Solid Tumours
Conditions
Keywords
Phase I, healthy, pharmacokinetics
Brief summary
Study to assess the effect of Selumetinib \[AZD6244; ARRY-142886\] \[Hyd-Sulfate\]), on QTc interval in healthy male volunteers.
Detailed description
A double-blind (Selumetinib \[AZD6244; ARRY-142886\] \[Hyd-Sulfate\]), Placebo-controlled, Open-Label (Moxifloxacin) Positive-controlled, Randomized, Three-period Crossover Study to Assess the Effects of Single Oral Dose of Selumetinib (75 mg) on QTc Interval Compared to Placebo, using AVELOX (Moxifloxacin) as a Positive Control, in Healthy Male Volunteers
Interventions
DRUGSelumetinib
Volunteers will receive 75 mg selumetinib oral dose (Treatment A)
DRUGMoxifloxacin
Volunteers will receive 400 mg Moxifloxacin oral dose (Treatment B)
DRUGselumetinib placebo
Volunteers will receive selumetinib placebo oral dose (Treatment C)
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
1. Have a body mass index (BMI) between 18 and 30 kg/m2 and weigh at least 50 kg and no more than 100 kg (inclusive). 2. Must have not smoked in the last 30 days prior to screening for this study. 3. Have a calculated creatinine clearance (CrCL) greater than 50 mL/min using the Cockcroft-Gault formula.
Exclusion criteria
1. Subjects of Japanese or non-Japanese Asian ethnicity. 2. Subjects where any one parent or grandparent (maternal or paternal) is Japanese or non-Japanese Asian (e.g. China, Taiwan, Korea, Philippines, Thailand, Vietnam, and Malaysia). Asian Indians are acceptable. 3. Past history of central serous retinopathy or retinal vein thrombosis,intraocular pressure greater than 21 mmHg or uncontrolled glaucoma. 4. Any clinically relevant abnormal findings in physical examination, hematology, clinical chemistry, urinalysis, vital signs or ECG at baseline in the opinion of the investigator. 5. History or presence of any clinically significant disease or disorder in the opinion of the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in QTcF | 30 min | Change from baseline in QTcF at 30 minutes (msec) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Selumetinib/Moxifloxacin/Selumetinib Placebo | 10 |
| Moxifloxacin/Selumetinib/Selumetinib Placebo | 9 |
| Moxifloxacin/Selumetinib Placebo/Selumetinib | 9 |
| Selumetinib Placebo/Moxifloxacin/Selumetinib | 9 |
| Selumetinib Placebo/Selumetinib/Moxifloxacin | 8 |
| Selumetinib/Selumetinib Placebo/Moxifloxacin | 9 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 | 2 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 1 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Selumetinib/Moxifloxacin/Selumetinib Placebo | Moxifloxacin/Selumetinib/Selumetinib Placebo | Moxifloxacin/Selumetinib Placebo/Selumetinib | Selumetinib Placebo/Moxifloxacin/Selumetinib | Selumetinib Placebo/Selumetinib/Moxifloxacin | Selumetinib/Selumetinib Placebo/Moxifloxacin | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 26 Years STANDARD_DEVIATION 7 | 25 Years STANDARD_DEVIATION 5 | 25 Years STANDARD_DEVIATION 4 | 31 Years STANDARD_DEVIATION 8 | 28 Years STANDARD_DEVIATION 8 | 30 Years STANDARD_DEVIATION 9 | 27 Years STANDARD_DEVIATION 7 |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 4 Participants | 5 Participants | 5 Participants | 3 Participants | 5 Participants | 25 Participants |
| Race/Ethnicity, Customized White | 7 Participants | 5 Participants | 4 Participants | 4 Participants | 5 Participants | 4 Participants | 29 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 10 Participants | 9 Participants | 9 Participants | 9 Participants | 8 Participants | 9 Participants | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 51 | 5 / 51 | 4 / 50 |
| serious Total, serious adverse events | 0 / 51 | 0 / 51 | 1 / 50 |
Outcome results
Primary
Change From Baseline in QTcF
Change from baseline in QTcF at 30 minutes (msec)
Time frame: 30 min
Population: All patients who had evaluable pharmacodynamic data available for at least one treatment group were included in the PD analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Moxifloxacin | Change From Baseline in QTcF | 2.0 msec |
| Placebo | Change From Baseline in QTcF | -4.1 msec |
| Selumetinib | Change From Baseline in QTcF | -4.2 msec |
Comparison: 47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.90% CI: [-1.8, 1.5]Mixed Models Analysis
Comparison: 47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.90% CI: [4.4, 7.7]Mixed Models Analysis
Primary
Change From Baseline in QTcF
Change from baseline in QTcF at 1 hour (msec)
Time frame: 1 hour
Population: All patients who had evaluable pharmacodynamic data available for at least one treatment group were included in the PD analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Moxifloxacin | Change From Baseline in QTcF | 7.9 msec |
| Placebo | Change From Baseline in QTcF | -1.4 msec |
| Selumetinib | Change From Baseline in QTcF | -1.7 msec |
Comparison: 47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.90% CI: [-2, 1.3]Mixed Models Analysis
Comparison: 47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.90% CI: [7.6, 10.8]Mixed Models Analysis
Primary
Change From Baseline in QTcF
Change from baseline in QTcF at 1 hour 30 min (msec)
Time frame: 1 hour 30 min
