Comparison Between Local Radiotherapy Alone or Combined With Obinutuzumab in Early Stage Follicular Lymphoma: the GAZEBO Trial From the Fondazione Italiana Linfomi

Follicular Lymphoma Clinical Trial

— FIL_GAZEBO  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05929222
• Other study ID #: FIL_GAZEBO
• Status: Recruiting
• Phase: Phase 3
• Start date: December 14, 2023
• Est. completion date: April 2031

Study information

• Verified date: December 2023
• Source: Fondazione Italiana Linfomi - ETS
• Contact: Uffici Studi FIL
• Phone: +390131033153
• Email: startup[@]filinf.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 190
• Est. completion date: April 2031
• Est. primary completion date: April 2031
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Follicular Lymphoma
• Lymphoma
• Lymphoma, Follicular

Intervention

Radiation:
• Radiotherapy
Involved-Site Radiation Therapy 24Gy

Other:
• Radiotherapy plus Obinutuzumab
Involved-Site Radiation Therapy 24Gy followed by Obinutuzumab 1000mg flat dose 4 doses weekly plus addition 4 doses every 3 weeks

Locations

Country	Name	City	State
Italy	Azienda Ospedaliera Nazionale Ss Antonio E Biagio E C Arrigo, SCDU Ematologia	Alessandria
Italy	AORN San Giuseppe Moscati Avellino, U.O.C. Ematologia e Trapianto Emopoietico	Avellino
Italy	Centro Di Riferimento Oncologico Di Aviano, S.O.C. Oncologia Medica e dei Tumori Immunocorrelati	Aviano
Italy	Istituto Tumori Bari Giovanni Paolo II, U.O. di Ematologia e Terapia Cellulare	Bari
Italy	Ospedale degli Infermi di Biella, SSD Ematologia	Biella
Italy	Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia, U.O. Ematologia	Brescia
Italy	ARNAS G. Brotzu, SC Ematologia e CTMO	Cagliari
Italy	Istituto Di Candiolo Fondazione Del Piemonte Per Loncologia IRCCS, Oncologia Medica	Candiolo
Italy	Istituto Oncologico Veneto, U.O.C. Oncoematologia	Castelfranco Veneto
Italy	Azienda Ospedaliero Universitaria Policlinico G Rodolico San Marco Di Catania, UOC Ematologia	Catania
Italy	Azienda Ospedaliera Santa Croce E Carle, S.C. di Ematologia	Cuneo
Italy	Careggi University Hospital, SOD Ematologia	Firenze
Italy	Ssd Ematologia ASLTO4, S.S.D. Ematologia	Ivrea
Italy	Ospedale Santa Maria Goretti, SOD Ematologia	Latina
Italy	Istituto Romagnolo Per Lo Studio Dei Tumori Dino Amadori IRST S.r.l., Oncoematologia	Meldola
Italy	Azienda Ospedali Riuniti Papardo-Piemonte, U.O. Ematologia	Messina
Italy	ASST Grande Ospedale Metropolitano Niguarda, SC Ematologia	Milano
Italy	Fondazione IRCCS Istituto Nazionale Dei Tumori, S.C. Ematologia e Trapianto Midollo Osseo Allogenico	Milano
Italy	Ospedale San Raffaele S.r.l., Unit? Linfomi - Dipartimento Oncoematologia	Milano
Italy	Azienda Ospedaliero Universitaria Di Modena, S.C. Ematologia	Modena
Italy	Azienda Ospedaliera S Gerardo Di Monza, Ematologia	Monza
Italy	Azienda Ospedaliera Universitaria Federico II Di Napoli, U.O.C. di Ematologia e Trapianti di Midollo	Napoli
Italy	Azienda Ospedaliero-Universitaria Maggiore Della Carita, SCDU Ematologia	Novara
Italy	Istituto Oncologico Veneto, UOC Oncologia 1	Padova
Italy	Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello, Oncoematologia	Palermo
Italy	Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone, U.O.C. Ematologia	Palermo
Italy	Fondazione IRCCS Policlinico San Matteo, U.O.C. Ematologia I	Pavia
Italy	Hospital Santa Maria Della Misericordia, S.C. di Ematologia con TMO	Perugia
Italy	Azienda Unità Sanitaria Locale Di Piacenza, U.O.Ematologia	Piacenza
Italy	Azienda Ospedaliero Universitaria Pisana, U.O. Ematologia	Pisa
Italy	Azienda Unita Sanitaria Locale Della Romagna, U.O.C. Ematologia	Ravenna
Italy	Azienda USL IRCCS Di Reggio Emilia, S.C. Ematologia	Reggio Emilia
Italy	Azienda Unita Sanitaria Locale Della Romagna, U.O. di Ematologia	Rimini
Italy	ASL Roma 1, UOSD Ematologia	Roma
Italy	Azienda Ospealiero Universitaria Policlinico Umberto I, Istituto Ematologia -Dipartimento di Medicina Traslazionale e di Precisione	Roma
Italy	Azienda Ospedaliera S Giovanni Addolorata, UOC Ematologia	Roma
Italy	Azienda Ospedaliero-Universitaria Sant Andrea, UOC Ematologia	Roma
Italy	Catholic University Of Sacred Heart, UOC Ematologia e Trapianto di cellule staminali emopoietiche	Roma
Italy	Fondazione Policlinico Universitario Campus Bio-Medico, UOC di Ematologia e Trapianto di Cellule Staminali	Roma
Italy	I.F.O. Istituti Fisioterapici Ospitalieri, UOSD Ematologia e Trapianto	Roma
Italy	Ospedale Di Sassuolo S.p.A., U.O.S.D. di Oncologia	Sassuolo
Italy	Azienda Ospedaliera Universitaria Senese, U.O.C. Ematologia	Siena
Italy	Azienda Socio Sanitaria Territoriale Della Valtellina E Dell Alto Lario, Medicina Interna	Sondrio
Italy	Azienda Ospedaliera S Maria Di Terni, S.C. Oncoematologia	Terni
Italy	Azienda Unita' Locale Socio Sanitaria N. 2 Marca Trevigiana, S.C di Ematologia	Treviso
Italy	Azienda Sanitaria Universitaria Friuli Centrale, SOC Clinica Ematologica	Udine
Italy	Azienda Ospedaliera Ospedale Di Circolo E Fondazione Macchi, U.O.C Ematologia	Varese
Italy	Azienda Ospedaliera Universitaria Integrata Verona, U.O.C. Ematologia	Verona

