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Erlotinib Plus Tivantinib (ARQ 197) Versus Single Agent Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer

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ClinicalTrials.gov Identifier: NCT01395758
Recruitment Status : Completed
First Posted : July 18, 2011
Results First Posted : April 3, 2018
Last Update Posted : April 3, 2018
Sponsor:
Information provided by (Responsible Party):
ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Metastatic Non-Small Cell Lung Cancer
Interventions Drug: ARQ 197 plus erlotinib
Drug: Pemetrexed, docetaxel or gemcitabine
Enrollment 96
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Tivantinib Plus Erlotinib Arm Chemotherapy Arm Crossover Arm
Hide Arm/Group Description Tivantinib 360 mg twice daily (BID) (total daily dose 720 mg) plus erlotinib 150 mg once daily (QD), tablets, orally in 3-week cycles until disease progression or unacceptable toxicity Investigator's choice of single agent chemotherapy (pemetrexed, docetaxel, or gemcitabine) administered in 3-week cycles according to the approved label until disease progression or unacceptable toxicity. Subjects who discontinued chemotherapy could be switched to the Crossover Arm (tivantinib plus erlotinib) and continue treatment until disease progression or unacceptable toxicity.

Following radiographically confirmed progression, subjects in the Chemotherapy Arm had the option to enroll in the Crossover Arm to receive tivantinib plus erlotinib.

Crossover subjects were treated with tivantinib 360 mg BID (total daily dose 720 mg) plus erlotinib 150 mg QD, tablets, orally in 3-week cycles until disease progression or unacceptable toxicity.

Period Title: Open-label Treatment Period
Started 51 45 0
Completed 47 45 0
Not Completed 4 0 0
Reason Not Completed
Withdrawal by Subject             4             0             0
Period Title: Crossover Period
Started 0 0 26
Completed 0 0 26
Not Completed 0 0 0
Arm/Group Title Tivantinib Plus Erlotinib Arm Chemotherapy Arm Total
Hide Arm/Group Description Tivantinib 360 mg BID (total daily dose 720 mg) plus erlotinib 150 mg QD, tablets, orally in 3-week cycles until disease progression or unacceptable toxicity Investigator's choice of single agent chemotherapy (pemetrexed, docetaxel, or gemcitabine) administered in 3-week cycles according to the approved label until disease progression or unacceptable toxicity. Subjects who discontinued chemotherapy could be switched to the crossover arm (tivantinib plus erlotinib) and continue treatment until disease progression or unacceptable toxicity. Total of all reporting groups
Overall Number of Baseline Participants 51 45 96
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 51 participants 45 participants 96 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
28
  54.9%
16
  35.6%
44
  45.8%
>=65 years
23
  45.1%
29
  64.4%
52
  54.2%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 51 participants 45 participants 96 participants
62.6  (9.23) 65.2  (9.55) 63.8  (9.43)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 51 participants 45 participants 96 participants
Female
33
  64.7%
30
  66.7%
63
  65.6%
Male
18
  35.3%
15
  33.3%
33
  34.4%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 51 participants 45 participants 96 participants
Hispanic or Latino
1
   2.0%
0
   0.0%
1
   1.0%
Not Hispanic or Latino
50
  98.0%
45
 100.0%
95
  99.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 51 participants 45 participants 96 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
1
   2.0%
2
   4.4%
3
   3.1%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
1
   2.0%
2
   4.4%
3
   3.1%
White
47
  92.2%
41
  91.1%
88
  91.7%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
2
   3.9%
0
   0.0%
2
   2.1%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 51 participants 45 participants 96 participants
51 45 96
Cigarette Use  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 51 participants 45 participants 96 participants
Yes
46
  90.2%
42
  93.3%
88
  91.7%
No
5
   9.8%
3
   6.7%
8
   8.3%
Weight  
Mean (Standard Deviation)
Unit of measure:  Kilograms
Number Analyzed 51 participants 45 participants 96 participants
72.50  (17.31) 68.86  (15.19) 70.79  (16.37)
Height  
Mean (Standard Deviation)
Unit of measure:  Centimeters
Number Analyzed 51 participants 45 participants 96 participants
166.38  (10.28) 164.88  (9.42) 165.68  (9.86)
Eastern Cooperative Oncology Group (ECOG) Performance Status Score   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 51 participants 45 participants 96 participants
Grade 0
12
  23.5%
8
  17.8%
20
  20.8%
Grade 1
32
  62.7%
33
  73.3%
65
  67.7%
Grade 2
7
  13.7%
4
   8.9%
11
  11.5%
[1]
Measure Description:

Grade 0: Normal activity, fully active. Able to carry on all pre-disease performance without restriction.

Grade 1: 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: In bed < 50% of the time. Ambulatory and capable of all self-care, but unable to carry out work activities. Up and about more than 50% of waking hours.

Confirmation of Kirsten rat sarcoma (KRAS) Mutation  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 51 participants 45 participants 96 participants
Yes
51
 100.0%
45
 100.0%
96
 100.0%
No
0
   0.0%
0
   0.0%
0
   0.0%
1.Primary Outcome
Title Progression-free Survival (PFS) Among Subjects With KRAS Mutation Positive NSCLC (ITT Population) Treated With Erlotinib Plus Tivantinib Compared to Single Agent Chemotherapy.
