Clinical trial NCT06706401: Lymphocyte-Sparing And Radio-Immunotherapy in Head and Neck Carcinoma
Official title: 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.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Oropharynx Cancer
Larynx Cancer
Hypopharynx Cancer
Primary Head and Neck Tumor
Keywords: Localised squamous cell carcinoma of head and neck
Previously untreated
Standard radiotherapy
Tailored radiotherapy
Vesanoid
Lead sponsor: Centre Leon Berard
Sponsor class: OTHER
First posted: 2024-11-26
Enrollment: 460
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: This trial is a 2\*2 factorial design, multicentric, randomised, Phase III study
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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.

Eligibility 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.

Primary outcomes:
measure: Event Free Survival (EFS)
timeFrame: At 6, 9, 15, 21 and 27 months from randomisation then annually assessed up to 2 years
Secondary outcomes:
measure: Local relapse Free Survival
timeFrame: At 6, 9, 15, 21 and 27 months from randomisation then annually assessed up to 2 years
measure: Regional relapse Free survival
timeFrame: At 6, 9, 15, 21 and 27 months from randomisation then annually assessed up to 2 years
measure: Metastasis Free Survival
timeFrame: At 6, 9, 15, 21 and 27 months from randomisation then annually assessed up to 2 years
measure: Rate of pathologically positive lymph nodes
timeFrame: At 4 months from the completion of (chemo)-radiotherapy
measure: Event Free Survival (EFS)
timeFrame: At 4 months from the completion of (chemo)-radiotherapy
measure: Overall survival
timeFrame: Until up to 2 years follow-up of the last patient enrolled
measure: Adverse events
timeFrame: From the date of first intake of study drug until 27 months after the randomisation of the last randomised patient
measure: Patient quality of life (EORTC QLQ-C30)
timeFrame: At randomisation, at 6, 9, 15, 21 and 27 months after randomisation and30 days after the last study treatments administration
measure: Patient quality of life (EQ5-DL)
timeFrame: At randomisation, at 6, 9, 15, 21 and 27 months after randomisation and30 days after the last study treatments administration
measure: Patient quality of life (EORTC QLQ-H&N43)
timeFrame: At randomisation, at 6, 9, 15, 21 and 27 months after randomisation and30 days after the last study treatments administration
measure: Health economic analysis
timeFrame: From the first patient enrolled to 2 years after treatment discontinuation of the last patient enrolled
measure: Immunomonitoring
timeFrame: Cycle 1 Day 1 pre-dose of Vesanoid, Day 1 of radiotherapy and end of radiotherapy (8 to 10 weeks after randomisation)
Other outcomes:
Locations:
city: Lyon
country: France
facility: Centre Léon Bérard
city: Villejuif
country: France
facility: Institut Gustave Roussy
Study officials:
affiliation: Centre Leon Berard
name: Vincent Grégoire, PhD
role: PRINCIPAL_INVESTIGATOR
References: