Phase III trial comparing local radiotherapy alone or with Obinutuzumab in early stage Follicular Lymphoma: the GAZEBO Trial.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione Italiana Linfomi Onlus

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

14 Dec 2023 → ongoing

Decision date (initial)

2023-10-16

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Roche S.p.A.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

To investigate the superiority in terms of Progression-Free Survival (PFS) for the combination of radiotherapy and obinutuzumab (experimental arm) vs. radiotherapy alone (standard arm).

Secondary objectives 12

1. 1. Compare the response rate and the duration of response in the two arms.
2. 2. Assessment of toxicity and safety profile of experimental treatment arm.
3. 3. Evaluation of the risk of transformation in both arms.
4. 4. To investigate the presence or absence of t(14;18) rearrangement by FISH; expression of selected tumour and microenvironment-related genes.
5. 5. To investigate the role in survival and response of conventional Minimal Residual Disease (MRD) and of MRD on plasmatic circulating tumour deoxyribonucleic acid (ctDNA) at different time points.
6. 6. To investigate the role on survival of different threshold of the quantitative PET indexes (QPI) at baseline (PET-0), i.e. SUVmax, Metabolic Tumour Volume (MTV) and Total Lesion Glycolysis (TLG).
7. 7. To investigate the role of liquid biopsy (i.e. lymphoma mutations on plasmatic ctDNA) at different time points.
8. 8. To assess the survival and response associated with the radiomic analysis, assessed on both CT and PET images (multimodal analysis).
9. 9. To correlate the MRD results with the radiomics results and survival.
10. 10. To evaluate the role of the genotype at diagnosis and at relapse.
11. 11. To investigate the role of liquid biopsy in anticipating clonal evolution.
12. 12. To assess the long-term outcome of the patients.

Conditions and MedDRA coding

Early stage Follicular Lymphoma

Regulatory references

Plan to share IPD

Yes

IPD plan description

No identifiable data, such as name, address, hospital name, date of birth, or any other identifying data, will be shared and should not be requested). For each data sharing request, it is essential that a proforma (available on request) is completed that describes the general purpose, specific aims, data items requested, analysis plan and acknowledgment of the trial management team. Requests will be reviewed based on scientific merit and ethical principles. Requestors who are granted access to the data will be required to complete a data sharing agreement that will be signed by the requester and FIL. In compliance with the national ethics guideline and applicable legislation, individual deindentified patients’ data (including study protocol, statistical analysis plan and data coding) can be shared until 5 years after the publication of the study.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. 1. Histological documented diagnosis of Follicular Lymphoma grade I-IIIA as defined in the 2017 edition of World Health Organization (WHO).
2. 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.
3. 3. Patients performing PET before surgery can also be enrolled without repeating PET after surgery.
4. 4. No previous treatment except for steroid pre-treatment.
5. 5. FLIPI < 2, FLIPI2 ≤ 2.
6. 6. Age ≥ 18 years.
7. 7. Negative bone marrow biopsy.
8. 8. Qualitative/quantitative PCR centralized assessment of BCL2/IGH positive cells in peripheral blood (PB) and bone marrow (BM).
9. 9. Centralized revision of the lymph node biopsy with FISH for t(14;18).
10. 10. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2.
11. 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. 12. Adequate renal function defined as follows: • Creatinine clearance ≥ 40 mL/min (Cockcroft–Gault formula).
13. 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. 14. Subject understands and voluntarily signs an informed consent form approved by an National Ethics Committee (NEC), prior to the initiation of any screening or study-specific procedures.
15. 15. Subject must be able to adhere to the study visit schedule and other protocol requirements.
16. 16. Life expectancy ≥ 3 months.
17. 17. Fertility and pregnancy prevention criteria a. 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 prepared 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 o practice effective barrier contraception during the entire study treatment period and through 3 months after the last dose of study drug, or o 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 17

1. 1. Histological diagnosis of Follicular lymphoma grade IIIb.
2. 14. 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.
3. 15. 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.
4. 16. If female, the patient is pregnant or breast-feeding.
5. 17. Patients participating in other clinical studies.
6. 2. Staging >II or B symptoms or bulky disease (> 7 cm).
7. 3. Stage II with distant involved sites, not includible in a single radiation field.
8. 4. Primary cutaneous follicular lymphoma.
9. 5. Known HIV positivity.
10. 6. Positive serology for hepatitis C (HC) defined as a positive test for HCAb, in which case reflexively perform a HCV RNA on the same sample to confirm the result, if negative, the patient is eligible.
11. 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 HBV-DNA 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.
12. 8. Central Nervous System (CNS) involvement with lymphoma.
13. 13. 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.
14. 9. History of severe or life-threatening allergic or anaphylactic reactions to humanized or murine monoclonal antibody therapy (or recombinant antibody-related fusion proteins)
15. 10. Known hypersensitivity to biopharmaceuticals produced in Chinese Hamster Ovary cells or any component of Obinutuzumab
16. 11. Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to start of treatment, congestive heart failure (NYHA III-IV), and arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalities
17. 12. Active autoimmune disease requiring treatment

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression-free survival (PFS) in the two arms.

Secondary endpoints 14

1. 1. Complete response (CR) rate according to the international criteria (Cheson 2014)
2. 2. Overall Response Rate (ORR) at every treatment phase
3. 3. Disease Free Survival (DFS)
4. 4. Event Free Survival (EFS)
5. 5. Molecular response reported as MRD negativity at end of treatment for positive patients at baseline by arms
6. 6. Rate of Adverse Events (named according to the latest version NCI CTCAE) by arms
7. 7. Prognostic and predictive impact on PFS in presence or absence of t(14;18) rearrangement by FISH; expression of selected tumour and microenvironment-related genes
8. 8. Prognostic role of conventional MRD and of MRD on plasmatic circulating tumour deoxyribonucleic acid (ctDNA) at different time points for PFS and relapse
9. 9. Prognostic and predictive value of different threshold of the metabolic response expressed as quantitative PET indexes (QPI) at baseline (PET-0), i.e. SUVmax, MTV and TLG
10. 10. Prognostic and predictive role of liquid biopsy (i.e. lymphoma mutations on plasmatic ctDNA) at different time points on PFS and relapse
11. 11. Prognostic and predictive value of radiomic analysis, assessed on both CT and PET images (multimodal analysis) on PFS
12. 12. Correlation of MRD results with the radiomics results and clinical outcomes
13. 13. Association between genotype at diagnosis and at relapse
14. 14. Association between liquid biopsy in anticipating clonal evolution.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione Italiana Linfomi Onlus

Sponsor organisation

Fondazione Italiana Linfomi Onlus

Address

Piazza Filippo Turati 5

City

Alexandria

Postcode

15121

Country

Italy

Scientific contact point

Organisation

Fondazione Italiana Linfomi Onlus

Contact name

Prof. Alessandro Pulsoni

Public contact point

Organisation

Fondazione Italiana Linfomi Onlus

Contact name

Start Up office

Locations

1 EU/EEA country · 48 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 14 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

11 submissions — initial application plus substantial / non-substantial modifications