Hide Description Progression is defined using Response Evaluation Criteria in Solid Tumors (RECIST v 1.1) criteria as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions or progression of existing non-target lesions are also considered progression.
Time Frame Date of randomization until disease progression per RECIST (v 1.1) or death from any cause, whichever came first, assessed up to 24 months.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Tivantinib Plus Erlotinib Arm Chemotherapy Arm
Hide Arm/Group Description:
Tivantinib 360 mg BID (total daily dose 720 mg) plus erlotinib 150 mg QD, tablets, orally in 3-week cycles until disease progression or unacceptable toxicity
Investigator's choice of single agent chemotherapy (pemetrexed, docetaxel, or gemcitabine) administered in 3-week cycles according to the approved label until disease progression or unacceptable toxicity. Subjects who discontinued chemotherapy could be switched to the crossover arm (tivantinib plus erlotinib) and continue treatment until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 51 45
Median (95% Confidence Interval)
Unit of Measure: weeks
7.3
(6.86 to 24.14)
18.6
(7.0 to 25.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tivantinib Plus Erlotinib Arm, Chemotherapy Arm
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5017
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
2.Secondary Outcome
Title Overall Survival (OS) Among All Eligible Subjects (ITT Population) Treated With Erlotinib Plus Tivantinib Compared to Chemotherapy.
Hide Description OS is calculated from the date of randomization until death from any cause.
Time Frame Date of randomization to the date of death from any cause, assessed up to 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Tivantinib Plus Erlotinib Arm Chemotherapy Arm
Hide Arm/Group Description:
Tivantinib 360 mg BID (total daily dose 720 mg) plus erlotinib 150 mg QD, tablets, orally in 3-week cycles until disease progression or unacceptable toxicity
Investigator's choice of single agent chemotherapy (pemetrexed, docetaxel, or gemcitabine) administered in 3-week cycles according to the approved label until disease progression or unacceptable toxicity. Subjects who discontinued chemotherapy could be switched to the crossover arm (tivantinib plus erlotinib) and continue treatment until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 51 45
Median (95% Confidence Interval)
Unit of Measure: months
6.8
(4.97 to 10.70)
8.5
(6.37 to 13.97)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tivantinib Plus Erlotinib Arm, Chemotherapy Arm
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4356
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
3.Secondary Outcome
Title Objective Response Rate (ORR) Among All Eligible Subjects (ITT Population) Treated With Erlotinib Plus Tivantinib Compared to Chemotherapy.
Hide Description Per RECIST v1.1, Complete Response (CR) = disappearance of all lesions and Partial Response (PR) = at least 30% decrease in the sum of diameters of target lesions. ORR = (CR+PR)/# subjects.
Time Frame Date of randomization to the date of death from any cause or to the date that the subject discontinues from the study, assessed up to 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Tivantinib Plus Erlotinib Arm Chemotherapy Arm
Hide Arm/Group Description:
Tivantinib 360 mg BID (total daily dose 720 mg) plus erlotinib 150 mg QD, tablets, orally in 3-week cycles until disease progression or unacceptable toxicity
Investigator's choice of single agent chemotherapy (pemetrexed, docetaxel, or gemcitabine) administered in 3-week cycles according to the approved label until disease progression or unacceptable toxicity. Subjects who discontinued chemotherapy could be switched to the crossover arm (tivantinib plus erlotinib) and continue treatment until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 51 45
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
4
   8.9%
4.Secondary Outcome
Title ORR Among Subjects in the Crossover Period Treated With Erlotinib Plus Tivantinib
Hide Description Per RECIST v1.1, CR = disappearance of all lesions and PR = at least 30% decrease in the sum of diameters of target lesions. ORR = (CR+PR)/# subjects.
Time Frame Date of randomization to the date of death from any cause or to the date that the subject discontinues from the study, assessed up to 24 months.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Tivantinib Plus Erlotinib Crossover Period
Hide Arm/Group Description:
Following radiographically-confirmed progression, subjects randomly assigned to receive chemotherapy had the option to receive erlotinib plus tivantinib and were followed for post-progression objective response rate. Subjects who elected to crossover followed the Erlotinib plus Tivantinib Arm Schedule of Visits, following a post-chemotherapy 21-day washout period, until discontinuation criteria were met.
Overall Number of Participants Analyzed 26
Measure Type: Count of Participants
Unit of Measure: Participants
2
   7.7%
Time Frame Adverse event data were collected from the date of the first dose of study drug and up to 30 days after the last dose of study medication.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Tivantinib Plus Erlotinib Arm Chemotherapy Arm
Hide Arm/Group Description Tivantinib 360 mg BID (total daily dose 720 mg) plus erlotinib 150 mg QD, tablets, orally in 3-week cycles until disease progression or unacceptable toxicity Investigator's choice of single agent chemotherapy (pemetrexed, docetaxel, or gemcitabine) administered in 3-week cycles according to the approved label until disease progression or unacceptable toxicity. Subjects who discontinued chemotherapy could be switched to the crossover arm (tivantinib plus erlotinib) and continue treatment until disease progression or unacceptable toxicity.
