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Randomized Phase II Study of AZD6244 (Mitogen-activated Protein Kinase Inhibitor) MEK-Inhibitor With Erlotinib in KRAS Wild Type Advanced Non-Small Cell Lung Cancer (NSCLC) and a Randomized Phase II Study of AZD6244 With Erlotinib in Mutant KRAS Adva...

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ClinicalTrials.gov Identifier: NCT01229150
Recruitment Status : Completed
First Posted : October 27, 2010
Results First Posted : October 29, 2014
Last Update Posted : May 23, 2017
Sponsor:
Collaborators:
University of California, Davis
University of Chicago
University of Southern California
City of Hope Medical Center
Information provided by (Responsible Party):
Arun Rajan, M.D., National Institutes of Health Clinical Center (CC)

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Non Small Cell Lung Carcinoma
Interventions Drug: AZD6244
Drug: Erlotinib
Drug: AZD6244 + Erlotinib
Enrollment 89

Recruitment Details  
Pre-assignment Details 89 participants were enrolled and 79 participants started. 10 patients should be classified as screen failures. Of the 10, one died during the screening process, and one patient withdrew during the screening process.
Arm/Group Title KRAS Mut 2 KRAS Mut 1 WT KRAS 1 WT KRAS 2
Hide Arm/Group Description

KRAS Mutant patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd (every day) + erlotinib mg qd.

KRAS Mutant patients randomized to monotherapy arm

AZD6244: For KRAS mutant patients randomized to the single agent arm, AZD6244 75 mg bid (twice a day).

Wild-Type KRAS patients randomized to monotherapy arm

Erlotinib: For Wild-Type KRAS patients randomized to the single agent arm, Erlotinib 150 mg qd

Wild-Type KRAS patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd + erl mg qd.

Period Title: Overall Study
Started 30 11 19 19
Completed 28 9 19 19
Not Completed 2 2 0 0
Reason Not Completed
Toxicity             2             2             0             0
Arm/Group Title KRAS Mut 2 KRAS Mut 1 WT KRAS 1 WT KRAS 2 Total
Hide Arm/Group Description

KRAS Mutant patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd (every day) + erlotinib mg qd.

KRAS Mutant patients randomized to monotherapy arm

AZD6244: For KRAS mutant patients randomized to the single agent arm, AZD6244 75 mg bid (twice a day).

Wild-Type KRAS patients randomized to monotherapy arm

Erlotinib: For Wild-Type KRAS patients randomized to the single agent arm, Erlotinib 150 mg qd

Wild-Type KRAS patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd + erl mg qd.

Total of all reporting groups
Overall Number of Baseline Participants 30 11 19 19 79
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants 11 participants 19 participants 19 participants 79 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
16
  53.3%
5
  45.5%
11
  57.9%
10
  52.6%
42
  53.2%
>=65 years
14
  46.7%
6
  54.5%
8
  42.1%
9
  47.4%
37
  46.8%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 30 participants 11 participants 19 participants 19 participants 79 participants
66.05  (9.648) 64.31  (13.76) 63.75  (13.6) 64.84  (8.10) 65.22  (9.46)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants 11 participants 19 participants 19 participants 79 participants
Female
16
  53.3%
7
  63.6%
9
  47.4%
6
  31.6%
38
  48.1%
Male
14
  46.7%
4
  36.4%
10
  52.6%
13
  68.4%
41
  51.9%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants 11 participants 19 participants 19 participants 79 participants
Hispanic or Latino
1
   3.3%
2
  18.2%
2
  10.5%
3
  15.8%
8
  10.1%
Not Hispanic or Latino
25
  83.3%
9
  81.8%
15
  78.9%
12
  63.2%
61
  77.2%
Unknown or Not Reported
4
  13.3%
0
   0.0%
2
  10.5%
4
  21.1%
10
  12.7%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants 11 participants 19 participants 19 participants 79 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
1
   3.3%
1
   9.1%
0
   0.0%
1
   5.3%
3
   3.8%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
3
  10.0%
2
  18.2%
4
  21.1%
4
  21.1%
13
  16.5%
White
26
  86.7%
8
  72.7%
14
  73.7%
13
  68.4%
61
  77.2%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
1
   5.3%
1
   5.3%
2
   2.5%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
United States Number Analyzed 30 participants 11 participants 19 participants 19 participants 79 participants
30
 100.0%
11
 100.0%
19
 100.0%
19
 100.0%
79
 100.0%
Histology  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants 11 participants 19 participants 19 participants 79 participants
Lung Cancer Adenocarcinoma
30
 100.0%
11
 100.0%
15
  78.9%
15
  78.9%
71
  89.9%
Squamous cell
0
   0.0%
0
   0.0%
4
  21.1%
4
  21.1%
8
  10.1%
Mutational Status   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants 11 participants 19 participants 19 participants 79 participants
EGFR Mutated (L858R)
30
 100.0%
11
 100.0%
1
   5.3%
1
   5.3%
43
  54.4%
EGFR Wild Type
0
   0.0%
0
   0.0%
18
  94.7%
18
  94.7%
36
  45.6%
KRAS G12A
6
  20.0%
0
   0.0%
0
   0.0%
0
   0.0%
6
   7.6%
KRAS G12C
8
  26.7%
4
  36.4%
0
   0.0%
0
   0.0%
12
  15.2%
KRAS G12D
1
   3.3%
1
   9.1%
0
   0.0%
0
   0.0%
2
   2.5%
KRAS G12K
1
   3.3%
1
   9.1%
0
   0.0%
0
   0.0%
2
   2.5%
KRAS G12R
0
   0.0%
1
   9.1%
0
   0.0%
0
   0.0%
1
   1.3%
KRAS G12S
1
   3.3%
0
   0.0%
0
   0.0%
0
   0.0%
1
   1.3%
KRAS G12V
9
  30.0%
4
  36.4%
0
   0.0%
0
   0.0%
13
  16.5%
KRAS Q61H
2
   6.7%
0
   0.0%
0
   0.0%
0
   0.0%
2
   2.5%
KRAS Q61L
2
   6.7%
0
   0.0%
0
   0.0%
0
   0.0%
2
   2.5%
KRAS
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
[1]
Measure Description: EGFR (epidermal growth factor receptor); KRAS (Kirsten Rat Sarcoma Viral Oncogene homolog). KRAS G12A (e.g. G is glycine, 12 is the codon or position and A is amino acid alanine); C is cysteine, D is aspartic acid, K is lysine, R is arginine, S is serine, V is valine, Q is glutamine, H is histidine, and L is leucine.
Eastern Cooperative Oncology Group (ECOG)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants 11 participants 19 participants 19 participants 79 participants
0
3
  10.0%
1
   9.1%
2
  10.5%
2
  10.5%
8
  10.1%
1
14
  46.7%
5
  45.5%
11
  57.9%
7
  36.8%
37
  46.8%
2
13
  43.3%
5
  45.5%
6
  31.6%
10
  52.6%
34
  43.0%
[1]
Measure Description: ECOG Performance Status criteria: Grade 0 is normal activity. Fully active, able to carry on all pre-disease performance without restriction. Grade 1 is symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature (e.g., light housework, office work). Grade 2 is in bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours.
No. of Prior Regimens  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants 11 participants 19 participants 19 participants 79 participants
1
12
  40.0%
6
  54.5%
10
  52.6%
8
  42.1%
36
  45.6%
2
18
  60.0%
5
  45.5%
9
  47.4%
11
  57.9%
43
  54.4%
Smoking  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants 11 participants 19 participants 19 participants 79 participants
Current
9
  30.0%
0
   0.0%
0
   0.0%
0
   0.0%
9
  11.4%
Former
21
  70.0%
11
 100.0%
13
  68.4%
16
  84.2%
61
  77.2%
Never-smoker
0
   0.0%
0
   0.0%
6
  31.6%
3
  15.8%
9
  11.4%
1.Primary Outcome
Title Progression Free Survival
Hide Description Time between the first day of treatment to the day of disease progression. Progressive disease is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that's the smallest on study). In addition to the relative increase of 20% of at least 5mm. (Note: the appearance of one or more lesions is also considered progression).
Time Frame 2.1 to 4 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title KRAS Mut 2 KRAS Mut 1 WT KRAS 1 WT KRAS 2
Hide Arm/Group Description:

