Investigating Safety, Tolerability and Efficacy of AZD5363 When Combined With Paclitaxel in Breast Cancer Patients

Study Overview
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Brief Summary
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The purpose of this study is to investigate the safety and efficacy of different doses and schedules of AZD5363, when in combination with paclitaxel, in treatment of patients with advanced or metastatic breast cancer. Also to investigate a selected dose and schedule of AZD5363 in combination with paclitaxel vs. paclitaxel in combination with placebo in treatment of patients with estrogen receptor-positive advanced or metastatic breast cancer, including a subgroup who have the phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA) tumour mutation.

Detailed Description
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This is a Phase I/II multicentre, study investigating the safety, tolerability and efficacy of a twice-daily oral formulation of AZD5363 when combined with a weekly intravenous paclitaxel infusion in patients with advanced or metastatic breast cancer. Study treatment is given in 28-day cycles, comprising three weeks on-therapy followed by one week off-therapy. The study will be conducted in two parts: Part A. Approximately 40 patients will be recruited to this Phase I multiple ascending-dose safety run-in evaluation of each of two intermittent dosing schedules (2 days per week or 4 days per week) of AZD5363 given in combination with weekly paclitaxel. The study population is female patients, 18 years or older, with advanced or metastatic breast cancer. The purpose of Part A is to assess the comparative safety, tolerability, pharmacokinetics and preliminary efficacy of both schedules to determine one dose and schedule of AZD5363 to take forward to study Part B in combination with weekly paclitaxel. Part A assessments will be made in dose-escalating cohorts of 3 to 6 patients to determine a recommended dose in each of the schedules. A total of 6 patients must be evaluated at a selected dose level for it to be confirmed as the recommended dose. All dose evaluations and recommendations will be conducted by a Safety Review Committee. Part A Patients will undergo assessments up to to withdrawal from the study or to discontinuation of study therapy. Part B. A minimum of 100 patients will be recruited to this Phase II double-blind, placebo-controlled, stratified and randomised evaluation of two treatment regimens: AZD5363 (at a dose selected and schedule from Part A) in combination with weekly paclitaxel vs. weekly paclitaxel plus placebo. The study population is female patients with Estrogen Receptor Positive advanced or metastatic breast cancer; of which approximately 50 will have the phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA) mutation. Part B patients will be stratified by PIK3CA tumour mutation status as: tumour mutation positive or tumour mutation not-detected. Under each stratum patients will be randomised to receive either paclitaxel + AZD5363 or paclitaxel + placebo. The purpose of Part B is to assess relative efficacy of both active and placebo regimens by comparison of: progression-free survival, overall survival, tumour response, safety and tolerability in the overall ER+ve advanced or metastatic breast cancer population, and in a subgroup of these patients with the PIK3CA tumour mutation. Patient safety and therapy tolerability will be monitored by an independent Safety Review Committee throuighout the course of Part B. Part B patients will be followed for assessment of overall survival, or to withdrawal from the study.

Official Title
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A Phase I/II Study of AZD5363 Combined With Paclitaxel in Patients With Advanced or Metastatic Breast Cancer. Comprising a Safety Run-In and a Placebo-controlled Randomised Expansion in ER+ve Patients Stratified by PIK3CA Mutation Status

Conditions
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Advanced or Metastatic Breast Cancer, ER+ve Advanced or Metastatic Breast Cancer

Intervention / Treatment
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* Drug: AZD5363 when combined with weekly paclitaxel.
* Drug: AZD5363 when combined with weekly paclitaxel.
* Drug: AZD5363when combined with weekly paclitaxel.
* Drug: A placebo in combination with weekly paclitaxel.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of informed consent. Female patient. Aged at least 18 years. Histological or cytological confirmation of breast cancer with evidence of advanced or metastatic disease (must be ER+ve, HER2-ve, in Part B). World Health Organisation (WHO) performance status 0-1 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks. Exclusion Criteria: Clinically significant abnormalities of glucose metabolism. Spinal cord compression or brain metastases unless asymptomatic, treated and stable (not requiring steroids). Evidence of severe or uncontrolled systemic diseases, including active bleeding diatheses or active infections including hepatitis B, C and HIV. Any prior exposure to agents which inhibit AKT as the primary pharmacological activity. Part A: more than two prior courses of chemotherapy (including taxanes) for advanced or metastatic breast cancer. Part B: any prior chemotherapy for advanced or metastatic breast cancer.