All-Cause Mortality
Tivantinib Plus Erlotinib Arm Chemotherapy Arm
Affected / at Risk (%) Affected / at Risk (%)
Total   3/51 (5.88%)   4/45 (8.89%) 
Hide Serious Adverse Events
Tivantinib Plus Erlotinib Arm Chemotherapy Arm
Affected / at Risk (%) Affected / at Risk (%)
Total   19/51 (37.25%)   25/45 (55.56%) 
Blood and lymphatic system disorders     
Anaemia  1  0/51 (0.00%)  2/45 (4.44%) 
Febrile neutropenia  1  0/51 (0.00%)  4/45 (8.89%) 
Neutropenia  1  1/51 (1.96%)  1/45 (2.22%) 
Thrombocytopenia  1  0/51 (0.00%)  1/45 (2.22%) 
Cardiac disorders     
Aortic valve incompetence  1  1/51 (1.96%)  0/45 (0.00%) 
Atrial fibrillation  1  2/51 (3.92%)  1/45 (2.22%) 
Myocardial infarction  1  1/51 (1.96%)  0/45 (0.00%) 
Ventricular tachycardia  1  0/51 (0.00%)  1/45 (2.22%) 
Gastrointestinal disorders     
Abdominal pain upper  1  0/51 (0.00%)  1/45 (2.22%) 
Diarrhoea  1  1/51 (1.96%)  0/45 (0.00%) 
General disorders     
Asthenia  1  0/51 (0.00%)  1/45 (2.22%) 
Disease progression  1  3/51 (5.88%)  4/45 (8.89%) 
Fatigue  1  1/51 (1.96%)  0/45 (0.00%) 
Non-cardiac chest pain  1  0/51 (0.00%)  1/45 (2.22%) 
Pain  1  0/51 (0.00%)  1/45 (2.22%) 
Pyrexia  1  0/51 (0.00%)  1/45 (2.22%) 
Hepatobiliary disorders     
Cholecystitis  1  0/51 (0.00%)  1/45 (2.22%) 
Infections and infestations     
Bacteraemia  1  2/51 (3.92%)  1/45 (2.22%) 
Endocarditis  1  1/51 (1.96%)  0/45 (0.00%) 
Enterocolitis infectious  1  1/51 (1.96%)  0/45 (0.00%) 
Lung infection  1  1/51 (1.96%)  0/45 (0.00%) 
Pneumonia  1  4/51 (7.84%)  4/45 (8.89%) 
Sepsis  1  2/51 (3.92%)  1/45 (2.22%) 
Urinary tract infection  1  0/51 (0.00%)  2/45 (4.44%) 
Injury, poisoning and procedural complications     
Pubis fracture  1  0/51 (0.00%)  1/45 (2.22%) 
Investigations     
Blood creatinine increased  1  0/51 (0.00%)  1/45 (2.22%) 
Metabolism and nutrition disorders     
Dehydration  1  2/51 (3.92%)  2/45 (4.44%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  0/51 (0.00%)  1/45 (2.22%) 
Back pain  1  2/51 (3.92%)  0/45 (0.00%) 
Muscular weakness  1  0/51 (0.00%)  1/45 (2.22%) 
Myalgia  1  0/51 (0.00%)  1/45 (2.22%) 
Pathological fracture  1  1/51 (1.96%)  0/45 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Malignant pleural effusion  1  0/51 (0.00%)  1/45 (2.22%) 
Metastases to oesophagus  1  1/51 (1.96%)  0/45 (0.00%) 
Nervous system disorders     
Cerebrovascular accident  1  1/51 (1.96%)  0/45 (0.00%) 
Depressed level of consciousness  1  1/51 (1.96%)  0/45 (0.00%) 
Dizziness  1  1/51 (1.96%)  0/45 (0.00%) 
Embolic stroke  1  1/51 (1.96%)  0/45 (0.00%) 
Psychiatric disorders     
Panic attack  1  1/51 (1.96%)  0/45 (0.00%) 
Renal and urinary disorders     
Nephrolithiasis  1  1/51 (1.96%)  0/45 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Acute respiratory failure  1  0/51 (0.00%)  1/45 (2.22%) 
Chronic obstructive pulmonary disease  1  2/51 (3.92%)  0/45 (0.00%) 
Dyspnoea  1  2/51 (3.92%)  2/45 (4.44%) 
Hypoxia  1  2/51 (3.92%)  1/45 (2.22%) 
Pleural effusion  1  3/51 (5.88%)  0/45 (0.00%) 
Pneumonitis  1  0/51 (0.00%)  2/45 (4.44%) 
Pulmonary embolism  1  1/51 (1.96%)  2/45 (4.44%) 
Respiratory failure  1  1/51 (1.96%)  0/45 (0.00%) 
Vascular disorders     