Population: All patients who had evaluable pharmacodynamic data available for at least one treatment group were included in the PD analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Moxifloxacin | Change From Baseline in QTcF | 8.1 msec |
| Placebo | Change From Baseline in QTcF | -1.8 msec |
| Selumetinib | Change From Baseline in QTcF | -0.9 msec |
Comparison: 47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.90% CI: [-0.7, 2.5]Mixed Models Analysis
Comparison: 47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.90% CI: [8.3, 11.5]Mixed Models Analysis
Primary
Change From Baseline in QTcF
Change from baseline in QTcF at 2 hours (msec)
Time frame: 2 hours
Population: All patients who had evaluable pharmacodynamic data available for at least one treatment group were included in the PD analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Moxifloxacin | Change From Baseline in QTcF | 7.9 msec |
| Placebo | Change From Baseline in QTcF | -2.3 msec |
| Selumetinib | Change From Baseline in QTcF | -1.9 msec |
Comparison: 47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.90% CI: [-1.2, 2]Mixed Models Analysis
Comparison: 47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.90% CI: [8.5, 11.8]Mixed Models Analysis
Primary
Change From Baseline in QTcF
Change from baseline in QTcF at 3 hours (msec)
Time frame: 3 hours
Population: All patients who had evaluable pharmacodynamic data available for at least one treatment group were included in the PD analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Moxifloxacin | Change From Baseline in QTcF | 8.8 msec |
| Placebo | Change From Baseline in QTcF | -3.2 msec |
| Selumetinib | Change From Baseline in QTcF | -3.3 msec |
Comparison: 47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.90% CI: [-1.8, 1.5]Mixed Models Analysis
Comparison: 47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.90% CI: [10.3, 13.6]Mixed Models Analysis
Primary
Change From Baseline in QTcF
Change from baseline in QTcF at 4 hours (msec)
Time frame: 4 hours
Population: All patients who had evaluable pharmacodynamic data available for at least one treatment group were included in the PD analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Moxifloxacin | Change From Baseline in QTcF | 8.6 msec |
| Placebo | Change From Baseline in QTcF | -2.2 msec |
| Selumetinib | Change From Baseline in QTcF | -3.7 msec |
Comparison: 47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.90% CI: [-3.1, 0.2]Mixed Models Analysis
Comparison: 47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.90% CI: [9.2, 12.5]Mixed Models Analysis
Primary
Change From Baseline in QTcF
Change from baseline in QTcF at 6 hours (msec)
Time frame: 6 hours
Population: All patients who had evaluable pharmacodynamic data available for at least one treatment group were included in the PD analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Moxifloxacin | Change From Baseline in QTcF | 4.7 msec |
| Placebo | Change From Baseline in QTcF | -4.1 msec |
| Selumetinib | Change From Baseline in QTcF | -5.9 msec |
Comparison: 47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.90% CI: [-3.4, -0.1]Mixed Models Analysis
Comparison: 47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.90% CI: [7.1, 10.4]Mixed Models Analysis
Primary
Change From Baseline in QTcF
Change from baseline in QTcF at 8 hours (msec)
Time frame: 8 hours
Population: All patients who had evaluable pharmacodynamic data available for at least one treatment group were included in the PD analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Moxifloxacin | Change From Baseline in QTcF | 3.6 msec |
| Placebo | Change From Baseline in QTcF | -5.3 msec |
| Selumetinib | Change From Baseline in QTcF | -6.5 msec |
Comparison: 47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.90% CI: [-2.9, 0.4]Mixed Models Analysis
Comparison: 47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.90% CI: [7.2, 10.5]Mixed Models Analysis
Primary
Change From Baseline in QTcF
Change from baseline in QTcF at 12 hours (msec)
Time frame: 12 hours
Population: All patients who had evaluable pharmacodynamic data available for at least one treatment group were included in the PD analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Moxifloxacin | Change From Baseline in QTcF | 4.2 msec |
| Placebo | Change From Baseline in QTcF | -3.4 msec |
| Selumetinib | Change From Baseline in QTcF | -8.2 msec |
Comparison: 47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.90% CI: [-6.4, -3.1]Mixed Models Analysis
Comparison: 47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.90% CI: [6, 9.3]Mixed Models Analysis
Primary
Change From Baseline in QTcF
Change from baseline in QTcF at 24 hours (msec)
Time frame: 24 hours
Population: All patients who had evaluable pharmacodynamic data available for at least one treatment group were included in the PD analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Moxifloxacin | Change From Baseline in QTcF | 2.4 msec |
| Placebo | Change From Baseline in QTcF | -1.6 msec |
| Selumetinib | Change From Baseline in QTcF | -4.1 msec |
Comparison: 47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.90% CI: [-4.1, -0.9]Mixed Models Analysis
Comparison: 47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.90% CI: [2.4, 5.7]Mixed Models Analysis