Melanoma
Conditions
Brief summary
This is a randomised, double-blind placebo controlled phase 2 trial. Patient will be randomly assigned 1:1 between 2 treatment arms. They will receive either docetaxel 75mg/m2 IV and placebo given bd, or AZD6244 75mg bd daily with docetaxel 75mg/m2 IV. Docetaxel will be administered every 3 weeks for a maximum 6 cycles, but AZD6244/placebo may be continued beyond this, until disease progression. The objective is to assess whether the combination of AZD6244 with docetaxel is worthy of evaluation in a definitive randomised study, with the null hypothesis being that the combination has activity similar to that of docetaxel alone in this population. After consent has been obtained mutational analysis of tumour BRAF will be performed on archival tumour tissue, where this information is not already known, to assess eligibility for the study. If there is no archival tissue a fresh biopsy will be requested from the patient. A blood sample will also be taken for future genetic analysis. Once taking part in the trial patients will need to attend their oncology unit regularly for monitoring and the delivery of treatment. Patients will undergo complete physical examination at screening, on C1D1, C1D8, C1D15, C2D1, C2D8 and day 1 of every subsequent cycle. Blood for haematology, biochemistry and clotting will be taken at each of these visits. A 12 lead ECG will be performed at screening . Disease assessment will be by CT scanning using modified RECIST criteria after 9 and 18 weeks, then every 3 months until disease progression.
Detailed description
No further information in addition to what has been provided in the brief summary
Interventions
DRUGDocetaxel and AZD6244
Docetaxel 75mg/m2 IV and AZD6244 75mg bd daily. Docetaxel will be administered every 3 weeks for a maximum 6 cycles, but AZD6244 may be continued beyond this, until disease progression.
DRUGDocetaxel and placebo
Docetaxel 75mg/m2 IV and placebo given bd. Docetaxel will be administered every 3 weeks for a maximum 6 cycles, but placebo may be continued beyond this, until disease progression.
Sponsors
University of Oxford
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Aged \>/= 16 years * Able to provide evidence from an accredited laboratory of wt BRAF status for their melanoma, or ascertainment of wt BRAF status from a sample of melanoma provided for mutational analysis in Oxford. * Unresectable stage 3 or 4, histologically proven cutaneous or unknown primary melanoma * At least 1 lesion, not previously irradiated, that can be accurately measured on CT or MRI as defined by modified RECIST criteria * ECOG performance score of 0 or 1. * Life expectancy of at least 12 weeks. * The patient is willing to give consent to the main study and able to comply with the protocol for the duration of the study, including scheduled follow-up visits and examinations. * Haematological and biochemical indices within the ranges shown below. Lab Test Value required Haemoglobin (Hb) \>10g/dL White Blood Count (WBC) \> 3x109/L Platelet count \> 100,000/μL Absolute Neutrophil count \> 1.5x109/L; Serum bilirubin ≤ 1.2 x ULN AST (SGOT) or ALT ≤ 2.5 x ULN LDH ≤ 2 x ULN Creatinine clearance (Cockcroft-Gault) \>50 ml/min
Exclusion criteria
* Any anti-cancer therapy (including radiotherapy and participation in other clinical trials) within 28 days prior to Day 1. * Prior DNA damaging agents or cytotoxic chemotherapy for metastatic melanoma. * Any unresolved toxicity from prior anti-cancer therapy that is greater than CTCAE grade 2. * Pregnancy or breastfeeding women. Female patients must have a negative urinary or serum pregnancy test or have evidence of post-menopausal status (defined as absence of menstruation for \> 12 months, bilateral oophrectomy or hysterectomy). * Grade ≥2 peripheral neuropathy at study entry. * Patients of reproductive potential who are not willing to use adequate contraceptive measures for the duration of the study (both male and female patients) * Known severe hypersensitivity reactions to docetaxel or other drugs formulated in polysorbate 80 * Ocular or mucosal malignant melanoma * Another active malignancy within the past five years. * Evidence of brain metastases, unless surgically resected/stereotactic radiosurgery treated brain metastasis with no evidence of relapse on cerebral MRI, or treated brain metastasis and stable off treatment, including steroids, for 3 months. * Clinically significant and uncontrolled major medical condition(s): such as active infection, bleeding diathesis. * Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV. * Cardiac conditions, including uncontrolled hypertension (BP\>160/100 despite treatment), heart failure NYHA class 2 or above, prior or current cardiomyopathy, myocardial infarction within 6 months or angina requiring nitrate therapy more than once a week. * Previous treatment with EGFR, ras, raf or MEK inhibitors. * Inability to swallow capsules, refractory nausea and vomiting, chronic gastrointestinal diseases (eg, inflammatory bowel disease) or significant bowel resection that would preclude adequate absorption. * Taking medication that significantly induces or inhibits CYP3A4.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. | This is defined as time from date of randomisation to the first of date of progression (using CT scan, x-ray, MRI scan and clinical examination) using modified RECIST (v1.1) criteria or date of death (events). For patients without an event, the time from date of randomisation to date last known alive will be the censored PFS time. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival Rate at 6 Months | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. | PFS at 6 months is defined as the percentage progression free survival at 6 months from the PFS Kaplan Meier graph. This would allow all patients randomised to be included. progression was diagnosed using CT scan, x-ray, MRI scan and clinical examination using modified RECIST(v1.1) criteria. |
| Overall Survival | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. | This is defined as the time from randomisation to death (event) or time from randomisation to date last known alive (censored time). |
