitaria Locale Della Romagna, U.O.C. Ematologia
city: Reggio Emilia
country: Italy
facility: Azienda USL IRCCS Di Reggio Emilia, S.C. Ematologia
city: Rimini
country: Italy
facility: Azienda Unita Sanitaria Locale Della Romagna, U.O. di Ematologia
city: Roma
country: Italy
facility: ASL Roma 1, UOSD Ematologia
city: Roma
country: Italy
facility: Azienda Ospealiero Universitaria Policlinico Umberto I, Istituto Ematologia -Dipartimento di Medicina Traslazionale e di Precisione
city: Roma
country: Italy
facility: Azienda Ospedaliera S Giovanni Addolorata, UOC Ematologia
city: Roma
country: Italy
facility: Azienda Ospedaliero-Universitaria Sant Andrea, UOC Ematologia
city: Roma
country: Italy
facility: Catholic University Of Sacred Heart, UOC Ematologia e Trapianto di cellule staminali emopoietiche
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Campus Bio-Medico, UOC di Ematologia e Trapianto di Cellule Staminali
city: Roma
country: Italy
facility: I.F.O. Istituti Fisioterapici Ospitalieri, UOSD Ematologia e Trapianto
city: Sassuolo
country: Italy
facility: Ospedale Di Sassuolo S.p.A., U.O.S.D. di Oncologia
city: Siena
country: Italy
facility: Azienda Ospedaliera Universitaria Senese, U.O.C. Ematologia
city: Sondrio
country: Italy
facility: Azienda Socio Sanitaria Territoriale Della Valtellina E Dell Alto Lario, Medicina Interna
city: Terni
country: Italy
facility: Azienda Ospedaliera S Maria Di Terni, S.C. Oncoematologia
city: Treviso
country: Italy
facility: Azienda Unita' Locale Socio Sanitaria N. 2 Marca Trevigiana, S.C di Ematologia
city: Udine
country: Italy
facility: Azienda Sanitaria Universitaria Friuli Centrale, SOC Clinica Ematologica
city: Varese
country: Italy
facility: Azienda Ospedaliera Ospedale Di Circolo E Fondazione Macchi, U.O.C Ematologia
city: Verona
country: Italy
facility: Azienda Ospedaliera Universitaria Integrata Verona, U.O.C. Ematologia
Study officials:
affiliation: Ospedale Santa Maria Goretti Latina
name: Alessandro Pulsoni, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Università di Pavia-Fondazione IRCCS Policlinico San Matteo
name: Andrea Filippi, MD
role: PRINCIPAL_INVESTIGATOR
References: