Breast Cancer, Prostate Cancer, Bone Neoplasms
Conditions
Keywords
breast cancer, prostate cancer, metastatic bone disease, Subjects with breast cancer or prostate cancer with metastatic bone disease
Brief summary
The purpose of this study is to determine the effect of AZD0530 on subjects with breast cancer or prostate cancer with metastatic bone disease in comparison to zoledronic acid.
Interventions
DRUGAZD0530
Daily oral dose
DRUGZoledronic Acid
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects 18 years or older with Prostate Cancer or Breast Cancer with Metastatic Bone Disease Have evidence of recurrence or disease progression * At least one radiographically confirmed metastatic bone lesion * No change of cancer therapy for at least 8 weeks before randomization
Exclusion criteria
* Have had any prior exposure to bisphosphonate * Have had hip fractures or bilateral hip prothesis fracture of any kind or surgery to bone within the past 12 months * Inadequate renal function or low haemoglobin * Inadequate liver function as demonstrated by serum bilirubin ≥2 times the upper limits of reference range (ULRR) or by alanine aminotransferase (ALT), aspartate aminotransferase(AST) or ALP ≥2.5 times the ULRR (≥5 times the ULRR in the presence of liver metastases). If bone metastases are present and liver function is otherwise considered adequate by the investigator then elevated ALP will not exclude the patient.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Baseline in Serum Beta C-terminal Cross-linking Telopeptide of Type I Collagen (betaCTX) at Week 4 | Baseline to Week 4 | Result at Week 4 minus result at baseline as a percentage of the result at baseline, based on log transformed data. Back transformation of the least squares (LS) mean. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Baseline in Serum Cross-linked C-terminal Telopeptide of Type I Collagen (ICTP) at Week 4 | Baseline to Week 4 | Result at Week 4 minus result at baseline as a percentage of the result at baseline, based on log transformed data. Back transformation of the least squares (LS) mean. |
| Percentage Change From Baseline in Serum N-terminal Propeptide of Type I Procollagen (PINP) at Week 4 | Baseline to Week 4 | Result at Week 4 minus result at baseline as a percentage of the result at baseline, based on log transformed data. Back transformation of the least squares (LS) mean. |
| Percentage Change From Baseline in Serum Tartrate-resistant Acid Phosphatase 5b (TRAP5b) at Week 4 | Baseline to Week 4 | Result at Week 4 minus result at baseline as a percentage of the result at baseline, based on log transformed data. Back transformation of the least squares (LS) mean. |
| Percentage Change From Baseline in Urine N-terminal Cross-linking Telopeptide of Type I Collagen Normalised to Creatinine (NTx/Cr) at Week 4 | Baseline to Week 4 | Result at Week 4 minus result at baseline as a percentage of the result at baseline, based on log transformed data. Back transformation of the least squares (LS) mean. |
| Percentage Change From Baseline in Urine Alpha-alpha C-terminal Cross-linking Telopeptide of Type I Collagen Normalised to Creatinine (aaCTx/Cr) at Week 4 | Baseline to Week 4 | Result at Week 4 minus result at baseline as a percentage of the result at baseline, based on log transformed data. Back transformation of the least squares (LS) mean. |
| Saracatinib: Area Under the Curve at Steady State (AUCss) | Pre-dose on days 8, 15, 29; 2 hours, 4 hours, 6 hours, 9 hours post dose on day 29 | Previous studies have shown that saracatinib reduces osteoclast function and bone resorption. Bone turnover, the combined result of bone formation and bone resorption, can be assessed in real time by measuring specific markers of bone turnover in serum and in urine. These markers were assessed in a study of patients with metastatic bone disease treated with saracatinib. Specific assays are available to quantitate these markers in serum and urine. In this study the effects of saracatinib on bone turnover were compared with the effects of zoledronic acid, a marketed drug known to inhibit bone resorption in cancer patients with bone metastatses. |
| Saracatinib: Plasma Clearance at Steady State (CLss/F) | Pre-dose on days 8, 15, 29; 2 hours, 4 hours, 6 hours, 9 hours post dose on day 29 | — |
