Table 2.

Trial summaries of group A and group B

Summary of g roup A
Setting	Patients undergoing surgical resection
Design	Modified TITE-CRM
Chemotherapy	Cisplatin 40 mg/m2 intravenous over 1 hour on day 8
AZD1775	AZD1775 PO BID for 3 days on days 1–3 and 8–10 dose-recommendation according to the modified TITE-CRM model
Surgery	Resection within 42 days of start of neoadjuvant treatment
DLT reporting period	The minimal reporting period is 30 days from start of treatment, but patients will be monitored up to 42 days for delay in surgery due to treatment-related toxicity
PK samples	Pharmacokinetic samples will be collected pre and post—the fifth dose of AZD1775 on days 3 and 10 (4 samples per patient)
PD markers	Assess CDK1, pCDK1, γH2AX, p53, p16, HH3, pHH3, Ki67, C3, CC3, p21, WEE1, pWEE1, PDL-1 and TILS, and other markers of particular interest
Follow-up	Clinically for at least 12 weeks from start of treatment
Summary of g roup B
Setting	Postoperative patients with high-risk disease (involved resection margins +/or extracapsular nodal spread) receiving chemoradiation
Design	Modified TITE-CRM
Chemotherapy	Cisplatin 40 mg/m2 intravenous over 1 hour on day 2 of weeks 1–5 of radiotherapy
Radiotherapy	External beam radiation therapy (30 fractions over 6 weeks) to start within 3 months of surgery. Dose levels are 65 Gy for positive margin, 60 Gy to lymph node levels that have been dissected and 54 Gy to elective lymph node areas. A dose of 65 Gy may also be applied to areas of gross extracapsular spread at the discretion of the treating clinician.
AZD1775	AZD1775 PO BID for 3 days on days 2–4 of weeks 1, 2, 4 and 5 (no treatment with AZD1775 during weeks 3 and 6). Dose recommendation will be according to modified TITE-CRM model.
DLT reporting period	The minimal reporting period is 56 days (8 weeks) from start of radiotherapy, but patients will be monitored for DLTs up to 84 days (12 weeks), that is, up to 6 weeks from the end of POCRT
PK samples	Pharmacokinetic samples will be collected pre and post—the fifth dose of AZD1775 on week 1—day 4 (2 samples per patient)

DLT, dose-limiting toxicity; PD, pharmacodynamic; PK, pharmacokinetic; POCRT, postoperative chemoradiation; TITE-CRM, time-to-event continual reassessment method.