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AZD6244 in Combination With Docetaxel Versus Docetaxel Alone in KRAS Mutation Positive NSCLC Patients

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ClinicalTrials.gov Identifier: NCT00890825
Recruitment Status : Completed
First Posted : April 30, 2009
Results First Posted : June 20, 2018
Last Update Posted : June 20, 2018
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Non Small Cell Lung Cancer
Interventions Drug: AZD6244
Drug: docetaxel
Drug: Placebo
Enrollment 88
Recruitment Details Selection of patients was in 2nd line patients with KRAS mutation positive locally advanced or metastatic NSCLC (Stage IIIB – IV).First patient enrolled: 20 April 2009.Last patient last visit: 30 June 2010.Data Cut Off (DCO): 01 May 2011
Pre-assignment Details  
Arm/Group Title AZD6244 + Docetaxel Placebo + Docetaxel
Hide Arm/Group Description AZD6244 75 mg bd + Docetaxel 75 mg/m^2 Placebo + Docetaxel 75 mg/m^2
Period Title: Overall Study
Started 44 43 [1]
Completed 30 29
Not Completed 14 14
Reason Not Completed
Withdrawal by Subject             1             0
Alive at data cut off (DCO)             13             14
[1]
A patient randomized to this arm was excluded from the safety population for not receiving treatment
Arm/Group Title AZD6244 + Docetaxel Placebo + Docetaxel Total
Hide Arm/Group Description AZD6244 75 mg bd + Docetaxel 75 mg/m^2 Placebo + Docetaxel 75 mg/m^2 Total of all reporting groups
Overall Number of Baseline Participants 44 43 87
Hide Baseline Analysis Population Description
Intention to treat (ITT) analysis set
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 44 participants 43 participants 87 participants
58.2  (9.22) 58.6  (8.38) 58.4  (8.77)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 44 participants 43 participants 87 participants
Age group : <=55 years
15
  34.1%
15
  34.9%
30
  34.5%
Age group : >55 years
29
  65.9%
28
  65.1%
57
  65.5%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 44 participants 43 participants 87 participants
Female
23
  52.3%
23
  53.5%
46
  52.9%
Male
21
  47.7%
20
  46.5%
41
  47.1%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 44 participants 43 participants 87 participants
White
41
  93.2%
40
  93.0%
81
  93.1%
Black or African American
1
   2.3%
1
   2.3%
2
   2.3%
Other
2
   4.5%
2
   4.7%
4
   4.6%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 44 participants 43 participants 87 participants
Hispanic or Latino
7
  15.9%
10
  23.3%
17
  19.5%
Not Hispanic or Latino
37
  84.1%
33
  76.7%
70
  80.5%
1.Primary Outcome
Title Overall Survival
Hide Description OS was calculated as the interval from the date of randomisation to the date of patient death (any cause). Patients who had not died at the time of the final analysis, or who withdrew consent, were censored at the last date the patient was known to be alive.
Time Frame At least 12 months since start of treatment.
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Hide Analysis Population Description
MITT
Arm/Group Title AZD6244 + Docetaxel Placebo + Docetaxel
Hide Arm/Group Description:
AZD6244 75 mg bd + Docetaxel 75 mg/m^2
Placebo + Docetaxel 75 mg/m^2
Overall Number of Participants Analyzed 43 40
Measure Type: Count of Participants
Unit of Measure: Participants
Died
29
  67.4%
27
  67.5%
Alive at DCO
13
  30.2%
13
  32.5%
Withdrawn
1
   2.3%
0
   0.0%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AZD6244 + Docetaxel, Placebo + Docetaxel
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2069
Comments One-sided p-value. The p-value is associated with the point estimate (e.g. HR comparing AZD6244 + Docetaxel vs Placebo + Docetaxel) on the outcome measure - Overall survival.
