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Randomized Phase II/III Trial of Radiotherapy With Concurrent Durvalumab vs. Radiotherapy With Concurrent Cetuximab in Patients With Stage III-IVB Head and Neck Cancer With a Contraindication to Cisplatin

Primary Objective Lead-In: To determine the safety of radiotherapy (RT) with concurrent and adjuvant anti-PD-L1 therapy [MEDI4736 (durvalumab)] is safe in patients with locoregionally advanced head and neck cancer (HNC) who have a contraindication to cisplatin. Phase II: To test the hypothesis that concurrent RT and anti-PD-L1 therapy improves PFS compared to standard therapy (RT with concurrent cetuximab) in patients with locoregionally advanced HNC who have a contraindication to cisplatin. Phase III: To test the hypothesis that concurrent RT and anti-PD-L1 therapy improves overall survival compared to standard therapy (RT with concurrent cetuximab) in patients with locoregionally advanced HNC who have a contraindication to cisplatin. Secondary Objectives To compare toxicity using CTCAE and PRO-CTCAE between patients treated with RT + anti-PD-L1 therapy versus RT/cetuximab. To test the effect of anti-PD-L1 therapy in the subpopulation of patients with tumors that overexpress PD-L1. To compare overall survival, response (at 4-month FDG-PET-CT), locoregional failure, distant metastasis, and competing mortality in the two arms by known risk factors, including p16 status and ω score. To test the hypothesis that MEDI4736 (durvalumab) therapy arm will have less decline in the physical function domain of European Organization for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-C30 Version 3.0) based on the change in score from baseline to 12 months from end of RT, compared to the cetuximab-RT arm in patients with locoregionally advanced HNC who have a contraindication to cisplatin. To test the hypothesis that MEDI4736 (durvalumab) therapy arm at 1 year (from end of RT) will have less decline in swallowing related QOL using the MDADI total composite score, based on the change in score from baseline to 12 months from end of RT, compared to the cetuximab-RT arm in patients who are medically unfit for cisplatin. To compare swallowing related performance and function short and long term using the PSS-HN To evaluate gastrostomy tube retention rates between arms Exploratory Objectives To test the hypothesis that radiation combined with MEDI4736 (durvalumab) enhances the adaptive immune response using three types of immunophenotyping compared to radiation combined with cetuximab. To compare overall QOL short term (end RT-8 months) and long term (12-24 months from end of RT) between arms using the EORTC QLQ-C30 Version 3.0/HN35. To evaluate swallowing related QOL short term (end RT-8 months) and long term (12-24 months from end of RT) using the EORTC HN35 swallowing domain and MDADI (subscales) between arms in patients with locoregionally advanced HNC who have a contraindication to cisplatin. To evaluate patient reported fatigue using the fatigue items in the EORTC QLQ and PRO-CTCAE. To compare clinician and patient reported toxicity using CTCAE and PRO CTCAE. To explore health utilities between cetuximab and MEDI4736 (durvalumab) RT using the EQ5D-5L.

Primary Objective Lead-In: To determine the safety of radiotherapy (RT) with concurrent and adjuvant anti-PD-L1 therapy [MEDI4736 (durvalumab)] is safe in patients with locoregionally advanced head and neck cancer (HNC) who have a contraindication to cisplatin. Phase II: To test the hypothesis that concurrent RT and anti-PD-L1 therapy improves PFS compared to standard therapy (RT with concurrent cetuximab) in patients with locoregionally advanced HNC who have a contraindication to cisplatin. Phase III: To test the hypothesis that concurrent RT and anti-PD-L1 therapy improves overall survival compared to standard therapy (RT with concurrent cetuximab) in patients with locoregionally advanced HNC who have a contraindication to cisplatin. Secondary Objectives To compare toxicity using CTCAE and PRO-CTCAE between patients treated with RT + anti-PD-L1 therapy versus RT/cetuximab. To test the effect of anti-PD-L1 therapy in the subpopulation of patients with tumors that overexpress PD-L1. To compare overall survival, response (at 4-month FDG-PET-CT), locoregional failure, distant metastasis, and competing mortality in the two arms by known risk factors, including p16 status and ω score. To test the hypothesis that MEDI4736 (durvalumab) therapy arm will have less decline in the physical function domain of European Organization for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-C30 Version 3.0) based on the change in score from baseline to 12 months from end of RT, compared to the cetuximab-RT arm in patients with locoregionally advanced HNC who have a contraindication to cisplatin. To test the hypothesis that MEDI4736 (durvalumab) therapy arm at 1 year (from end of RT) will have less decline in swallowing related QOL using the MDADI total composite score, based on the change in score from baseline to 12 months from end of RT, compared to the cetuximab-RT arm in patients who are medically unfit for cisplatin. To compare swallowing related performance and function short and long term using the PSS-HN To evaluate gastrostomy tube retention rates between arms Exploratory Objectives To test the hypothesis that radiation combined with MEDI4736 (durvalumab) enhances the adaptive immune response using three types of immunophenotyping compared to radiation combined with cetuximab. To compare overall QOL short term (end RT-8 months) and long term (12-24 months from end of RT) between arms using the EORTC QLQ-C30 Version 3.0/HN35. To evaluate swallowing related QOL short term (end RT-8 months) and long term (12-24 months from end of RT) using the EORTC HN35 swallowing domain and MDADI (subscales) between arms in patients with locoregionally advanced HNC who have a contraindication to cisplatin. To evaluate patient reported fatigue using the fatigue items in the EORTC QLQ and PRO-CTCAE. To compare clinician and patient reported toxicity using CTCAE and PRO CTCAE. To explore health utilities between cetuximab and MEDI4736 (durvalumab) RT using the EQ5D-5L.