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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

  Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Reporting Groups
  Description
KRAS Mut 2

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 Mut 1

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).

WT KRAS 1

Wild-Type KRAS patients randomized to monotherapy arm

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

WT KRAS 2

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.


Participant Flow:   Overall Study
    KRAS Mut 2   KRAS Mut 1   WT KRAS 1   WT KRAS 2
STARTED   30   11   19   19 
COMPLETED   28   9   19   19 
NOT COMPLETED   2   2   0   0 
Toxicity                2                2                0                0 



  Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
KRAS Mut 2

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 Mut 1

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).

WT KRAS 1

Wild-Type KRAS patients randomized to monotherapy arm

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

WT KRAS 2

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 Total of all reporting groups

Baseline Measures
   KRAS Mut 2   KRAS Mut 1   WT KRAS 1   WT KRAS 2   Total 
Overall Participants Analyzed 
[Units: Participants]
 30   11   19   19   79 
Age 
[Units: Participants]
Count of 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 
[Units: Years]
Mean (Standard Deviation)
 66.05  (9.648)   64.31  (13.76)   63.75  (13.6)   64.84  (8.10)   65.22  (9.46) 
Sex: Female, Male 
[Units: Participants]
Count of 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) 
[Units: Participants]
Count of 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) 
[Units: Participants]
Count of 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 
[Units: Participants]
Count of Participants
         
United States   30   11   19   19   79 
Histology 
[Units: Participants]
Count of Participants
         
Lung Cancer Adenocarcinoma   30   11   15   15   71 
Squamous cell   0   0   4   4   8 
Mutational Status [1] 
[Units: Participants]
Count of Participants
         
EGFR Mutated (L858R)   30   11   1   1   43 
EGFR Wild Type   0   0   18   18   36 
KRAS G12A   6   0   0   0   6 
KRAS G12C   8   4   0   0   12 
KRAS G12D   1   1   0   0   2 
KRAS G12K   1   1   0   0   2 
KRAS G12R   0   1   0   0   1 
KRAS G12S   1   0   0   0   1 
KRAS G12V   9   4   0   0   13 
KRAS Q61H   2   0   0   0   2 
KRAS Q61L   2   0   0   0   2 
KRAS   0   0   0   0   0 
[1] 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] 
[Units: Participants]
Count of Participants
         
 3   1   2   2   8 
 14   5   11   7   37 
 13   5   6   10   34 
[1] 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 
[Units: Participants]
Count of Participants
         
 12   6   10   8   36 
 18   5   9   11   43 
Smoking 
[Units: Participants]
Count of Participants
         
Current   9   0   0   0   9 
Former   21   11   13   16   61 
Never-smoker   0   0   6   3   9 


  Outcome Measures

1.  Primary:   Progression Free Survival   [ Time Frame: 2.1 to 4 months ]

2.  Primary:   Objective Response   [ Time Frame: Up to 37 months ]

3.  Secondary:   Number of Participants With Adverse Events   [ Time Frame: 42 months ]

4.  Secondary:   Percentage of Participants With Disease Control/Stabilization   [ Time Frame: 3 cycles or up to 84 days ]

5.  Secondary:   Overall Survival   [ Time Frame: Up to 26 months ]

6.  Secondary:   Percentage of Th17 in Cluster of Differentiation 4 (CD4)+T Cells at Baseline in Relation to Response   [ Time Frame: Pretreatment - Cycle 1 Day 1 ]

7.  Secondary:   Number of Participants With a Reduction in Phosphorylated Extracellular Signal-Regulated Kinases (p-ERK) in Lymphocytes   [ 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) ]

8.  Other Pre-specified:   Number of Participants With Changes in a Tumor's MIB-1 (Ki-67) Rate   [ Time Frame: At enrollment ]

9.  Other Pre-specified:   Change in T Cell Immunoglobulin Mucin 3 (TIM-3) on Tregs   [ 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) ]

10.  Other Pre-specified:   Change in Cytotoxic T-lymphocyte Associated Protein 4 (CTLA-4) Expression on Tregs   [ 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) ]

11.  Other Pre-specified:   Change in Programmed Cell Death-1 (PD-1) Expression on Tregs   [ 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) ]

12.  Other Pre-specified:   Change in Programmed Cell Death-1 (PD-1) Expression on Cluster of Differentiation 8 (CD8)+T Cells   [ 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) ]

13.  Other Pre-specified:   Phospho-ERK (p-ERK), Phospho Protein Kinase B (p-AKt) and Phosphatase and Tensin Homolog (PTEN) Expression Testing   [ Time Frame: At enrollment ]

14.  Other Pre-specified:   Number of Participants With Overexpression of Estimated Glomerular Filtration Rate (EGFR) and c-MET   [ Time Frame: At enrollment ]

15.  Other Pre-specified:   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   [ Time Frame: At enrollment ]


  Serious Adverse Events


  Other Adverse Events

Time Frame No text entered.
Additional 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.