Method Regression, Cox
Comments Analysis adjusted for the following covariates; WHO PS, gender, histology and smoking status
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.80
Confidence Interval (2-Sided) 80%
0.56 to 1.14
Estimation Comments A Hazard Ratio less than 1 favoured AZD6244 + Docetaxel
2.Secondary Outcome
Title Progression Free Survival
Hide Description PFS was defined as the interval between the date of randomisation and the earlier date of objective disease progression per RECIST criteria or death due to any cause in the absence of progression. Patients who did not progress or die at the time of analysis were censored at the time of their latest evaluable objective tumour assessment. This also included patients who withdrew consent.
Time Frame At least 12 months after start of treatment
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Hide Analysis Population Description
MITT
Arm/Group Title AZD6244 + Docetaxel Placebo + Docetaxel
Hide Arm/Group Description:
AZD6244 75 mg bd + Docetaxel 75 mg/m^2
Placebo + Docetaxel 75 mg/m^2
Overall Number of Participants Analyzed 43 40
Measure Type: Count of Participants
Unit of Measure: Participants
Progression
35
  81.4%
36
  90.0%
Prog. after >2 missed or non-eval. assessments
1
   2.3%
2
   5.0%
No progression
7
  16.3%
2
   5.0%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AZD6244 + Docetaxel, Placebo + Docetaxel
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0138
Comments One-sided p-value. The p-value is associated with the point estimate (e.g. HR comparing AZD6244 + Docetaxel vs Placebo + Docetaxel) on the outcome measure.
Method Regression, Cox
Comments The model allowed for the effect of treatment and included terms for WHO PS, gender, histology, and smoking status.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.58
Confidence Interval (2-Sided) 80%
0.42 to 0.79
Estimation Comments A Hazard Ratio (HR) < 1 favoured AZD6244 + Docetaxel
3.Secondary Outcome
Title Objective Response Rate
Hide Description ORR is defined as the ratio of proportions, patients with at least one visit response of CR or PR in AZD6244 + Docetaxel vs Placebo + Docetaxel.
Time Frame At least 12 months after start of treatment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
MITT
Arm/Group Title AZD6244 + Docetaxel Placebo + Docetaxel
Hide Arm/Group Description:
AZD6244 75 mg bd + Docetaxel 75 mg/m^2
Placebo + Docetaxel 75 mg/m^2
Overall Number of Participants Analyzed 43 40
Measure Type: Count of Participants
Unit of Measure: Participants
Response
16
  37.2%
0
   0.0%
No response
27
  62.8%
40
 100.0%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AZD6244 + Docetaxel, Placebo + Docetaxel
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.0001
Comments Two-sided P-value
Method Fisher Exact
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 37.2
Confidence Interval (2-Sided) 95%
23 to 53
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Duration of Response
Hide Description Duration of response is defined as the time from the date of first documented response until date of documented progression or death in the absence of disease progression, the end of response should coincide with the date of progression or death from any cause used for the PFS endpoint.
Time Frame At least 12 months after start of treatment
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Hide Analysis Population Description
MITT
Arm/Group Title AZD6244 + Docetaxel Placebo + Docetaxel
Hide Arm/Group Description:
AZD6244 75 mg bd + Docetaxel 75 mg/m^2
Placebo + Docetaxel 75 mg/m^2
Overall Number of Participants Analyzed 43 40
Mean (Standard Error)
Unit of Measure: Days
193.4  (0.207) NA [1]   (NA)
[1]
No instance of complete or partial response was recorded for this arm.
5.Secondary Outcome
Title Change From Baseline in Tumour Size at 6 Week.
Hide Description Percentage change from baseline in tumour size at 6 week. Values calculated as tumour sizes at 6 weeks minus value at baseline.