| Objective Response Rate | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. | Objective response rate calculated as number of patients with Complete Response (CR) or Partial response (PR) over all patients randomised. The numerator of the objective response rate is the number of patients achieving a CR or PR. The denominator is all patients randomised. RECIST(v1.1) criteria was used for assessment. |
| Overall Survival Results - Post Final Analysis | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. | OS analysis was carried out at the final analysis time point on data taken on 01Oct2012. Another data extraction was taken on 05Mar2013 in order to carry out posthoc analyses, OS was analysed again on this data. OS is time from randomisation to death (event) or time from randomisation to date last known alive (censored time). |
| Vital Signs - Temperature | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm. | Vital signs - temperature. |
| Vital Signs - Pulse Rate | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm. | Vital signs - pulse rate. |
| Vital Signs - Systolic Blood Pressure | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm. | Vital signs - systolic blood pressure. |
| Vital Signs - Diastolic Blood Pressure | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm. | Vital signs - diastolic blood pressure. |
| Weight | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm. | Weight. |
| Haematology - Haemoglobin | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm. | Haematology - haemoglobin. |
| Haematology - White Cell Count | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are median values across all time-points for all patients in that arm. | Haematology - white cell count. |
| Haematology - Neutrophils | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm. | Haematology - neutrophils. |
| Haematology - Platelets | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm. | Haematology - platelets. |
| Biochemistry - Phosphate | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm. | Biochemistry - phosphate. |
| Biochemistry - Calcium | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm. | Biochemistry - calcium. |
| Biochemistry - Sodium | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm. | Biochemistry - sodium. |
| Biochemistry - Potassium | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm. | Biochemistry - potassium. |
| Biochemistry - Urea | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm. | Biochemistry - urea. |
| Biochemistry - Bilirubin | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm. | Biochemistry - bilirubin. |
| Biochemistry - Alkaline Phosphatase | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm. | Biochemistry - alkaline phosphatase. |
| Biochemistry - ALT | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm. | Biochemistry - ALT. |
| Biochemistry - AST | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm. | Biochemistry - AST. |
| Biochemistry - Albumin | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm. | Biochemistry - albumin. |
| Biochemistry - GGT | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm. | Biochemistry - GGT. |
| Biochemistry - Total Protein | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm. | Biochemistry - total protein. |
| Biochemistry - LDH | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm. | Biochemistry - LDH. |
| Biochemistry - Creatinine | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm. | Biochemistry - creatinine. |
| Physical Assessment - General Appearance | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm. | Physical assessment - general appearance. |
| Physical Exam - Skin | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm. | Physical exam - skin. |
| Physical Exam - Head and Neck | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm. | Physical exam - head and neck. |
| Physical Exam - Chest | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm. | Physical exam - chest. |
| Physical Exam - Cardiovascular | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm. | Physical exam - cardiovascular. |
| Physical Exam - Abdomen | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm. | Physical exam - abdomen. |
| Physical Exam - Lymph Nodes | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm. | Physical exam - lymph nodes. |
| Physical Exam - Extremities | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm. | Physical exam - extremities. |
| Physical Exam - Musculoskeletal | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm. | Physical exam - musculoskeletal. |
| Physical Exam - Neurological | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm. | Physical exam - neurological. |
| ECG - Post-dose | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm. | ECG - post-dose. |
| Urinalysis | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm. | Urinalysis. |
| Physical Exam - Other | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm. | Physical exam - other. |
| ECG - Pre-dose | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm. | ECG - pre-dose. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival: Sensitivity Analysis 1 | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. | Same as for primary analysis. This is defined as time from date of randomisation to the first of date of progression (using CT scan, x-ray, MRI scan and clinical examination) using modified RECIST v1.1 criteria or date of death (events). For patients without an event, the time from date of randomisation to date last known alive will be the censored PFS time. |
| Progression Free Survival- Per Protocol Analysis | From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. | Same as for primary analysis. This is defined as time from date of randomisation to the first of date of progression (using CT scan, x-ray, MRI scan and clinical examination) using modified RECIST v1.1. criteria or date of death (events). For patients without an event, the time from date of randomisation to date last known alive will be the censored PFS time. |
Countries
United Kingdom
Participant flow
Recruitment details
Recruitment of 83 participants from 16 centres (hospitals) took place between October 2010 and May 2012. Participants attended clinic visits according to the protocol.