KRAS Mutant patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd (every day) + erlotinib mg qd.

KRAS Mutant patients randomized to monotherapy arm

AZD6244: For KRAS mutant patients randomized to the single agent arm, AZD6244 75 mg bid (twice a day).

Wild-Type KRAS patients randomized to monotherapy arm

Erlotinib: For Wild-Type KRAS patients randomized to the single agent arm, Erlotinib 150 mg qd

Wild-Type KRAS patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd + erl mg qd.

Overall Number of Participants Analyzed 30 11 19 19
Median (95% Confidence Interval)
Unit of Measure: Months
2.3
(2.0 to 4.6)
4.0
(2.9 to 7.8)
2.4
(1.3 to 3.7)
2.1
(1.8 to 5.1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection KRAS Mut 2, KRAS Mut 1
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.24
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection WT KRAS 1, WT KRAS 2
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.75
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
2.Primary Outcome
Title Objective Response
Hide Description Objective response is complete response + partial response. Complete response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10mm. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Time Frame Up to 37 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
There were no partial or complete responses in the KRAS mut 1 arm.
Arm/Group Title KRAS Mut 2 KRAS Mut 1 WT KRAS 1 WT KRAS 2
Hide Arm/Group Description:

KRAS Mutant patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd (every day) + erlotinib mg qd.

KRAS Mutant patients randomized to monotherapy arm

AZD6244: For KRAS mutant patients randomized to the single agent arm, AZD6244 75 mg bid (twice a day).

Wild-Type KRAS patients randomized to monotherapy arm

Erlotinib: For Wild-Type KRAS patients randomized to the single agent arm, Erlotinib 150 mg qd

Wild-Type KRAS patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd + erl mg qd.

Overall Number of Participants Analyzed 30 11 19 19
Measure Type: Number
Unit of Measure: participants
3 0 1 2
3.Secondary Outcome
Title Number of Participants With Adverse Events
Hide Description Here is the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.
Time Frame 42 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The combination of toxicities allows for a more robust understanding of the combined therapy toxicities. The dosage of the combination of erlotinib plus AZD6244 was the same whether the pt has a KRAS mutation versus KRAS wild type. KRAS is a molecular mutation and does not change whether or not a pt has toxicities to the combination of therapies.
Arm/Group Title KRAS Mut 2 & WT KRAS 2 KRAS Mut 1 WT KRAS 1
Hide Arm/Group Description:

KRAS Mutant patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS 2 patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd (every day) + erlotinib mg qd.

KRAS Mutant patients randomized to monotherapy arm

AZD6244: For KRAS mutant patients randomized to the single agent arm, AZD6244 75 mg bid (twice a day).

Wild-Type KRAS patients randomized to monotherapy arm

Erlotinib: For Wild-Type KRAS patients randomized to the single agent arm, Erlotinib 150 mg qd

Overall Number of Participants Analyzed 49 11 19
Measure Type: Number
Unit of Measure: Participants
49 9 18
4.Secondary Outcome
Title Percentage of Participants With Disease Control/Stabilization
Hide Description Disease control/stabilization is the percentage of participants with partial response (PR) + complete response (CR) + stable disease (SD). Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Complete response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10mm. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. (Note: the appearance of one or more new lesions is also considered progressions.), taking as reference the smallest sum diameters.
Time Frame 3 cycles or up to 84 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title KRAS Mut 2 KRAS Mut 1 WT KRAS 1 WT KRAS 2
Hide Arm/Group Description:

KRAS Mutant patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd (every day) + erlotinib mg qd.

KRAS Mutant patients randomized to monotherapy arm

AZD6244: For KRAS mutant patients randomized to the single agent arm, AZD6244 75 mg bid (twice a day).

Wild-Type KRAS patients randomized to monotherapy arm

Erlotinib: For Wild-Type KRAS patients randomized to the single agent arm, Erlotinib 150 mg qd

Wild-Type KRAS patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd + erl mg qd.

Overall Number of Participants Analyzed 30 11 19 19
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
43
(25.5 to 52.6)
89
(51.8 to 99.7)
47
(24.4 to 71.1)
35.3
(14.2 to 61.7)
5.Secondary Outcome
Title Overall Survival
Hide Description Time between the first day of treatment to the time of death.
Time Frame Up to 26 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title KRAS Mut 2 KRAS Mut 1 WT KRAS 1 WT KRAS 2
Hide Arm/Group Description:

KRAS Mutant patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd (every day) + erlotinib mg qd.

KRAS Mutant patients randomized to monotherapy arm

AZD6244: For KRAS mutant patients randomized to the single agent arm, AZD6244 75 mg bid (twice a day).

Wild-Type KRAS patients randomized to monotherapy arm

Erlotinib: For Wild-Type KRAS patients randomized to the single agent arm, Erlotinib 150 mg qd

Wild-Type KRAS patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd + erl mg qd.