Time Frame 6 weeks after first dose of treatment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
MITT
Arm/Group Title AZD6244 + Docetaxel Placebo + Docetaxel
Hide Arm/Group Description:
AZD6244 75 mg bd + Docetaxel 75 mg/m^2
Placebo + Docetaxel 75 mg/m^2
Overall Number of Participants Analyzed 43 40
Least Squares Mean (80% Confidence Interval)
Unit of Measure: Percentage change from baseline
-16.98
(-27.1 to -6.85)
0.05
(-9.84 to 9.93)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AZD6244 + Docetaxel, Placebo + Docetaxel
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.004
Comments One-sided p-value. The p-value is associated with the point estimate comparing AZD6244 + Docetaxel vs Placebo + Docetaxel on the outcome measure.
Method ANCOVA
Comments LS means were adjusted for baseline tumour size, time from baseline scan to randomisation, WHO PS, gender, histology, and smoking status.
Method of Estimation Estimation Parameter LSmeans difference
Estimated Value -17.03
Confidence Interval (2-Sided) 80%
-25.2 to -8.86
Estimation Comments (AZD6244 + Docetaxel) - (Placebo + Docetaxel)
6.Secondary Outcome
Title Change From Baseline in Tumour Size at Week 12
Hide Description Percentage change from baseline in tumour size at Week 12. Values calculated as tumour sizes at 12 weeks minus value at baseline.
Time Frame 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
MITT
Arm/Group Title AZD6244 + Docetaxel Placebo + Docetaxel
Hide Arm/Group Description:
AZD6244 75 mg bd + Docetaxel 75 mg/m^2
Placebo + Docetaxel 75 mg/m^2
Overall Number of Participants Analyzed 43 40
Least Squares Mean (80% Confidence Interval)
Unit of Measure: Percent change from baseline
-19.38
(-34.7 to -4.09)
6.62
(-8.31 to 21.54)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AZD6244 + Docetaxel, Placebo + Docetaxel
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.004
Comments One-sided p-value. The p-value is associated with the point estimate comparing AZD6244 + Docetaxel vs Placebo + Docetaxel on the outcome measure.
Method ANCOVA
Comments LS means were adjusted for baseline tumour size, time from baseline scan to randomisation, WHO PS, gender, histology, and smoking status
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -26.0
Confidence Interval (2-Sided) 80%
-38.34 to -13.7
Estimation Comments (AZD6244 + Docetaxel) - (Placebo + Docetaxel)
7.Secondary Outcome
Title Alive and Progression-Free at 6 Months
Hide Description Percentage of patients alive and progression-free at 6 months
Time Frame 6 months after first dose of treatment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
MITT
Arm/Group Title AZD6244 + Docetaxel Placebo + Docetaxel
Hide Arm/Group Description:
AZD6244 75 mg bd + Docetaxel 75 mg/m^2
Placebo + Docetaxel 75 mg/m^2
Overall Number of Participants Analyzed 43 40
Measure Type: Number
Unit of Measure: percentage
37.1 15.8
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AZD6244 + Docetaxel, Placebo + Docetaxel
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0158
Comments One-sided p-value. The p-value is associated with the point estimate (e.g. HR comparing AZD6244 + Docetaxel vs Placebo + Docetaxel) on the outcome measure.
