Advanced or Metastatic Breast Cancer, ER+ve Advanced or Metastatic Breast Cancer
Conditions
Keywords
advanced breast cancer,, metastatic breast cancer,, ER+ve breast cancer,, Estrogen receptor positive breast cancer,, PIK3CA mutated advanced or metastatic breast cancer, AKT inhibitor
Brief summary
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
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.
Interventions
DRUGAZD5363 when combined with weekly paclitaxel.
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.
DRUGAZD5363when combined with weekly paclitaxel.
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.
DRUGA placebo in combination with weekly paclitaxel.
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.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 130 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-limiting Toxicity (DLT) Events - Part A | During Part A DLT evaluation period (Cycle 1, up to 28 days) | 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 |
| Progression Free Survival (PFS) - Part B | 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Objective Response (BOR) | From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days). | 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. |
| Overall Objective Response Rate | From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days). | 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 |
| Number of Subjects Without Progression Disease at Week 12 - Part A | up to 12 weeks | 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. |
| Change in Tumour Size at 12 Weeks | RECIST tumour assessments every 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 |
| Durable Response Rate (DRR) - Part B | From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days). | 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. |
| Overall Survival - Part B | 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). | 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. |
| Duration of Response (DOR) - Part B | From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days). | 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. |
| Objective Response Rate (ORR) at Week 12 | RECIST tumour assessments every 12 weeks | 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 |
Countries
Bulgaria, Canada, Czechia, France, Japan, Mexico, Peru, Singapore, South Korea, Spain, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part A Schedule 1 560 mg bd Schedule 1 - AZD5363 560 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks. | 12 |
| Part A Schedule 1 640 mg bd Schedule 1 - AZD5363 640 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks. | 8 |
| Part A Schedule 2 360 mg bd Schedule 2 - AZD5363 360 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks. | 5 |
| Part A Schedule 2 400 mg bd Schedule 2 - AZD5363 400 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks. | 7 |
| Part A Schedule 2 480 mg bd Schedule 2 - AZD5363 480 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks. | 6 |
| Part B AZD5363 (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly | 54 |
| Part B Placebo (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly | 56 |
| Total | 148 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 1 | 2 | 1 |
| Overall Study | Any reason not specifically recorded | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Death | 0 | 0 | 1 | 1 | 0 | 11 | 16 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Progressive disease | 6 | 3 | 4 | 5 | 5 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 1 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Part A Schedule 1 640 mg bd | Part A Schedule 2 360 mg bd | Part A Schedule 2 400 mg bd | Part A Schedule 2 480 mg bd | Part A Schedule 1 560 mg bd | Part B AZD5363 | Part B Placebo | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 58.8 Years STANDARD_DEVIATION 12.78 | 56.6 Years STANDARD_DEVIATION 10.26 | 47.1 Years STANDARD_DEVIATION 9.41 | 49.8 Years STANDARD_DEVIATION 13.12 | 52.2 Years STANDARD_DEVIATION 9.92 | 54.3 Years STANDARD_DEVIATION 10.01 | 57.4 Years STANDARD_DEVIATION 11.38 | 58.8 Years STANDARD_DEVIATION 11.24 |
| Age, Customized <50 | 3 Participants | 1 Participants | 4 Participants | 2 Participants | 5 Participants | 19 Participants | 16 Participants | 50 Participants |
| Age, Customized >=50 - <65 | 2 Participants | 3 Participants | 3 Participants | 3 Participants | 5 Participants | 24 Participants | 26 Participants | 66 Participants |
| Age, Customized >=65 | 3 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 11 Participants | 14 Participants | 32 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 15 Participants | 16 Participants | 31 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 12 Participants | 15 Participants | 28 Participants |
| Race/Ethnicity, Customized Black Or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 7 Participants | 10 Participants |
| Race/Ethnicity, Customized White | 8 Participants | 5 Participants | 7 Participants | 6 Participants | 10 Participants | 24 Participants | 18 Participants | 78 Participants |
| Sex: Female, Male Female | 8 Participants | 5 Participants | 7 Participants | 6 Participants | 12 Participants | 54 Participants | 56 Participants | 148 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 8 | 1 / 5 | 1 / 7 | 0 / 6 | 13 / 54 | 15 / 56 |
| other Total, other adverse events | 12 / 12 | 8 / 8 | 5 / 5 | 7 / 7 | 6 / 6 | 50 / 54 | 48 / 55 |
| serious Total, serious adverse events | 3 / 12 | 3 / 8 | 0 / 5 | 1 / 7 | 4 / 6 | 13 / 54 | 8 / 55 |
Outcome results
Primary
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
Time frame: During Part A DLT evaluation period (Cycle 1, up to 28 days)
Population: All Part A patients who either completed the DLT evaluation period with at least 80% of specified dose (of AZD5363 or paxlitaxel) or who experienced a DLT. DLT events were not assessed for Part B participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A Schedule 1 560 mg bd | Dose-limiting Toxicity (DLT) Events - Part A | 0 participants |
| Part A Schedule 1 640 mg bd | Dose-limiting Toxicity (DLT) Events - Part A | 2 participants |
| Part A Schedule 2 360 mg bd | Dose-limiting Toxicity (DLT) Events - Part A | 0 participants |
| Part A Schedule 2 400 mg bd | Dose-limiting Toxicity (DLT) Events - Part A | 0 participants |
| Part A Schedule 2 480 mg bd | Dose-limiting Toxicity (DLT) Events - Part A | 2 participants |
Primary
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.
