This is a Phase I, multi-center, dose-escalation study to assess the safety, tolerability and pharmacokinetics of oral therapy with AZD1775 (adavosertib) when combined with a fixed-dose of MEDI4736 (durvalumab). Immunogenicity, pharmacodynamics, and preliminary anti-tumour activity in patients with refractory solid tumours will also be investigated. In the initial design of this study a novel combination of AZD1775 (adavosertib) and MEDI4736 (durvalumab) was tested. The starting dose of AZD1775 (adavosertib) was 125 mg BID, over 5 days with 9 days off in 14-day cycles. This was designated Schedule A. This dose was not well tolerated. Two of six patients experienced dose limiting toxicity (DLT). The protocol was amended to include three additional dosing schedules. designated Schedules B, C, and D. In Schedule B patients will receive MEDI4736 (durvalumab) on Day 1, AZD1775 (adavosertib) on Days 15-17 and Days 22-24 of a 28-day cycle. In Schedule C, patients will receive MEDI4736 (durvalumab) on Day 1, AZD1775 (adavosertib) on Days 8-10, Days 15-17 and Days 22-24 of 28-day cycles. In Schedule D, patients will receive MEDI4736 (durvalumab) on Day 1 and AZD1775 (adavosertib) on Days 15-19 and Days 22-26 of a 28-day cycle. AZD1775 (adavosertib) will be dosed on a maximum of 6 days (Schedule B), 9 days (Schedule C), or 10 days (Schedule D) in each 28-day cycle. In all schedules, dexamethasone will be administered as an anti-emetic on the first day of each of the AZD1775 (adavosertib) consecutive dosing day blocks including the lead-in portion for Schedules B, C, and D. AZD1775 (adavosertib) will be administered at least 1 week after MEDI4736 (durvalumab) administration. Three to six patients will be enrolled in dose level 1 of Schedule B and evaluated for safety over a 28-day cycle prior to opening Schedule C dose level 1 for enrolment. Following safety evaluation of three to six patients in Schedule C dose level 1, a decision will be made by the Safety Review Team (SRT) to move forward with one or both schedules for further dose escalation. Three to six patients will be enrolled in Schedule D dose level 1 and evaluated for safety over a 28-day cycle. Patients in Schedule D will be evaluated for escalation independently of those in Schedules A, B, and C. Dose escalation will continue until identification of the Maximum Tolerated Dose (MTD). Once the MTD is determined this cohort will be expanded to a total of 18 patients to collect further safety data and for preliminary assessment of efficacy. Alternative dose levels/cohorts and/or schedules may be explored if emerging data suggest these would be more appropriate. The first day of Cycle 1 in Schedules B, C, and D will be preceded by a lead-in period of AZD1775 (adavosertib) monotherapy to enable serial sampling for assessment of pharmacokinetic parameters.
This study will assess the safety, tolerability, and pharmacokinetics of AZD1775 (adavosertib) given orally in combination with intravenous MEDI4736 (durvalumab). Secondly, the immunogenicity, pharmacodynamics, and preliminary anti-tumour activity will be determined in patients with refractory solid tumours.