Trial Outcomes & Findings for Cetuximab With or Without Tivantinib in Treating Patients With Head and Neck Cancer That Is Recurrent, Metastatic, or Cannot Be Removed by Surgery (NCT NCT01696955)

Last Updated: 2018-12-19

Results Overview

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

81 participants

Primary outcome timeframe

Up to 1 year

Results posted on

2018-12-19

Participant Flow

Participant milestones

Participant milestones
Measure	Arm I (Cetuximab and Tivantinib) Patients receive cetuximab 500mg/m2 IV over 60-120 minutes on days 1 and 15 and tivantinib 360mg PO BID on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cetuximab: Given IV Tivantinib: Given PO	Arm II (Cetuximab) Patients receive cetuximab 500 mg/m2 IV over 60-120 minutes on days 1 and 15. Patients who fail (progress) on cetuximab as a single agent may then receive single agent tivantinib PO BID on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cetuximab: Given IV
Main Study STARTED	42	39
Main Study COMPLETED	40	38
Main Study NOT COMPLETED	2	1
Failure on Cetuximab-Received Tivantinib STARTED	0	15
Failure on Cetuximab-Received Tivantinib COMPLETED	0	15
Failure on Cetuximab-Received Tivantinib NOT COMPLETED	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm I (Cetuximab and Tivantinib) Patients receive cetuximab 500mg/m2 IV over 60-120 minutes on days 1 and 15 and tivantinib 360mg PO BID on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cetuximab: Given IV Tivantinib: Given PO	Arm II (Cetuximab) Patients receive cetuximab 500 mg/m2 IV over 60-120 minutes on days 1 and 15. Patients who fail (progress) on cetuximab as a single agent may then receive single agent tivantinib PO BID on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cetuximab: Given IV
Main Study Protocol Violation	1	0
Main Study Withdrawal by Subject	1	1

Baseline Characteristics

Cetuximab With or Without Tivantinib in Treating Patients With Head and Neck Cancer That Is Recurrent, Metastatic, or Cannot Be Removed by Surgery

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm I (Cetuximab and Tivantinib) n=40 Participants Patients receive cetuximab 500mg/m2 IV over 60-120 minutes on days 1 and 15 and tivantinib 360mg PO BID on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cetuximab: Given IV Tivantinib: Given PO	Arm II (Cetuximab) n=38 Participants Patients receive cetuximab 500mg/m2 IV over 60-120 minutes on days 1 and 15. Patients who fail (progress) on cetuximab as a single agent may then receive single agent tivantinib PO BID on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cetuximab: Given IV	Total n=78 Participants Total of all reporting groups
Age, Continuous	60.5 years n=5 Participants	63.6 years n=7 Participants	62.0 years n=5 Participants
Sex: Female, Male Female	6 Participants n=5 Participants	6 Participants n=7 Participants	12 Participants n=5 Participants
Sex: Female, Male Male	34 Participants n=5 Participants	32 Participants n=7 Participants	66 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants
Race (NIH/OMB) White	32 Participants n=5 Participants	33 Participants n=7 Participants	65 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Region of Enrollment United States	40 Participants n=5 Participants	38 Participants n=7 Participants	78 Participants n=5 Participants

PRIMARY outcome

Timeframe: Up to 1 year

Outcome measures

Outcome measures
Measure	Arm I (Cetuximab and Tivantinib) n=40 Participants Patients receive cetuximab 500mg/m2 IV over 60-120 minutes on days 1 and 15 and tivantinib 360mg PO BID on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cetuximab: Given IV Tivantinib: Given PO	Arm II (Cetuximab) n=38 Participants Patients receive cetuximab 500mg/m2 IV over 60-120 minutes on days 1 and 15. Patients who fail (progress) on cetuximab as a single agent may then receive single agent tivantinib PO BID on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cetuximab: Given IV
Overall Response Rate Complete response	1 Participants	0 Participants
Overall Response Rate Partial response	2 Participants	3 Participants

SECONDARY outcome

Timeframe: Baseline to 8 weeks

Population: Assay not performed.

Change in copy number from baseline to 8 weeks

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline to 8 weeks

Population: Assay not performed.

Change in c-MET expression from baseline to 8 weeks

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline to 8 weeks

Population: Patients with baseline and 8 week measurements available

Early change in tumor burden measured using the sum of longest diameters of target lesions, expressed as percent change from baseline.

