Tolerance and Efficacy of Pembrolizumab or Cetuximab Combined With RT in Patients With Locally Advanced HNSCC

Study Overview
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Brief Summary
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The general aim of the study is to evaluate the anti-tumour activity and the tolerance profile of Pembrolizumab + RT in comparison to cetuximab + RT in patients with locally advanced HNSCC and to explore potential correlations between treatment outcome and the immune landscape.

Detailed Description
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A majority of HNSCC are locally advanced and commonly treated with concomitant chemo-radiotherapy (CT-RT). However, a large proportion of patients with locally advanced stage are not suitable for receiving cisplatinum-based chemotherapy (CT) concomitant with radiotherapy (RT) either due to age, general and/or medical condition(s). An alternative standard treatment has been established, combining RT and cetuximab. However, both CT-RT and cetuximab-RT which are considered as standard approaches in locally advanced non operated HNSCC are associated with poor outcome in patients with the most advanced T stage (T4) and/or N stage (>=N2) and/or HPV negative tumours. A new and promising approach could target immune response. Pembrolizumab is a high-affinity monoclonal anti-PD1 antibody which showed antitumor activity in melanoma and NSCLC. In the KEYNOTE-012 (multi-center, nonrandomized Phase Ib HNSCC), Pembrolizumab was well tolerated and safe with no serious drug related AEs reported. About 51% (26/51) of patients had decreased tumor burden which was seen both in HPV (-) and HPV(+) HNSCC. This observation led to the hypothesis generated in the current study that Pembrolizumab is potentially a very active drug in HNSCC and that the combination of Pembrolizumab with radiotherapy will be well tolerated, given the very good toxicity profile of the drug and will improve the outcome of patients with locally advanced HNSCC non suitable for CT-RT, as compared to the treatment of reference combining cetuximab and RT.

Official Title
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A Phase II Randomized Study to Determine the Tolerance and Efficacy of Pembrolizumab or Cetuximab Combined With Radiation Therapy in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck

Conditions
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Squamous Cell Carcinoma of the Head and Neck

Intervention / Treatment
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* Drug: Pembrolizumab
* Drug: Cetuximab
* Radiation: Radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Age ≥18 ≤ 80 years. Performance Status ECOG 0-1 Histologically confirmed diagnosis of previously untreated locally advanced HNSCC (Stage III, IVa and IVb according to the American Joint Committee on Cancer Staging System) of one or more of the following sites: oral cavity, oropharynx, hypopharynx and larynx Availability of pre-treatment tumour tissue (for biomarker analysis, PD -L1, TILs and immune-monitoring) p16 expression from tumor sample (immunohistochemistry) Recording of the smoking history No viral infection (HIV, Hepatitis B/C) No autoimmune disease No immunodeficiency or immunosuppressive therapy No active CNS disease No interstitial lung disease No active infection Women of child-bearing potential: negative serum pregnancy test at screening and use of appropriate contraception methods from study entry Patients not proposed cisplatin-based chemotherapy because of age, general condition, if medically unfit or patient refusal. Adequate organ laboratory values Health insurance coverage Exclusion Criteria: Nasopharyngeal, paranasal sinuses, nasal cavity tumours or thyroid cancers; Squamous cell cancer involving cervical neck nodes with unknown primary site; Metastatic disease; 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, prior neoadjuvant therapy, prior surgical resection, or use of any investigational agent; Weight loss of >10% during the last 3 weeks prior the screening visit; Concurrent treatment with any other systemic anti-cancer therapy that is not specified in the protocol; Concomitant treatment with any drug on the prohibited medication list such as live vaccines (for details, see the protocol); History of another malignancy within the last 3 years (exception of in situ carcinoma and skin carcinomas); If female, pregnant or lactating; 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. Known hypersensitivity reaction to study medication; Any social, personal, medical 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Pembrolizumab and radiotherapy<br>200 mg IV infusion every 3 weeks, i.e. on day 1, 22, 43 during the course of radiotherapy | Drug: Pembrolizumab<br>* 200mg IV infusion every 3 weeks, i.e. on day 1, 22, 43 during the course of radiotherapy. Radiotherapy will be delivered daily for 5 days per week to a total dose of 69.96 Gy in 2.12 Gy daily fractions over 6.5 weeks (33 fractions).<br>* Other names: antibody;Radiation: Radiotherapy<br>* Radiotherapy will be delivered daily for 5 days per week to a total dose of 69.96 Gy in 2.12 Gy daily fractions over 6.5 weeks (33 fractions).<br>* Other names: Conventional Radiotherapy;|
| Active Comparator: Cetuximab and radiotherapy<br>Loading dose of 400 mg/m² IV on Day-8, followed by weekly dose of 250 mg/m² IV during the whole course of radiotherapy. | Drug: Cetuximab<br>* Loading dose of 400 mg/m² IV on Day-8, followed by weekly dose of 250 mg/m² IV during the whole course of radiotherapy. Radiotherapy will be delivered daily for 5 days per week to a total dose of 69.96 Gy in 2.12 Gy daily fractions over 6.5 weeks (33 fractions).<br>* Other names: antibody;Radiation: Radiotherapy<br>* Radiotherapy will be delivered daily for 5 days per week to a total dose of 69.96 Gy in 2.12 Gy daily fractions over 6.5 weeks (33 fractions).<br>* Other names: Conventional Radiotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Locoregional Control | To compare between the 2 arms the rate of patients achieving Locoregional Control (LRC) at 15 months from the end of radiation therapy | 15 months from the end of radiation therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | Minimum time from randomization to progression/relapse at any site (local, regional or distant) as defined by RECIST 1.1 criteria or to death from any cause. Patients who don't have any of these events are censored at the date of last follow-up. | At 24 months after treatment initiation | 
| Locoregional progression and distant metastasis | To estimate the respective contribution of locoregional progression, distant progression and death as first event in the progression-free survival, the cumulative incidences of these three types of events were calculated within a competing risk framework. | At 24 months after treatment initiation | 
| Overall survival | Time to death from any cause measured from randomization. | At 24 months after treatment initiation | 
| Acute adverse events | According to NCI-CTCAE version 4, the maximal grade of each toxicity observed during immune-radiotherapy will be used. All grades of toxicity will be tabulated by type of toxicity and by treatment arm. | At 24 months after treatment initiation | 
| Delayed toxicity According to RTOG late toxicity scale | According to RTOG late toxicity scale | At 24 months after treatment initiation | 
| Duration of the feeding tube dependence | It will be presented by treatment arm and analysed by Student t-test. | At 24 months after treatment initiation | 
| Compliance to Pembrolizumab and Cetuximab | Insufficient compliance to cetuximab or Pembrolizumab is defined as a patient receiving less than 75% of the planned dose, even if the dose reduction is due to toxicity | At 24 months after treatment initiation | 
| Health related quality of life (QL) | Assessment by EORTC QLQ-C30 and H&N35 questionnaires | At 24 months after treatment initiation | 
| Impact of p16 / HPV tumor status on the efficacy of the 2 regimens in patients with oropharyngeal initial tumor | Assessment by CISH DNA method | At 24 months after treatment initiation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Determine the tolerance and efficacy of Pembrolizumab