| Percentage Change From Baseline in Serum Bone-specific Alkaline Phosphatase (bALP) at Week 4 | Baseline to Week 4 | Result at Week 4 minus result at baseline as a percentage of the result at baseline, based on log transformed data. Back transformation of the least squares (LS) mean. |
| Saracatinib: Minimum Plasma Concentration at Steady State (Css,Min) | Pre-dose on days 8, 15, 29; 2 hours, 4 hours, 6 hours, 9 hours post dose on day 29 | — |
| Saracatinib: Time to Cssmax (Tmax) | Pre-dose on days 8, 15, 29; 2 hours, 4 hours, 6 hours, 9 hours post dose on day 29 | — |
| N-desmethyl Metabolite of Saracatinib: Area Under the Curve at Steady State (AUCss) | Pre-dose on days 8, 15, 29; 2 hours, 4 hours, 6 hours, 9 hours post dose on day 29 | — |
| N-desmethyl Metabolite of Saracatinib: Maximum Plasma Concentration at Steady State (Css,Max) | Pre-dose on days 8, 15, 29; 2 hours, 4 hours, 6 hours, 9 hours post dose on day 29 | — |
| N-desmethyl Metabolite of Saracatinib: Minimum Plasma Concentration at Steady State (Css,Min) | Pre-dose on days 8, 15, 29; 2 hours, 4 hours, 6 hours, 9 hours post dose on day 29 | — |
| N-desmethyl Metabolite of Saracatinib: AUCss Metabolite to Parent Ratio | Pre-dose on days 8, 15, 29; 2 hours, 4 hours, 6 hours, 9 hours post dose on day 29 | — |
| N-desmethyl Metabolite of Saracatinib: Time to Cssmax (Tmax) | Pre-dose on days 8, 15, 29; 2 hours, 4 hours, 6 hours, 9 hours post dose on day 29 | — |
| Saracatinib: Maximum Plasma Concentration at Steady State (Css,Max) | Pre-dose on days 8, 15, 29; 2 hours, 4 hours, 6 hours, 9 hours post dose on day 29 | — |
Countries
Canada, Denmark, Norway, Portugal, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Randomised=full analysis set: AZD0530 175mg=69, Zoledronic acid 4mg=70; safety set: AZD0530 175mg=68, Zoledronic acid 4mg=69
Participants by arm
| Arm | Count |
|---|---|
| AZD0530 175 mg AZD0530 (saracatinib) 175 mg once daily | 69 |
| Zoledronic Acid 4 mg Zoledronic Acid 4 mg on Day 1 of the 4-week treatment period | 70 |
| Total | 139 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 10 | 0 |
| Overall Study | AZ study team decision | 0 | 1 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Dev. of study specific discon. criteria | 1 | 0 |
| Overall Study | Incorrectly enrolled | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | AZD0530 175 mg | Zoledronic Acid 4 mg | Total |
|---|---|---|---|
| Age Continuous | 67.6 Years STANDARD_DEVIATION 8.35 | 67.3 Years STANDARD_DEVIATION 11.58 | 67.4 Years STANDARD_DEVIATION 10.07 |
| Sex: Female, Male Female | 11 Participants | 12 Participants | 23 Participants |
| Sex: Female, Male Male | 58 Participants | 58 Participants | 116 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 51 / 68 | 46 / 69 |
| serious Total, serious adverse events | 11 / 68 | 4 / 69 |
Outcome results
Primary
Percentage Change From Baseline in Serum Beta C-terminal Cross-linking Telopeptide of Type I Collagen (betaCTX) at Week 4
Result at Week 4 minus result at baseline as a percentage of the result at baseline, based on log transformed data. Back transformation of the least squares (LS) mean.
Time frame: Baseline to Week 4
Population: The number of participants analyzed reflected the number of paired serum samples per participant that yielded valid assay results, not the total number of participants or completers. The number of evaluable paired serum samples will therefore be a subset of the total number of participants.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| AZD0530 175 mg | Percentage Change From Baseline in Serum Beta C-terminal Cross-linking Telopeptide of Type I Collagen (betaCTX) at Week 4 | -71.1 Percentage change in betaCTX |
| Zoledronic Acid 4 mg | Percentage Change From Baseline in Serum Beta C-terminal Cross-linking Telopeptide of Type I Collagen (betaCTX) at Week 4 | -68.4 Percentage change in betaCTX |
Secondary
N-desmethyl Metabolite of Saracatinib: Area Under the Curve at Steady State (AUCss)
Time frame: Pre-dose on days 8, 15, 29; 2 hours, 4 hours, 6 hours, 9 hours post dose on day 29
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD0530 175 mg | N-desmethyl Metabolite of Saracatinib: Area Under the Curve at Steady State (AUCss) | 1069 ng.h/ml |
Secondary
N-desmethyl Metabolite of Saracatinib: AUCss Metabolite to Parent Ratio
Time frame: Pre-dose on days 8, 15, 29; 2 hours, 4 hours, 6 hours, 9 hours post dose on day 29