Deep vein thrombosis  1  1/51 (1.96%)  0/45 (0.00%) 
Embolism  1  2/51 (3.92%)  0/45 (0.00%) 
Superior vena cava syndrome  1  0/51 (0.00%)  1/45 (2.22%) 
1
Term from vocabulary, MedDRA (15.1)
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Tivantinib Plus Erlotinib Arm Chemotherapy Arm
Affected / at Risk (%) Affected / at Risk (%)
Total   51/51 (100.00%)   45/45 (100.00%) 
Blood and lymphatic system disorders     
Anaemia  1  22/51 (43.14%)  22/45 (48.89%) 
Febrile neutropenia  1  0/51 (0.00%)  1/45 (2.22%) 
Leukocytosis  1  1/51 (1.96%)  1/45 (2.22%) 
Leukopenia  1  1/51 (1.96%)  7/45 (15.56%) 
Lymphadenopathy  1  0/51 (0.00%)  1/45 (2.22%) 
Lymphopenia  1  4/51 (7.84%)  7/45 (15.56%) 
Neutropenia  1  3/51 (5.88%)  16/45 (35.56%) 
Thrombocytopenia  1  2/51 (3.92%)  9/45 (20.00%) 
Cardiac disorders     
Arrhythmia  1  1/51 (1.96%)  1/45 (2.22%) 
Atrial fibrillation  1  3/51 (5.88%)  1/45 (2.22%) 
Atrial flutter  1  0/51 (0.00%)  1/45 (2.22%) 
Bradycardia  1  1/51 (1.96%)  0/45 (0.00%) 
Cardiomegaly  1  1/51 (1.96%)  0/45 (0.00%) 
Palpitations  1  3/51 (5.88%)  2/45 (4.44%) 
Pericardial effusion  1  1/51 (1.96%)  0/45 (0.00%) 
Sinus bradycardia  1  1/51 (1.96%)  0/45 (0.00%) 
Tachycardia  1  2/51 (3.92%)  4/45 (8.89%) 
Ventricular tachycardia  1  0/51 (0.00%)  1/45 (2.22%) 
Ear and labyrinth disorders     
Hyperacusis  1  0/51 (0.00%)  1/45 (2.22%) 
Tinnitus  1  0/51 (0.00%)  1/45 (2.22%) 
Endocrine disorders     
Inappropriate antidiuretic hormone secretion  1  1/51 (1.96%)  0/45 (0.00%) 
Eye disorders     
Conjunctivitis  1  0/51 (0.00%)  1/45 (2.22%) 
Dry eye  1  0/51 (0.00%)  1/45 (2.22%) 
Eye pain  1  1/51 (1.96%)  0/45 (0.00%) 
Lacrimation increased  1  2/51 (3.92%)  4/45 (8.89%) 
Ocular discomfort  1  0/51 (0.00%)  2/45 (4.44%) 
Photopsia  1  0/51 (0.00%)  2/45 (4.44%) 
Vision blurred  1  1/51 (1.96%)  2/45 (4.44%) 
Vitreous floaters  1  0/51 (0.00%)  1/45 (2.22%) 
Gastrointestinal disorders     
Abdominal discomfort  1  0/51 (0.00%)  2/45 (4.44%) 
Abdominal distension  1  2/51 (3.92%)  0/45 (0.00%) 
Abdominal pain  1  2/51 (3.92%)  2/45 (4.44%) 
Abdominal pain lower  1  0/51 (0.00%)  1/45 (2.22%) 
Abdominal pain upper  1  2/51 (3.92%)  0/45 (0.00%) 
Abdominal tenderness  1  1/51 (1.96%)  1/45 (2.22%) 
Cheilitis  1  1/51 (1.96%)  0/45 (0.00%) 
Constipation  1  14/51 (27.45%)  11/45 (24.44%) 
Diarrhoea  1  22/51 (43.14%)  14/45 (31.11%) 
Dry mouth  1  4/51 (7.84%)  1/45 (2.22%) 
Dyspepsia  1  5/51 (9.80%)  0/45 (0.00%) 
Dysphagia  1  2/51 (3.92%)  3/45 (6.67%) 
Epigastric discomfort  1  0/51 (0.00%)  1/45 (2.22%) 
Flatulence  1  2/51 (3.92%)  0/45 (0.00%) 
Gastrooesophageal reflux disease  1  3/51 (5.88%)  0/45 (0.00%) 
Glossodynia  1  1/51 (1.96%)  1/45 (2.22%) 
Inguinal hernia  1  1/51 (1.96%)  0/45 (0.00%) 
Lip disorder  1  1/51 (1.96%)  0/45 (0.00%) 
Lip swelling  1  2/51 (3.92%)  0/45 (0.00%) 
Nausea  1  17/51 (33.33%)  21/45 (46.67%) 
Oesophagitis  1  1/51 (1.96%)  0/45 (0.00%) 
Oral pain  1  0/51 (0.00%)  1/45 (2.22%) 
Paraesthesia oral  1  0/51 (0.00%)  1/45 (2.22%) 
Retching  1  1/51 (1.96%)  0/45 (0.00%) 
Stomatitis  1  2/51 (3.92%)  1/45 (2.22%) 
Tongue discolouration  1  1/51 (1.96%)  0/45 (0.00%) 
Vomiting  1  8/51 (15.69%)  8/45 (17.78%) 