Participants by arm
| Arm | Count |
|---|---|
| Docetaxel and AZD6244 Docetaxel with AZD6244
Docetaxel and AZD6244: Docetaxel 75mg/m2 IV and AZD6244 75mg bd daily. Docetaxel will be administered every 3 weeks for a maximum 6 cycles, but AZD6244 may be continued beyond this, until disease progression. | 41 |
| Docetaxel and Placebo Docetaxel without AZD6244
Docetaxel and placebo: Docetaxel 75mg/m2 IV and placebo given bd. Docetaxel will be administered every 3 weeks for a maximum 6 cycles, but placebo may be continued beyond this, until disease progression. | 42 |
| Total | 83 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Randomised and found to be too unwell to start treatment | 2 | 0 |
| Overall Study | Randomised, later found to be ineligible and did not start treatment | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Docetaxel and Placebo | Docetaxel and AZD6244 |
|---|---|---|---|
| Abnormal ECG | 8 Participants | 4 Participants | 4 Participants |
| Abnormal Urinalysis | 17 Participants | 8 Participants | 9 Participants |
| Age, Continuous | 59.3 years STANDARD_DEVIATION 12.6 | 59.2 years STANDARD_DEVIATION 13.3 | 59.5 years STANDARD_DEVIATION 12 |
| Biochemistry ALT | 24 U/L | 22 U/L | 26 U/L |
| Biochemistry AST | 23 U/L | 22 U/L | 24 U/L |
| Biochemistry: Bilirubin | 9 µmol/L | 8 µmol/L | 10 µmol/L |
| Biochemistry: Creatine clearance | 98 ml/min | 94 ml/min | 111 ml/min |
| Body Surface Area (BSA) | 1.980 m^2 STANDARD_DEVIATION 0.249 | 1.939 m^2 STANDARD_DEVIATION 0.26 | 2.022 m^2 STANDARD_DEVIATION 0.232 |
| Conmeds | 68 Participants | 33 Participants | 35 Participants |
| Diastolic BP | 83.5 mmHg | 82 mmHg | 85 mmHg |
| ECOG Performance Score 0 | 62 Participants | 34 Participants | 28 Participants |
| ECOG Performance Score 1 | 21 Participants | 8 Participants | 13 Participants |
| Haematology Neutrophils | 5 cells x 10^9/L | 5 cells x 10^9/L | 5 cells x 10^9/L |
| Haematology Platelets | 259 cells x 10^9/L | 255 cells x 10^9/L | 259 cells x 10^9/L |
| Haematology White cell count | 8 cells x 10^9/L | 7 cells x 10^9/L | 8 cells x 10^9/L |
| Haematology: Haemoglobin | 14 g/dL | 14 g/dL | 14 g/dL |
| Height | 1.72 meters STANDARD_DEVIATION 0.1 | 1.70 meters STANDARD_DEVIATION 0.1 | 1.74 meters STANDARD_DEVIATION 0.1 |
| LDH Above Upper limit normal | 47 Participants | 27 Participants | 20 Participants |
| LDH Below Upper limit normal | 36 Participants | 15 Participants | 21 Participants |
| Physical examination Abdomen | 7 Participants | 2 Participants | 5 Participants |
| Physical examination Cardiovascular | 0 Participants | 0 Participants | 0 Participants |
| Physical examination Chest | 9 Participants | 5 Participants | 4 Participants |
| Physical examination Extremities/back | 14 Participants | 7 Participants | 7 Participants |
| Physical examination General appearance | 1 Participants | 1 Participants | 0 Participants |
| Physical examination HEENT | 5 Participants | 4 Participants | 1 Participants |
| Physical examination Lymph nodes | 15 Participants | 8 Participants | 7 Participants |
| Physical examination Musculoskeletal | 6 Participants | 4 Participants | 2 Participants |
| Physical examination Neurological | 3 Participants | 2 Participants | 1 Participants |
| Physical examination Other body system | 6 Participants | 4 Participants | 2 Participants |
| Physical examination Skin | 34 Participants | 13 Participants | 21 Participants |
| Region of Enrollment United Kingdom | 83 Participants | 42 Participants | 41 Participants |
| Sex: Female, Male Female | 25 Participants | 15 Participants | 10 Participants |
| Sex: Female, Male Male | 58 Participants | 27 Participants | 31 Participants |
| Smoking status Never smoked | 27 Participants | 12 Participants | 15 Participants |
| Smoking status No, but smoked in the past | 49 Participants | 27 Participants | 22 Participants |
| Smoking status Yes | 7 Participants | 3 Participants | 4 Participants |
| Stage M0 or M1a or M1b | 18 Participants | 10 Participants | 8 Participants |
| Stage M1c | 65 Participants | 32 Participants | 33 Participants |
| Target lesion Sum LD | 71 mm | 56 mm | 98 mm |
| Vital Signs: Pulse rate | 71.5 Beats per minutes | 72 Beats per minutes | 70 Beats per minutes |
| Vital Signs: Systolic blood pressure | 137 mmHg | 136 mmHg | 137 mmHg |
| Vital Signs: temperature | 36.4 degrees C | 36.5 degrees C | 36.2 degrees C |
| Weight | 85.7 kg STANDARD_DEVIATION 19.3 | 83.0 kg STANDARD_DEVIATION 19.5 | 88.4 kg STANDARD_DEVIATION 19 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 26 / 41 | 28 / 42 |
| other Total, other adverse events | 35 / 41 | 40 / 42 |
| serious Total, serious adverse events | 29 / 41 | 20 / 42 |
Outcome results
Primary
Progression Free Survival
This is defined as time from date of randomisation to the first of date of progression (using CT scan, x-ray, MRI scan and clinical examination) using modified RECIST (v1.1) criteria or date of death (events). For patients without an event, the time from date of randomisation to date last known alive will be the censored PFS time.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months.