Overall Number of Participants Analyzed 30 11 19 19
Median (95% Confidence Interval)
Unit of Measure: Months
21.8 [1] 
(5.7 to NA)
10.5 [1] 
(5.7 to NA)
6.3
(2.6 to 19.5)
12.9
(3.5 to 25.4)
[1]
The upper end of the confidence interval is undefined because there were too few events to calculate.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection WT KRAS 1, WT KRAS 2
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.51
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection KRAS Mut 2, KRAS Mut 1
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.81
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
6.Secondary Outcome
Title Percentage of Th17 in Cluster of Differentiation 4 (CD4)+T Cells at Baseline in Relation to Response
Hide Description First the number of T cells that are CD4+ is determined by staining with an antibody to CD4 and measured in a flow cytometer. Then the number of Th17+ cells is determined by staining with an antibody to IL-17 and measured in a flow cytometer. Then the percentage of CD4+ cells that are also Th17 cells is determined as a simple ratio, i.e. Th17cells/CD4 cells. This ratio is reported here for each category of KRAS mutation status for whom we had patients.
Time Frame Pretreatment - Cycle 1 Day 1
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
No participants were analyzed in the WT KRAS 1 cohort because no samples were available for analysis. For all other cohorts, the numbers analyzed indicates some samples were either not drawn or could not be located.
Arm/Group Title KRAS Mut 2 KRAS Mut 1 WT KRAS 2
Hide Arm/Group Description:

KRAS Mutant patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd (every day) + erlotinib mg qd.

KRAS Mutant patients randomized to monotherapy arm

AZD6244: For KRAS mutant patients randomized to the single agent arm, AZD6244 75 mg bid (twice a day).

Wild-Type KRAS patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd + erl mg qd.

Overall Number of Participants Analyzed 15 4 9
Mean (Standard Deviation)
Unit of Measure: Percentage of Th17 in CD4+T Cells
0.19  (0.18) 0.11  (0.05) 0.34  (0.27)
7.Secondary Outcome
Title Number of Participants With a Reduction in Phosphorylated Extracellular Signal-Regulated Kinases (p-ERK) in Lymphocytes
Hide Description Level of p-ERK was measured by the median channel cumber of fluorescence intensity. Data are relative to the level before therapy begins(C1D1).Then we see what the level was after therapy & compare. Every value after therapy is compared to pre-therapy, & every patient is their own control. To do that, we make C1D1 equal to 1 for every patient & then compare the pERK level after therapy by looking at the fold change in pERK level.
Time Frame Cycle 1 Day 1 pre-treatment with Cycle 1 Day 2 (1 day after starting treatment), and Cycle 1 Day 14 (2 weeks after starting treatment)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Re: number of participants analyzed: Samples were either not drawn or could not be located. WT KRAS 1/WT KRAS 2 are missing because the effect of treatment on the Ras-Raf-MEK-ERK pathway as measured by a reduction in phosphorylated extracellular signal-regulated kinases (p-ERK) in lymphocytes was evaluated in patients with KRAS-mutated tumors only.
Arm/Group Title KRAS Mut 2 KRAS Mut 1
Hide Arm/Group Description:

KRAS Mutant patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd (every day) + erlotinib mg qd.

KRAS Mutant patients randomized to monotherapy arm

AZD6244: For KRAS mutant patients randomized to the single agent arm, AZD6244 75 mg bid (twice a day).

Overall Number of Participants Analyzed 17 4
Measure Type: Number
Unit of Measure: participants
Cycle 1 Day 1 NA [1]  NA [1] 
Cycle 1 day 2 17 4
Cycle 1 day 14 14 2
[1]
C1D1 is NA because every other time point, pERK level was normalized against C1D1; all the C1D1 values were set to 1.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection KRAS Mut 1
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0007
Comments P-value was determined by comparison by the level of p-ERK at cycle 1 day 1 to cycle 1 day 2.
Method Wilcoxon matched-pairs signed rank test
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection KRAS Mut 1
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments P-value was determined by comparison by the level of p-ERK at cycle 1 day 1 to cycle 1 day 14.
Method Wilcoxon matched-pairs signed rank test
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection KRAS Mut 1
Comments 4 patients in this group; statistically underpowered.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0209
Comments P-value was determined by comparison by the level of p-ERK at cycle 1 day 2 and cycle 1 day 14.
Method Wilcoxon matched-pairs signed rank test
Comments [Not Specified]
8.Other Pre-specified Outcome
Title Number of Participants With Changes in a Tumor's MIB-1 (Ki-67) Rate
Hide Description Changes in a tumor's MIB-1 (Ki-67) rate was to be assessed by immunohistochemistry.
Time Frame At enrollment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Tumor MIB-1 (Ki-67) rate testing was not done because it was too costly.
Arm/Group Title KRAS Mut 2 KRAS Mut 1 WT KRAS 1 WT KRAS 2
Hide Arm/Group Description:

KRAS Mutant patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd (every day) + erlotinib mg qd.

KRAS Mutant patients randomized to monotherapy arm

AZD6244: For KRAS mutant patients randomized to the single agent arm, AZD6244 75 mg bid (twice a day).

Wild-Type KRAS patients randomized to monotherapy arm

Erlotinib: For Wild-Type KRAS patients randomized to the single agent arm, Erlotinib 150 mg qd

Wild-Type KRAS patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd + erl mg qd.

Overall Number of Participants Analyzed 0 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
9.Other Pre-specified Outcome
Title Change in T Cell Immunoglobulin Mucin 3 (TIM-3) on Tregs
Hide Description Fold change from cycle 1 day 1 was determined by TIM-3 expression level on Tregs measured by the median channel number of fluorescence intensity.
Time Frame Cycle 1 Day 1 pre-treatment with Cycle 1 Day 2 (1 day after starting treatment), and Cycle 1 Day 14 (2 weeks after starting treatment)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
These are exploratory results and a normal range has not been defined for fold change. No participants were analyzed in the WT KRAS 1 cohort because no samples were available for analysis. Missing numbers in the other cohorts were either not drawn, misplaced or the samples were not viable.
Arm/Group Title KRAS Mut 2 KRAS Mut 1 WT KRAS 2
Hide Arm/Group Description:

KRAS Mutant patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd (every day) + erlotinib mg qd.

KRAS Mutant patients randomized to monotherapy arm

AZD6244: For KRAS mutant patients randomized to the single agent arm, AZD6244 75 mg bid (twice a day).

Wild-Type KRAS patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd + erl mg qd.

Overall Number of Participants Analyzed 17 4 8
Mean (Standard Deviation)
Unit of Measure: Fold change
Cycle 1 Day 2 1.01  (0.09) 1.01  (0.12) 1.11  (0.13)
Cycle 1 Day 14 0.98  (0.10) 0.84  (0.07) 0.96  (0.11)
10.Other Pre-specified Outcome
Title Change in Cytotoxic T-lymphocyte Associated Protein 4 (CTLA-4) Expression on Tregs
Hide Description The fold change from cycle 1 day 1 was determined by the level of CTLA-4 expression on Tregs measured by the median channel number of fluorescence intensity.
Time Frame Cycle 1 Day 1 pre-treatment with Cycle 1 Day 2 (1 day after starting treatment), and Cycle 1 Day 14 (2 weeks after starting treatment)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
These are exploratory results and a normal range has not been defined for fold change. No participants were analyzed in the WT KRAS 1 cohort because no samples were available for analysis. Missing numbers in the other cohorts were either not drawn, misplaced or the samples were not viable.
Arm/Group Title KRAS Mut 2 KRAS Mut 1 WT KRAS 2
Hide Arm/Group Description:

KRAS Mutant patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd (every day) + erlotinib mg qd.