General disorders     
Asthenia  1  3/51 (5.88%)  3/45 (6.67%) 
Catheter site erythema  1  1/51 (1.96%)  0/45 (0.00%) 
Catheter site pain  1  0/51 (0.00%)  1/45 (2.22%) 
Chest discomfort  1  3/51 (5.88%)  4/45 (8.89%) 
Chest pain  1  5/51 (9.80%)  3/45 (6.67%) 
Chills  1  0/51 (0.00%)  3/45 (6.67%) 
Face oedema  1  0/51 (0.00%)  2/45 (4.44%) 
Facial pain  1  2/51 (3.92%)  0/45 (0.00%) 
Fatigue  1  23/51 (45.10%)  26/45 (57.78%) 
Feeling of body temperature change  1  1/51 (1.96%)  0/45 (0.00%) 
Gait disturbance  1  1/51 (1.96%)  1/45 (2.22%) 
Generalised oedema  1  0/51 (0.00%)  1/45 (2.22%) 
Influenza like illness  1  0/51 (0.00%)  1/45 (2.22%) 
Injection site pain  1  0/51 (0.00%)  1/45 (2.22%) 
Injection site swelling  1  0/51 (0.00%)  1/45 (2.22%) 
Mucosal inflammation  1  3/51 (5.88%)  2/45 (4.44%) 
Nodule  1  0/51 (0.00%)  1/45 (2.22%) 
Oedema  1  1/51 (1.96%)  0/45 (0.00%) 
Oedema peripheral  1  6/51 (11.76%)  11/45 (24.44%) 
Pain  1  1/51 (1.96%)  2/45 (4.44%) 
Pyrexia  1  2/51 (3.92%)  8/45 (17.78%) 
Swelling  1  1/51 (1.96%)  0/45 (0.00%) 
Systemic inflammatory response syndrome  1  0/51 (0.00%)  1/45 (2.22%) 
Temperature intolerance  1  1/51 (1.96%)  0/45 (0.00%) 
Hepatobiliary disorders     
Cholecystitis  1  0/51 (0.00%)  1/45 (2.22%) 
Hyperbilirubinaemia  1  2/51 (3.92%)  0/45 (0.00%) 
Infections and infestations     
Bronchitis  1  1/51 (1.96%)  2/45 (4.44%) 
Cellulitis  1  0/51 (0.00%)  1/45 (2.22%) 
Endocarditis  1  1/51 (1.96%)  0/45 (0.00%) 
Fungal infection  1  1/51 (1.96%)  0/45 (0.00%) 
Genital herpes  1  0/51 (0.00%)  1/45 (2.22%) 
Herpes virus infection  1  1/51 (1.96%)  0/45 (0.00%) 
Herpes zoster  1  1/51 (1.96%)  0/45 (0.00%) 
Infection  1  0/51 (0.00%)  2/45 (4.44%) 
Influenza  1  0/51 (0.00%)  1/45 (2.22%) 
Laryngitis  1  1/51 (1.96%)  0/45 (0.00%) 
Lung infection  1  1/51 (1.96%)  1/45 (2.22%) 
Nasopharyngitis  1  0/51 (0.00%)  2/45 (4.44%) 
Oral candidiasis  1  1/51 (1.96%)  4/45 (8.89%) 
Oral herpes  1  0/51 (0.00%)  1/45 (2.22%) 
Paronychia  1  2/51 (3.92%)  0/45 (0.00%) 
Pneumonia  1  6/51 (11.76%)  3/45 (6.67%) 
Rash pustular  1  2/51 (3.92%)  0/45 (0.00%) 
Respiratory tract infection  1  1/51 (1.96%)  0/45 (0.00%) 
Sepsis  1  0/51 (0.00%)  1/45 (2.22%) 
Sialoadenitis  1  1/51 (1.96%)  0/45 (0.00%) 
Sinusitis  1  0/51 (0.00%)  1/45 (2.22%) 
Skin infection  1  2/51 (3.92%)  1/45 (2.22%) 
Tooth infection  1  0/51 (0.00%)  1/45 (2.22%) 
Upper respiratory tract infection  1  1/51 (1.96%)  2/45 (4.44%) 
Urinary tract infection  1  3/51 (5.88%)  7/45 (15.56%) 
Vaginal infection  1  1/51 (1.96%)  0/45 (0.00%) 
Vulvovaginal mycotic infection  1  0/51 (0.00%)  1/45 (2.22%) 
Wound abscess  1  1/51 (1.96%)  0/45 (0.00%) 
Injury, poisoning and procedural complications     
Contrast media reaction  1  0/51 (0.00%)  1/45 (2.22%) 
Contusion  1  2/51 (3.92%)  1/45 (2.22%) 
Excoriation  1  0/51 (0.00%)  1/45 (2.22%) 
Fall  1  2/51 (3.92%)  1/45 (2.22%) 
Infusion related reaction  1  0/51 (0.00%)  1/45 (2.22%) 
Laceration  1  1/51 (1.96%)  1/45 (2.22%) 
Pubis fracture  1  0/51 (0.00%)  1/45 (2.22%) 
Tooth fracture  1  0/51 (0.00%)  2/45 (4.44%) 
Investigations     
Alanine aminotransferase increased  1  4/51 (7.84%)  4/45 (8.89%) 
