Changes to adverse event collection requirements post resection surgery. Changes to eligibility criteria relating to patients with a previous primary HNSCC, inclusion of supraglottis and T4 larynx tumours. Changes to treatment with medications known to cause QTc prolongation.

Changes to the eligibility criteria relating to HPV status. Update to disease assessment criteria and timing of informed consent.

Revision to the eligibility criteria to include HPV positive patients and patients who had current or previous malignancies of other types. Changes to the HIV exclusion criteria and testing requirements. Changes to timings of the pAKT sampling and tumour processing for RNA sequencing. Minimum number of days dosing reduced to 20 days and maximum reduced to 29 days. This amendment was approved by the Medicines and Healthcare products Regulatory Agency (MHRA) on 28 September 2016 but was not approved by the Research Ethics Committee (REC). The REC provided Grounds for Non Acceptance and requested an explanation as to why the serology PCR sequencing had been removed from the protocol and what the new testing would be.

Following the temporary halt of the trial on 26 May 2017 and review of the safety data, an amendment was submitted to reopen the trial and update the protocol as follows: An update to clarify which staff members were blinded to the treatment assigned to patients as documented in the AMG 319 blinding manual. Blinded data was reviewed by the Sponsor’s independent Protocol Safety Review Board (PSRB). Following this review, the PSRB recommended that a small number of the Sponsor's team were unblinded in order to confirm that those patients who had been treated on the trial and who had experienced the more severe adverse events while on treatment had received AMG 319 rather than placebo. A specific procedure for unblinding trial data in this instance was established. Reduction of the AMG 319/placebo dose level from 400 mg once daily to 300 mg once daily. Further dose reductions of the fixed dose were permitted if one or more patients experienced either a clinically significant ≥Grade 3 toxicity considered to be immunologically mediated or a drug related toxicity which caused the patient to receive less than 80% of their planned doses. The potential dose de-escalation options were 200 mg once daily, followed by 100 mg once daily, after which point no further dose reductions would be allowed and the trial could be terminated.