Frequency Threshold
Threshold above which other adverse events are reported   0%  

Reporting Groups
  Description
KRAS Mut 2 & WT KRAS 2

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 Mut 1

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).

WT KRAS 1

Wild-Type KRAS patients randomized to monotherapy arm

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


Other Adverse Events
    KRAS Mut 2 & WT KRAS 2   KRAS Mut 1   WT KRAS 1
Total, Other (not including serious) Adverse Events       
# participants affected / at risk   49/49 (100.00%)   9/11 (81.82%)   18/19 (94.74%) 
Blood and lymphatic system disorders       
Anemia † 1       
# participants affected / at risk   24/49 (48.98%)   4/11 (36.36%)   2/19 (10.53%) 
# events   54   4   4 
Cardiac disorders       
Palpitations † 1       
# participants affected / at risk   0/49 (0.00%)   0/11 (0.00%)   2/19 (10.53%) 
# events   0   0   2 
Sinus tachycardia † 1       
# participants affected / at risk   7/49 (14.29%)   0/11 (0.00%)   1/19 (5.26%) 
# events   7   0   1 
Cardiac disorders - Other, specify † 1 [3]       
# participants affected / at risk   0/49 (0.00%)   1/11 (9.09%)   0/19 (0.00%) 
# events   0   2   0 
Heart failure † 1       
# participants affected / at risk   0/49 (0.00%)   1/11 (9.09%)   0/19 (0.00%) 
# events   0   1   0 
Left ventricular systolic dysfunction † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Ventricular tachycardia † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Ear and labyrinth disorders       
Tinnitus † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   1/19 (5.26%) 
# events   2   0   1 
Ear pain † 1       
# participants affected / at risk   2/49 (4.08%)   0/11 (0.00%)   0/19 (0.00%) 
# events   2   0   0 
Vertigo † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Endocrine disorders       
Cushingoid † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Hypothryoidism † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Eye disorders       
Dry eye † 1       
# participants affected / at risk   6/49 (12.24%)   0/11 (0.00%)   2/19 (10.53%) 
# events   7   0   2 
Floaters † 1       
# participants affected / at risk   2/49 (4.08%)   1/11 (9.09%)   1/19 (5.26%) 
# events   3   1   1 
Blurred vision † 1       
# participants affected / at risk   10/49 (20.41%)   0/11 (0.00%)   0/19 (0.00%) 
# events   13   0   0 
Eye disorders- Other, specify † 1 [4]       
# participants affected / at risk   4/49 (8.16%)   0/11 (0.00%)   0/19 (0.00%) 
# events   5   0   0 
Eye pain † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Eyelid function disorder † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Watering eyes † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Gastrointestinal disorders       
Abdominal pain † 1       
# participants affected / at risk   9/49 (18.37%)   1/11 (9.09%)   3/19 (15.79%) 
# events   11   2   4 
Cheilitis † 1       
# participants affected / at risk   4/49 (8.16%)   1/11 (9.09%)   1/19 (5.26%) 
# events   4   2   1 
Constipation † 1       
# participants affected / at risk   6/49 (12.24%)   5/11 (45.45%)   1/19 (5.26%) 
# events   7   9   1 
Diarrhea † 1       
# participants affected / at risk   43/49 (87.76%)   4/11 (36.36%)   8/19 (42.11%) 
# events   94   6   16 
Dry mouth † 1       
# participants affected / at risk   6/49 (12.24%)   3/11 (27.27%)   3/19 (15.79%) 
# events   7   3   3 
Dyspepsia † 1       
# participants affected / at risk   7/49 (14.29%)   1/11 (9.09%)   1/19 (5.26%) 
# events   9   1   1 
Flatulence † 1       
# participants affected / at risk   0/49 (0.00%)   0/11 (0.00%)   1/19 (5.26%) 
# events   0   0   1 
Gastroesophageal reflux disease † 1       
# participants affected / at risk   3/49 (6.12%)   0/11 (0.00%)   2/19 (10.53%) 
# events   4   0   2 
Mucositis oral † 1       
# participants affected / at risk   11/49 (22.45%)   1/11 (9.09%)   1/19 (5.26%) 
# events   15   1   1 
Nausea † 1       
