LYSARI – LYmphocyte-Sparing And Radio-Immunotherapy in Head and neck carcinoma - A multicenter, randomised 2*2 factorial design comparing standard to reduced-target volume radiotherapy with or without all-trans retinoic acid (ATRA) in patients with lateralised oropharyngeal, laryngeal and hypopharyngeal squamous cell carcinoma.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Leon Berard

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Pathological Conditions, Signs and Symptoms [C23], Diseases [C] - Neoplasms [C04]

Trial duration

6 Mar 2025 → ongoing

Decision date (initial)

2024-10-23

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Agence nationale de la recherche - appel à projets Recherche Hospitalo-Universitaire en Santé RHU

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

To assess the effect of ATRA (Vesanoid) and the effect of tailored RT in patients with localised squamous celle carcinoma of head and neck and eligible to RT.

Secondary objectives 5

1. To further assess the clinical activity of the proposed strategy
2. To evaluate the safety profile of the proposed combinations in the target population
3. To assess the impact of the proposed combinations on patient’ quality of life in the target population
4. To perform an economic analysis of the use of a tailored-RT with or without N-803. A cost-effectiveness methodology will be implemented, which involves computing costs and efficacy for each of the four treatment arms
5. Exploratory objectives: To study the impact of treatment on lymphocytes number and function and to study blood biomarkers predictive of response/toxicity following treatment

Conditions and MedDRA coding

Patients with lateralised oropharyngeal, laryngeal and hypopharyngeal squamous cell carcinoma

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. I1. Male or female patients aged ≥ 18 years old at time of inform consent signature
2. I10. Patient should understand, sign, and date the written voluntary informed consent form prior to any protocol-specific procedures performed and should be able and willing to comply with study visits and procedures as per protocol.
3. I2. Patients with primary head and neck tumour up to, but not crossing the midline, previously untreated with histologically-confirmed squamous cell carcinoma of: 1) the oropharynx p16-, larynx or hypopharynx : T1/N2a-N2b, T2/N0-N2b, T3/N0-N2b (UICC 8th Ed.), or 2) the oropharynx p16+ : T1/N1 (multiple nodes), T2-T3/N0-N1 (UICC 8th Ed.)
4. I3. Patients with lymph node staging assessed by a FDG-PET/CT with no contralateral nodal uptake
5. I4. Patients amenable to treatment with RT or concomitant chemo-radiotherapy.as decided by the treating physician as a function of tumor stage, tumor location, performance of the patients
6. I5. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1
7. I6. Adequate hematologic and end-organ function, defined by the following laboratory test results obtained within 7 days prior to randomisation : 1) Hematological (without transfusion within 2 weeks) - Neutrophils count > 1,5x10.9 /L - Platelets count > 75x10.9/L - WBC≥ 3.0x10.9/L 2) Hepatic function - o Total Bilirubin < 1.5 × ULN (except for Gilbert's syndrome which will allow bilirubin ≤ 3 ULN), - Alanine aminotransferase (ALT) ≤ 2.5×ULN - Aspartate aminotransferase (AST) ≤ 2.5×ULN - Albumin >3.0g/dL 3) Renal function - Serum creatinine < 1.5xULN
8. I7. QTcF ≤450ms for men and 470ms for women, from 3 electrocardiograms on screening ECG, within 7 days prior randomisation
9. I8. Women patients of child-bearing potential are eligible, provided they have a negative serum or urine pregnancy test within 7 days prior randomisation, and agrees to use adequate contraception for up to 1 month after the end of study treatments.
10. I9 Fertile men must agree to use an effective method of contraception during the study and for up to 1 month after the end of study treatments.
11. I11. Patients must be covered by a medical insurance in country where applicable.

Exclusion criteria 15

1. E1. Patient with primary tumor crossing the midline or patients with bilateral primary tumors.
2. E2. Patients with T1-N0 (p16-), T1-N1 (p16-), T1-N0 (p16+), T4 (p16- and p16+), bilateral lymph nodes or nodal disease more than 6 cm (p16- and p16+).
3. E3. Patients with unknown primary tumor size as per TNM i.e. T0-N1 to T0-N3, p16- or p16+.
4. E4. Patients with contralateral FDG-PET/CT nodal uptake.
5. E5. Patient with any previous anti-cancer therapy for HNSCC (all prior treatments are forbidden: chemotherapy, radiotherapy, targeted therapy, immunotherapy or any other therapy approved or experimental).
6. E6. Patient with malignancies other than HNSCC within 3 years prior to randomisation with the exception of adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localised prostate cancer treated surgically with curative intent.
7. E7. Patient with ongoing or anticipation of need for systemic immunosuppressive medication (including, but not limited to, glucocorticoids, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-alpha agents); with the exceptions of intranasal, inhaled or topical corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.
8. E8. Patient with ongoing or anticipation of need for systemic immunostimulatory agents (including, but not limited to, interferons and IL-2).
9. E9. Patient with concurrent treatment with any other anti-cancer treatment, approved or investigational agent or participation in another clinical trial with therapeutic intent.
10. E10. Patient with infectious diseases: - severe infection within 4 weeks prior to randomisation, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, - active hepatitis B (chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test at screening), - active hepatitis C. Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV RNA at screening, - HIV infection, - active tuberculosis.
11. E11. Patient with any psychological, cognitive, familial, sociological or geographical condition potentially hampering compliance with the study protocol, completion of patient reported measures and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
12. E12. Patient with known hypersensitivity to tretinoin, other retinoids, soya, peanut or to any of the excipients of vesanoid listed in section 6.3.
13. E13. Patient with known malabsorption syndrome and/or unable to swallow oral medication.
14. E14. Patient with ongoing or expected need for concomitant treatment with vitamin A, tetracyclines, other retinoids, anti-fibrinolytic agent, and strong inducers or inhibitors of CYP3A4.
15. E15. Pregnant or lactating woman.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Event Free Survival (EFS)

Secondary endpoints 5

1. Local relapse free survival; Regional relapse free survival; Metastases free survival; Rate of pathologically positive lymph nodes at neck node dissection performed at 4 months after the completion of (chemo)-radiotherapy for those patients benefiting from a neck node dissection; EFS considering that pathologically positive lymph nodes at neck node dissection performed at 4 months after the completion of (chemo)-radiotherapy is not an event and Overall survival
2. Incidence of AEs using NCI CTCAE 5.0
3. Changes from baseline in i) Global Health Scale/Quality of Life and Fatigue using European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire and EQ5D and ii) swallowing and Pain using EORTC QLQ-H&N43 questionnaire
4. * Cost-effectiveness (based on efficacy) * Analysis and Cost-Utility (based on QALY) Analysis
5. Exploratory objetives: Immunomonitoring on isolated PBMCs

Investigational products

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

Test 1

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Leon Berard

Sponsor organisation

Centre Leon Berard

Address

28 Rue Laennec

City

Lyon

Postcode

69008

Country

France

Scientific contact point

Organisation

Centre Leon Berard

Contact name

Oncology doctor

Public contact point

Organisation

Centre Leon Berard

Contact name

Oncology doctor

Locations

3 EU/EEA countries · 17 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 50 files

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

Application history

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