Study of Adavosertib(AZD1775) in Japanese Patients With Advanced Solid Tumours

Objectives:

Primary objective:

Part A:

To assess the safety and tolerability, describe any dose-limiting toxicity (DLT) for adavosertib

Secondary objective:

To determine the PK profile of adavosertib To describe adavosertib's preliminary anti-tumour activity using the Response Evaluation Criteria in Solid Tumours (RECIST) v1.1

Part B:

To assess the safety and tolerability, describe any dose-limiting toxicity (DLT) for adavosertib in combination with gemcitabine

Secondary objective:

To determine the PK profile of adavosertib plus gemcitabine To describe preliminary anti-tumour activity of adavosertib in combination with gemcitabine using the Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 To assess the drug interaction between adavosertib and gemcitabine

Overall design:

This is a phase I, open-label study to assess the safety, tolerability, PK and anti-tumour activity of adavosertib in Japanese patients with advanced solid tumours. This study consists of 2 parts, monotherapy (part A) and chemotherapy combination (part B). At least 3, or up to 6, evaluable Japanese patients with advanced solid tumours will be enrolled in each cohort. The total number of subjects will depend upon the available data in each cohort and the Safety Review Committee (SRC)'s decision.

Number of Subjects:

At least 3, or up to 6, evaluable Japanese patients with advanced solid tumours will be enrolled in each cohort.

Treatments and treatment duration:

Subjects in each part will receive the study treatments as described below:

Part A: Adavosertib by mouth (PO) once daily (QD) for 5 days ON and 2 days OFF for week 1 and 2 of a 21 days cycle.

Part B: Adavosertib PO will be taken QD on Days 2, 3, 9, 10, 16, and 17. Gemcitabine will be administered by intravenous infusion according to institutional standards on Days 1, 8, and 15 of each 28-day cycle.

Subjects will be allowed to continue adavosertib until disease progression, intolerable toxicity, or discontinuation criteria have been met.

Major Inclusion Criteria:

• Japanese patients ≥20 years of age at the time of study entry
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0, 1
• Adequate bone marrow reserve or organ function
• Female patients who are not of child-bearing potential, and fertile females of childbearing potential who agree to use adequate contraceptive measures
• Male patients should be willing to use barrier contraception
• Predicted life expectancy ≥12 weeks
• Part A : Histologically or cytologically documented locally advanced or metastatic solid tumour, excluding lymphoma, for which standard therapy does not exist or has proven ineffective or intolerable
• Part B : Histologically or cytologically documented locally advanced or metastatic solid tumour, excluding lymphoma, for which standard therapy does not exist or has proven ineffective or intolerable and additionally, tumours for which gemcitabine is expected to be effective.
• Measurable or non-measurable disease according to RECIST v1.1

Major Exclusion Criteria:

• Use of anti-cancer treatment drug ≤21 days or 5 half-lives (whichever is shorter) prior to Cycle 1 Day 1
• Use of an investigational drug during the past 30 days or 5 half-lives (whichever is longer) prior to Cycle 1 Day 1
• Common Terminology Criteria for Adverse Events (CTCAE) Grade >1 toxicity from prior therapy
• Inability to swallow oral medication or any other condition that may impact adavosertib intake/absorption
• Known malignant central nervous system (CNS) disease other than neurologically stable, treated brain metastases
• Any of the cardiac diseases currently or within the last 6 months
• Any underlying medical condition that would impair the patient's ability to receive study treatment
• Other invasive malignancy within 5 years prior to Cycle 1 Day 1 except for non-invasive malignancies
• Part B : Presence of apparent radiological findings for interstitial pneumonitis or pulmonary fibrosis with pulmonary symptoms