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Intermittent schedule (2/5)<br>See intervention description below. | Drug: AZD5363 when combined with weekly paclitaxel.<br>* AZD5363: oral capsule, twice daily in a weekly 2 days on-treatment, 5 days-off, schedule. Treatment to begin the day following the first dose of paclitaxel and to continue until treatment withdrawal. Paclitaxel: intravenously once a week. AZD5363 and paclitaxel will be received for 3 consecutive weeks, followed by one week off-therapy in 4-week cycles.<br>|
| Experimental: Part A: Intermittent schedule (4/3)<br>See intervention description below. | Drug: AZD5363 when combined with weekly paclitaxel.<br>* AZD5363: oral capsule, twice daily in a weekly 4 days on-treatment, 3 days-off, schedule. Treatment to begin the day following the first dose of paclitaxel and to continue until treatment withdrawal. Paclitaxel: intravenously once a week. AZD5363 and paclitaxel will be received for 3 consecutive weeks, followed by one week off-therapy in 4-week cycles.<br>|
| Active Comparator: Part B: AZD5363 combined with paclitaxel<br>See intervention description below. | Drug: AZD5363when combined with weekly paclitaxel.<br>* Either a 2/5 or 3/4 intermittent dosing schedule of AZD5363 based on the outcome of Part A. Dosage: oral formulation, twice daily. Treatment to begin the day following the first dose of paclitaxel and to continue until treatment withdrawal. Paclitaxel: intravenously once a week. AZD5363 and paclitaxel will be received for 3 consecutive weeks, followed by one week off-therapy in 4-week cycles.<br>|
| Placebo Comparator: Part B: paclitaxel combined with placebo<br>See intervention description below. | Drug: A placebo in combination with weekly paclitaxel.<br>* Either a 2/5 or 3/4 intermittent dosing schedule of placebo matched to AZD5363 based on the outcome of Part A. Dosage: oral formulation, twice daily. Treatment to begin the day following the first dose of paclitaxel and to continue until treatment withdrawal. Paclitaxel: intravenously once a week. placebo and paclitaxel will be received for 3 consecutive weeks, followed by one week off-therapy in 4-week cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting Toxicity (DLT) Events - Part A | An Adverse Event (AE) or laboratory abnormality considered to be related to study drug, that starts at any time during the DLT evaluation period (Cycle 1) and is dose limiting | During Part A DLT evaluation period (Cycle 1, up to 28 days) | 
| Progression Free Survival (PFS) - Part B | Time from randomisation to date of objective disease progression or death (by any cause in the absence of progression). Progression defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a >= 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on the study, and an absolute increase of >=5mm, or progression of non-target lesions or the appearance of new lesions. | From randomisation date to date of objective disease progression or death (by any cause) whichever came first, assessed every 12 wks (median total treatment duration AZD5363=325.5 days; Placebo=245 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Tumour Size at 12 Weeks | Percentage change from baseline to week 12 in sum of longest diameters of target lesions as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1). Based on patients with measurable disease who had sufficient data available to either calculate or impute a change at 12 weeks | RECIST tumour assessments every 12 weeks | 
| Objective Response Rate (ORR) at Week 12 | Percentage of patients who have at least one visit response of Complete Response or Partial Response prior to any evidence of progression at week 12 as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm; Objective Response Rate (ORR) = CR + PR | RECIST tumour assessments every 12 weeks | 
| Best Objective Response (BOR) | Number of patients, taking their BOR, which is their best objective tumour response based on RECIST measurements throughout the whole study as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm. | From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days). | 
| Overall Objective Response Rate | Percentage of patients, taking their best objective tumour response based on RECIST measurements throughout the whole study as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm. Overall Response Rate (ORR) = CR + PR | From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days). | 
| Number of Subjects Without Progression Disease at Week 12 - Part A | Percentage of patients with a 12 week visit response of CR, PR or SD (as defined by RECIST 1.1) with no evidence of previous progression as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm. | up to 12 weeks | 
| Duration of Response (DOR) - Part B | Date of first documentation of response (Complete Response/Partial Response) until the date of disease progression as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm.. If a subject does not progress following a response, then their DOR will use the PFS censoring time. | From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days). | 
| Durable Response Rate (DRR) - Part B | Percentage of patients who have a Complete Response (CR) or Partial Response (PR) lasting continuously for at least 24 weeks as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: PR, >=30% decrease in the sum of the longest diameter of target lesions; CR, disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm. | From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days). | 
| Overall Survival - Part B | The interval between the date of randomisation and the date of patient death due to any cause. All Part B patients were analysed, number of deaths is presented. | From date of randomisation, assessed every 12 weeks, up until the time of final statistical analysis. (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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advanced breast cancer,, metastatic breast cancer,, ER+ve breast cancer,, Estrogen receptor positive breast cancer,, PIK3CA mutated advanced or metastatic breast cancer, AKT inhibitor