KRAS Mutant patients randomized to monotherapy arm

AZD6244: For KRAS mutant patients randomized to the single agent arm, AZD6244 75 mg bid (twice a day).

Wild-Type KRAS patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd + erl mg qd.

Overall Number of Participants Analyzed 17 4 10
Mean (Standard Deviation)
Unit of Measure: Fold change
Cycle 1 Day 2 0.95  (0.17) 0.85  (0.10) 1.15  (0.28)
Cycle 1 Day 14 1.25  (0.46) 0.89  (0.29) 1.49  (0.61)
11.Other Pre-specified Outcome
Title Change in Programmed Cell Death-1 (PD-1) Expression on Tregs
Hide Description Fold change from cycle 1 day 1 was determined by the PD-1 expression level on Tregs measured by the median channel number of fluorescence intensity.
Time Frame Cycle 1 Day 1 pre-treatment with Cycle 1 Day 2 (1 day after starting treatment), and Cycle 1 Day 14 (2 weeks after starting treatment)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
These are exploratory results and a normal range has not been defined for fold change. No participants were analyzed in the WT KRAS 1 cohort because no samples were available for analysis. Missing numbers in the other cohorts were either not drawn, misplaced or the samples were not viable.
Arm/Group Title KRAS Mut 2 KRAS Mut 1 WT KRAS 2
Hide Arm/Group Description:

KRAS Mutant patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd (every day) + erlotinib mg qd.

KRAS Mutant patients randomized to monotherapy arm

AZD6244: For KRAS mutant patients randomized to the single agent arm, AZD6244 75 mg bid (twice a day).

Wild-Type KRAS patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd + erl mg qd.

Overall Number of Participants Analyzed 17 4 10
Mean (Standard Deviation)
Unit of Measure: Fold change
Cycle 1 Day 2 0.99  (0.28) 0.96  (0.09) 1.33  (0.57)
Cycle 1 Day 14 1.31  (0.42) 0.98  (0.04) 2.31  (1.77)
12.Other Pre-specified Outcome
Title Change in Programmed Cell Death-1 (PD-1) Expression on Cluster of Differentiation 8 (CD8)+T Cells
Hide Description Fold change from cycle 1 day 1 was determined by programmed cell death-1 (PD-1) expression on CD8+ T cells measured by the median channel number of fluorescence intensity.
Time Frame Cycle 1 Day 1 pre-treatment with Cycle 1 Day 2 (1 day after starting treatment), and Cycle 1 Day 14 (2 weeks after starting treatment)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
These are exploratory results and a normal range has not been defined for fold change. No participants were analyzed in the WT KRAS 1 cohort because no samples were available for analysis. Missing numbers in the other cohorts were either not drawn, misplaced or the samples were not viable.
Arm/Group Title KRAS Mut 2 KRAS Mut 1 WT KRAS 2
Hide Arm/Group Description:

KRAS Mutant patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd (every day) + erlotinib mg qd.

KRAS Mutant patients randomized to monotherapy arm

AZD6244: For KRAS mutant patients randomized to the single agent arm, AZD6244 75 mg bid (twice a day).

Wild-Type KRAS patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd + erl mg qd.

Overall Number of Participants Analyzed 17 4 10
Mean (Standard Deviation)
Unit of Measure: Fold change
Cycel 1 Day 2 1.05  (0.15) 1.09  (0.33) 1.19  (0.40)
Cycle 1 Day 14 1.16  (0.27) 1.14  (0.34) 1.26  (0.25)
13.Other Pre-specified Outcome
Title Phospho-ERK (p-ERK), Phospho Protein Kinase B (p-AKt) and Phosphatase and Tensin Homolog (PTEN) Expression Testing
Hide Description p-ERK, p-AKt and PTEN protein expression testing was to be assessed by immunohistochemistry.
Time Frame At enrollment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Zero participants were analyzed because most of the immunohistochemistry (IHC) specialty assays (e.g. IHC, fluoresense in situ hybridization (FISH), polymerase chain reaction (PCR) were not available (still are not performed in path) and required funding for development that was not provided.
Arm/Group Title KRAS Mut 2 KRAS Mut 1 WT KRAS 1 WT KRAS 2
Hide Arm/Group Description:

KRAS Mutant patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd (every day) + erlotinib mg qd.

KRAS Mutant patients randomized to monotherapy arm

AZD6244: For KRAS mutant patients randomized to the single agent arm, AZD6244 75 mg bid (twice a day).

Wild-Type KRAS patients randomized to monotherapy arm

Erlotinib: For Wild-Type KRAS patients randomized to the single agent arm, Erlotinib 150 mg qd

Wild-Type KRAS patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd + erl mg qd.

Overall Number of Participants Analyzed 0 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
14.Other Pre-specified Outcome
Title Number of Participants With Overexpression of Estimated Glomerular Filtration Rate (EGFR) and c-MET
Hide Description Number of participants with over expression of EGFR and c-MET was to be assessed by fluoresense in situ hybridization (FISH).
Time Frame At enrollment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Zero participants were analyzed because most of the immunohistochemistry (IHC) specialty assays (e.g. IHC, fluoresense in situ hybridization (FISH), polymerase chain reaction (PCR) were not available (still are not performed in path) and required funding for development that was not provided.
Arm/Group Title KRAS Mut 2 KRAS Mut 1 WT KRAS 1 WT KRAS 2
Hide Arm/Group Description:

KRAS Mutant patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd (every day) + erl (erlotinib) mg qd.

KRAS Mutant patients randomized to monotherapy arm

AZD6244: For KRAS mutant patients randomized to the single agent arm, AZD6244 75 mg bid (twice a day).

Wild-Type KRAS patients randomized to monotherapy arm

Erlotinib: For Wild-Type KRAS patients randomized to the single agent arm, Erlotinib 150 mg qd (every day)

Wild-Type KRAS patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd (every day) + erl (erlotinib) mg qd.

