A Phase 1 Study of AZD9833 in Japanese Women With ER Positive, HER2 Negative Advanced Breast Cancer

Study Overview
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Brief Summary
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This is a Phase 1, open-label study designed to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of AZD9833 in Japanese women with endocrineresistant ER+ HER2- breast cancer that is not amenable to treatment with curative intent. This study consists of 2 cohorts, Cohort1 and Cohort2. In cohort 1 (for tolerability evaluation), a minimum of 3, or up to 6, evaluable Japanese patients with ER+ HER2- breast cancer will be enrolled. In cohort 2 (for exploratory research), at least 6 to maximum 12 evaluable Japanese patients with ER+ HER2- breast cancer will be enrolled.

Detailed Description
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Objectives: Primary objective: To investigate the safety and tolerability of AZD9833 in Japanese women with ER+ HER2- advanced breast cancer Secondary objective: To assess the anti-tumor activity and efficacy of AZD9833 Exploratory objectives: To investigate AZD9833 activity in tumor cells Overall design: This is a Phase 1, open-label study designed to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of AZD9833 in Japanese women with endocrineresistant ER+ HER2- breast cancer that is not amenable to treatment with curative intent. Eligible patients will receive AZD9833. In cohort 1 (for tolerability evaluation), a minimum of 3 to maximum 6 evaluable patients will be enrolled. For cohort 2, if paired biopsy after administration of the study drug becomes inoperable during administration of the study drug, additional subjects can be added to obtain an evaluable biopsy sample. In cohort 2 (for exploratory research), eligible patients will receive AZD9833 once daily and at least 6 to maximum 12 patients will be enrolled. In cohort 2, paired biopsy sample will be collected from at least 6 and maximum 12 patients. If paired biopsy after administration of the study drug becomes inoperable during administration of the study drug, additional subjects can be added to obtain an evaluable biopsy sample. Number of Subjects: Maximum 18 evaluable subjects will be enrolled in this study.

Official Title
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A Phase 1, Open-label Study to Assess the Safety, Tolerability, Pharmacokinetics and Anti- Tumor Activity of AZD9833 in Japanese Women With ER Positive, HER2 Negative Advanced Breast Cancer

Conditions
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ER+ HER2- Advanced Breast Cancer

Intervention / Treatment
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* Drug: AZD9833


Participation Criteria
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Eligibility Criteria
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Major Inclusion Criteria: Signed written informed consent. >= 20 years. Any menopausal status: Pre and Post menopausal defined according to standard criteria in the protocol. Histological or cytological confirmation of adenocarcinoma of the breast. Documented positive estrogen receptor status of primary or metastatic tumor tissue, according to the local laboratory parameters. HER-2 negative. Metastatic or locoregionally recurrent disease and radiological or objective evidence of progression on or after the last systemic therapy prior to starting IMP. Prior chemotherapy, endocrine therapy and other therapy in the advanced setting is restricted as follows: No more than 2 lines of chemotherapy for advanced disease. Recurrence or progression on at least one line of endocrine therapy in the advanced/metastatic disease setting. There is no limit on the number of lines of prior endocrine therapies. Prior treatment with CDK4/6 inhibitors is permitted. At least one lesion (measurable and/or non-measurable, as per RECIST 1.1) that can be accurately assessed at baseline and is suitable for repeated assessment by computed tomography (CT), magnetic resonance imaging (MRI), or plain X-ray; or clinical examination. Eastern Cooperative Oncology Group (ECOG)/World Health Organisation (WHO) performance status 0 to 1 Major Exclusion Criteria: Intervention with any of the following: Any cytotoxic chemotherapy, investigational agents, or other anti-cancer drugs for the treatment of advanced breast cancer from a previous treatment regimen or clinical study within 14 days of the first dose of study treatment. Medications or herbal supplements known to be strong inhibitors/inducers of cytochrome P450 (CYP) 3A4/5 sensitive CYP2B6 substrates and drugs which are substrates of CYP2C9 and/or CYP2C19. Drugs that are known to prolong QT and have a known risk of Torsades de Pointes. Radiotherapy with a limited field of radiation for palliation within one week of the first dose of IMP, radiotherapy to more than 30% of the bone marrow or a wide field of radiation within 4 weeks of the first dose of IMP. Major surgical procedure or significant traumatic injury. Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting IMP. Presence of life-threatening metastatic visceral disease. Evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses. Refractory nausea and vomiting, uncontrolled chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of AZD9833. History of another primary malignancy. Male subjects are excluded from this study. History of hypersensitivity to active or inactive excipients of AZD9833. The following cardiovascular criteria: QTcF >470 ms, resting heart rate <45 bpm, clinically significant abnormalities of resting electrocardiogram, uncontrolled hypertension, symptomatic hypotension, factors that increase the risk for QTc prolongation, left ventricular ejection fraction <50%. Inadequate bone marrow reserve or organ function Involvement in the planning and conduct of the study. Judgment by the investigator that the patient should not participate in the study.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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Female