Population: The primary analysis was intention to treat and involved all patients who were randomly assigned.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Progression Free Survival | 4.23 months |
| Docetaxel and Placebo | Progression Free Survival | 3.93 months |
p-value: 0.1390% CI: [0.498, 1.138]Regression, Cox
Comparison: This is a sensitivity analysis of the primary outcome. This includes all 83 patients but the analysis additionally adjusted for LDH, target lesion sum and time interval between randomisation and baseline CT scan as well as mstatus, performance statusp-value: 0.11390% CI: [0.465, 1.123]Regression, Cox
Comparison: This is a sensitivity analysis, including all 83 randomised patients. Patients are assessed periodically for the response (progression), the time when the event occurred is not directly observed but is known to take place within some time interval. Progression is known only to have occurred at some time between visits, the exact time is not known. We carried out interval censored analysis to demonstrate if allowing for interval censoring gives a different interpretation of the primary outcome.p-value: 0.3016Generalised log-rank
Comparison: Sensitivity analysis adjusting for centre. All 83 randomised patients were included in analysis. Centres were the three biggest recruiters and all other 13 centres are combined.p-value: 0.30590% CI: [0.602, 3.016]Regression, Cox
Secondary
Biochemistry - Albumin
Biochemistry - albumin.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Biochemistry - Albumin | 37 grams per litre |
| Docetaxel and Placebo | Biochemistry - Albumin | 40 grams per litre |
Secondary
Biochemistry - Alkaline Phosphatase
Biochemistry - alkaline phosphatase.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Biochemistry - Alkaline Phosphatase | 93 IU per litre |
| Docetaxel and Placebo | Biochemistry - Alkaline Phosphatase | 85 IU per litre |
Secondary
Biochemistry - ALT
Biochemistry - ALT.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Biochemistry - ALT | 32 IU per litre |
| Docetaxel and Placebo | Biochemistry - ALT | 21 IU per litre |
Secondary
Biochemistry - AST
Biochemistry - AST.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Biochemistry - AST | 32 IU per litre |
| Docetaxel and Placebo | Biochemistry - AST | 20 IU per litre |
Secondary
Biochemistry - Bilirubin
Biochemistry - bilirubin.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Biochemistry - Bilirubin | 7 umol per litre |
| Docetaxel and Placebo | Biochemistry - Bilirubin | 7 umol per litre |
Secondary
Biochemistry - Calcium
Biochemistry - calcium.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Biochemistry - Calcium | 2.28 mmol per litre |
| Docetaxel and Placebo | Biochemistry - Calcium | 2.34 mmol per litre |
Secondary
Biochemistry - Creatinine
Biochemistry - creatinine.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Biochemistry - Creatinine | 113.6 milligrams per decalitre |
| Docetaxel and Placebo | Biochemistry - Creatinine | 98.3 milligrams per decalitre |
Secondary
Biochemistry - GGT
Biochemistry - GGT.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Biochemistry - GGT | 41 grams per litre |
| Docetaxel and Placebo | Biochemistry - GGT | 30 grams per litre |
Secondary
Biochemistry - LDH
Biochemistry - LDH.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Biochemistry - LDH | 305 Units per litre |
| Docetaxel and Placebo | Biochemistry - LDH | 386.5 Units per litre |
Secondary
Biochemistry - Phosphate
Biochemistry - phosphate.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Biochemistry - Phosphate | 1.245 mmol per litre |
| Docetaxel and Placebo | Biochemistry - Phosphate | 1 mmol per litre |
Secondary
Biochemistry - Potassium
Biochemistry - potassium.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Biochemistry - Potassium | 4.3 mmol per litre |
| Docetaxel and Placebo | Biochemistry - Potassium | 4.3 mmol per litre |
Secondary
Biochemistry - Sodium
Biochemistry - sodium.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Biochemistry - Sodium | 139 mmol per litre |
| Docetaxel and Placebo | Biochemistry - Sodium | 139 mmol per litre |
Secondary
Biochemistry - Total Protein
Biochemistry - total protein.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Biochemistry - Total Protein | 66 grams per litre |
| Docetaxel and Placebo | Biochemistry - Total Protein | 67 grams per litre |
Secondary
Biochemistry - Urea
Biochemistry - urea.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Biochemistry - Urea | 5.7 mmol per litre |
| Docetaxel and Placebo | Biochemistry - Urea | 5.2 mmol per litre |
Secondary
ECG - Post-dose
ECG - post-dose.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Docetaxel and AZD6244 | ECG - Post-dose | Normal | 32 Data points |
| Docetaxel and AZD6244 | ECG - Post-dose | Abnormal | 5 Data points |
| Docetaxel and AZD6244 | ECG - Post-dose | Not evaluated | 31 Data points |
| Docetaxel and Placebo | ECG - Post-dose | Normal | 34 Data points |
| Docetaxel and Placebo | ECG - Post-dose | Abnormal | 6 Data points |
| Docetaxel and Placebo | ECG - Post-dose | Not evaluated | 87 Data points |
Secondary
ECG - Pre-dose
ECG - pre-dose.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Docetaxel and AZD6244 | ECG - Pre-dose | Normal | 39 Data points |
| Docetaxel and AZD6244 | ECG - Pre-dose | Abnormal | 5 Data points |
| Docetaxel and AZD6244 | ECG - Pre-dose | Not evalauated | 23 Data points |
| Docetaxel and Placebo | ECG - Pre-dose | Normal | 39 Data points |
| Docetaxel and Placebo | ECG - Pre-dose | Abnormal | 6 Data points |
| Docetaxel and Placebo | ECG - Pre-dose | Not evalauated | 77 Data points |
Secondary
Haematology - Haemoglobin
Haematology - haemoglobin.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.