Aspartate aminotransferase increased  1  2/51 (3.92%)  3/45 (6.67%) 
Blood alkaline phosphatase decreased  1  0/51 (0.00%)  1/45 (2.22%) 
Blood alkaline phosphatase increased  1  1/51 (1.96%)  2/45 (4.44%) 
Blood bilirubin increased  1  5/51 (9.80%)  1/45 (2.22%) 
Blood chloride decreased  1  1/51 (1.96%)  1/45 (2.22%) 
Blood creatinine increased  1  3/51 (5.88%)  5/45 (11.11%) 
Blood lactate dehydrogenase increased  1  2/51 (3.92%)  3/45 (6.67%) 
Blood phosphorus decreased  1  1/51 (1.96%)  0/45 (0.00%) 
Blood phosphorus increased  1  0/51 (0.00%)  1/45 (2.22%) 
Blood urea increased  1  0/51 (0.00%)  1/45 (2.22%) 
Brain natriuretic peptide increased  1  1/51 (1.96%)  0/45 (0.00%) 
Breath sounds abnormal  1  1/51 (1.96%)  0/45 (0.00%) 
CD4 lymphocytes decreased  1  1/51 (1.96%)  0/45 (0.00%) 
Fibrin D dimer increased  1  0/51 (0.00%)  1/45 (2.22%) 
Haematocrit decreased  1  0/51 (0.00%)  1/45 (2.22%) 
Haemoglobin decreased  1  0/51 (0.00%)  1/45 (2.22%) 
International normalised ratio increased  1  0/51 (0.00%)  1/45 (2.22%) 
Liver function test abnormal  1  0/51 (0.00%)  1/45 (2.22%) 
Lymphocyte count decreased  1  2/51 (3.92%)  1/45 (2.22%) 
Neutrophil count decreased  1  1/51 (1.96%)  2/45 (4.44%) 
Neutrophil count increased  1  0/51 (0.00%)  1/45 (2.22%) 
Orthostatic heart rate response increased  1  0/51 (0.00%)  1/45 (2.22%) 
Protein total decreased  1  2/51 (3.92%)  0/45 (0.00%) 
Transaminases increased  1  3/51 (5.88%)  1/45 (2.22%) 
Troponin I increased  1  0/51 (0.00%)  1/45 (2.22%) 
Urine output decreased  1  0/51 (0.00%)  1/45 (2.22%) 
Weight decreased  1  6/51 (11.76%)  3/45 (6.67%) 
White blood cell count decreased  1  2/51 (3.92%)  2/45 (4.44%) 
White blood cell count increased  1  0/51 (0.00%)  2/45 (4.44%) 
Metabolism and nutrition disorders     
Decreased appetite  1  17/51 (33.33%)  16/45 (35.56%) 
Dehydration  1  0/51 (0.00%)  4/45 (8.89%) 
Hypercalcaemia  1  2/51 (3.92%)  0/45 (0.00%) 
Hyperglycaemia  1  5/51 (9.80%)  9/45 (20.00%) 
Hyperkalaemia  1  1/51 (1.96%)  2/45 (4.44%) 
Hyperuricaemia  1  0/51 (0.00%)  1/45 (2.22%) 
Hypoalbuminaemia  1  7/51 (13.73%)  6/45 (13.33%) 
Hypocalcaemia  1  3/51 (5.88%)  2/45 (4.44%) 
Hypoglycaemia  1  1/51 (1.96%)  1/45 (2.22%) 
Hypokalaemia  1  6/51 (11.76%)  8/45 (17.78%) 
Hypomagnesaemia  1  8/51 (15.69%)  3/45 (6.67%) 
Hyponatraemia  1  5/51 (9.80%)  4/45 (8.89%) 
Hypophosphataemia  1  6/51 (11.76%)  1/45 (2.22%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  6/51 (11.76%)  3/45 (6.67%) 
Arthritis  1  0/51 (0.00%)  1/45 (2.22%) 
Back pain  1  5/51 (9.80%)  7/45 (15.56%) 
Bone pain  1  1/51 (1.96%)  2/45 (4.44%) 
Flank pain  1  2/51 (3.92%)  1/45 (2.22%) 
Groin pain  1  1/51 (1.96%)  0/45 (0.00%) 
Intervertebral disc disorder  1  0/51 (0.00%)  1/45 (2.22%) 
Intervertebral disc protrusion  1  0/51 (0.00%)  1/45 (2.22%) 
Muscle spasms  1  2/51 (3.92%)  1/45 (2.22%) 
Muscular weakness  1  3/51 (5.88%)  2/45 (4.44%) 
Musculoskeletal chest pain  1  3/51 (5.88%)  2/45 (4.44%) 
Musculoskeletal discomfort  1  1/51 (1.96%)  0/45 (0.00%) 
Musculoskeletal pain  1  1/51 (1.96%)  1/45 (2.22%) 
Myalgia  1  1/51 (1.96%)  7/45 (15.56%) 
Neck pain  1  2/51 (3.92%)  1/45 (2.22%) 