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD0530 175 mg | N-desmethyl Metabolite of Saracatinib: AUCss Metabolite to Parent Ratio | 0.1420 Ratio |
Secondary
N-desmethyl Metabolite of Saracatinib: Maximum Plasma Concentration at Steady State (Css,Max)
Time frame: Pre-dose on days 8, 15, 29; 2 hours, 4 hours, 6 hours, 9 hours post dose on day 29
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD0530 175 mg | N-desmethyl Metabolite of Saracatinib: Maximum Plasma Concentration at Steady State (Css,Max) | 62.80 ng/ml |
Secondary
N-desmethyl Metabolite of Saracatinib: Minimum Plasma Concentration at Steady State (Css,Min)
Time frame: Pre-dose on days 8, 15, 29; 2 hours, 4 hours, 6 hours, 9 hours post dose on day 29
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD0530 175 mg | N-desmethyl Metabolite of Saracatinib: Minimum Plasma Concentration at Steady State (Css,Min) | 34.30 ng/ml |
Secondary
N-desmethyl Metabolite of Saracatinib: Time to Cssmax (Tmax)
Time frame: Pre-dose on days 8, 15, 29; 2 hours, 4 hours, 6 hours, 9 hours post dose on day 29
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD0530 175 mg | N-desmethyl Metabolite of Saracatinib: Time to Cssmax (Tmax) | 2.0 h |
Secondary
Percentage Change From Baseline in Serum Bone-specific Alkaline Phosphatase (bALP) at Week 4
Result at Week 4 minus result at baseline as a percentage of the result at baseline, based on log transformed data. Back transformation of the least squares (LS) mean.
Time frame: Baseline to Week 4
Population: The number of participants analyzed reflected the number of paired serum samples per participant that yielded valid assay results, not the total number of participants or completers. The number of evaluable paired serum samples will therefore be a subset of the total number of participants.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| AZD0530 175 mg | Percentage Change From Baseline in Serum Bone-specific Alkaline Phosphatase (bALP) at Week 4 | -13.2 Percentage change in bALP |
| Zoledronic Acid 4 mg | Percentage Change From Baseline in Serum Bone-specific Alkaline Phosphatase (bALP) at Week 4 | -3.1 Percentage change in bALP |
Secondary
Percentage Change From Baseline in Serum Cross-linked C-terminal Telopeptide of Type I Collagen (ICTP) at Week 4
Result at Week 4 minus result at baseline as a percentage of the result at baseline, based on log transformed data. Back transformation of the least squares (LS) mean.
Time frame: Baseline to Week 4
Population: The number of participants analyzed reflected the number of paired serum samples per participant that yielded valid assay results, not the total number of participants or completers. The number of evaluable paired serum samples will therefore be a subset of the total number of participants.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| AZD0530 175 mg | Percentage Change From Baseline in Serum Cross-linked C-terminal Telopeptide of Type I Collagen (ICTP) at Week 4 | -40.2 Percentage change in ICTP |
| Zoledronic Acid 4 mg | Percentage Change From Baseline in Serum Cross-linked C-terminal Telopeptide of Type I Collagen (ICTP) at Week 4 | 7.4 Percentage change in ICTP |
Secondary
Percentage Change From Baseline in Serum N-terminal Propeptide of Type I Procollagen (PINP) at Week 4
Result at Week 4 minus result at baseline as a percentage of the result at baseline, based on log transformed data. Back transformation of the least squares (LS) mean.
Time frame: Baseline to Week 4
Population: The number of participants analyzed reflected the number of paired serum samples per participant that yielded valid assay results, not the total number of participants or completers. The number of evaluable paired serum samples will therefore be a subset of the total number of participants.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| AZD0530 175 mg | Percentage Change From Baseline in Serum N-terminal Propeptide of Type I Procollagen (PINP) at Week 4 | -26.1 Percentage change in PINP |
| Zoledronic Acid 4 mg | Percentage Change From Baseline in Serum N-terminal Propeptide of Type I Procollagen (PINP) at Week 4 | -29.5 Percentage change in PINP |
Secondary
Percentage Change From Baseline in Serum Tartrate-resistant Acid Phosphatase 5b (TRAP5b) at Week 4
Result at Week 4 minus result at baseline as a percentage of the result at baseline, based on log transformed data. Back transformation of the least squares (LS) mean.