Population: Whole study
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Haematology - Haemoglobin | 12.5 grams per litre |
| Docetaxel and Placebo | Haematology - Haemoglobin | 12.9 grams per litre |
Secondary
Haematology - Neutrophils
Haematology - neutrophils.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Haematology - Neutrophils | 5.4 10^9 cells litre |
| Docetaxel and Placebo | Haematology - Neutrophils | 5.7 10^9 cells litre |
Secondary
Haematology - Platelets
Haematology - platelets.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Haematology - Platelets | 267 10^9 cells litre |
| Docetaxel and Placebo | Haematology - Platelets | 290.5 10^9 cells litre |
Secondary
Haematology - White Cell Count
Haematology - white cell count.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are median values across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Haematology - White Cell Count | 7.75 10^9 cells litre |
| Docetaxel and Placebo | Haematology - White Cell Count | 8.405 10^9 cells litre |
Secondary
Objective Response Rate
Objective response rate calculated as number of patients with Complete Response (CR) or Partial response (PR) over all patients randomised. The numerator of the objective response rate is the number of patients achieving a CR or PR. The denominator is all patients randomised. RECIST(v1.1) criteria was used for assessment.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months.
Population: intention to treat
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Docetaxel and AZD6244 | Objective Response Rate | Partial response | 12 Participants |
| Docetaxel and AZD6244 | Objective Response Rate | Progressive disease | 5 Participants |
| Docetaxel and AZD6244 | Objective Response Rate | Stable disease | 14 Participants |
| Docetaxel and AZD6244 | Objective Response Rate | Not applicable | 9 Participants |
| Docetaxel and AZD6244 | Objective Response Rate | Complete response | 1 Participants |
| Docetaxel and Placebo | Objective Response Rate | Not applicable | 2 Participants |
| Docetaxel and Placebo | Objective Response Rate | Complete response | 0 Participants |
| Docetaxel and Placebo | Objective Response Rate | Partial response | 6 Participants |
| Docetaxel and Placebo | Objective Response Rate | Stable disease | 15 Participants |
| Docetaxel and Placebo | Objective Response Rate | Progressive disease | 19 Participants |
Comparison: Objective response rate calculated as number of patients with CR or PR over all patients randomised.p-value: 0.059Chi-squared
Secondary
Overall Survival
This is defined as the time from randomisation to death (event) or time from randomisation to date last known alive (censored time).
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Overall Survival | 9.5 months |
| Docetaxel and Placebo | Overall Survival | 11.367 months |
p-value: 0.16990% CI: [0.797, 2.369]Regression, Cox
Secondary
Overall Survival Results - Post Final Analysis
OS analysis was carried out at the final analysis time point on data taken on 01Oct2012. Another data extraction was taken on 05Mar2013 in order to carry out posthoc analyses, OS was analysed again on this data. OS is time from randomisation to death (event) or time from randomisation to date last known alive (censored time).
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months.
Population: Intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Overall Survival Results - Post Final Analysis | 9.5 months |
| Docetaxel and Placebo | Overall Survival Results - Post Final Analysis | 11.37 months |
Comparison: Analysis adjusted for with Mstatus and Performance Scorep-value: 0.31890% CI: [0.71, 1.84]Regression, Cox
Secondary
Physical Assessment - General Appearance
Physical assessment - general appearance.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Docetaxel and AZD6244 | Physical Assessment - General Appearance | Normal | 181 Data points |
| Docetaxel and AZD6244 | Physical Assessment - General Appearance | Abnormal | 35 Data points |
| Docetaxel and AZD6244 | Physical Assessment - General Appearance | Not evaluated | 18 Data points |
| Docetaxel and Placebo | Physical Assessment - General Appearance | Normal | 162 Data points |
| Docetaxel and Placebo | Physical Assessment - General Appearance | Abnormal | 24 Data points |
| Docetaxel and Placebo | Physical Assessment - General Appearance | Not evaluated | 12 Data points |
Secondary
Physical Exam - Abdomen
Physical exam - abdomen.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Docetaxel and AZD6244 | Physical Exam - Abdomen | Normal | 205 Data points |
| Docetaxel and AZD6244 | Physical Exam - Abdomen | Abnormal | 5 Data points |
| Docetaxel and AZD6244 | Physical Exam - Abdomen | Not evaluated | 24 Data points |
| Docetaxel and Placebo | Physical Exam - Abdomen | Normal | 163 Data points |
| Docetaxel and Placebo | Physical Exam - Abdomen | Abnormal | 24 Data points |
| Docetaxel and Placebo | Physical Exam - Abdomen | Not evaluated | 10 Data points |
Secondary
Physical Exam - Cardiovascular
Physical exam - cardiovascular.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Docetaxel and AZD6244 | Physical Exam - Cardiovascular | Normal | 204 Data points |
| Docetaxel and AZD6244 | Physical Exam - Cardiovascular | Abnormal | 7 Data points |
| Docetaxel and AZD6244 | Physical Exam - Cardiovascular | Not evaluated | 23 Data points |
| Docetaxel and Placebo | Physical Exam - Cardiovascular | Normal | 180 Data points |
