A Study to Evaluate Pazopanib in Comparison to Pemetrexed... | NCT01313663

Label	Type	Description	Intervention Names
Pazopanib	Experimental	oral agent, administered at 800 mg daily (400 mg tablets x 2). Dose can be reduced, interrupted or discontinued due to adverse events or intolerance	Drug: pazopanib
Pemetrexed	Active Comparator	pemetrexed IV 500 mg/m2 once every 3 weeks	Drug: pemetrexed

Name	Type	Description	Arm Group Labels	Other Names
pazopanib	Drug	oral agent, administered at 800 mg daily (400 mg tablets x 2). Dose can be reduced, interrupted or discontinued due to adverse events or intolerance	Pazopanib

Measure	Description	Time Frame
Progression Free Survival (PFS)	PFS is defined as the interval between the date of randomization and the first documented sign of investigator-assessed (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) disease progression (PD) or death, whichever occurs first. The date of documented PD is the date of lesion evaluation in the case of radiological PD and the date of symptomatic cancer progression in the case of symptomatic progression (radiological confirmation is required). PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started. If the participant received subsequent anti-cancer therapy prior to the date of documented progression or death, PFS was to be censored at the last adequate assessment (LAA) prior to the initiation of therapy. Otherwise, if the participant did not have a documented date of progression or death, PFS was to be censored at the date of the LAA.	From randomization until the first documented sign of investigator-assessed disease progression or death, whichever occurred first (average of 10 study weeks)

Measure	Description	Time Frame
Overall Survival	Overall survival is defined as the interval between the date of randomization and the date of death from any cause.	From randomization until disease progression or death (up to Study Week 78)
Number of Participants (Par.) With the Indicated Best Overall Response

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Signed written Informed Consent.
Subjects must complete 4 to 6 cycles of chemotherapy with carboplatin + pemetrexed or cisplatin + pemetrexed and have had SD, PR or CR at the time of screening/enrolment as the best response.
Prior surgery and/or localized irradiation for NSCLC is permitted as long as it was a minimum of 4 weeks before entering the study. Subjects with recurrence after previous NSCLC that has been treated with surgery and adjuvant chemotherapy or a radio-chemotherapy regimen with curative intent are eligible, provided 1 year has passed since this treatment ended.
Histologically or cytologically confirmed diagnosis of predominantly non-squamous cell Stage IVA Wet (with cytology positive Malignant Pleural Effusion (MPE)) or Stage IVB (metastatic) NSCLC.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Life expectancy of at least 12 weeks.
Must have measurable disease per Response Evaluation Criteria In Solid Tumors (RECIST). A measurable lesion is defined as a lesion that can be accurately measured in at least one dimension with the longest diameter ≥ 20 mm using conventional techniques, or ≥ 10 mm with spiral computed tomography (CT) scan.
Able to swallow and retain oral medication.
Adequate organ system function.
Women of childbearing potential must have a negative pregnancy test within <= 7 days prior to administration or dispensing of study treatment and agree to use effective contraception.
Age ≥ 18 years of legal age of consent if different from 18 years.

Exclusion Criteria:

History of active or any other malignancy other than lung cancer in the 2 yrs prior to the first dose of study drug other than NSCLC. Exception: Subjects with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible.
History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS metastases, are asymptomatic, and have had no requirement for steroids or anti- seizure medications for 4 months prior to first dose of study drug. Screening with CNS imaging studies (computed tomography [CT] or magnetic resonance imaging [MRI]) is required only if clinically indicated or if the subject has a history of CNS metastases.
Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to:
Active peptic ulcer disease
Known intraluminal metastatic lesion/s with risk of bleeding
Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or other gastrointestinal conditions with increased risk of perforation
History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 28 days prior to beginning study treatment
Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to:

Malabsorption syndrome Major resection of the stomach or small bowel

Presence of uncontrolled infection.
Corrected QT interval (QTc) > 480 msecs using Bazett's formula
History of any one or more of the following cardiovascular conditions within the past 6 months:

Cardiac angioplasty or stenting Myocardial infarction Unstable angina Coronary artery bypass graft surgery Symptomatic peripheral vascular disease Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA).