Outcome measures

Outcome measures
Measure	Arm I (Cetuximab and Tivantinib) n=32 Participants Patients receive cetuximab 500mg/m2 IV over 60-120 minutes on days 1 and 15 and tivantinib 360mg PO BID on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cetuximab: Given IV Tivantinib: Given PO	Arm II (Cetuximab) n=31 Participants Patients receive cetuximab 500mg/m2 IV over 60-120 minutes on days 1 and 15. Patients who fail (progress) on cetuximab as a single agent may then receive single agent tivantinib PO BID on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cetuximab: Given IV
Change in Tumor Burden	15.0 percent change Standard Deviation 6.1	9.0 percent change Standard Deviation 5.5

SECONDARY outcome

Timeframe: Up to 5 years

Time from randomization until death or date last known alive

Outcome measures

Outcome measures
Measure	Arm I (Cetuximab and Tivantinib) n=40 Participants Patients receive cetuximab 500mg/m2 IV over 60-120 minutes on days 1 and 15 and tivantinib 360mg PO BID on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cetuximab: Given IV Tivantinib: Given PO	Arm II (Cetuximab) n=38 Participants Patients receive cetuximab 500mg/m2 IV over 60-120 minutes on days 1 and 15. Patients who fail (progress) on cetuximab as a single agent may then receive single agent tivantinib PO BID on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cetuximab: Given IV
Overall Survival	7.4 months Interval 4.7 to 10.3	8.6 months Interval 5.7 to 11.5

SECONDARY outcome

Timeframe: Up to 3 years

Time from randomization until disease progression/death from any cause or date last know progression-free

Outcome measures

Outcome measures
Measure	Arm I (Cetuximab and Tivantinib) n=40 Participants Patients receive cetuximab 500mg/m2 IV over 60-120 minutes on days 1 and 15 and tivantinib 360mg PO BID on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cetuximab: Given IV Tivantinib: Given PO	Arm II (Cetuximab) n=38 Participants Patients receive cetuximab 500mg/m2 IV over 60-120 minutes on days 1 and 15. Patients who fail (progress) on cetuximab as a single agent may then receive single agent tivantinib PO BID on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cetuximab: Given IV
Progression-free Survival	3.5 months Interval 1.8 to 3.9	3.5 months Interval 2.0 to 3.9

SECONDARY outcome

Timeframe: Up to 1 year

Population: This outcome pertains only to Tivantinib after Cetuximab failure and therefore Arm 1 contains 0 analyzed.

Outcome measures

Outcome measures
Measure	Arm I (Cetuximab and Tivantinib) Patients receive cetuximab 500mg/m2 IV over 60-120 minutes on days 1 and 15 and tivantinib 360mg PO BID on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cetuximab: Given IV Tivantinib: Given PO	Arm II (Cetuximab) n=15 Participants Patients receive cetuximab 500mg/m2 IV over 60-120 minutes on days 1 and 15. Patients who fail (progress) on cetuximab as a single agent may then receive single agent tivantinib PO BID on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cetuximab: Given IV
Overall Response Rate of Single-agent Tivantinib After Failure of Cetuximab	—	0 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Up to 3 years

Population: This outcome pertains only to Tivantinib after Cetuximab Failure and therefore Arm 1 contains 0 analyzed.

Non-serious adverse events, CTCAE (4.0)

Outcome measures

Outcome measures
Measure	Arm I (Cetuximab and Tivantinib) Patients receive cetuximab 500mg/m2 IV over 60-120 minutes on days 1 and 15 and tivantinib 360mg PO BID on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cetuximab: Given IV Tivantinib: Given PO	Arm II (Cetuximab) n=15 Participants Patients receive cetuximab 500mg/m2 IV over 60-120 minutes on days 1 and 15. Patients who fail (progress) on cetuximab as a single agent may then receive single agent tivantinib PO BID on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cetuximab: Given IV
Number of Participants With Adverse Events While on Single-agent Tivantinib After Failure of Cetuximab	—	9 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 3 years

Population: This outcome pertains only to Tivantinib after Cetuximab Failure and therefore Arm 1 contains 0 analyzed.

CTCAE (4.0)

Outcome measures

Outcome measures
Measure	Arm I (Cetuximab and Tivantinib) Patients receive cetuximab 500mg/m2 IV over 60-120 minutes on days 1 and 15 and tivantinib 360mg PO BID on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cetuximab: Given IV Tivantinib: Given PO	Arm II (Cetuximab) n=15 Participants Patients receive cetuximab 500mg/m2 IV over 60-120 minutes on days 1 and 15. Patients who fail (progress) on cetuximab as a single agent may then receive single agent tivantinib PO BID on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cetuximab: Given IV
Number of Patients With Serious Adverse Events While on Single-agent Tivantinib After Failure of Cetuximab	—	4 Participants

Adverse Events

Arm I (Cetuximab and Tivantinib)

Serious events: 19 serious events

Other events: 38 other events

Deaths: 36 deaths

Arm II (Cetuximab)

