Lymphocyte-Sparing And Radio-Immunotherapy in Head and Neck Carcinoma (Lysari)

Léon Bérard Center

Status and phase: Enrolling; Phase 3

Conditions: Primary Head and Neck Tumor; Oropharynx Cancer; Hypopharynx Cancer; Larynx Cancer

Treatments: Drug: Cetuximab; Drug: Cisplatin; Radiation: Tailored radiotherapy; Drug: Vesanoid; Radiation: Standard radiotherapy

Study type: Interventional

Funder types: Other

Identifiers

NCT06706401

ET 22-156

Details and patient eligibility

About

The aim of this study is to investigate the effect of ATRA (Vesanoid) and the effect of tailored radiotherapy in patients with squamous cell carcinoma of the oropharynx, larynx or hypopharynx.

Full description

Following validation of eligibility criteria, patients will be randomised (1:1:1:1) to receive:

• Arm A: Standard radiotherapy then follow-up
• Arm B: Tailored radiotherapy and ATRA (Vesanoid)
• Arm C: Standard radiotherapy and ATRA (Vesanoid)
• Arm D: Tailored radiotherapy then follow-up

This randomised phase III clinical trial will provide the clinical proof-of-concept that unilateral irradiation for lateralized tumors and the addition of ATRA (Vesanoid) to radiotherapy in HNSCC prevents severe lymphopenia and immunosenescence and therefore, may foster a radiation-induced anticancer immune response sufficient to increase event-free survival at 2 years.

Enrollment: 460 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion criteria :

I1. Male or female patients aged ≥ 18 years old at time of inform consent signature.

I2. Patients with primary head and neck tumour up to, but not crossing the midline, previously untreated with histologically-confirmed squamous cell carcinoma of:

• the oropharynx p16-, larynx or hypopharynx : T1/N2a-N2b, T2/N0-N2b, T3/N0-N2b (UICC 8th Ed.), or
• the oropharynx p16+ : T1/N1 (multiple nodes), T2-T3/N0-N1 (UICC 8th Ed.).

I3. Patients with lymph node staging assessed by an FDG-PET/CT with no contralateral nodal uptake.

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.

I5. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.

I6. Adequate hematologic and end-organ function, defined by the following laboratory test results obtained within 7 days prior to randomisation :

Hematological (without transfusion within 2 weeks) :

• Neutrophils count > 1.5 × 109 /L
• Platelets count > 75 × 109 /L
• WBC≥ 3.0 × 109 /L

Hepatic function :

• 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

Renal function :

• Serum creatinine < 1.5 ×ULN.

I7. QTcF ≤450ms for men and 470ms for women, from 3 electrocardiograms on screening ECG, within 7 days prior randomisation.

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.

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.

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.

I11. Patients must be covered by a medical insurance in country where applicable.

Exclusion criteria :

E1. Patient with primary tumor crossing the midline or patients with bilateral primary tumors.

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+).

E3. Patients with unknown primary tumor size as per TNM i.e. T0-N1 to T0-N3, p16- or p16+.

E4. Patients with contralateral FDG-PET/CT nodal uptake.

E5. Patient with any previous anti-cancer therapy for HNSCC (all prior treatment are forbidden: chemotherapy, radiotherapy, targeted therapy, immunotherapy or any other therapy approved or experimental).

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.

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.

E8. Patient with ongoing or anticipation of need for systemic immunostimulatory agents (including, but not limited to, interferons and IL-2).

E9. Patient with concurrent treatment with any other anti-cancer treatment, approved or investigational agent or participation in another clinical trial with therapeutic intent.

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.

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.

E12. Patient with known hypersensitivity to tretinoin, other retinoids, soya, peanut or to any of the excipients of vesanoid.

E13. Patient with known malabsorption syndrome and/or unable to swallow oral medication.

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.

E15.Pregnant or lactating woman.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: None (Open label)

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460 participants in 4 patient groups

Standard radiotherapy

Active Comparator group

Description:

Patient will receive 6 to 8 weeks of standard (chemo)radiotherapy then will be followed until document progression disease, death, withdrawal of consent or end of trial (whichever occurs first). In addition of radiotherapy, patient will receive cisplatin or cetuximab (standard of care treatments).

Treatment:

Radiation: Standard radiotherapy

Drug: Cetuximab

Drug: Cisplatin

Tailored radiotherapy and ATRA (Vesanoid)

Experimental group

Description:

ATRA will be administered per os 1 week before the start of (chemo)radiotherapy (daily administration for 3 days). Then, patient will receive 6 to 8 weeks of tailored (chemo)radiotherapy. In addition of radiotherapy, patient will receive cisplatin or cetuximab (standard of care treatments). Subsequently, ATRA will be administered per os for 3 days every 3 weeks for a total of 4 courses starting 2 to 3 weeks after the end of (chemo)radiotherapy. Finally, the patient will be followed until document progression disease, death, withdrawal of consent or end of trial (whichever occurs first).

Treatment:

Drug: Vesanoid

Radiation: Tailored radiotherapy

Drug: Cetuximab

Drug: Cisplatin

Standard radiotherapy and ATRA (Vesanoid)

Experimental group

Description:

ATRA will be administered per os 1 week before the start of (chemo)radiotherapy (daily administration for 3 days). In addition of radiotherapy, patient will receive cisplatin or cetuximab (standard of care treatments).Then, patient will receive 6 to 8 weeks of standard (chemo)radiotherapy. Subsequently, ATRA will be administered per os for 3 days every 3 weeks for a total of 4 courses starting 2 to 3 weeks after the end of (chemo)radiotherapy. Finally, the patient will be followed until document progression disease, death, withdrawal of consent or end of trial (whichever occurs first).

Treatment:

Radiation: Standard radiotherapy

Drug: Vesanoid

Drug: Cetuximab

Drug: Cisplatin

Tailored radiotherapy

Experimental group

Description:

Patient will receive 6 to 8 weeks of tailored (chemo)radiotherapy then will be followed until document progression disease, death, withdrawal of consent or end of trial (whichever occurs first). In addition of radiotherapy, patient will receive cisplatin or cetuximab (standard of care treatments).

Treatment:

Radiation: Tailored radiotherapy

Drug: Cetuximab

Drug: Cisplatin