Pain in extremity  1  4/51 (7.84%)  2/45 (4.44%) 
Pain in jaw  1  0/51 (0.00%)  1/45 (2.22%) 
Pathological fracture  1  0/51 (0.00%)  1/45 (2.22%) 
Spinal pain  1  1/51 (1.96%)  0/45 (0.00%) 
Spondyloarthropathy  1  1/51 (1.96%)  0/45 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Haemangioma of bone  1  1/51 (1.96%)  0/45 (0.00%) 
Seborrhoeic keratosis  1  0/51 (0.00%)  1/45 (2.22%) 
Nervous system disorders     
Ageusia  1  0/51 (0.00%)  1/45 (2.22%) 
Aphasia  1  0/51 (0.00%)  1/45 (2.22%) 
Brain oedema  1  0/51 (0.00%)  1/45 (2.22%) 
Cerebral infarction  1  1/51 (1.96%)  0/45 (0.00%) 
Cognitive disorder  1  1/51 (1.96%)  0/45 (0.00%) 
Dizziness  1  3/51 (5.88%)  6/45 (13.33%) 
Dysarthria  1  0/51 (0.00%)  1/45 (2.22%) 
Dysgeusia  1  6/51 (11.76%)  5/45 (11.11%) 
Dysgraphia  1  0/51 (0.00%)  1/45 (2.22%) 
Headache  1  1/51 (1.96%)  5/45 (11.11%) 
Hyperaesthesia  1  0/51 (0.00%)  1/45 (2.22%) 
Hypoaesthesia  1  1/51 (1.96%)  1/45 (2.22%) 
Memory impairment  1  1/51 (1.96%)  0/45 (0.00%) 
Migraine with aura  1  0/51 (0.00%)  1/45 (2.22%) 
Motor dysfunction  1  0/51 (0.00%)  1/45 (2.22%) 
Neuralgia  1  2/51 (3.92%)  0/45 (0.00%) 
Neuropathy peripheral  1  2/51 (3.92%)  5/45 (11.11%) 
Paraesthesia  1  1/51 (1.96%)  1/45 (2.22%) 
Restless legs syndrome  1  2/51 (3.92%)  0/45 (0.00%) 
Sciatica  1  0/51 (0.00%)  1/45 (2.22%) 
Somnolence  1  1/51 (1.96%)  2/45 (4.44%) 
Syncope  1  1/51 (1.96%)  1/45 (2.22%) 
Tremor  1  1/51 (1.96%)  2/45 (4.44%) 
Vasogenic cerebral oedema  1  0/51 (0.00%)  1/45 (2.22%) 
Psychiatric disorders     
Anxiety  1  6/51 (11.76%)  9/45 (20.00%) 
Confusional state  1  1/51 (1.96%)  2/45 (4.44%) 
Delirium  1  1/51 (1.96%)  1/45 (2.22%) 
Depression  1  5/51 (9.80%)  6/45 (13.33%) 
Insomnia  1  3/51 (5.88%)  8/45 (17.78%) 
Mental status changes  1  0/51 (0.00%)  1/45 (2.22%) 
Panic attack  1  0/51 (0.00%)  1/45 (2.22%) 
Renal and urinary disorders     
Haematuria  1  0/51 (0.00%)  2/45 (4.44%) 
Incontinence  1  1/51 (1.96%)  0/45 (0.00%) 
Micturition urgency  1  0/51 (0.00%)  2/45 (4.44%) 
Nephrolithiasis  1  1/51 (1.96%)  0/45 (0.00%) 
Oliguria  1  0/51 (0.00%)  1/45 (2.22%) 
Pollakiuria  1  2/51 (3.92%)  0/45 (0.00%) 
Proteinuria  1  0/51 (0.00%)  1/45 (2.22%) 
Renal failure acute  1  1/51 (1.96%)  0/45 (0.00%) 
Urinary incontinence  1  1/51 (1.96%)  0/45 (0.00%) 
Urinary retention  1  0/51 (0.00%)  1/45 (2.22%) 
Reproductive system and breast disorders     
Breast discomfort  1  0/51 (0.00%)  1/45 (2.22%) 
Breast mass  1  0/51 (0.00%)  1/45 (2.22%) 
Penile erythema  1  1/51 (1.96%)  0/45 (0.00%) 
Varicocele  1  1/51 (1.96%)  0/45 (0.00%) 
Vulvovaginal dryness  1  1/51 (1.96%)  0/45 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Chronic obstructive pulmonary disease  1  1/51 (1.96%)  0/45 (0.00%) 
Cough  1  16/51 (31.37%)  10/45 (22.22%) 
Dysphonia  1  3/51 (5.88%)  1/45 (2.22%) 
Dyspnoea  1  12/51 (23.53%)  14/45 (31.11%) 
Dyspnoea exertional  1  5/51 (9.80%)  3/45 (6.67%) 
Epistaxis  1  2/51 (3.92%)  5/45 (11.11%) 
Haemoptysis  1  3/51 (5.88%)  2/45 (4.44%) 
Hiccups  1  0/51 (0.00%)  1/45 (2.22%) 
Hypercapnia  1  0/51 (0.00%)  1/45 (2.22%) 
Hypoxia  1  5/51 (9.80%)  6/45 (13.33%) 
