Study on the Efficacy of Treatment by Radiotherapy and Pembrolizumab in Newly Diagnosed Metastatic Head & Neck Cancers

Study Overview
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Brief Summary
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Study to evaluate the efficacy of treatment by radiotherapy and pembrolizumab in newly diagnosed metastatic head & neck cancers

Detailed Description
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Comparative interventional prospective phase 3, randomised, open-label, multicentric trial comparing the combination of radiotherapy and pembrolizumab alone or with chemotherapy to systemic treatment as first line treatment of patients with newly diagnosed head and neck squamous cell carcinoma with synchronous metastases.

Official Title
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Randomized Trial of Loco-regional Radiotherapy Added to Pembrolizumab Alone or With Chemotherapy Versus Systemic Treatment Alone for Patients With Newly Diagnosed Head and Neck Squamous Cell Carcinoma With Synchronous Metastases

Conditions
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Squamous Cell Carcinoma of Head and Neck

Intervention / Treatment
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* Drug: Pembrolizumab
* Radiation: Loco-regional radiotherapy
* Drug: Chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must have signed a written informed consent form prior to any study specific procedures. When the patient is physically unable to give their written consent, a trusted person of their choice, independent from the investigator or the sponsor, can confirm in writing the patient's consent. Newly diagnosed histologically confirmed squamous cell carcinoma of head and neck (oral cavity, oropharynx, hypopharynx, and larynx) with confirmed distant metastases at presentation (T1-4 N0-3 M1). Histological confirmation is required in case of a single metastatic lesion. Eligible for treatment by pembrolizumab according to the European Marketing Authorization Patient ≥18 years old Performance status: 0-1 (WHO) Combined Positive Score (CPS) ≥1 for primary tumor (as determined per local practice) Subjects must have at least one measurable lesion as per RECIST v1.1 to assess efficacy Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to randomization: Absolute neutrophil count ≥1.5 × 10⁹/L Platelet ≥100 × 10⁹/L Hemoglobin ≥90 g/L Aspartate aminotransferase (AST) and alanine aminotransferase (ALT), ≤3 × upper limit of normal (ULN), (unless documented liver metastases where ≤5 x ULN is permitted) Bilirubin ≤1.5 × ULN. Serum albumin ≥25 g/L Creatinine clearance ≥30 mL/min (calculated per institutional guidelines or by Cockcroft-Gault or Modification of Diet in Renal Disease (MDRD) formula) Corrected serum calcium of ≤11.5 mg/dL or ≤2.6 mmol/L. Patient must agree to use adequate contraception methods for the duration of the study treatment and up to 4 months after the last dose of pembrolizumab administration Patients must be affiliated to a Social Security System (or equivalent) Exclusion Criteria: Symptomatic central nervous system (CNS) metastases and / or carcinomatous meningitis History of another malignancy within 2 years prior to study inclusion, with the exception of completely resected basal or squamous cell skin cancer, or successfully treated in-situ carcinoma Prior radiotherapy in the head and neck region Any prior or current treatment for invasive head and neck cancer. This will include but is not limited to: prior tyrosine kinase inhibitors, any monoclonal antibody, chemotherapy, anti-PD-1/PD-L1 and CTLA-4, prior radiotherapy (RT), or use of any investigational agent Known Acquired Immune Deficiency Syndrome (AIDS) Known currently active infection including hepatitis B or hepatitis C Patient having received live attenuated vaccine within 28 days prior to enrolment Pregnant or breast feeding woman Active autoimmune disease except vitiligo, type-1 diabetes, hypothyroid stabilized with hormonal substitution, or psoriasis which do not require systemic treatment Active immunodeficiency or ongoing immunosuppressive therapy Active symptomatic interstitial lung disease Significant disease which, in the judgment of the investigator, as a result of the medical interview, physical examinations, or screening investigations would make the patient inappropriate for entry into the trial Any social, personal, medical, geographic and/or psychologic factor(s) that could interfere with the observance of the patient to the protocol and/or the follow-up and/or the signature of the informed consent Prior organ transplantation including allogenic stem-cell transplantation Other severe acute or chronic medical conditions including colitis, pneumonitis, pulmonary fibrosis or psychiatric conditions including active suicidal ideation; or laboratory abnormalities that may increase the risk associated with study participation and, in the judgment of the investigator, would make the patient inappropriate for entry into this study Person deprived of their liberty or under protective custody or guardianship Patient who have taken any investigational medicinal product or have used an investigational device within 30 days prior to study inclusion

