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

Advanced Solid Tumours Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04462952
• Other study ID #: D601HC00008
• Status: Completed
• Phase: Phase 1
• Start date: June 24, 2020
• Est. completion date: September 22, 2021

Study information

• Verified date: July 2022
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 6
• Est. completion date: September 22, 2021
• Est. primary completion date: September 22, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years to 120 Years

Eligibility

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

Related Conditions & MeSH terms

• Advanced Solid Tumours
• Neoplasms

Intervention

Drug:
• Adavosertib (AZD1775)
Adavosertib taken orally

Locations

Country	Name	City	State
Japan	Research Site	Chuo-ku

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Country where clinical trial is conducted

Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Part B: The ctDNA samples will be analysed for predictive biomarkers of response to treatment.	The samples may be used to develop and validate future in vitro diagnostic tests to identify patients most likely to respond to the treatment.	Part B: at screening
Other	Part B: The ctDNA samples will be used for additional exploratory research for efficacy, tolerability, or safety assessment.	These samples will be used for additional exploratory research which may include but is not limited to interrogation of changes in genetic alterations associated with response or resistance to treatment as well as the dynamics of the biomarkers on treatment and potential mechanisms of resistance to treatment.	Part B: Cycle 1 Day 1 (predose), discontinuation, and progression (each cycle is 28 days).
Other	Part A: Optional exploratory biomarker research in genetic samples from subjects who have consented to participate in the genetic analysis component of the study and exploratory biomarker research for efficacy, tolerability, or safety assessment.	To conduct potential future exploratory research into factors that may influence the progression of cancer and/or response to adavosertib.	Part A: Cycle 1 Day 1 (each cycle is 21 days).
Other	Part B:Exploratory analyses may be undertaken on the data generated from tumour tissue to identify biomarkers of sensitivity and resistance to treatment and to increase our understanding of the disease (consenting participants only.)	To conduct potential future exploratory research into factors that may influence the progression of cancer and/or response to adavosertib. This exploratory analysis may include immunological biomarkers such as PD-L1 expression and tumour infiltrating lymphocytes.	Part B: at screening
Primary	Incidence of Adverse events	Investigate the safety and tolerability of adavosertib	From the informed consent to 30 days post last dose
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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)