Overall Number of Participants Analyzed 0 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
15.Other Pre-specified Outcome
Title Number of Participants Who Underwent Mutational Analysis for Estimated Glomerular Filtration Rate (EGFR), Mitogen-activated Protein Kinase 1 (MEK 1), Proto-oncogene B-Raf (BRAF), and LKB1
Hide Description Number of participants who underwent mutational analysis for EGFR, MEK 1, BRAF, and LKB1 was to be assessed by polymerase chain reaction (PCR).
Time Frame At enrollment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Zero participants were analyzed because most of the immunohistochemistry (IHC) specialty assays (e.g. IHC, fluoresense in situ hybridization (FISH), polymerase chain reaction (PCR) were not available (still are not performed in path) and required funding for development that was not provided.
Arm/Group Title KRAS Mut 2 KRAS Mut 1 WT KRAS 1 WT KRAS 2
Hide Arm/Group Description:

KRAS Mutant patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd (every day) + erlotinib mg qd.

KRAS Mutant patients randomized to monotherapy arm

AZD6244: For KRAS mutant patients randomized to the single agent arm, AZD6244 75 mg bid (twice a day).

Wild-Type KRAS patients randomized to monotherapy arm

Erlotinib: For Wild-Type KRAS patients randomized to the single agent arm, Erlotinib 150 mg qd

Wild-Type KRAS patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd + erl mg qd.

Overall Number of Participants Analyzed 0 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
Time Frame [Not Specified]
Adverse Event Reporting Description The combination of toxicities allows for a more robust understanding of the combined therapy toxicities. The dosage of the combination of erlotinib plus AZD6244 was the same whether the pt has a KRAS mutation versus KRAS wild type. KRAS is a molecular mutation and does not change whether or not a pt has toxicities to the combination of therapies.
 
Arm/Group Title KRAS Mut 2 & WT KRAS 2 KRAS Mut 1 WT KRAS 1
Hide Arm/Group Description

KRAS Mutant patients randomized to combination therapy arm

AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS 2 patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd (every day) + erlotinib mg qd.

KRAS Mutant patients randomized to monotherapy arm

AZD6244: For KRAS mutant patients randomized to the single agent arm, AZD6244 75 mg bid (twice a day).

Wild-Type KRAS patients randomized to monotherapy arm

Erlotinib: For Wild-Type KRAS patients randomized to the single agent arm, Erlotinib 150 mg qd