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radiotherapy added to systemic treatment<br>Pembrolizumab 200 mg every 3 weeks until disease progression or unacceptable toxicity. Loco-regional radiotherapy will start at D8 after the first administration of pembrolizumab (D1) with 54 Gy/18 fractions in the head and neck region. If the investigator decides before randomization to add chemotherapy with pembrolizumab, the chemotherapy will start from cycle 3 or 4 of pembrolizumab (after radiotherapy administration) and will combine carboplatin AUC 5 mg/mL/min or cisplatin 100 mg/m² every 3 weeks with 5-FU 1000 mg/m²/day during 4 days every 3 weeks for a maximum of 6 cycles | Drug: Pembrolizumab<br>* Pembrolizumab 200 mg every 3 weeks until disease progression (as confirmed according to response evaluation criteria in solid tumors version 1.1 (RECIST v1.1)) or unacceptable toxicity. The treatment of pembrolizumab should not be delayed because of radiotherapy planning.<br>* Other names: KEYTRUDA;Radiation: Loco-regional radiotherapy<br>* The loco-regional radiotherapy will start at D8 after the first administration of pembrolizumab (D1) (if delayed, RT should be started no later than three weeks after the first administration of pembrolizumab, i.e. before the second administration of pembrolizumab if possible), with 54 Gy/18 fractions in the head and neck region. The volume of RT will include only involved loco-regional tumor region and no prophylactic neck volume will be necessary.<br>Drug: Chemotherapy<br>* If the investigator decides before randomization to add chemotherapy with pembrolizumab, the chemotherapy will be composed of carboplatin AUC 5 mg/mL/min or cisplatin 100 mg/m² every 3 weeks with 5-FU 1000 mg/m²/day during 4 days every 3 weeks for a maximum of 6 cycles<br>|
| Active Comparator: Systemic treatment<br>Pembrolizumab 200 mg every 3 weeks until disease progression or unacceptable toxicity. If the investigator decides before randomization to add chemotherapy with pembrolizumab, the chemotherapy will be composed of carboplatin AUC 5 mg/mL/min or cisplatin 100 mg/m² every 3 weeks with 5-FU 1000 mg/m²/day during 4 days every 3 weeks for a maximum of 6 cycles | Drug: Pembrolizumab<br>* Pembrolizumab 200 mg every 3 weeks until disease progression (as confirmed according to response evaluation criteria in solid tumors version 1.1 (RECIST v1.1)) or unacceptable toxicity. The treatment of pembrolizumab should not be delayed because of radiotherapy planning.<br>* Other names: KEYTRUDA;Drug: Chemotherapy<br>* If the investigator decides before randomization to add chemotherapy with pembrolizumab, the chemotherapy will be composed of carboplatin AUC 5 mg/mL/min or cisplatin 100 mg/m² every 3 weeks with 5-FU 1000 mg/m²/day during 4 days every 3 weeks for a maximum of 6 cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | The progression-free survival is the length of time during and after the treatment of a disease that a patient lives with the disease but it does not get worse. | From randomization to disease progression or death, up to 3 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | The overall survival is the length of time from randomization that patients enrolled in the study are still alive. The outcome is to evaluate whether the radiotherapy improves overall survival compared to standard of care. | From randomization to death from any cause, up to 5 years. | 
| Quality of life questionnaire - Core 30 (QLQ-C30) | Developed by the EORTC, this self-reported questionnaire assesses the health-related quality of life of cancer patients in clinical trials. The questionnaire includes five functional scales (physical, everyday activity, cognitive, emotional, and social), three symptom scales (fatigue, pain, nausea and vomiting), a health/quality of life overall scale, and a number of additional elements assessing common symptoms (including dyspnea, loss of appetite, insomnia, constipation, and diarrhea), as well as, the perceived financial impact of the disease. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. | At baseline, 4 months, 6 months, 12 months, 18 months, 2 years, 3 years, and 4 years | 
| Quality of Life Questionnaire - Head & Neck Cancer Module (QLQ-H&N35) | The head & neck cancer module is a 35-item questionnaire designed for use among a wide range of patients with head & neck cancer, varying in disease stage and treatment modality. It includes 7 multi-item scales that assess pain (4 items), swallowing (4 items), senses (2 items), speech (3 items), social eating (4 items), social contact (5 items), and sexuality (2 items). There are also 11 single items. Using a 4-point Likert scale (1 = not at all, 2 = a little, 3 = quite a bit, and 4 = very much), patients indicate the degree to which they have experienced symptoms. For all items and scales, high scores indicate more problems. | At baseline, 4 months, 6 months, 12 months, 18 months, 2 years, 3 years, and 4 years | 
| Objective response rate (ORR) | The Objective response rate is defined as the presence of a partial response (PR) or complete response (CR) observed at week 18. The investigator will evaluate the objective response using RECIST v1.1. | At 18 weeks and 21 weeks | 
| Loco-regional progression | Locoregional disease progression is defined as the time from randomization to the first documented locoregional progression evaluated by RECIST v1.1. | From randomization to loco-regional progression, up to 5 years. | 
| Distant progression | Distant progression is defined as the time from randomization to the first documented distant disease progression evaluated by RECIST v1.1. | From randomization to distant progression, up to 5 years. | 
| Progression-free survival 2 (PFS2) | Progression-free survival 2 is defined as time from randomization to a second tumor progression (according to RECIST V1.1) on next-line treatment (given after a first progression) or death from any cause. Patients who did not have a progression after the initial treatment are counted as an event at the time of death if they died whatever the cause of death or are censored at the time of last news if they are alive. Patients who had a progression after the initial treatment are counted as an event when they progressed again under or after the treatment of the first progression (if they start a new treatment, i.e. a third treatment, they are also counted as an event) or when they died whatever the cause of death or they are censored at the time of last news if they are alive without new progression after the first progression. | Up to 5 years after randomization. | 
| Incidence of Treatment Adverse Events | The tolerance and safety will be evaluated by toxicity (acute [<1 months after the end of pembrolizumab] and late [≥1 month after the end of pembrolizumab]), assessed using the Common terminology criteria for adverse events version 5.0 (CTCAE v5.0). | Throughout study completion, up to 5 years. | 
| Compliance to treatment | Compliance to treatment is defined by the difference on recieved study regimen compared to the planned study regimen. | Throughout study treatment, up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic, Radiotherapy, pembrolizumab, Squamous Cell Carcinoma, Head and Neck, Carcinoma