Time frame: 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)
Population: Intent to Treat (ITT), all randomised patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part B AZD5363 | Progression Free Survival (PFS) - Part B | 10.9 Months |
| Part B Placebo | Progression Free Survival (PFS) - Part B | 8.4 Months |
p-value: 0.30880% CI: [0.6, 1.06]Regression, Cox
Secondary
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.
Time frame: From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A Schedule 1 560 mg bd | Best Objective Response (BOR) | Stable Disease (SD) | 7 Participants |
| Part A Schedule 1 560 mg bd | Best Objective Response (BOR) | Complete Response (CR) | 0 Participants |
| Part A Schedule 1 560 mg bd | Best Objective Response (BOR) | Not Evaluable (NE) | 1 Participants |
| Part A Schedule 1 560 mg bd | Best Objective Response (BOR) | Partial Response (PR) | 0 Participants |
| Part A Schedule 1 560 mg bd | Best Objective Response (BOR) | Progression | 4 Participants |
| Part A Schedule 1 640 mg bd | Best Objective Response (BOR) | Not Evaluable (NE) | 1 Participants |
| Part A Schedule 1 640 mg bd | Best Objective Response (BOR) | Progression | 1 Participants |
| Part A Schedule 1 640 mg bd | Best Objective Response (BOR) | Stable Disease (SD) | 4 Participants |
| Part A Schedule 1 640 mg bd | Best Objective Response (BOR) | Partial Response (PR) | 2 Participants |
| Part A Schedule 1 640 mg bd | Best Objective Response (BOR) | Complete Response (CR) | 0 Participants |
| Part A Schedule 2 360 mg bd | Best Objective Response (BOR) | Partial Response (PR) | 1 Participants |
| Part A Schedule 2 360 mg bd | Best Objective Response (BOR) | Not Evaluable (NE) | 0 Participants |
| Part A Schedule 2 360 mg bd | Best Objective Response (BOR) | Stable Disease (SD) | 3 Participants |
| Part A Schedule 2 360 mg bd | Best Objective Response (BOR) | Progression | 1 Participants |
| Part A Schedule 2 360 mg bd | Best Objective Response (BOR) | Complete Response (CR) | 0 Participants |
| Part A Schedule 2 400 mg bd | Best Objective Response (BOR) | Stable Disease (SD) | 4 Participants |
| Part A Schedule 2 400 mg bd | Best Objective Response (BOR) | Complete Response (CR) | 0 Participants |
| Part A Schedule 2 400 mg bd | Best Objective Response (BOR) | Partial Response (PR) | 1 Participants |
| Part A Schedule 2 400 mg bd | Best Objective Response (BOR) | Progression | 1 Participants |
| Part A Schedule 2 400 mg bd | Best Objective Response (BOR) | Not Evaluable (NE) | 1 Participants |
| Part A Schedule 2 480 mg bd | Best Objective Response (BOR) | Complete Response (CR) | 0 Participants |
| Part A Schedule 2 480 mg bd | Best Objective Response (BOR) | Not Evaluable (NE) | 1 Participants |
| Part A Schedule 2 480 mg bd | Best Objective Response (BOR) | Stable Disease (SD) | 3 Participants |
| Part A Schedule 2 480 mg bd | Best Objective Response (BOR) | Progression | 2 Participants |
| Part A Schedule 2 480 mg bd | Best Objective Response (BOR) | Partial Response (PR) | 0 Participants |
| Part B AZD5363 | Best Objective Response (BOR) | Complete Response (CR) | 3 Participants |
| Part B AZD5363 | Best Objective Response (BOR) | Not Evaluable (NE) | 2 Participants |
| Part B AZD5363 | Best Objective Response (BOR) | Progression | 6 Participants |
| Part B AZD5363 | Best Objective Response (BOR) | Partial Response (PR) | 29 Participants |
| Part B AZD5363 | Best Objective Response (BOR) | Stable Disease (SD) | 14 Participants |
| Part B Placebo | Best Objective Response (BOR) | Progression | 8 Participants |
| Part B Placebo | Best Objective Response (BOR) | Partial Response (PR) | 28 Participants |
| Part B Placebo | Best Objective Response (BOR) | Stable Disease (SD) | 14 Participants |
| Part B Placebo | Best Objective Response (BOR) | Complete Response (CR) | 4 Participants |
| Part B Placebo | Best Objective Response (BOR) | Not Evaluable (NE) | 2 Participants |
Secondary
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
Time frame: RECIST tumour assessments every 12 weeks
Population: Part A:Full Analysis Set (FAS) Part B: Intent to Treat (ITT)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A Schedule 1 560 mg bd | Change in Tumour Size at 12 Weeks | -11.0 % change from baseline | Standard Deviation 33.42 |
| Part A Schedule 1 640 mg bd | Change in Tumour Size at 12 Weeks | -15.7 % change from baseline | Standard Deviation 13.33 |
| Part A Schedule 2 360 mg bd | Change in Tumour Size at 12 Weeks | -19.1 % change from baseline | Standard Deviation 17.73 |
| Part A Schedule 2 400 mg bd | Change in Tumour Size at 12 Weeks | -18.3 % change from baseline | Standard Deviation 37.74 |
| Part A Schedule 2 480 mg bd | Change in Tumour Size at 12 Weeks | -10.2 % change from baseline | Standard Deviation 24.84 |
| Part B AZD5363 | Change in Tumour Size at 12 Weeks | -34.2 % change from baseline | Standard Deviation 28.91 |
| Part B Placebo | Change in Tumour Size at 12 Weeks | -25.4 % change from baseline | Standard Deviation 35.87 |
p-value: 0.08180% CI: [-17.1, -0.8]ANCOVA
Secondary
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.