# participants affected / at risk   27/49 (55.10%)   3/11 (27.27%)   9/19 (47.37%) 
# events   48   5   11 
Stomach pain † 1       
# participants affected / at risk   3/49 (6.12%)   0/11 (0.00%)   1/19 (5.26%) 
# events   3   0   1 
Vomiting † 1       
# participants affected / at risk   19/49 (38.78%)   1/11 (9.09%)   2/19 (10.53%) 
# events   38   1   2 
Esophageal pain † 1       
# participants affected / at risk   0/49 (0.00%)   1/11 (9.09%)   0/19 (0.00%) 
# events   0   1   0 
Bloating † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Dysphagia † 1       
# participants affected / at risk   2/49 (4.08%)   0/11 (0.00%)   0/19 (0.00%) 
# events   2   0   0 
Esophagitis † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Gastric hemorrhage † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Gastrointestinal disorders - Other, specify (bloody stools) † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Gastrointestinal pain † 1       
# participants affected / at risk   2/49 (4.08%)   0/11 (0.00%)   0/19 (0.00%) 
# events   2   0   0 
Hemorrhoidal hemorrhage † 1       
# participants affected / at risk   2/49 (4.08%)   0/11 (0.00%)   0/19 (0.00%) 
# events   2   0   0 
Hemorrhoids † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Oral dysesthesia † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Oral pain † 1       
# participants affected / at risk   2/49 (4.08%)   0/11 (0.00%)   0/19 (0.00%) 
# events   4   0   0 
Rectal hemorrhage † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
General disorders       
Chills † 1       
# participants affected / at risk   7/49 (14.29%)   0/11 (0.00%)   3/19 (15.79%) 
# events   8   0   3 
Edema limbs † 1       
# participants affected / at risk   19/49 (38.78%)   6/11 (54.55%)   2/19 (10.53%) 
# events   26   10   3 
Fatigue † 1       
# participants affected / at risk   25/49 (51.02%)   2/11 (18.18%)   6/19 (31.58%) 
# events   47   4   7 
Fever † 1       
# participants affected / at risk   6/49 (12.24%)   1/11 (9.09%)   2/19 (10.53%) 
# events   6   1   2 
Non-cardiac chest pain † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   2/19 (10.53%) 
# events   2   0   2 
Pain † 1       
# participants affected / at risk   10/49 (20.41%)   3/11 (27.27%)   2/19 (10.53%) 
# events   12   4   2 
Edema face † 1       
# participants affected / at risk   4/49 (8.16%)   1/11 (9.09%)   0/19 (0.00%) 
# events   6   1   0 
Malaise † 1       
# participants affected / at risk   1/49 (2.04%)   1/11 (9.09%)   0/19 (0.00%) 
# events   1   1   0 
Death NOS † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Flu like symptoms † 1       
# participants affected / at risk   2/49 (4.08%)   0/11 (0.00%)   0/19 (0.00%) 
# events   2   0   0 
Gait disturbance † 1       
# participants affected / at risk   2/49 (4.08%)   0/11 (0.00%)   0/19 (0.00%) 
# events   3   0   0 
General disorders and adminstration site conditions - Other, specify † 1 [5]       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Infections and infestations       
Conjunctivitis † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   1/19 (5.26%) 
# events   1   0   2 
Infections and infestations-Other, specify † 1 [6]       
# participants affected / at risk   0/49 (0.00%)   0/11 (0.00%)   1/19 (5.26%) 
# events   0   0   1 
Lung infection † 1       
# participants affected / at risk   3/49 (6.12%)   0/11 (0.00%)   1/19 (5.26%) 
# events   3   0   1 
Paronychia † 1       
# participants affected / at risk   9/49 (18.37%)   0/11 (0.00%)   2/19 (10.53%) 
# events   13   0   4 
Skin infection † 1       
# participants affected / at risk   1/49 (2.04%)   1/11 (9.09%)   2/19 (10.53%) 
# events   1   1   3 
Upper respiratory infection † 1       
# participants affected / at risk   6/49 (12.24%)   1/11 (9.09%)   1/19 (5.26%) 
# events   6   1   1 
Urinary tract infection † 1       
