Trial Outcomes & Findings for Erlotinib Plus Tivantinib (ARQ 197) Versus Single Agent Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NCT NCT01395758)

Last Updated: 2018-04-03

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

96 participants

Primary outcome timeframe

Date of randomization until disease progression per RECIST (v 1.1) or death from any cause, whichever came first, assessed up to 24 months.

Results posted on

2018-04-03

Participant Flow

Participant milestones

Participant milestones
Measure	Tivantinib Plus Erlotinib Arm 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	Chemotherapy Arm 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.	Crossover Arm 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.
Open-label Treatment Period STARTED	51	45	0
Open-label Treatment Period COMPLETED	47	45	0
Open-label Treatment Period NOT COMPLETED	4	0	0
Crossover Period STARTED	0	0	26
Crossover Period COMPLETED	0	0	26
Crossover Period NOT COMPLETED	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Tivantinib Plus Erlotinib Arm 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	Chemotherapy Arm 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.	Crossover Arm 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.
Open-label Treatment Period Withdrawal by Subject	4	0	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tivantinib Plus Erlotinib Arm n=51 Participants 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	Chemotherapy Arm n=45 Participants 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 n=96 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Age, Categorical Between 18 and 65 years	28 Participants n=99 Participants	16 Participants n=107 Participants	44 Participants n=206 Participants
Age, Categorical >=65 years	23 Participants n=99 Participants	29 Participants n=107 Participants	52 Participants n=206 Participants
Age, Continuous	62.6 years STANDARD_DEVIATION 9.23 • n=99 Participants	65.2 years STANDARD_DEVIATION 9.55 • n=107 Participants	63.8 years STANDARD_DEVIATION 9.43 • n=206 Participants
Sex: Female, Male Female	33 Participants n=99 Participants	30 Participants n=107 Participants	63 Participants n=206 Participants
Sex: Female, Male Male	18 Participants n=99 Participants	15 Participants n=107 Participants	33 Participants n=206 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=99 Participants	0 Participants n=107 Participants	1 Participants n=206 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	50 Participants n=99 Participants	45 Participants n=107 Participants	95 Participants n=206 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Asian	1 Participants n=99 Participants	2 Participants n=107 Participants	3 Participants n=206 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Black or African American	1 Participants n=99 Participants	2 Participants n=107 Participants	3 Participants n=206 Participants
Race (NIH/OMB) White	47 Participants n=99 Participants	41 Participants n=107 Participants	88 Participants n=206 Participants
Race (NIH/OMB) More than one race	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants n=99 Participants	0 Participants n=107 Participants	2 Participants n=206 Participants
Region of Enrollment United States	51 participants n=99 Participants	45 participants n=107 Participants	96 participants n=206 Participants
Cigarette Use Yes	46 Participants n=99 Participants	42 Participants n=107 Participants	88 Participants n=206 Participants
Cigarette Use No	5 Participants n=99 Participants	3 Participants n=107 Participants	8 Participants n=206 Participants
Weight	72.50 kilograms STANDARD_DEVIATION 17.31 • n=99 Participants	68.86 kilograms STANDARD_DEVIATION 15.19 • n=107 Participants	70.79 kilograms STANDARD_DEVIATION 16.37 • n=206 Participants
Height	166.38 centimeters STANDARD_DEVIATION 10.28 • n=99 Participants	164.88 centimeters STANDARD_DEVIATION 9.42 • n=107 Participants	165.68 centimeters STANDARD_DEVIATION 9.86 • n=206 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status Score Grade 0	12 Participants n=99 Participants	8 Participants n=107 Participants	20 Participants n=206 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status Score Grade 1	32 Participants n=99 Participants	33 Participants n=107 Participants	65 Participants n=206 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status Score Grade 2	7 Participants n=99 Participants	4 Participants n=107 Participants	11 Participants n=206 Participants
Confirmation of Kirsten rat sarcoma (KRAS) Mutation Yes	51 Participants n=99 Participants	45 Participants n=107 Participants	96 Participants n=206 Participants
Confirmation of Kirsten rat sarcoma (KRAS) Mutation No	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants

PRIMARY outcome

Timeframe: Date of randomization until disease progression per RECIST (v 1.1) or death from any cause, whichever came first, assessed up to 24 months.