| Docetaxel and Placebo | Physical Exam - Cardiovascular | Abnormal | 6 Data points |
| Docetaxel and Placebo | Physical Exam - Cardiovascular | Not evaluated | 11 Data points |
Secondary
Physical Exam - Chest
Physical exam - chest.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Docetaxel and AZD6244 | Physical Exam - Chest | Normal | 187 Data points |
| Docetaxel and AZD6244 | Physical Exam - Chest | Abnormal | 29 Data points |
| Docetaxel and AZD6244 | Physical Exam - Chest | Not evaluated | 18 Data points |
| Docetaxel and Placebo | Physical Exam - Chest | Normal | 170 Data points |
| Docetaxel and Placebo | Physical Exam - Chest | Abnormal | 16 Data points |
| Docetaxel and Placebo | Physical Exam - Chest | Not evaluated | 11 Data points |
Secondary
Physical Exam - Extremities
Physical exam - extremities.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Docetaxel and AZD6244 | Physical Exam - Extremities | Abnormal | 83 Data points |
| Docetaxel and AZD6244 | Physical Exam - Extremities | Not evaluated | 37 Data points |
| Docetaxel and AZD6244 | Physical Exam - Extremities | Normal | 114 Data points |
| Docetaxel and Placebo | Physical Exam - Extremities | Abnormal | 37 Data points |
| Docetaxel and Placebo | Physical Exam - Extremities | Not evaluated | 21 Data points |
| Docetaxel and Placebo | Physical Exam - Extremities | Normal | 139 Data points |
Secondary
Physical Exam - Head and Neck
Physical exam - head and neck.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Docetaxel and AZD6244 | Physical Exam - Head and Neck | Normal | 139 Data points |
| Docetaxel and AZD6244 | Physical Exam - Head and Neck | Abnormal | 61 Data points |
| Docetaxel and AZD6244 | Physical Exam - Head and Neck | Not evaluated | 34 Data points |
| Docetaxel and Placebo | Physical Exam - Head and Neck | Normal | 146 Data points |
| Docetaxel and Placebo | Physical Exam - Head and Neck | Abnormal | 23 Data points |
| Docetaxel and Placebo | Physical Exam - Head and Neck | Not evaluated | 28 Data points |
Secondary
Physical Exam - Lymph Nodes
Physical exam - lymph nodes.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Docetaxel and AZD6244 | Physical Exam - Lymph Nodes | Normal | 162 Data points |
| Docetaxel and AZD6244 | Physical Exam - Lymph Nodes | Abnormal | 19 Data points |
| Docetaxel and AZD6244 | Physical Exam - Lymph Nodes | Not evaluated | 53 Data points |
| Docetaxel and Placebo | Physical Exam - Lymph Nodes | Normal | 148 Data points |
| Docetaxel and Placebo | Physical Exam - Lymph Nodes | Abnormal | 27 Data points |
| Docetaxel and Placebo | Physical Exam - Lymph Nodes | Not evaluated | 22 Data points |
Secondary
Physical Exam - Musculoskeletal
Physical exam - musculoskeletal.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Docetaxel and AZD6244 | Physical Exam - Musculoskeletal | Normal | 156 Data points |
| Docetaxel and AZD6244 | Physical Exam - Musculoskeletal | Abnormal | 19 Data points |
| Docetaxel and AZD6244 | Physical Exam - Musculoskeletal | Not evaluated | 59 Data points |
| Docetaxel and Placebo | Physical Exam - Musculoskeletal | Normal | 149 Data points |
| Docetaxel and Placebo | Physical Exam - Musculoskeletal | Abnormal | 13 Data points |
| Docetaxel and Placebo | Physical Exam - Musculoskeletal | Not evaluated | 35 Data points |
Secondary
Physical Exam - Neurological
Physical exam - neurological.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Docetaxel and AZD6244 | Physical Exam - Neurological | Normal | 149 Data points |
| Docetaxel and AZD6244 | Physical Exam - Neurological | Abnormal | 7 Data points |
| Docetaxel and AZD6244 | Physical Exam - Neurological | Not evaluated | 78 Data points |
| Docetaxel and Placebo | Physical Exam - Neurological | Normal | 129 Data points |
| Docetaxel and Placebo | Physical Exam - Neurological | Abnormal | 19 Data points |
| Docetaxel and Placebo | Physical Exam - Neurological | Not evaluated | 49 Data points |
Secondary
Physical Exam - Other
Physical exam - other.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Docetaxel and AZD6244 | Physical Exam - Other | Normal | 4 Data points |
| Docetaxel and AZD6244 | Physical Exam - Other | Abnormal | 40 Data points |
| Docetaxel and AZD6244 | Physical Exam - Other | Not evaluated | 8 Data points |
| Docetaxel and Placebo | Physical Exam - Other | Normal | 4 Data points |
| Docetaxel and Placebo | Physical Exam - Other | Abnormal | 31 Data points |
| Docetaxel and Placebo | Physical Exam - Other | Not evaluated | 12 Data points |
Secondary
Physical Exam - Skin
Physical exam - skin.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Docetaxel and AZD6244 | Physical Exam - Skin | Normal | 56 Data points |
| Docetaxel and AZD6244 | Physical Exam - Skin | Abnormal | 155 Data points |
| Docetaxel and AZD6244 | Physical Exam - Skin | Not evaluated | 23 Data points |
| Docetaxel and Placebo | Physical Exam - Skin | Normal | 86 Data points |
| Docetaxel and Placebo | Physical Exam - Skin | Abnormal | 99 Data points |
| Docetaxel and Placebo | Physical Exam - Skin | Not evaluated | 12 Data points |
Secondary
Progression Free Survival Rate at 6 Months
PFS at 6 months is defined as the percentage progression free survival at 6 months from the PFS Kaplan Meier graph. This would allow all patients randomised to be included. progression was diagnosed using CT scan, x-ray, MRI scan and clinical examination using modified RECIST(v1.1) criteria.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months.
