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

Study Overview
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Brief Summary
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This is a phase I, open-label study to assess the safety, tolerability, pharmacokinetics(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 to confirm the tolerability.

Detailed Description
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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.

Official Title
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A Phase I, Open-label Study to Assess the Safety, Tolerability, Pharmacokinetics and Anti-Tumour Activity of Adavosertib (AZD1775) in Monotherapy and in Combination With Chemotherapy in Japanese Patients With Advanced Solid Tumours

Conditions
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Advanced Solid Tumours

Intervention / Treatment
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* Drug: Adavosertib (AZD1775)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Adavosertib (AZD1775) monotherapy<br>Dose escalation of adavosertib monotherapy for patients with advanced solid tumours | Drug: Adavosertib (AZD1775)<br>* Adavosertib taken orally<br>|
| Experimental: Adavosertib (AZD1775) in combination with gemcitabine<br>Dose escalation of adavosertib in combination with gemcitabine for patients with advanced solid tumours | Drug: Adavosertib (AZD1775)<br>* Adavosertib taken orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse events | Investigate the safety and tolerability of adavosertib | From the informed consent to 30 days post last dose | 
| Incidence of Dose-limiting toxicity (DLTs) | Investigate the safety and tolerability of adavosertib | From the first dose of Cycle 1 up to the assessment prior to the planned first dose of Cycle 2 (each cycle is 21 days for Part A and 28 days for Part B) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma drug concentration observed (Cmax). | PK parameters will be derived using standard, non-compartmental methods | Part A:Samples will be collected on Cycle1Day1,5, C2D5, C3D5 and C5D5. Part B:Samples will be collected on C1D2,3 and even Cycle D2 for adavosertib and C1D1 for gemcitabine. (each cycle is 21 days for Part A, 28 days for Part B) | 
| Time of maximum plasma drug concentration observed (tmax). | PK parameters will be derived using standard, non-compartmental methods | Part A:Samples will be collected on Cycle1Day1,5, C2D5, C3D5 and C5D5. Part B:Samples will be collected on C1D2,3 and even Cycle D2 for adavosertib and C1D1 for gemcitabine. (each cycle is 21 days for Part A, 28 days for Part B) | 
| Area under the plasma concentration-time curve from zero to 24 hours (AUC0-24). | PK parameters will be derived using standard, non-compartmental methods | Part A:Samples will be collected on Cycle1Day1,5, C2D5, C3D5 and C5D5. Part B:Samples will be collected on C1D2,3 and even Cycle D2 for adavosertib and C1D1 for gemcitabine. (each cycle is 21 days for Part A, 28 days for Part B) | 
| trough plasma concentration (Ctrough). | PK parameters will be derived using standard, non-compartmental methods | Part A:Samples will be collected on Cycle1Day1,5, C2D5, C3D5 and C5D5. Part B:Samples will be collected on C1D2,3 and even Cycle D2 for adavosertib and C1D1 for gemcitabine. (each cycle is 21 days for Part A, 28 days for Part B) | 
| Objective response rate (ORR) | Defined as the proportion of subjects who have a best overall response of confirmed complete response (CR) or confirmed partial response (PR) | Assessed every 9 weeks in Part A and every 8 weeks in Part B with RECIST from the first dose of adavosertib until disease progression. Expected to be for up to 3 months. | 
| Disease control rate (DCR) | Defined as the proportion of subjects who have a best overall response of confirmed CR,confirmed PR, or stable disease (SD) | Assessed every 9 weeks in Part A and every 8 weeks in Part B with RECIST from the first dose of adavosertib until disease progression. Expected to be for up to 3 months. | 
| Duration of response (DoR) | Defined as the duration from the date of first documentation of response (CR or PR), which is subsequently confirmed, to the date of documented disease progression or death due to any cause in the absence of disease progression | Assessed every 9 weeks in Part A and every 8 weeks in Part B with RECIST from the first dose of adavosertib until disease progression. Expected to be for up to 3 months. | 
| Progressionfree free survival (PFS) | Defined as the time from the first dose of study treatment until the date of objective disease progression or death by any cause (in the absence of progression), regardless of whether the subject withdraws from the study or receives another anti-cancer therapy prior to progression | Assessed every 9 weeks with RECIST from the first dose of adavosertib until disease progression. Expected to be for up to 3 months. | 
| Part B: the drug interaction between adavosertib and gemcitabine. | PK parameters will be derived using standard, non-compartmental methods | Part B : Samples will be collected on Cycle 1 Day 2,3 and even Cycle Day 2 for adavosertib and Cycle 1 Day 1 for gemcitabine. (each cycle is 28 days) |