All-Cause Mortality
KRAS Mut 2 & WT KRAS 2 KRAS Mut 1 WT KRAS 1
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   17/49 (34.69%)      4/11 (36.36%)      8/19 (42.11%)    
Show Serious Adverse Events Hide Serious Adverse Events
KRAS Mut 2 & WT KRAS 2 KRAS Mut 1 WT KRAS 1
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   30/49 (61.22%)      6/11 (54.55%)      11/19 (57.89%)    
Blood and lymphatic system disorders       
Anemia  1  3/49 (6.12%)  4 0/11 (0.00%)  0 0/19 (0.00%)  0
Cardiac disorders       
Atrial fibrillation  1  1/49 (2.04%)  1 1/11 (9.09%)  1 0/19 (0.00%)  0
Heart failure  1  1/49 (2.04%)  1 1/11 (9.09%)  1 0/19 (0.00%)  0
Cardiac disorders - Other, specify (left ventricular systolic dysfunction)  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Myocardial infarction  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Pericardial effusion  1  2/49 (4.08%)  2 0/11 (0.00%)  0 0/19 (0.00%)  0
Gastrointestinal disorders       
Abdominal pain  1  1/49 (2.04%)  1 1/11 (9.09%)  1 0/19 (0.00%)  0
Constipation  1  1/49 (2.04%)  1 1/11 (9.09%)  1 0/19 (0.00%)  0
Ileal obstruction  1  0/49 (0.00%)  0 1/11 (9.09%)  1 0/19 (0.00%)  0
Nausea  1  3/49 (6.12%)  3 1/11 (9.09%)  1 0/19 (0.00%)  0
Vomiting  1  2/49 (4.08%)  2 1/11 (9.09%)  1 0/19 (0.00%)  0
Diarrhea  1  6/49 (12.24%)  6 0/11 (0.00%)  0 0/19 (0.00%)  0
Dysphagia  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Gastric hemorrhage  1  3/49 (6.12%)  3 0/11 (0.00%)  0 0/19 (0.00%)  0
Gastrointestinal disorders - Other, specify (bile duct obstruction)  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
General disorders       
Death NOS  1  16/49 (32.65%)  16 4/11 (36.36%)  4 8/19 (42.11%)  8
Fatigue  1  6/49 (12.24%)  6 1/11 (9.09%)  1 0/19 (0.00%)  0
Edema limbs  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Infections and infestations       
Lung infection  1  1/49 (2.04%)  1 1/11 (9.09%)  1 1/19 (5.26%)  1
Investigations       
INR increased  1  1/49 (2.04%)  1 0/11 (0.00%)  0 1/19 (5.26%)  1
Creatinine increased  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Ejection fraction decreased  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Metabolism and nutrition disorders       
Dehydration  1  6/49 (12.24%)  6 0/11 (0.00%)  0 0/19 (0.00%)  0
Hypoalbuminemia  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Hyponatremia  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Chest wall pain  1  1/49 (2.04%)  1 1/11 (9.09%)  1 0/19 (0.00%)  0
Generalized muscle weakness  1  1/49 (2.04%)  1 1/11 (9.09%)  1 0/19 (0.00%)  0
Muscle weakness lower limb  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Neoplasms benign, malignant and unspecified  1 [1]  4/49 (8.16%)  4 0/11 (0.00%)  0 2/19 (10.53%)  2
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify  1 [2]  4/49 (8.16%)  4 0/11 (0.00%)  0 0/19 (0.00%)  0
Nervous system disorders       
Transient ischemic attacks  1  0/49 (0.00%)  0 0/11 (0.00%)  0 1/19 (5.26%)  1
Nervous system disorders - Other, specify  1 [3]  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Psychiatric disorders       
Confusion  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Renal and urinary disorders       
Acute kidney injury  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Dyspnea  1  4/49 (8.16%)  4 0/11 (0.00%)  0 2/19 (10.53%)  2
Adult respiratory distress syndrome  1  1/49 (2.04%)  2 0/11 (0.00%)  0 0/19 (0.00%)  0
Hypoxia  1  2/49 (4.08%)  3 0/11 (0.00%)  0 0/19 (0.00%)  0
Pleural effusion  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Pneumonitis  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Respiratory failure  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Vascular disorders       
Hypertension  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Hypotension  1  2/49 (4.08%)  2 0/11 (0.00%)  0 0/19 (0.00%)  0
Thromboembolic event  1  2/49 (4.08%)  2 0/11 (0.00%)  0 0/19 (0.00%)  0
1
Term from vocabulary, CTCAE (4.0)
Indicates events were collected by systematic assessment
[1]
(inclu cysts and polyps) - Other specify (death)
[2]
progressive disease; disease progression
[3]
sudden left leg numbness
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
KRAS Mut 2 & WT KRAS 2 KRAS Mut 1 WT KRAS 1
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   49/49 (100.00%)      9/11 (81.82%)      18/19 (94.74%)    
Blood and lymphatic system disorders       
Anemia  1  24/49 (48.98%)  54 4/11 (36.36%)  4 2/19 (10.53%)  4
Cardiac disorders       
Palpitations  1  0/49 (0.00%)  0 0/11 (0.00%)  0 2/19 (10.53%)  2
Sinus tachycardia  1  7/49 (14.29%)  7 0/11 (0.00%)  0 1/19 (5.26%)  1
Cardiac disorders - Other, specify  1 [1]  0/49 (0.00%)  0 1/11 (9.09%)  2 0/19 (0.00%)  0
Heart failure  1  0/49 (0.00%)  0 1/11 (9.09%)  1 0/19 (0.00%)  0
Left ventricular systolic dysfunction  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Ventricular tachycardia  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Ear and labyrinth disorders       
Tinnitus  1  1/49 (2.04%)  2 0/11 (0.00%)  0 1/19 (5.26%)  1
Ear pain  1  2/49 (4.08%)  2 0/11 (0.00%)  0 0/19 (0.00%)  0
Vertigo  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Endocrine disorders       
Cushingoid  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Hypothryoidism  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Eye disorders       
Dry eye  1  6/49 (12.24%)  7 0/11 (0.00%)  0 2/19 (10.53%)  2
Floaters  1  2/49 (4.08%)  3 1/11 (9.09%)  1 1/19 (5.26%)  1
Blurred vision  1  10/49 (20.41%)  13 0/11 (0.00%)  0 0/19 (0.00%)  0
Eye disorders- Other, specify  1 [2]  4/49 (8.16%)  5 0/11 (0.00%)  0 0/19 (0.00%)  0
Eye pain  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Eyelid function disorder  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Watering eyes  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Gastrointestinal disorders       
Abdominal pain  1  9/49 (18.37%)  11 1/11 (9.09%)  2 3/19 (15.79%)  4
Cheilitis  1  4/49 (8.16%)  4 1/11 (9.09%)  2 1/19 (5.26%)  1
Constipation  1  6/49 (12.24%)  7 5/11 (45.45%)  9 1/19 (5.26%)  1
Diarrhea  1  43/49 (87.76%)  94 4/11 (36.36%)  6 8/19 (42.11%)  16
Dry mouth  1  6/49 (12.24%)  7 3/11 (27.27%)  3 3/19 (15.79%)  3
Dyspepsia  1  7/49 (14.29%)  9 1/11 (9.09%)  1 1/19 (5.26%)  1
Flatulence  1  0/49 (0.00%)  0 0/11 (0.00%)  0 1/19 (5.26%)  1
Gastroesophageal reflux disease  1  3/49 (6.12%)  4 0/11 (0.00%)  0 2/19 (10.53%)  2