Population: Intention to treat i.e. all randomised patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Docetaxel and AZD6244 | Progression Free Survival Rate at 6 Months | 40 percentage of participants |
| Docetaxel and Placebo | Progression Free Survival Rate at 6 Months | 26 percentage of participants |
p-value: 0.18790% CI: [-3.4, 31.4]Log Rank
Secondary
Urinalysis
Urinalysis.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Docetaxel and AZD6244 | Urinalysis | Abnormal | 130 Data points |
| Docetaxel and AZD6244 | Urinalysis | Not evaluated | 37 Data points |
| Docetaxel and AZD6244 | Urinalysis | Normal | 205 Data points |
| Docetaxel and Placebo | Urinalysis | Not evaluated | 19 Data points |
| Docetaxel and Placebo | Urinalysis | Abnormal | 117 Data points |
| Docetaxel and Placebo | Urinalysis | Normal | 229 Data points |
Secondary
Vital Signs - Diastolic Blood Pressure
Vital signs - diastolic blood pressure.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Vital Signs - Diastolic Blood Pressure | 82 Mg mercury |
| Docetaxel and Placebo | Vital Signs - Diastolic Blood Pressure | 79 Mg mercury |
Secondary
Vital Signs - Pulse Rate
Vital signs - pulse rate.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Vital Signs - Pulse Rate | 78 Beats per minute |
| Docetaxel and Placebo | Vital Signs - Pulse Rate | 84 Beats per minute |
Secondary
Vital Signs - Systolic Blood Pressure
Vital signs - systolic blood pressure.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.
Population: Whole study
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Vital Signs - Systolic Blood Pressure | 131 Mg mercury |
| Docetaxel and Placebo | Vital Signs - Systolic Blood Pressure | 130 Mg mercury |
Secondary
Vital Signs - Temperature
Vital signs - temperature.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Vital Signs - Temperature | 36.2 Degree celsius |
| Docetaxel and Placebo | Vital Signs - Temperature | 36.3 Degree celsius |
Secondary
Weight
Weight.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.
Population: Intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Weight | 90.425 Kg |
| Docetaxel and Placebo | Weight | 83.45 Kg |
Post Hoc
Objective Response Rate in Patients With Mutated NRAS
Best overall response as reported for evaluable/measurable scans including target, non-target and new lesions. Response assessed using RECIST(v1.1) criteria. Data from Mar2013 which was post final data lock
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months.
Population: Per protocol population and only those with NRAS status=mutated
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Docetaxel and AZD6244 | Objective Response Rate in Patients With Mutated NRAS | Partial response | 6 Participants |
| Docetaxel and AZD6244 | Objective Response Rate in Patients With Mutated NRAS | Progressive disease | 2 Participants |
| Docetaxel and AZD6244 | Objective Response Rate in Patients With Mutated NRAS | Stable disease | 7 Participants |
| Docetaxel and AZD6244 | Objective Response Rate in Patients With Mutated NRAS | Not applicable | 4 Participants |
| Docetaxel and AZD6244 | Objective Response Rate in Patients With Mutated NRAS | Complete response | 1 Participants |
| Docetaxel and Placebo | Objective Response Rate in Patients With Mutated NRAS | Not applicable | 0 Participants |
| Docetaxel and Placebo | Objective Response Rate in Patients With Mutated NRAS | Complete response | 0 Participants |
| Docetaxel and Placebo | Objective Response Rate in Patients With Mutated NRAS | Partial response | 2 Participants |
| Docetaxel and Placebo | Objective Response Rate in Patients With Mutated NRAS | Stable disease | 9 Participants |
| Docetaxel and Placebo | Objective Response Rate in Patients With Mutated NRAS | Progressive disease | 6 Participants |
Post Hoc
Objective Response Rate in Patients With WT NRAS
Best overall response as reported for evaluable/measurable scans including target, non-target and new lesions. Response assessed using RECIST(v1.1) criteria. Data from Mar2013 which was post final data lock
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months.
Population: Per protocol population and only those with NRAS status- wild type
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Docetaxel and AZD6244 | Objective Response Rate in Patients With WT NRAS | Partial response | 2 Participants |
| Docetaxel and AZD6244 | Objective Response Rate in Patients With WT NRAS | Progressive disease | 3 Participants |
| Docetaxel and AZD6244 | Objective Response Rate in Patients With WT NRAS | Stable disease | 4 Participants |
| Docetaxel and AZD6244 | Objective Response Rate in Patients With WT NRAS | Not applicable | 0 Participants |
| Docetaxel and AZD6244 | Objective Response Rate in Patients With WT NRAS | Complete response | 0 Participants |
| Docetaxel and Placebo | Objective Response Rate in Patients With WT NRAS | Not applicable | 0 Participants |
| Docetaxel and Placebo | Objective Response Rate in Patients With WT NRAS | Complete response | 0 Participants |
| Docetaxel and Placebo | Objective Response Rate in Patients With WT NRAS | Partial response | 2 Participants |
| Docetaxel and Placebo | Objective Response Rate in Patients With WT NRAS | Stable disease | 4 Participants |
| Docetaxel and Placebo | Objective Response Rate in Patients With WT NRAS | Progressive disease | 8 Participants |
Post Hoc
Overall Survival in Patients With NRAS Data
Outcome is time from randomisation to death in subset of patients with NRAS mutational data available and in the per-protocol population. NRAS mutational analysis (wild type or mutated) for all patients was derived from archival melanoma tumour tissue samples.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months.