Serious events: 18 serious events

Other events: 35 other events

Deaths: 35 deaths

Single-agent Tivantinib After Failure of Cetuximab

Serious events: 4 serious events

Other events: 9 other events

Deaths: 2 deaths

Serious adverse events

Other adverse events

Additional Information

Theodore Karrison

University of Chicago

Phone: 773-702-9326

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	Arm I (Cetuximab and Tivantinib) n=40 participants at risk Patients receive cetuximab 500mg/m2 IV over 60-120 minutes on days 1 and 15 and tivantinib 360mg PO BID on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cetuximab: Given IV Tivantinib: Given PO	Arm II (Cetuximab) n=38 participants at risk Patients receive cetuximab 500mg/m2 IV over 60-120 minutes on days 1 and 15. Patients who fail (progress) on cetuximab as a single agent may then receive single agent tivantinib PO BID on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cetuximab: Given IV	Single-agent Tivantinib After Failure of Cetuximab n=15 participants at risk Patients receive cetuximab 500mg/m2 IV over 60-120 minutes on days 1 and 15.
Investigations Alkaline phosphatase increased	0.00% 0/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	2.6% 1/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Blood and lymphatic system disorders Anemia	5.0% 2/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Nervous system disorders Ataxia	0.00% 0/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	2.6% 1/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Cardiac disorders Atrial fibrillation	0.00% 0/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	2.6% 1/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	6.7% 1/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Investigations Blood bilirubin increased	0.00% 0/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	2.6% 1/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
General disorders Pain	0.00% 0/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	2.6% 1/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	6.7% 1/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Investigations Cardiac arrest	2.5% 1/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Psychiatric disorders Confusion	0.00% 0/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	2.6% 1/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Gastrointestinal disorders Constipation	2.5% 1/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	2.6% 1/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
General disorders Death NOS	0.00% 0/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	5.3% 2/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Metabolism and nutrition disorders Dehydration	5.0% 2/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	7.9% 3/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Gastrointestinal disorders Dysphagia	0.00% 0/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	2.6% 1/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Respiratory, thoracic and mediastinal disorders Dyspnea	2.5% 1/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	6.7% 1/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
General disorders Fatigue	5.0% 2/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Blood and lymphatic system disorders Febrile neutropenia	7.5% 3/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	6.7% 1/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
General disorders Fever	2.5% 1/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Hepatobiliary disorders Hepatic failure	2.5% 1/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Metabolism and nutrition disorders Hypercalcemia	2.5% 1/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	2.6% 1/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Metabolism and nutrition disorders Hypomagnesemia	2.5% 1/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	2.6% 1/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Metabolism and nutrition disorders Hypophosphatemia	2.5% 1/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Vascular disorders Hypotension	2.5% 1/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	2.6% 1/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	2.6% 1/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
General disorders Infusion related reaction	2.5% 1/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Respiratory, thoracic and mediastinal disorders Laryngeal edema	2.5% 1/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Infections and infestations Lung infection	2.5% 1/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	2.6% 1/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	13.3% 2/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Gastrointestinal disorders Nausea	2.5% 1/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	12.5% 5/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	5.3% 2/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	6.7% 1/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Nervous system disorders Nervous system disorders - Other, specify	2.5% 1/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Investigations Neutrophil count decreased	10.0% 4/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Respiratory, thoracic and mediastinal disorders Pleural effusion	2.5% 1/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Respiratory, thoracic and mediastinal disorders Pneumonitis	2.5% 1/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	2.6% 1/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Respiratory, thoracic and mediastinal disorders Pneumothorax	2.5% 1/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Skin and subcutaneous tissue disorders Rash acneiform	0.00% 0/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	2.6% 1/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Respiratory, thoracic and mediastinal disorders Respiratory, thoracic and mediastinal disorders - Other, specify	0.00% 0/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	2.6% 1/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Infections and infestations Sepsis	2.5% 1/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	5.3% 2/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Cardiac disorders Sinus bradycardia	0.00% 0/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	2.6% 1/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Infections and infestations Skin infection	0.00% 0/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	2.6% 1/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Surgical and medical procedures Surgical and medical procedures - Other, specify	0.00% 0/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	2.6% 1/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Nervous system disorders Syncope	0.00% 0/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	2.6% 1/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Injury, poisoning and procedural complications Tracheal hemorrhage	2.5% 1/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Infections and infestations Urinary tract infection	2.5% 1/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Gastrointestinal disorders Vomiting	2.5% 1/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	6.7% 1/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Investigations White blood cell decreased	7.5% 3/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	6.7% 1/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
General disorders Edema face	0.00% 0/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	6.7% 1/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.
Infections and infestations Infections - Other	0.00% 0/40 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	0.00% 0/38 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.	6.7% 1/15 • 3 years Note: Adverse events reported in Arm II were prior to any crossover to combination therapy.