# participants affected / at risk   5/49 (10.20%)   0/11 (0.00%)   2/19 (10.53%) 
# events   5   0   3 
Mucosal infection † 1       
# participants affected / at risk   0/49 (0.00%)   1/11 (9.09%)   0/19 (0.00%) 
# events   0   1   0 
Otitis externa † 1       
# participants affected / at risk   2/49 (4.08%)   0/11 (0.00%)   0/19 (0.00%) 
# events   2   0   0 
Otitis media † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Periorbital infection † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Sinusitis † 1       
# participants affected / at risk   2/49 (4.08%)   0/11 (0.00%)   0/19 (0.00%) 
# events   2   0   0 
Vaginal infection † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Investigations       
Activated partial thromboplastin time prolonged † 1       
# participants affected / at risk   3/49 (6.12%)   1/11 (9.09%)   2/19 (10.53%) 
# events   3   1   4 
Alanine aminotransferase increased † 1       
# participants affected / at risk   27/49 (55.10%)   5/11 (45.45%)   4/19 (21.05%) 
# events   51   7   6 
Aspartate aminotransferase increased † 1       
# participants affected / at risk   34/49 (69.39%)   5/11 (45.45%)   4/19 (21.05%) 
# events   65   10   7 
Blood bilirubin increased † 1       
# participants affected / at risk   13/49 (26.53%)   0/11 (0.00%)   2/19 (10.53%) 
# events   16   0   4 
CPK increased † 1       
# participants affected / at risk   15/49 (30.61%)   5/11 (45.45%)   1/19 (5.26%) 
# events   39   10   1 
Creatinine increased † 1       
# participants affected / at risk   13/49 (26.53%)   2/11 (18.18%)   2/19 (10.53%) 
# events   19   2   2 
Lymphocyte count decreased † 1       
# participants affected / at risk   21/49 (42.86%)   1/11 (9.09%)   8/19 (42.11%) 
# events   56   1   9 
Platelet count decreased † 1       
# participants affected / at risk   14/49 (28.57%)   3/11 (27.27%)   1/19 (5.26%) 
# events   23   3   1 
Weight loss † 1       
# participants affected / at risk   10/49 (20.41%)   0/11 (0.00%)   2/19 (10.53%) 
# events   12   0   2 
Alkaline phosphatase increased † 1       
# participants affected / at risk   13/49 (26.53%)   3/11 (27.27%)   0/19 (0.00%) 
# events   19   4   0 
White blood cell decreased † 1       
# participants affected / at risk   8/49 (16.33%)   2/11 (18.18%)   0/19 (0.00%) 
# events   9   5   0 
Ejection fraction decreased † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
INR increased † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Neutrophil count decreased † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Metabolism and nutrition disorders       
Anorexia † 1       
# participants affected / at risk   17/49 (34.69%)   4/11 (36.36%)   9/19 (47.37%) 
# events   23   4   10 
Hyperkalemia † 1       
# participants affected / at risk   4/49 (8.16%)   2/11 (18.18%)   2/19 (10.53%) 
# events   4   2   2 
Hypermagnesemia † 1       
# participants affected / at risk   2/49 (4.08%)   0/11 (0.00%)   1/19 (5.26%) 
# events   2   0   1 
Hypernatremia † 1       
# participants affected / at risk   2/49 (4.08%)   0/11 (0.00%)   1/19 (5.26%) 
# events   3   0   3 
Hypoalbuminemia † 1       
# participants affected / at risk   36/49 (73.47%)   7/11 (63.64%)   5/19 (26.32%) 
# events   64   9   6 
Hypoglycemia † 1       
# participants affected / at risk   5/49 (10.20%)   0/11 (0.00%)   2/19 (10.53%) 
# events   6   0   7 
Hypokalemia † 1       
# participants affected / at risk   11/49 (22.45%)   1/11 (9.09%)   1/19 (5.26%) 
# events   13   1   1 
Hypomagnesemia † 1       
# participants affected / at risk   19/49 (38.78%)   3/11 (27.27%)   4/19 (21.05%) 
# events   29   5   4 
Hyponatremia † 1       
# participants affected / at risk   22/49 (44.90%)   0/11 (0.00%)   4/19 (21.05%) 
# events   31   0   11 
Hypophosphatemia † 1       
# participants affected / at risk   9/49 (18.37%)   1/11 (9.09%)   4/19 (21.05%) 
# events   15   2   6 
Hypercalcemia † 1       