Outcome measures

Outcome measures
Measure	Tivantinib Plus Erlotinib Arm n=51 Participants 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	Chemotherapy Arm n=45 Participants 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.
Progression-free Survival (PFS) Among Subjects With KRAS Mutation Positive NSCLC (ITT Population) Treated With Erlotinib Plus Tivantinib Compared to Single Agent Chemotherapy.	7.3 weeks Interval 6.86 to 24.14	18.6 weeks Interval 7.0 to 25.0

SECONDARY outcome

Timeframe: Date of randomization to the date of death from any cause, assessed up to 24 months

OS is calculated from the date of randomization until death from any cause.

Outcome measures

Outcome measures
Measure	Tivantinib Plus Erlotinib Arm n=51 Participants 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	Chemotherapy Arm n=45 Participants 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 Survival (OS) Among All Eligible Subjects (ITT Population) Treated With Erlotinib Plus Tivantinib Compared to Chemotherapy.	6.8 months Interval 4.97 to 10.7	8.5 months Interval 6.37 to 13.97

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Tivantinib Plus Erlotinib Arm n=51 Participants 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	Chemotherapy Arm n=45 Participants 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.
Objective Response Rate (ORR) Among All Eligible Subjects (ITT Population) Treated With Erlotinib Plus Tivantinib Compared to Chemotherapy.	0 Participants	4 Participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Tivantinib Plus Erlotinib Arm n=26 Participants 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	Chemotherapy Arm 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.
ORR Among Subjects in the Crossover Period Treated With Erlotinib Plus Tivantinib	2 Participants	—

Adverse Events

Tivantinib Plus Erlotinib Arm

Serious events: 19 serious events

Other events: 51 other events

Deaths: 3 deaths

Chemotherapy Arm

Serious events: 25 serious events

Other events: 45 other events

Deaths: 4 deaths

Serious adverse events

Other adverse events

Additional Information

Brian Schwartz, MD Chief Medical Officer

ArQule, Inc.