Mucositis oral  1  11/49 (22.45%)  15 1/11 (9.09%)  1 1/19 (5.26%)  1
Nausea  1  27/49 (55.10%)  48 3/11 (27.27%)  5 9/19 (47.37%)  11
Stomach pain  1  3/49 (6.12%)  3 0/11 (0.00%)  0 1/19 (5.26%)  1
Vomiting  1  19/49 (38.78%)  38 1/11 (9.09%)  1 2/19 (10.53%)  2
Esophageal pain  1  0/49 (0.00%)  0 1/11 (9.09%)  1 0/19 (0.00%)  0
Bloating  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Dysphagia  1  2/49 (4.08%)  2 0/11 (0.00%)  0 0/19 (0.00%)  0
Esophagitis  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Gastric hemorrhage  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Gastrointestinal disorders - Other, specify (bloody stools)  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Gastrointestinal pain  1  2/49 (4.08%)  2 0/11 (0.00%)  0 0/19 (0.00%)  0
Hemorrhoidal hemorrhage  1  2/49 (4.08%)  2 0/11 (0.00%)  0 0/19 (0.00%)  0
Hemorrhoids  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Oral dysesthesia  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Oral pain  1  2/49 (4.08%)  4 0/11 (0.00%)  0 0/19 (0.00%)  0
Rectal hemorrhage  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
General disorders       
Chills  1  7/49 (14.29%)  8 0/11 (0.00%)  0 3/19 (15.79%)  3
Edema limbs  1  19/49 (38.78%)  26 6/11 (54.55%)  10 2/19 (10.53%)  3
Fatigue  1  25/49 (51.02%)  47 2/11 (18.18%)  4 6/19 (31.58%)  7
Fever  1  6/49 (12.24%)  6 1/11 (9.09%)  1 2/19 (10.53%)  2
Non-cardiac chest pain  1  1/49 (2.04%)  2 0/11 (0.00%)  0 2/19 (10.53%)  2
Pain  1  10/49 (20.41%)  12 3/11 (27.27%)  4 2/19 (10.53%)  2
Edema face  1  4/49 (8.16%)  6 1/11 (9.09%)  1 0/19 (0.00%)  0
Malaise  1  1/49 (2.04%)  1 1/11 (9.09%)  1 0/19 (0.00%)  0
Death NOS  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Flu like symptoms  1  2/49 (4.08%)  2 0/11 (0.00%)  0 0/19 (0.00%)  0
Gait disturbance  1  2/49 (4.08%)  3 0/11 (0.00%)  0 0/19 (0.00%)  0
General disorders and adminstration site conditions - Other, specify  1 [3]  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Infections and infestations       
Conjunctivitis  1  1/49 (2.04%)  1 0/11 (0.00%)  0 1/19 (5.26%)  2
Infections and infestations-Other, specify  1 [4]  0/49 (0.00%)  0 0/11 (0.00%)  0 1/19 (5.26%)  1
Lung infection  1  3/49 (6.12%)  3 0/11 (0.00%)  0 1/19 (5.26%)  1
Paronychia  1  9/49 (18.37%)  13 0/11 (0.00%)  0 2/19 (10.53%)  4
Skin infection  1  1/49 (2.04%)  1 1/11 (9.09%)  1 2/19 (10.53%)  3
Upper respiratory infection  1  6/49 (12.24%)  6 1/11 (9.09%)  1 1/19 (5.26%)  1
Urinary tract infection  1  5/49 (10.20%)  5 0/11 (0.00%)  0 2/19 (10.53%)  3
Mucosal infection  1  0/49 (0.00%)  0 1/11 (9.09%)  1 0/19 (0.00%)  0
Otitis externa  1  2/49 (4.08%)  2 0/11 (0.00%)  0 0/19 (0.00%)  0
Otitis media  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Periorbital infection  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Sinusitis  1  2/49 (4.08%)  2 0/11 (0.00%)  0 0/19 (0.00%)  0
Vaginal infection  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Investigations       
Activated partial thromboplastin time prolonged  1  3/49 (6.12%)  3 1/11 (9.09%)  1 2/19 (10.53%)  4
Alanine aminotransferase increased  1  27/49 (55.10%)  51 5/11 (45.45%)  7 4/19 (21.05%)  6
Aspartate aminotransferase increased  1  34/49 (69.39%)  65 5/11 (45.45%)  10 4/19 (21.05%)  7
Blood bilirubin increased  1  13/49 (26.53%)  16 0/11 (0.00%)  0 2/19 (10.53%)  4
CPK increased  1  15/49 (30.61%)  39 5/11 (45.45%)  10 1/19 (5.26%)  1
Creatinine increased  1  13/49 (26.53%)  19 2/11 (18.18%)  2 2/19 (10.53%)  2
Lymphocyte count decreased  1  21/49 (42.86%)  56 1/11 (9.09%)  1 8/19 (42.11%)  9
Platelet count decreased  1  14/49 (28.57%)  23 3/11 (27.27%)  3 1/19 (5.26%)  1
Weight loss  1  10/49 (20.41%)  12 0/11 (0.00%)  0 2/19 (10.53%)  2
Alkaline phosphatase increased  1  13/49 (26.53%)  19 3/11 (27.27%)  4 0/19 (0.00%)  0
White blood cell decreased  1  8/49 (16.33%)  9 2/11 (18.18%)  5 0/19 (0.00%)  0
Ejection fraction decreased  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
INR increased  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Neutrophil count decreased  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Metabolism and nutrition disorders       
Anorexia  1  17/49 (34.69%)  23 4/11 (36.36%)  4 9/19 (47.37%)  10
Hyperkalemia  1  4/49 (8.16%)  4 2/11 (18.18%)  2 2/19 (10.53%)  2
Hypermagnesemia  1  2/49 (4.08%)  2 0/11 (0.00%)  0 1/19 (5.26%)  1
Hypernatremia  1  2/49 (4.08%)  3 0/11 (0.00%)  0 1/19 (5.26%)  3
Hypoalbuminemia  1  36/49 (73.47%)  64 7/11 (63.64%)  9 5/19 (26.32%)  6
Hypoglycemia  1  5/49 (10.20%)  6 0/11 (0.00%)  0 2/19 (10.53%)  7
Hypokalemia  1  11/49 (22.45%)  13 1/11 (9.09%)  1 1/19 (5.26%)  1
Hypomagnesemia  1  19/49 (38.78%)  29 3/11 (27.27%)  5 4/19 (21.05%)  4
Hyponatremia  1  22/49 (44.90%)  31 0/11 (0.00%)  0 4/19 (21.05%)  11
Hypophosphatemia  1  9/49 (18.37%)  15 1/11 (9.09%)  2 4/19 (21.05%)  6
Hypercalcemia  1  6/49 (12.24%)  7 2/11 (18.18%)  4 0/19 (0.00%)  0
Hyperglycemia  1  5/49 (10.20%)  6 2/11 (18.18%)  3 0/19 (0.00%)  0
Hyperuricemia  1  2/49 (4.08%)  2 1/11 (9.09%)  3 0/19 (0.00%)  0
Dehydration  1  6/49 (12.24%)  8 0/11 (0.00%)  0 0/19 (0.00%)  0
Hypocalcemia  1  5/49 (10.20%)  6 0/11 (0.00%)  0 0/19 (0.00%)  0
Metabolism and nutrition disorders - Other, specify  1 [5]  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Back pain  1  5/49 (10.20%)  5 0/11 (0.00%)  0 1/19 (5.26%)  1
Bone pain  1  1/49 (2.04%)  1 0/11 (0.00%)  0 1/19 (5.26%)  1
Chest wall pain  1  1/49 (2.04%)  2 1/11 (9.09%)  1 1/19 (5.26%)  1
Flank pain  1  0/49 (0.00%)  0 0/11 (0.00%)  0 1/19 (5.26%)  1
Myalgia  1  5/49 (10.20%)  5 0/11 (0.00%)  0 2/19 (10.53%)  2
Pain in extremity  1  5/49 (10.20%)  6 1/11 (9.09%)  1 2/19 (10.53%)  2
Arthritis  1  0/49 (0.00%)  0 1/11 (9.09%)  1 0/19 (0.00%)  0
Myositis  1  0/49 (0.00%)  0 1/11 (9.09%)  2 0/19 (0.00%)  0
Neck pain  1  0/49 (0.00%)  0 1/11 (9.09%)  2 0/19 (0.00%)  0
Arthralgia  1  3/49 (6.12%)  3 0/11 (0.00%)  0 0/19 (0.00%)  0
Buttock pain  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Neoplasms benign, malignant and unspecified (incl cysts and polyps)  1 [6]  0/49 (0.00%)  0 0/11 (0.00%)  0 1/19 (5.26%)  1
Tumor pain  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Nervous system disorders       
Dysgeusia  1  12/49 (24.49%)  13 1/11 (9.09%)  1 1/19 (5.26%)  3
Headache  1  9/49 (18.37%)  12 0/11 (0.00%)  0 3/19 (15.79%)  4