# participants affected / at risk   6/49 (12.24%)   2/11 (18.18%)   0/19 (0.00%) 
# events   7   4   0 
Hyperglycemia † 1       
# participants affected / at risk   5/49 (10.20%)   2/11 (18.18%)   0/19 (0.00%) 
# events   6   3   0 
Hyperuricemia † 1       
# participants affected / at risk   2/49 (4.08%)   1/11 (9.09%)   0/19 (0.00%) 
# events   2   3   0 
Dehydration † 1       
# participants affected / at risk   6/49 (12.24%)   0/11 (0.00%)   0/19 (0.00%) 
# events   8   0   0 
Hypocalcemia † 1       
# participants affected / at risk   5/49 (10.20%)   0/11 (0.00%)   0/19 (0.00%) 
# events   6   0   0 
Metabolism and nutrition disorders - Other, specify † 1 [7]       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Musculoskeletal and connective tissue disorders       
Back pain † 1       
# participants affected / at risk   5/49 (10.20%)   0/11 (0.00%)   1/19 (5.26%) 
# events   5   0   1 
Bone pain † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   1/19 (5.26%) 
# events   1   0   1 
Chest wall pain † 1       
# participants affected / at risk   1/49 (2.04%)   1/11 (9.09%)   1/19 (5.26%) 
# events   2   1   1 
Flank pain † 1       
# participants affected / at risk   0/49 (0.00%)   0/11 (0.00%)   1/19 (5.26%) 
# events   0   0   1 
Myalgia † 1       
# participants affected / at risk   5/49 (10.20%)   0/11 (0.00%)   2/19 (10.53%) 
# events   5   0   2 
Pain in extremity † 1       
# participants affected / at risk   5/49 (10.20%)   1/11 (9.09%)   2/19 (10.53%) 
# events   6   1   2 
Arthritis † 1       
# participants affected / at risk   0/49 (0.00%)   1/11 (9.09%)   0/19 (0.00%) 
# events   0   1   0 
Myositis † 1       
# participants affected / at risk   0/49 (0.00%)   1/11 (9.09%)   0/19 (0.00%) 
# events   0   2   0 
Neck pain † 1       
# participants affected / at risk   0/49 (0.00%)   1/11 (9.09%)   0/19 (0.00%) 
# events   0   2   0 
Arthralgia † 1       
# participants affected / at risk   3/49 (6.12%)   0/11 (0.00%)   0/19 (0.00%) 
# events   3   0   0 
Buttock pain † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Neoplasms benign, malignant and unspecified (incl cysts and polyps) † 1 [8]       
# participants affected / at risk   0/49 (0.00%)   0/11 (0.00%)   1/19 (5.26%) 
# events   0   0   1 
Tumor pain † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Nervous system disorders       
Dysgeusia † 1       
# participants affected / at risk   12/49 (24.49%)   1/11 (9.09%)   1/19 (5.26%) 
# events   13   1   3 
Headache † 1       
# participants affected / at risk   9/49 (18.37%)   0/11 (0.00%)   3/19 (15.79%) 
# events   12   0   4 
Paresthesia † 1       
# participants affected / at risk   3/49 (6.12%)   0/11 (0.00%)   1/19 (5.26%) 
# events   3   0   1 
Nervous system disorders - Other, specify † 1 [9]       
# participants affected / at risk   0/49 (0.00%)   1/11 (9.09%)   0/19 (0.00%) 
# events   0   1   0 
Peripheral sensory neuropathy † 1       
# participants affected / at risk   1/49 (2.04%)   1/11 (9.09%)   0/19 (0.00%) 
# events   1   3   0 
Ataxia † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Dizziness † 1       
# participants affected / at risk   13/49 (26.53%)   0/11 (0.00%)   0/19 (0.00%) 
# events   14   0   0 
Dysesthesia † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Lethargy † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Nervous system disorders - Other, specify † 1 [10]       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Presyncope † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Syncope † 1       
# participants affected / at risk   3/49 (6.12%)   0/11 (0.00%)   0/19 (0.00%) 
# events   3   0   0 
Psychiatric disorders       
Anxiety † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   3/19 (15.79%) 
# events   1   0   4 
Depression † 1       
# participants affected / at risk   1/49 (2.04%)   1/11 (9.09%)   2/19 (10.53%) 
# events   1   1   2 
Insomnia † 1       