Lung infiltration  1  0/51 (0.00%)  1/45 (2.22%) 
Nasal congestion  1  1/51 (1.96%)  4/45 (8.89%) 
Nasal dryness  1  1/51 (1.96%)  0/45 (0.00%) 
Oropharyngeal discomfort  1  0/51 (0.00%)  1/45 (2.22%) 
Oropharyngeal pain  1  2/51 (3.92%)  2/45 (4.44%) 
Paranasal sinus hypersecretion  1  1/51 (1.96%)  0/45 (0.00%) 
Pleural effusion  1  1/51 (1.96%)  3/45 (6.67%) 
Pneumonia aspiration  1  0/51 (0.00%)  1/45 (2.22%) 
Pneumonitis  1  0/51 (0.00%)  1/45 (2.22%) 
Pneumothorax  1  0/51 (0.00%)  1/45 (2.22%) 
Productive cough  1  3/51 (5.88%)  2/45 (4.44%) 
Respiratory distress  1  0/51 (0.00%)  1/45 (2.22%) 
Respiratory tract congestion  1  1/51 (1.96%)  1/45 (2.22%) 
Respiratory tract inflammation  1  0/51 (0.00%)  1/45 (2.22%) 
Rhinorrhoea  1  1/51 (1.96%)  0/45 (0.00%) 
Sneezing  1  1/51 (1.96%)  0/45 (0.00%) 
Tachypnoea  1  0/51 (0.00%)  1/45 (2.22%) 
Wheezing  1  3/51 (5.88%)  5/45 (11.11%) 
Skin and subcutaneous tissue disorders     
Alopecia  1  4/51 (7.84%)  8/45 (17.78%) 
Decubitus ulcer  1  0/51 (0.00%)  1/45 (2.22%) 
Dermatitis acneiform  1  14/51 (27.45%)  0/45 (0.00%) 
Drug eruption  1  2/51 (3.92%)  0/45 (0.00%) 
Dry skin  1  7/51 (13.73%)  0/45 (0.00%) 
Ecchymosis  1  0/51 (0.00%)  2/45 (4.44%) 
Erythema  1  3/51 (5.88%)  4/45 (8.89%) 
Hyperhidrosis  1  0/51 (0.00%)  3/45 (6.67%) 
Nail bed disorder  1  0/51 (0.00%)  1/45 (2.22%) 
Night sweats  1  1/51 (1.96%)  1/45 (2.22%) 
Onychoclasis  1  1/51 (1.96%)  1/45 (2.22%) 
Palmar-plantar erythrodysaesthesia syndrome  1  0/51 (0.00%)  1/45 (2.22%) 
Petechiae  1  0/51 (0.00%)  2/45 (4.44%) 
Pruritus  1  6/51 (11.76%)  0/45 (0.00%) 
Rash  1  22/51 (43.14%)  7/45 (15.56%) 
Rash erythematous  1  1/51 (1.96%)  0/45 (0.00%) 
Rash generalised  1  1/51 (1.96%)  0/45 (0.00%) 
Rash macular  1  0/51 (0.00%)  1/45 (2.22%) 
Rash papular  1  1/51 (1.96%)  1/45 (2.22%) 
Rash pruritic  1  0/51 (0.00%)  1/45 (2.22%) 
Skin mass  1  1/51 (1.96%)  0/45 (0.00%) 
Skin ulcer  1  1/51 (1.96%)  0/45 (0.00%) 
Vascular disorders     
Deep vein thrombosis  1  1/51 (1.96%)  1/45 (2.22%) 
Embolism  1  1/51 (1.96%)  0/45 (0.00%) 
Flushing  1  1/51 (1.96%)  1/45 (2.22%) 
Hot flush  1  1/51 (1.96%)  0/45 (0.00%) 
Hypertension  1  3/51 (5.88%)  2/45 (4.44%) 
Hypotension  1  0/51 (0.00%)  7/45 (15.56%) 
Lymphoedema  1  0/51 (0.00%)  2/45 (4.44%) 
Microangiopathy  1  0/51 (0.00%)  1/45 (2.22%) 
Orthostatic hypotension  1  1/51 (1.96%)  1/45 (2.22%) 
Phlebitis  1  0/51 (0.00%)  1/45 (2.22%) 
Phlebitis superficial  1  0/51 (0.00%)  1/45 (2.22%) 
1
Term from vocabulary, MedDRA (15.1)
Indicates events were collected by systematic assessment
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
Layout table for Results Point of Contact information
Name/Title: Brian Schwartz, MD Chief Medical Officer
Organization: ArQule, Inc.
Phone: 781-994-0300
EMail: ClinicalTrials@arqule.com
Layout table for additonal information
Responsible Party: ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
ClinicalTrials.gov Identifier: NCT01395758    
Other Study ID Numbers: ARQ 197-218
First Submitted: July 1, 2011
First Posted: July 18, 2011
Results First Submitted: January 31, 2018
Results First Posted: April 3, 2018
Last Update Posted: April 3, 2018