Method Log Rank
Comments Confidence interval (CI) used Greenwood's formula for the standard error of a survival estimate
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.54
Confidence Interval (2-Sided) 80%
0.37 to 0.78
Estimation Comments A hazard ratio (HR) <1 favours AZD6244 75 mg bd+Docetaxel
Time Frame Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title AZD6244 + Docetaxel Placebo + Docetaxel
Hide Arm/Group Description AZD6244 75 mg bd + Docetaxel 75 mg/m^2 Placebo + Docetaxel 75 mg/m^2
All-Cause Mortality
AZD6244 + Docetaxel Placebo + Docetaxel
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
AZD6244 + Docetaxel Placebo + Docetaxel
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   26/44 (59.09%)      13/42 (30.95%)    
Blood and lymphatic system disorders     
Febrile neutropena  1  6/44 (13.64%)  6 0/42 (0.00%)  0
Neutropena  1  3/44 (6.82%)  3 3/42 (7.14%)  3
Cardiac disorders     
Acute coronary syndrome  1  1/44 (2.27%)  1 0/42 (0.00%)  0
Atrial flutter  1  0/44 (0.00%)  0 1/42 (2.38%)  1
Cardiac arrest  1  0/44 (0.00%)  0 1/42 (2.38%)  1
Pericardial effusion  1  1/44 (2.27%)  1 0/42 (0.00%)  0
Sinus bradycardia  1  1/44 (2.27%)  1 0/42 (0.00%)  0
Gastrointestinal disorders     
Vomiting  1  1/44 (2.27%)  1 1/42 (2.38%)  1
Abdominal pain  1  1/44 (2.27%)  1 0/42 (0.00%)  0
Colitis  1  1/44 (2.27%)  1 0/42 (0.00%)  0
Dyspepsia  1  0/44 (0.00%)  0 1/42 (2.38%)  1
Gastric ulcer haemorrhage  1  1/44 (2.27%)  1 0/42 (0.00%)  0
Retroperitoneal haematoma  1  1/44 (2.27%)  1 0/42 (0.00%)  0
General disorders     
Face oedema  1  2/44 (4.55%)  2 0/42 (0.00%)  0
Pyrexia  1  1/44 (2.27%)  1 0/42 (0.00%)  0
Immune system disorders     
Drug hypersensitivity  1  1/44 (2.27%)  1 0/42 (0.00%)  0
Infections and infestations     
Pneumonia  1  4/44 (9.09%)  4 0/42 (0.00%)  0
Lower respiratory tract infection bacterial  1  1/44 (2.27%)  1 1/42 (2.38%)  1
Cystitis  1  0/44 (0.00%)  0 1/42 (2.38%)  1
Empyema  1  1/44 (2.27%)  1 0/42 (0.00%)  0
Influenza  1  0/44 (0.00%)  0 1/42 (2.38%)  1
Neutropenic infection  1  1/44 (2.27%)  1 0/42 (0.00%)  0
Respiratory tract infection viral  1  0/44 (0.00%)  0 1/42 (2.38%)  1
Sepsis  1  1/44 (2.27%)  1 0/42 (0.00%)  0
Urinary tract infection  1  1/44 (2.27%)  1 0/42 (0.00%)  0
Investigations     
Blood creatine phosphokinase increased  1  1/44 (2.27%)  1 0/42 (0.00%)  0
Creatinine renal clearance decreased  1  1/44 (2.27%)  1 0/42 (0.00%)  0
Electrocardiogram t wave inversion  1  1/44 (2.27%)  1 0/42 (0.00%)  0
Neutrophil count decreased  1  1/44 (2.27%)  1 0/42 (0.00%)  0
Metabolism and nutrition disorders     
Decreased appetite  1  0/44 (0.00%)  0 1/42 (2.38%)  1
Musculoskeletal and connective tissue disorders     
Back pain  1  0/44 (0.00%)  0 2/42 (4.76%)  2
Pain in extremity  1  0/44 (0.00%)  0 1/42 (2.38%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Tumour necrosis  1  1/44 (2.27%)  1 0/42 (0.00%)  0
Tumour pain  1  1/44 (2.27%)  1 0/42 (0.00%)  0
Nervous system disorders     
Syncope  1  1/44 (2.27%)  1 0/42 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Respiratory failure  1  3/44 (6.82%)  3 2/42 (4.76%)  2
Interstitial lung disease  1  2/44 (4.55%)  2 0/42 (0.00%)  0