# participants affected / at risk   4/49 (8.16%)   1/11 (9.09%)   2/19 (10.53%) 
# events   4   1   2 
Agitation † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Confusion † 1       
# participants affected / at risk   3/49 (6.12%)   0/11 (0.00%)   0/19 (0.00%) 
# events   3   0   0 
Psychiatric disorders - Other, specify (emotional) † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Renal and urinary disorders       
Renal and urinary disorders - Other, specify (urinary burning) † 1       
# participants affected / at risk   0/49 (0.00%)   0/11 (0.00%)   1/19 (5.26%) 
# events   0   0   1 
Urinary frequency † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   1/19 (5.26%) 
# events   1   0   1 
Urinary tract pain † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   1/19 (5.26%) 
# events   1   0   1 
Cystitis noninfective † 1       
# participants affected / at risk   2/49 (4.08%)   0/11 (0.00%)   0/19 (0.00%) 
# events   2   0   0 
Hematuria † 1       
# participants affected / at risk   2/49 (4.08%)   0/11 (0.00%)   0/19 (0.00%) 
# events   2   0   0 
Urinary retention † 1       
# participants affected / at risk   3/49 (6.12%)   0/11 (0.00%)   0/19 (0.00%) 
# events   3   0   0 
Urinary urgency † 1       
# participants affected / at risk   2/49 (4.08%)   0/11 (0.00%)   0/19 (0.00%) 
# events   2   0   0 
Reproductive system and breast disorders       
Dyspareunia † 1       
# participants affected / at risk   0/49 (0.00%)   0/11 (0.00%)   1/19 (5.26%) 
# events   0   0   1 
Vaginal inflammation † 1       
# participants affected / at risk   0/49 (0.00%)   0/11 (0.00%)   1/19 (5.26%) 
# events   0   0   2 
Respiratory, thoracic and mediastinal disorders       
Cough † 1       
# participants affected / at risk   9/49 (18.37%)   2/11 (18.18%)   9/19 (47.37%) 
# events   13   2   16 
Dyspnea † 1       
# participants affected / at risk   10/49 (20.41%)   4/11 (36.36%)   7/19 (36.84%) 
# events   12   7   8 
Epistaxis † 1       
# participants affected / at risk   3/49 (6.12%)   0/11 (0.00%)   1/19 (5.26%) 
# events   3   0   1 
Hypoxia † 1       
# participants affected / at risk   3/49 (6.12%)   0/11 (0.00%)   2/19 (10.53%) 
# events   4   0   2 
Laryngeal inflammation † 1       
# participants affected / at risk   2/49 (4.08%)   0/11 (0.00%)   1/19 (5.26%) 
# events   2   0   1 
Nasal congestion † 1       
# participants affected / at risk   0/49 (0.00%)   0/11 (0.00%)   1/19 (5.26%) 
# events   0   0   1 
Pleural effusion † 1       
# participants affected / at risk   3/49 (6.12%)   0/11 (0.00%)   1/19 (5.26%) 
# events   3   0   1 
Productive cough † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   2/19 (10.53%) 
# events   1   0   2 
Respiratory, thoracic and mediastinal disorders - Other, specify † 1 [11]       
# participants affected / at risk   0/49 (0.00%)   0/11 (0.00%)   1/19 (5.26%) 
# events   0   0   1 
Hiccups † 1       
# participants affected / at risk   0/49 (0.00%)   1/11 (9.09%)   0/19 (0.00%) 
# events   0   1   0 
Hoarseness † 1       
# participants affected / at risk   4/49 (8.16%)   2/11 (18.18%)   0/19 (0.00%) 
# events   4   2   0 
Pneumonitis † 1       
# participants affected / at risk   1/49 (2.04%)   1/11 (9.09%)   0/19 (0.00%) 
# events   1   1   0 
Pneumothorax † 1       
# participants affected / at risk   0/49 (0.00%)   1/11 (9.09%)   0/19 (0.00%) 
# events   0   1   0 
Wheezing † 1       
# participants affected / at risk   5/49 (10.20%)   1/11 (9.09%)   0/19 (0.00%) 
# events   6   1   0 
Respiratory, thoracic and mediastinal disorders † 1 [12]       
# participants affected / at risk   0/49 (0.00%)   1/11 (9.09%)   0/19 (0.00%) 
# events   0   1   0 
Allergic rhinitis † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Laryngeal hemorrhage † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Postnasal drip † 1       