Time frame: Baseline to Week 4
Population: The number of participants analyzed reflected the number of paired serum samples per participant that yielded valid assay results, not the total number of participants or completers. The number of evaluable paired serum samples will therefore be a subset of the total number of participants.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| AZD0530 175 mg | Percentage Change From Baseline in Serum Tartrate-resistant Acid Phosphatase 5b (TRAP5b) at Week 4 | -36.9 Percentage change in TRAP5b |
| Zoledronic Acid 4 mg | Percentage Change From Baseline in Serum Tartrate-resistant Acid Phosphatase 5b (TRAP5b) at Week 4 | -43.4 Percentage change in TRAP5b |
Secondary
Percentage Change From Baseline in Urine Alpha-alpha C-terminal Cross-linking Telopeptide of Type I Collagen Normalised to Creatinine (aaCTx/Cr) at Week 4
Result at Week 4 minus result at baseline as a percentage of the result at baseline, based on log transformed data. Back transformation of the least squares (LS) mean.
Time frame: Baseline to Week 4
Population: The number of participants analyzed reflected the number of paired serum samples per participant that yielded valid assay results, not the total number of participants or completers. The number of evaluable paired serum samples will therefore be a subset of the total number of participants.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| AZD0530 175 mg | Percentage Change From Baseline in Urine Alpha-alpha C-terminal Cross-linking Telopeptide of Type I Collagen Normalised to Creatinine (aaCTx/Cr) at Week 4 | -68.2 Percentage change in aaCTx/Cr |
| Zoledronic Acid 4 mg | Percentage Change From Baseline in Urine Alpha-alpha C-terminal Cross-linking Telopeptide of Type I Collagen Normalised to Creatinine (aaCTx/Cr) at Week 4 | -82.8 Percentage change in aaCTx/Cr |
Secondary
Percentage Change From Baseline in Urine N-terminal Cross-linking Telopeptide of Type I Collagen Normalised to Creatinine (NTx/Cr) at Week 4
Result at Week 4 minus result at baseline as a percentage of the result at baseline, based on log transformed data. Back transformation of the least squares (LS) mean.
Time frame: Baseline to Week 4
Population: The number of participants analyzed reflected the number of paired serum samples per participant that yielded valid assay results, not the total number of participants or completers. The number of evaluable paired serum samples will therefore be a subset of the total number of participants.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| AZD0530 175 mg | Percentage Change From Baseline in Urine N-terminal Cross-linking Telopeptide of Type I Collagen Normalised to Creatinine (NTx/Cr) at Week 4 | -57.2 Percentage change in NTx/Cr |
| Zoledronic Acid 4 mg | Percentage Change From Baseline in Urine N-terminal Cross-linking Telopeptide of Type I Collagen Normalised to Creatinine (NTx/Cr) at Week 4 | -70.1 Percentage change in NTx/Cr |
Secondary
Saracatinib: Area Under the Curve at Steady State (AUCss)
Previous studies have shown that saracatinib reduces osteoclast function and bone resorption. Bone turnover, the combined result of bone formation and bone resorption, can be assessed in real time by measuring specific markers of bone turnover in serum and in urine. These markers were assessed in a study of patients with metastatic bone disease treated with saracatinib. Specific assays are available to quantitate these markers in serum and urine. In this study the effects of saracatinib on bone turnover were compared with the effects of zoledronic acid, a marketed drug known to inhibit bone resorption in cancer patients with bone metastatses.
Time frame: Pre-dose on days 8, 15, 29; 2 hours, 4 hours, 6 hours, 9 hours post dose on day 29
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD0530 175 mg | Saracatinib: Area Under the Curve at Steady State (AUCss) | 7261 ng•hr/ml |
Secondary
Saracatinib: Maximum Plasma Concentration at Steady State (Css,Max)
Time frame: Pre-dose on days 8, 15, 29; 2 hours, 4 hours, 6 hours, 9 hours post dose on day 29
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD0530 175 mg | Saracatinib: Maximum Plasma Concentration at Steady State (Css,Max) | 396.0 ng/ml |
Secondary
Saracatinib: Minimum Plasma Concentration at Steady State (Css,Min)
Time frame: Pre-dose on days 8, 15, 29; 2 hours, 4 hours, 6 hours, 9 hours post dose on day 29
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD0530 175 mg | Saracatinib: Minimum Plasma Concentration at Steady State (Css,Min) | 229.0 ng/ml |
Secondary
Saracatinib: Plasma Clearance at Steady State (CLss/F)
Time frame: Pre-dose on days 8, 15, 29; 2 hours, 4 hours, 6 hours, 9 hours post dose on day 29
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD0530 175 mg | Saracatinib: Plasma Clearance at Steady State (CLss/F) | 24.10 L/h |
Secondary
Saracatinib: Time to Cssmax (Tmax)
Time frame: Pre-dose on days 8, 15, 29; 2 hours, 4 hours, 6 hours, 9 hours post dose on day 29
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD0530 175 mg | Saracatinib: Time to Cssmax (Tmax) | 4.0 h |