Population: Per protocol population and only those with NRAS data
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Overall Survival in Patients With NRAS Data | 12.07 months |
| Docetaxel and Placebo | Overall Survival in Patients With NRAS Data | 11.9 months |
p-value: 0.07295% CI: [0.16, 1.6]Regression, Cox
95% CI: [0.73, 5.33]
Post Hoc
Overall Survival in Patients With NRAS Data- Sensitivity
Outcome is time from randomisation to death in subset of patients with NRAS mutational data available and in the per-protocol population and excluding patients found to have BRAF mutation on retesting (the inclusion criteria for the trial is those with wildtype BRAF). NRAS mutational analysis (wild type or mutated) for all patients was derived from archival melanoma tumour tissue samples.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months.
Population: Per-protocol population, including only patients with NRAS data and excluding patients found to have BRAF mutation on retesting
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Overall Survival in Patients With NRAS Data- Sensitivity | 12.07 months |
| Docetaxel and Placebo | Overall Survival in Patients With NRAS Data- Sensitivity | 11.9 months |
95% CI: [0.73, 5.38]
p-value: 0.1295% CI: [0.18, 1.97]Regression, Cox
Post Hoc
Overall Survival Results - Post Final Analysis- Per-protocol
OS analysis was carried out at the final analysis time point on data taken on 01Oct2012. Another data extraction was taken on 05Mar2013 in order to carry out posthoc analyses, OS was analysed again on this data. OS is time from randomisation to death (event) or time from randomisation to date last known alive (censored time).
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months.
Population: Per protocol population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Overall Survival Results - Post Final Analysis- Per-protocol | 10.9 months |
| Docetaxel and Placebo | Overall Survival Results - Post Final Analysis- Per-protocol | 11.77 months |
p-value: 0.34890% CI: [0.68, 1.87]Regression, Cox
Post Hoc
Progression Free Survival: in Patients With NRAS Data
Outcome is time from randomisation to progression or death in subset of patients with NRAS mutational data available and in the per-protocol population. progression was diagnosed using CT scan, x-ray, MRI scan and clinical examination using modified RECIST(v1.1) criteria. NRAS mutational analysis (wild type or mutated) for all patients was derived from archival melanoma tumour tissue samples.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months.
Population: per protocol population and only those with NRAS status
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Progression Free Survival: in Patients With NRAS Data | 4.4 months |
| Docetaxel and Placebo | Progression Free Survival: in Patients With NRAS Data | 4.1 months |
Comparison: Model with interaction term between NRAS status and treatment group and stratification variablesp-value: 0.82495% CI: [0.25, 1.53]Regression, Cox
Post Hoc
Progression Free Survival: in Patients With NRAS Data- Sensitivity
Outcome is time from randomisation to progression or death in subset of patients with NRAS mutational data available and in the per-protocol population and excluding patients found to have BRAF mutation on retesting (the inclusion criteria for the trial is those with wildtype BRAF). progression was diagnosed using CT scan, x-ray, MRI scan and clinical examination using modified RECIST(v1.1) criteria. NRAS mutational analysis (wild type or mutated) for all patients was derived from archival melanoma tumour tissue samples.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months.
Population: per-protocol population and only patients with NRAS mutational data and excluding patients found to have BRAF mutation on retesting
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Progression Free Survival: in Patients With NRAS Data- Sensitivity | 4.4 months |
| Docetaxel and Placebo | Progression Free Survival: in Patients With NRAS Data- Sensitivity | 4.1 months |
p-value: 0.79790% CI: [0.24, 1.58]Regression, Cox
95% CI: [0.35, 1.45]
Other Pre-specified
Progression Free Survival- Per Protocol Analysis
Same as for primary analysis. This is defined as time from date of randomisation to the first of date of progression (using CT scan, x-ray, MRI scan and clinical examination) using modified RECIST v1.1. criteria or date of death (events). For patients without an event, the time from date of randomisation to date last known alive will be the censored PFS time.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months.
Population: Per-protocol population, this is the primary analysis population excluding four patients who did not start treatment and two patients who were later found to be ineligible.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Progression Free Survival- Per Protocol Analysis | 4.3 months |
| Docetaxel and Placebo | Progression Free Survival- Per Protocol Analysis | 4.067 months |
Comparison: This is the per-protocol analysis of the primary outcome.p-value: 0.10690% CI: [0.468, 1.109]Regression, Cox
Other Pre-specified
Progression Free Survival: Sensitivity Analysis 1
Same as for primary analysis. This is defined as time from date of randomisation to the first of date of progression (using CT scan, x-ray, MRI scan and clinical examination) using modified RECIST v1.1 criteria or date of death (events). For patients without an event, the time from date of randomisation to date last known alive will be the censored PFS time.
Time frame: From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months.
Population: This is a sensitivity analysis of the primary outcome and includes randomised patients that had CT scans as per protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and AZD6244 | Progression Free Survival: Sensitivity Analysis 1 | 4.1 months |
| Docetaxel and Placebo | Progression Free Survival: Sensitivity Analysis 1 | 3.333 months |
Comparison: This is a sensitivity analysis of the primary outcome.p-value: 0.46890% CI: [0.649, 1.612]Regression, Cox