# participants affected / at risk   2/49 (4.08%)   0/11 (0.00%)   0/19 (0.00%) 
# events   4   0   0 
Pulmonary edema † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Respiratory failure † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Respiratory, thoracic and mediastinal disorders - Other, specify † 1 [13]       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Sore throat † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Skin and subcutaneous tissue disorders       
Alopecia † 1       
# participants affected / at risk   10/49 (20.41%)   0/11 (0.00%)   2/19 (10.53%) 
# events   10   0   2 
Hypertrichosis † 1       
# participants affected / at risk   0/49 (0.00%)   0/11 (0.00%)   1/19 (5.26%) 
# events   0   0   1 
Pain of skin † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   1/19 (5.26%) 
# events   1   0   1 
Palmar-plantar erythrodysesthesia syndrome † 1       
# participants affected / at risk   3/49 (6.12%)   0/11 (0.00%)   1/19 (5.26%) 
# events   3   0   1 
Pruritis † 1       
# participants affected / at risk   12/49 (24.49%)   1/11 (9.09%)   5/19 (26.32%) 
# events   14   1   6 
Rash acneiform † 1       
# participants affected / at risk   22/49 (44.90%)   4/11 (36.36%)   8/19 (42.11%) 
# events   39   5   14 
Rash maculo-papular † 1       
# participants affected / at risk   27/49 (55.10%)   4/11 (36.36%)   8/19 (42.11%) 
# events   51   6   12 
Skin and subcutaneous tissue disorders-Other, specify † 1 [14]       
# participants affected / at risk   0/49 (0.00%)   0/11 (0.00%)   3/19 (15.79%) 
# events   0   0   6 
Skin ulceration † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   1/19 (5.26%) 
# events   1   0   1 
Dry skin † 1       
# participants affected / at risk   19/49 (38.78%)   2/11 (18.18%)   6/19 (31.58%) 
# events   21   2   9 
Erythema multiforme † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Hirsutism † 1       
# participants affected / at risk   3/49 (6.12%)   0/11 (0.00%)   0/19 (0.00%) 
# events   3   0   0 
Periorbital edema † 1       
# participants affected / at risk   3/49 (6.12%)   0/11 (0.00%)   0/19 (0.00%) 
# events   4   0   0 
Skin and subcutaneous tissue disorders - Other, specify † 1 [15]       
# participants affected / at risk   3/49 (6.12%)   0/11 (0.00%)   0/19 (0.00%) 
# events   3   0   0 
Skin hyperpigmentation † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   2   0   0 
Vascular disorders       
Hypertension † 1       
# participants affected / at risk   8/49 (16.33%)   0/11 (0.00%)   2/19 (10.53%) 
# events   15   0   4 
Hematoma † 1       
# participants affected / at risk   0/49 (0.00%)   1/11 (9.09%)   0/19 (0.00%) 
# events   0   1   0 
Hypotension † 1       
# participants affected / at risk   3/49 (6.12%)   0/11 (0.00%)   0/19 (0.00%) 
# events   4   0   0 
Thromboembolic event † 1       
# participants affected / at risk   1/49 (2.04%)   0/11 (0.00%)   0/19 (0.00%) 
# events   1   0   0 
Events were collected by systematic assessment
1 Term from vocabulary, CTCAE (4.0)
[3] diastolic dysfunction
[4] decreased vision; eye lash thickening; glare; left lower eyelid excoriation; red, green eyes spots
[5] Feverish
[6] urinary tract infection
[7] intolerance to cold
[8] Other, specify (progressive disease)
[9] left foot numbness
[10] sensitivity to cold
[11] Runny nose, non allergy
[12] Other, specify (decreased breath sounds)
[13] diminished breath sounds
[14] dermatitis, rash in peri-anal area; erythematous rash; ingrown toenail; L arm abrasions from fall; nail overgrowth; erythema on the nose
[15] contact dermatitis; skin eczematous dry patches on dorsum of both feet; skin bleeding



  Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information

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
e-mail: rajana@mail.nih.gov


Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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