Paresthesia  1  3/49 (6.12%)  3 0/11 (0.00%)  0 1/19 (5.26%)  1
Nervous system disorders - Other, specify  1 [7]  0/49 (0.00%)  0 1/11 (9.09%)  1 0/19 (0.00%)  0
Peripheral sensory neuropathy  1  1/49 (2.04%)  1 1/11 (9.09%)  3 0/19 (0.00%)  0
Ataxia  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Dizziness  1  13/49 (26.53%)  14 0/11 (0.00%)  0 0/19 (0.00%)  0
Dysesthesia  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Lethargy  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Nervous system disorders - Other, specify  1 [8]  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Presyncope  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Syncope  1  3/49 (6.12%)  3 0/11 (0.00%)  0 0/19 (0.00%)  0
Psychiatric disorders       
Anxiety  1  1/49 (2.04%)  1 0/11 (0.00%)  0 3/19 (15.79%)  4
Depression  1  1/49 (2.04%)  1 1/11 (9.09%)  1 2/19 (10.53%)  2
Insomnia  1  4/49 (8.16%)  4 1/11 (9.09%)  1 2/19 (10.53%)  2
Agitation  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Confusion  1  3/49 (6.12%)  3 0/11 (0.00%)  0 0/19 (0.00%)  0
Psychiatric disorders - Other, specify (emotional)  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Renal and urinary disorders       
Renal and urinary disorders - Other, specify (urinary burning)  1  0/49 (0.00%)  0 0/11 (0.00%)  0 1/19 (5.26%)  1
Urinary frequency  1  1/49 (2.04%)  1 0/11 (0.00%)  0 1/19 (5.26%)  1
Urinary tract pain  1  1/49 (2.04%)  1 0/11 (0.00%)  0 1/19 (5.26%)  1
Cystitis noninfective  1  2/49 (4.08%)  2 0/11 (0.00%)  0 0/19 (0.00%)  0
Hematuria  1  2/49 (4.08%)  2 0/11 (0.00%)  0 0/19 (0.00%)  0
Urinary retention  1  3/49 (6.12%)  3 0/11 (0.00%)  0 0/19 (0.00%)  0
Urinary urgency  1  2/49 (4.08%)  2 0/11 (0.00%)  0 0/19 (0.00%)  0
Reproductive system and breast disorders       
Dyspareunia  1  0/49 (0.00%)  0 0/11 (0.00%)  0 1/19 (5.26%)  1
Vaginal inflammation  1  0/49 (0.00%)  0 0/11 (0.00%)  0 1/19 (5.26%)  2
Respiratory, thoracic and mediastinal disorders       
Cough  1  9/49 (18.37%)  13 2/11 (18.18%)  2 9/19 (47.37%)  16
Dyspnea  1  10/49 (20.41%)  12 4/11 (36.36%)  7 7/19 (36.84%)  8
Epistaxis  1  3/49 (6.12%)  3 0/11 (0.00%)  0 1/19 (5.26%)  1
Hypoxia  1  3/49 (6.12%)  4 0/11 (0.00%)  0 2/19 (10.53%)  2
Laryngeal inflammation  1  2/49 (4.08%)  2 0/11 (0.00%)  0 1/19 (5.26%)  1
Nasal congestion  1  0/49 (0.00%)  0 0/11 (0.00%)  0 1/19 (5.26%)  1
Pleural effusion  1  3/49 (6.12%)  3 0/11 (0.00%)  0 1/19 (5.26%)  1
Productive cough  1  1/49 (2.04%)  1 0/11 (0.00%)  0 2/19 (10.53%)  2
Respiratory, thoracic and mediastinal disorders - Other, specify  1 [9]  0/49 (0.00%)  0 0/11 (0.00%)  0 1/19 (5.26%)  1
Hiccups  1  0/49 (0.00%)  0 1/11 (9.09%)  1 0/19 (0.00%)  0
Hoarseness  1  4/49 (8.16%)  4 2/11 (18.18%)  2 0/19 (0.00%)  0
Pneumonitis  1  1/49 (2.04%)  1 1/11 (9.09%)  1 0/19 (0.00%)  0
Pneumothorax  1  0/49 (0.00%)  0 1/11 (9.09%)  1 0/19 (0.00%)  0
Wheezing  1  5/49 (10.20%)  6 1/11 (9.09%)  1 0/19 (0.00%)  0
Respiratory, thoracic and mediastinal disorders  1 [10]  0/49 (0.00%)  0 1/11 (9.09%)  1 0/19 (0.00%)  0
Allergic rhinitis  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Laryngeal hemorrhage  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Postnasal drip  1  2/49 (4.08%)  4 0/11 (0.00%)  0 0/19 (0.00%)  0
Pulmonary edema  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Respiratory failure  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Respiratory, thoracic and mediastinal disorders - Other, specify  1 [11]  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Sore throat  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Skin and subcutaneous tissue disorders       
Alopecia  1  10/49 (20.41%)  10 0/11 (0.00%)  0 2/19 (10.53%)  2
Hypertrichosis  1  0/49 (0.00%)  0 0/11 (0.00%)  0 1/19 (5.26%)  1
Pain of skin  1  1/49 (2.04%)  1 0/11 (0.00%)  0 1/19 (5.26%)  1
Palmar-plantar erythrodysesthesia syndrome  1  3/49 (6.12%)  3 0/11 (0.00%)  0 1/19 (5.26%)  1
Pruritis  1  12/49 (24.49%)  14 1/11 (9.09%)  1 5/19 (26.32%)  6
Rash acneiform  1  22/49 (44.90%)  39 4/11 (36.36%)  5 8/19 (42.11%)  14
Rash maculo-papular  1  27/49 (55.10%)  51 4/11 (36.36%)  6 8/19 (42.11%)  12
Skin and subcutaneous tissue disorders-Other, specify  1 [12]  0/49 (0.00%)  0 0/11 (0.00%)  0 3/19 (15.79%)  6
Skin ulceration  1  1/49 (2.04%)  1 0/11 (0.00%)  0 1/19 (5.26%)  1
Dry skin  1  19/49 (38.78%)  21 2/11 (18.18%)  2 6/19 (31.58%)  9
Erythema multiforme  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
Hirsutism  1  3/49 (6.12%)  3 0/11 (0.00%)  0 0/19 (0.00%)  0
Periorbital edema  1  3/49 (6.12%)  4 0/11 (0.00%)  0 0/19 (0.00%)  0
Skin and subcutaneous tissue disorders - Other, specify  1 [13]  3/49 (6.12%)  3 0/11 (0.00%)  0 0/19 (0.00%)  0
Skin hyperpigmentation  1  1/49 (2.04%)  2 0/11 (0.00%)  0 0/19 (0.00%)  0
Vascular disorders       
Hypertension  1  8/49 (16.33%)  15 0/11 (0.00%)  0 2/19 (10.53%)  4
Hematoma  1  0/49 (0.00%)  0 1/11 (9.09%)  1 0/19 (0.00%)  0
Hypotension  1  3/49 (6.12%)  4 0/11 (0.00%)  0 0/19 (0.00%)  0
Thromboembolic event  1  1/49 (2.04%)  1 0/11 (0.00%)  0 0/19 (0.00%)  0
1
Term from vocabulary, CTCAE (4.0)
Indicates events were collected by systematic assessment
[1]
diastolic dysfunction
[2]
decreased vision; eye lash thickening; glare; left lower eyelid excoriation; red, green eyes spots
[3]
Feverish
[4]
urinary tract infection
[5]
intolerance to cold
[6]
Other, specify (progressive disease)
[7]
left foot numbness
[8]
sensitivity to cold
[9]
Runny nose, non allergy
[10]
Other, specify (decreased breath sounds)
[11]
diminished breath sounds
[12]
dermatitis, rash in peri-anal area; erythematous rash; ingrown toenail; L arm abrasions from fall; nail overgrowth; erythema on the nose
[13]
contact dermatitis; skin eczematous dry patches on dorsum of both feet; skin bleeding
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT 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: Dr. Arun Rajan
Organization: National Cancer Institute
Phone: 301-594-5322
Responsible Party: Arun Rajan, M.D., National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT01229150     History of Changes
Obsolete Identifiers: NCT01239290
Other Study ID Numbers: 100218
10-C-0218
First Submitted: October 26, 2010
First Posted: October 27, 2010
Results First Submitted: October 23, 2014
Results First Posted: October 29, 2014
Last Update Posted: May 23, 2017