Phone: 781-994-0300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Tivantinib Plus Erlotinib Arm n=51 participants at risk 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	Chemotherapy Arm n=45 participants at risk 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.
Vascular disorders Superior vena cava syndrome	0.00% 0/51 • 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.	2.2% 1/45 • 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.
Blood and lymphatic system disorders Anaemia	0.00% 0/51 • 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.	4.4% 2/45 • 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.
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/51 • 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.	8.9% 4/45 • 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.
Blood and lymphatic system disorders Neutropenia	2.0% 1/51 • 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.	2.2% 1/45 • 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.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/51 • 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.	2.2% 1/45 • 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.
Cardiac disorders Aortic valve incompetence	2.0% 1/51 • 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.	0.00% 0/45 • 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.
Cardiac disorders Atrial fibrillation	3.9% 2/51 • 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.	2.2% 1/45 • 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.
Cardiac disorders Myocardial infarction	2.0% 1/51 • 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.	0.00% 0/45 • 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.
Cardiac disorders Ventricular tachycardia	0.00% 0/51 • 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.	2.2% 1/45 • 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.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/51 • 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.	2.2% 1/45 • 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.
Gastrointestinal disorders Diarrhoea	2.0% 1/51 • 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.	0.00% 0/45 • 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.
General disorders Asthenia	0.00% 0/51 • 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.	2.2% 1/45 • 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.
General disorders Disease progression	5.9% 3/51 • 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.	8.9% 4/45 • 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.
General disorders Fatigue	2.0% 1/51 • 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.	0.00% 0/45 • 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.
General disorders Non-cardiac chest pain	0.00% 0/51 • 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.	2.2% 1/45 • 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.
General disorders Pain	0.00% 0/51 • 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.	2.2% 1/45 • 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.
General disorders Pyrexia	0.00% 0/51 • 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.	2.2% 1/45 • 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.
Hepatobiliary disorders Cholecystitis	0.00% 0/51 • 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.	2.2% 1/45 • 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.
Infections and infestations Bacteraemia	3.9% 2/51 • 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.	2.2% 1/45 • 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.
Infections and infestations Endocarditis	2.0% 1/51 • 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.	0.00% 0/45 • 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.
Infections and infestations Enterocolitis infectious	2.0% 1/51 • 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.	0.00% 0/45 • 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.
Infections and infestations Lung infection	2.0% 1/51 • 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.	0.00% 0/45 • 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.
Infections and infestations Pneumonia	7.8% 4/51 • 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.	8.9% 4/45 • 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.
Infections and infestations Sepsis	3.9% 2/51 • 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.	2.2% 1/45 • 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.
Infections and infestations Urinary tract infection	0.00% 0/51 • 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.	4.4% 2/45 • 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.
Injury, poisoning and procedural complications Pubis fracture	0.00% 0/51 • 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.	2.2% 1/45 • 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.
Investigations Blood creatinine increased	0.00% 0/51 • 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.	2.2% 1/45 • 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.
Metabolism and nutrition disorders Dehydration	3.9% 2/51 • 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.	4.4% 2/45 • 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.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/51 • 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.	2.2% 1/45 • 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.
Musculoskeletal and connective tissue disorders Back pain	3.9% 2/51 • 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.	0.00% 0/45 • 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.
Musculoskeletal and connective tissue disorders Muscular weakness	0.00% 0/51 • 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.	2.2% 1/45 • 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.
Musculoskeletal and connective tissue disorders Myalgia	0.00% 0/51 • 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.	2.2% 1/45 • 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.
Musculoskeletal and connective tissue disorders Pathological fracture	2.0% 1/51 • 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.	0.00% 0/45 • 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant pleural effusion	0.00% 0/51 • 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.	2.2% 1/45 • 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to oesophagus	2.0% 1/51 • 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.	0.00% 0/45 • 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.
Nervous system disorders Cerebrovascular accident	2.0% 1/51 • 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.	0.00% 0/45 • 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.
Nervous system disorders Depressed level of consciousness	2.0% 1/51 • 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.	0.00% 0/45 • 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.
Nervous system disorders Dizziness	2.0% 1/51 • 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.	0.00% 0/45 • 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.
Nervous system disorders Embolic stroke	2.0% 1/51 • 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.	0.00% 0/45 • 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.
Psychiatric disorders Panic attack	2.0% 1/51 • 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.	0.00% 0/45 • 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.
Renal and urinary disorders Nephrolithiasis	2.0% 1/51 • 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.	0.00% 0/45 • 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.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.00% 0/51 • 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.	2.2% 1/45 • 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.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	3.9% 2/51 • 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.	0.00% 0/45 • 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.
Respiratory, thoracic and mediastinal disorders Dyspnoea	3.9% 2/51 • 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.	4.4% 2/45 • 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.
Respiratory, thoracic and mediastinal disorders Hypoxia	3.9% 2/51 • 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.	2.2% 1/45 • 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.
Respiratory, thoracic and mediastinal disorders Pleural effusion	5.9% 3/51 • 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.	0.00% 0/45 • 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.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.00% 0/51 • 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.	4.4% 2/45 • 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.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	2.0% 1/51 • 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.	4.4% 2/45 • 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.
Respiratory, thoracic and mediastinal disorders Respiratory failure	2.0% 1/51 • 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.	0.00% 0/45 • 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.
Vascular disorders Deep vein thrombosis	2.0% 1/51 • 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.	0.00% 0/45 • 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.
Vascular disorders Embolism	3.9% 2/51 • 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.	0.00% 0/45 • 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.