Evaluation of Lymphocyte-Sparing Radiotherapy and All-Trans Retinoic Acid in Lateralized Oropharyngeal, Laryngeal, and Hypopharyngeal Squamous Cell Carcinoma

Trial ID: 2022-501315-13-00
Protocol: LYSARI/ET22-156
Sponsor: Centre Leon Berard

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Diseases & Conditions

Squamous cell carcinoma of the hypopharynx Laryngeal squamous cell carcinoma

Objectives

The primary objective of the study is to assess the effect of **all-trans retinoic acid (ATRA)** and tailored radiotherapy (RT) in patients with localized squamous cell carcinoma of the head and neck who are eligible for RT. This is clinically relevant as it aims to optimize treatment strategies for this patient population, potentially improving therapeutic outcomes and minimizing adverse effects associated with standard treatment protocols.

Secondary objectives include:

Further assessing the clinical activity of the proposed strategy.
Evaluating the safety profile of the proposed combinations in the target population.
Assessing the impact of the proposed combinations on patients' quality of life.
Performing an economic analysis of the use of tailored RT with or without N-803, utilizing a cost-effectiveness methodology to compute costs and efficacy for each of the four treatment arms.

Participants

The clinical trial involves **patients with lateralised oropharyngeal, laryngeal, and hypopharyngeal squamous cell carcinoma**. The study population includes both male and female participants aged 18 years and older. Participants are required to have a primary head and neck tumor that is localized and has not crossed the midline, with histologically confirmed squamous cell carcinoma. The trial does not include a vulnerable population. Participants must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Adequate hematologic and end-organ function is necessary, as defined by specific laboratory test results. Fertile men and women of child-bearing potential must agree to use effective contraception during the study and for up to one month after the end of study treatments. The sponsor has not provided information on the total number of participants. Participants' lifestyle considerations, such as diet and physical activity, are not specified in the available data.

Plans and Procedures

The clinical trial is designed to evaluate the effects of **all-trans retinoic acid (ATRA)** and tailored radiotherapy (RT) in patients with localized squamous cell carcinoma of the head and neck. This is a multicenter, randomized, 2x2 factorial design trial comparing standard to reduced-target volume radiotherapy, with or without ATRA, in patients with lateralized oropharyngeal, laryngeal, and hypopharyngeal squamous cell carcinoma. The trial is not classified as low intervention and is categorized under phase 5. The estimated recruitment start date is July 4, 2024, with an anticipated end date of May 3, 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age, tumor characteristics, and overall health status. Eligible participants must be at least 18 years old, have a primary head and neck tumor not crossing the midline, and meet specific hematologic and organ function requirements. The trial will include follow-up visits to monitor treatment effects and adverse events, with the primary endpoint being event-free survival. Secondary endpoints include local and regional relapse-free survival, metastasis-free survival, and overall survival, among others.

The trial involves the administration of **cetuximab**, **cisplatin**, and ATRA, with cetuximab and cisplatin given intravenously and ATRA administered orally. The maximum treatment period for cetuximab and cisplatin is 8 weeks, while ATRA is administered for up to 15 weeks. Participants are expected to be involved in the study for the duration of the treatment period and follow-up assessments. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study procedures.

Treatment

The clinical trial involves the administration of **CETUXIMAB**, a monoclonal antibody classified under the ATC code L01XC06. It is formulated for intravenous administration and is provided in a pharmaceutical form identified as PHF00230MIG. The maximum daily dose is 400 mg/m², with a total maximum dose of 2150 mg/m² over a treatment period of up to 8 weeks. **Cetuximab** is utilized as an antineoplastic agent in this study, and its administration is monitored to ensure compliance with the dosing schedule.

**CISPLATIN** is another experimental medication used in this trial, categorized under the ATC code L01XA01. It is a chemical compound administered intravenously, with a pharmaceutical form designated as PHF00015MIG. The maximum daily dose is 40 mg/m², and the total maximum dose is 320 mg/m² over a treatment period of up to 8 weeks. **Cisplatin** serves as an antineoplastic agent, and its administration is carefully monitored to maintain adherence to the prescribed dosing regimen.

The trial also includes **TRETINOIN**, known by its ATC code L01XF01, which is administered orally. It is provided in a pharmaceutical form labeled as PHF00007MIG. The maximum daily dose is 150 mg/m², with a total maximum dose of 2250 mg/m² over a treatment period of up to 15 weeks. **Tretinoin** is used as an antineoplastic agent in this study, and participant compliance with the oral dosing schedule is closely monitored.

In addition to the experimental medications, the study may involve standard-of-care therapies as deemed necessary by the clinical investigators. The trial design ensures rigorous monitoring of drug administration and participant adherence to the treatment protocols to achieve the study's objectives effectively.

Efficacy

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Event Free Survival (EFS)**, which will be measured to evaluate the effect of the treatment on the progression of the disease. Secondary endpoints include local relapse-free survival, regional relapse-free survival, metastases-free survival, and the rate of pathologically positive lymph nodes at neck node dissection performed four months after the completion of (chemo)-radiotherapy for patients undergoing this procedure. Additionally, EFS will be considered, excluding pathologically positive lymph nodes at neck node dissection as an event, and overall survival will be assessed.

Further secondary endpoints involve the incidence of adverse events (AEs) using the NCI CTCAE 5.0 criteria, and changes from baseline in global health scale/quality of life and fatigue, measured using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire and EQ5D. Swallowing and pain will be evaluated using the EORTC QLQ-H&N43 questionnaire. Cost-effectiveness and cost-utility analyses based on quality-adjusted life years (QALY) will also be conducted to assess the economic impact of the treatment.

Inclusion and Exclusion Criteria

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Inclusion Criteria

I1. Male or female patients aged ≥ 18 years old at time of inform consent signature
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.
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.)
I3. Patients with lymph node staging assessed by a 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 : 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
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.
I11. Patients must be covered by a medical insurance in country where applicable.

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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 treatments 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 listed in section 6.3.
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.