Sponsors (2)

Lead Sponsor	Collaborator
Fondazione Italiana Linfomi - ETS	Roche Pharma AG

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free survival (PFS)	Time between the randomization to first documentation of recurrence, progression or death from any cause at 2 years	From treatment start up to 33 months (9 months treatment period and 24 months of follow-up)
Secondary	Complete response rate (CRR)	Complete response (CR) rate according to the international criteria (Cheson 2014)	From therapy start up to end of treatment (9 months)
Secondary	Overall response rate (ORR)	ORR will be defined as the proportion of patients who have a partial or complete response at every treatment phase	From therapy start up to end of treatment (9 months)
Secondary	Disease Free Survival (DFS)	Time between the first documentation of Complete Response 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	From post radiotherapy assessment up to 45 months (9 months treatment phase plus 36 months of follow-up)
Secondary	Event Free Survival (EFS)	Time between the randomization 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	From therapy start up to 45 months (9 months treatment phase plus 36 months of follow-up)
Secondary	Number of patients with Molecular Response at end of treatment	MRD negativity at end of treatment for positive patients at baseline	From therapy start up to end of treatment (9 months)
Secondary	Rate of Adverse Events	Incidence and severity of AEs in both arms according to latest CTCAE criteria	From therapy start up to 45 months (9 months treatment phase plus 36 months of follow-up)
Secondary	Prognostic and predictive impact of presence/abscence of t(14;18) rearrangement measured by FISH	Prognostic and predictive impact on PFS in presence or absence of t(14;18) rearrangement measured by FISH	From therapy start up to 45 months (9 months treatment phase plus 36 months of follow-up)
Secondary	Prognostic role of Minimal Residual Disease by conventional (BCL2/IGH rearrangement by ddPCR) and ctDNA method	Prognostic role of conventional MRD (BCL2/IGH rearrangement by ddPCR) and of MRD on plasmatic circulating tumour deoxyribonucleic acid (ctDNA) at different time points for PFS and relapse	From therapy start up to 45 months (9 months treatment phase plus 36 months of follow-up)
Secondary	Prognostic and predictive value of different threshold of metabolic response expressed as SUVmax, MTV and TLG at baseline (PET-0);	Prognostic and predictive value of different threshold of metabolic response expressed as quantitative PET indexes (QPI) at baseline (PET-0), i.e. SUVmax, MTV and TLG;	At baseline (before therapy start)
Secondary	Prognostic and predictive role of liquid biopsy by DNA sequencing for lymphoma mutations	Prognostic and predictive role of liquid biopsy by DNA sequencing for lymphoma mutations at different time points on PFS and relapse	From therapy start up to 45 months (9 months treatment phase plus 36 months of follow-up)
Secondary	Prognostic and predictive value of radiological markers assessed by Machine Learning tools (pyRadiomics)	Prognostic and predictive value of radiomic analysis on PFS, assessed on both CT and PET scans by Machine Learning tools (pyRadiomics);	From therapy start up to 45 months (9 months treatment phase plus 36 months of follow-up)
Secondary	Correlation of MRD results with the radiomics results and clinical outcomes	Correlation of MRD results with the radiomics results and clinical outcomes	From therapy start up to 45 months (9 months treatment phase plus 36 months of follow-up)
Secondary	Comparison between genotype at diagnosis and at relapse assessed by RNA sequencing (CIBERSORTx)	Comparison between genotype at diagnosis and at relapse assessed by RNA sequencing (CIBERSORTx)	From therapy start up to 45 months (9 months treatment phase plus 36 months of follow-up)
Secondary	Evaluation of liquid biopsy as a tool to identity specific mutations predictive for clonal evolution of lymphoma	Evaluation of liquid biopsy as a tool to identity specific mutations predictive for clonal evolution of lymphoma	From therapy start up to 45 months (9 months treatment phase plus 36 months of follow-up)