Time frame: From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).
Population: Part B, ITT analysis set. Not collected in Part A
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part B AZD5363 | Durable Response Rate (DRR) - Part B | 48.1 % of participants |
| Part B Placebo | Durable Response Rate (DRR) - Part B | 37.5 % of participants |
p-value: 0.13980% CI: [0.93, 2.54]Regression, Logistic
Secondary
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.
Time frame: From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).
Population: Part B, all patients with a response in the ITT analysis set. Not collected in Part A
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part B AZD5363 | Duration of Response (DOR) - Part B | 8.3 Months |
| Part B Placebo | Duration of Response (DOR) - Part B | 8.2 Months |
Secondary
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.
Time frame: up to 12 weeks
Population: Part A Full Analysis Set (FAS). Not recorded in Part B.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A Schedule 1 560 mg bd | Number of Subjects Without Progression Disease at Week 12 - Part A | 6 Participants |
| Part A Schedule 1 640 mg bd | Number of Subjects Without Progression Disease at Week 12 - Part A | 5 Participants |
| Part A Schedule 2 360 mg bd | Number of Subjects Without Progression Disease at Week 12 - Part A | 3 Participants |
| Part A Schedule 2 400 mg bd | Number of Subjects Without Progression Disease at Week 12 - Part A | 4 Participants |
| Part A Schedule 2 480 mg bd | Number of Subjects Without Progression Disease at Week 12 - Part A | 2 Participants |
Secondary
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
Time frame: RECIST tumour assessments every 12 weeks
Population: Part A:Full Analysis Set (FAS) Part B: Intent to Treat (ITT)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A Schedule 1 560 mg bd | Objective Response Rate (ORR) at Week 12 | 41.7 % of participants |
| Part A Schedule 1 640 mg bd | Objective Response Rate (ORR) at Week 12 | 12.5 % of participants |
| Part A Schedule 2 360 mg bd | Objective Response Rate (ORR) at Week 12 | 0 % of participants |
| Part A Schedule 2 400 mg bd | Objective Response Rate (ORR) at Week 12 | 0 % of participants |
| Part A Schedule 2 480 mg bd | Objective Response Rate (ORR) at Week 12 | 0 % of participants |
| Part B AZD5363 | Objective Response Rate (ORR) at Week 12 | 50 % of participants |
| Part B Placebo | Objective Response Rate (ORR) at Week 12 | 42.9 % of participants |
Secondary
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
Time frame: From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).
Population: Part A:Full Analysis Set (FAS) Part B: Intent to Treat (ITT)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A Schedule 1 560 mg bd | Overall Objective Response Rate | 0 % of participants |
| Part A Schedule 1 640 mg bd | Overall Objective Response Rate | 25 % of participants |
| Part A Schedule 2 360 mg bd | Overall Objective Response Rate | 20 % of participants |
| Part A Schedule 2 400 mg bd | Overall Objective Response Rate | 14.3 % of participants |
| Part A Schedule 2 480 mg bd | Overall Objective Response Rate | 0 % of participants |
| Part B AZD5363 | Overall Objective Response Rate | 59.3 % of participants |
| Part B Placebo | Overall Objective Response Rate | 57.1 % of participants |
Secondary
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.
Time frame: 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).
Population: Part B Intent to Treat (ITT). Not collected in Part A
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part B AZD5363 | Overall Survival - Part B | 32.8 months |
| Part B Placebo | Overall Survival - Part B | NA months |
p-value: 0.48280% CI: [0.48, 1.24]Log Rank