Pulmonary embolism  1  2/44 (4.55%)  2 0/42 (0.00%)  0
Dyspnoea  1  0/44 (0.00%)  0 1/42 (2.38%)  1
Dyspnoea exertional  1  1/44 (2.27%)  1 0/42 (0.00%)  0
Pneumonitis  1  0/44 (0.00%)  0 1/42 (2.38%)  1
Pneumothorax  1  1/44 (2.27%)  1 0/42 (0.00%)  0
Pulmonary haemorrhage  1  1/44 (2.27%)  1 0/42 (0.00%)  0
Skin and subcutaneous tissue disorders     
Dermatitis acneiform  1  1/44 (2.27%)  1 0/42 (0.00%)  0
Psoriasis  1  1/44 (2.27%)  1 0/42 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA version 14
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
AZD6244 + Docetaxel Placebo + Docetaxel
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   43/44 (97.73%)      42/42 (100.00%)    
Blood and lymphatic system disorders     
Neutropenia  1  17/44 (38.64%)  17 15/42 (35.71%)  15
Anaemia  1  7/44 (15.91%)  7 5/42 (11.90%)  5
Febrile neutropenia  1  7/44 (15.91%)  7 0/42 (0.00%)  0
Eye disorders     
Vision blurred  1  6/44 (13.64%)  6 1/42 (2.38%)  1
Gastrointestinal disorders     
Diarrhoea  1  32/44 (72.73%)  32 7/42 (16.67%)  7
Nausea  1  19/44 (43.18%)  19 12/42 (28.57%)  12
Vomiting  1  19/44 (43.18%)  19 9/42 (21.43%)  9
Stomatitis  1  16/44 (36.36%)  16 8/42 (19.05%)  8
Constipation  1  14/44 (31.82%)  14 8/42 (19.05%)  8
Abdominal pain upper  1  8/44 (18.18%)  8 4/42 (9.52%)  4
Dyspepsia  1  8/44 (18.18%)  8 4/42 (9.52%)  4
Abdominal pain  1  8/44 (18.18%)  8 1/42 (2.38%)  1
General disorders     
Fatigue  1  12/44 (27.27%)  12 14/42 (33.33%)  14
Asthenia  1  31/44 (70.45%)  31 28/42 (66.67%)  28
Oedema peripheral  1  18/44 (40.91%)  18 7/42 (16.67%)  7
Pyrexia  1  12/44 (27.27%)  12 5/42 (11.90%)  5
Metabolism and nutrition disorders     
Decreased appetite  1  15/44 (34.09%)  15 11/42 (26.19%)  11
Dehydration  1  5/44 (11.36%)  5 1/42 (2.38%)  1
Musculoskeletal and connective tissue disorders     
Myalgia  1  6/44 (13.64%)  6 7/42 (16.67%)  7
Musculoskeletal chest pain  1  3/44 (6.82%)  3 8/42 (19.05%)  8
Arthralgia  1  2/44 (4.55%)  2 8/42 (19.05%)  8
Back pain  1  2/44 (4.55%)  2 6/42 (14.29%)  6
Nervous system disorders     
Headache  1  6/44 (13.64%)  6 5/42 (11.90%)  5
Dysgeusia  1  5/44 (11.36%)  5 2/42 (4.76%)  2
Neuropathy peripheral  1  5/44 (11.36%)  5 1/42 (2.38%)  1
Respiratory, thoracic and mediastinal disorders     
Cough  1  10/44 (22.73%)  10 8/42 (19.05%)  8
Dysonoea exertional  1  8/44 (18.18%)  8 10/42 (23.81%)  10
Dyspnoea  1  5/44 (11.36%)  5 10/42 (23.81%)  10
Epistaxis  1  7/44 (15.91%)  7 2/42 (4.76%)  2
Skin and subcutaneous tissue disorders     
Alopecia  1  13/44 (29.55%)  13 9/42 (21.43%)  9
Dermatitis acneiform  1  17/44 (38.64%)  17 2/42 (4.76%)  2
Dry skin  1  10/44 (22.73%)  10 4/42 (9.52%)  4
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA version 14
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Tracy Cunningham
Organization: AstraZeneca
Phone: 1-877-400-4656
Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT00890825     History of Changes
Other Study ID Numbers: D1532C00016
First Submitted: April 29, 2009
First Posted: April 30, 2009
Results First Submitted: June 14, 2017
Results First Posted: June 20, 2018
Last Update Posted: June 20, 2018