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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD9833 monotherapy<br>Dose escalation of AZD9833 monotherapy for patients with ER+ HER2- advanced breast cancer | Drug: AZD9833<br>* AZD9833 taken orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of subjects with dose-limiting toxicity, as defined in the protocol. | Dose-limiting toxicity as described in the protocol that is not related to disease progression, intercurrent illness or concomitant medications and that, despite optimal therapeutic intervention, meets protocol-defined criteria. | From the first dose of study treatment up to and including Cycle1 Day28. | 
| The number of subjects with treatment-related adverse events as assessed by CTCAE v5.0. | Safety data will be assessed as the number of subjects with treatment-related adverse events. | Minimum observation period 28 days on treatment or 28 days with at least 75% of the required dose and will continue until the subject is off the study (approximately 1 year). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | Antitumour activity by evaluation of tumour response assessments using Response Evaluation Criteria in Solid Tumours (RECIST 1.1) | At Cycle3 Day1, Cycle5 Day1, Cycle7 Day1 (each cycle is 28 days) and every 12 weeks until the end of the study (approximately 1 year). | 
| Duration of Response | Antitumour activity by evaluation of tumour response assessments using Response Evaluation Criteria in Solid Tumours (RECIST 1.1) | At Cycle3 Day1, Cycle5 Day1, Cycle7 Day1 (each cycle is 28 days) and every 12 weeks until the end of the study (approximately 1 year). | 
| Clinical benefit rate at 24 weeks | Antitumour activity by evaluation of tumour response assessments using Response Evaluation Criteria in Solid Tumours (RECIST 1.1) | Up to 24 weeks | 
| Percentage Change in Tumour Size | Antitumour activity by evaluation of tumour response assessments using Response Evaluation Criteria in Solid Tumours (RECIST 1.1) | At Cycle3 Day1, Cycle5 Day1, Cycle7 Day1 (each cycle is 28 days) and every 12 weeks until the end of the study (approximately 1 year). | 
| Progression Free Survival | Antitumour activity by evaluation of tumour response assessments using Response Evaluation Criteria in Solid Tumours (RECIST 1.1) | Up to objective disease progression or death (approximately 1 year). | 
| Maximum Observed Plasma Concentration (Cmax) of AZD9833 | Blood samples will be collected to assess plasma concentrations of AZD9833 at a series of timepoints to derive Cmax | At predefined intervals throughout the AZD9833 treatment period (approximately 12 weeks ) | 
| Time to observed Cmax (Tmax) for AZD9833 | Blood samples will be collected to assess plasma concentrations of AZD9833 at a series of timepoints to derive Tmax | At predefined intervals throughout the AZD9833 treatment period (approximately 12 weeks ) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer, Phase 1, Safety, Tolerability, Pharmacokinetics, ER Positive, HER2 Negative, Advanced Breast Cancer