- Poorly controlled hypertension, defined as systolic blood pressure (SBP) of ≥140 mmHg or diastolic blood pressure (DBP) of

90mmHg.

Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. Blood pressure (BP) must be re-assessed on two occasions that are separated by a minimum of 1 hour; on each of these occasions, the mean (of 3 readings) SBP / DBP values from each BP assessment must be <140/90 mmHg in order for a subject to be eligible for the study.

History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months. Note: Subjects with recent DVT who have been treated with therapeutic anti- coagulating agents for at least 6 weeks are eligible.
Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major).
Evidence of active bleeding or bleeding diathesis.
Recent hemoptysis (>=½ teaspoon of red blood within 8 weeks before first dose of study drug).
Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels (Note: tumor abutting the vessel is acceptable, but contiguous tumor and vessel is not; CT with contrast is strongly recommended to evaluate such lesions).
Any serious and/or unstable pre-existing medical, psychiatric, or other condition that would make the subject inappropriate for study participation including any serious condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures.
Use of any prohibited medication within the timeframes listed in the protocol.
Prior use of an investigational agent within 28 days or 5 half-lives, whichever is longer, prior the first dose of study drug.
Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 (except the value for hemoglobin; see Table 1) and/or that is progressing in severity, except alopecia.
Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib and/or pemetrexed.
Inability to interrupt aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) 2 days before, the day of, and 2 days after the dose of pemetrexed. If a subject is taking an NSAID (COX-2 inhibitors included) or salicylate with a long half-life (e.g.

naproxen, piroxicam, diflusinal, nabumetone, rofecoxib, or celecoxib) it should not be taken 5 days before, the day of, and 2 days after the dose of pemetrexed.

Inability or unwillingness to take folic acid, vitamin B12 supplementation, or dexamethasone.
Have clinically significant third-space fluid collections (e.g., ascites or pleural effusions) that cannot be controlled by drainage or other procedures prior to Day 1, Cycle 1.
Treatment with any of the following anti-cancer therapies:

radiation therapy, surgery or tumor embolization within 14 days prior to the first dose of pazopanib OR chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal therapy within 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of pazopanib

Name	Affiliation	Role
GSK Clinical Trials	GlaxoSmithKline	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
GSK Investigational Site		Tucson	Arizona	85704	United States
GSK Investigational Site

ID	Title	Description
FG000	Pemetrexed 500 mg/m^2	Participants received an intravenous (IV) infusion of pemetrexed (500 mg per meters squared [mg/m^2]) over 10 minutes on Day 1 of each 21-day cycle. Participants received study treatment until disease progression, death, unacceptable adverse event, withdrawal of consent, or physician decision. Participants who withdrew due to an adverse event or disease progression were followed for survival.

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Progression Free Survival (PFS)

PFS is defined as the interval between the date of randomization and the first documented sign of investigator-assessed (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) disease progression (PD) or death, whichever occurs first. The date of documented PD is the date of lesion evaluation in the case of radiological PD and the date of symptomatic cancer progression in the case of symptomatic progression (radiological confirmation is required). PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started. If the participant received subsequent anti-cancer therapy prior to the date of documented progression or death, PFS was to be censored at the last adequate assessment (LAA) prior to the initiation of therapy. Otherwise, if the participant did not have a documented date of progression or death, PFS was to be censored at the date of the LAA.

Intent-to-Treat (ITT) Population: all participants who were randomized to study treatment regardless of whether or not treatment was administered

Posted

Median

90% Confidence Interval

weeks

From randomization until the first documented sign of investigator-assessed disease progression or death, whichever occurred first (average of 10 study weeks)

ID	Title	Description
OG000	Pemetrexed 500 mg/m^2	Participants received an intravenous (IV) infusion of pemetrexed (500 mg per meters squared [mg/m^2]) over 10 minutes on Day 1 of each 21-day cycle. Participants received study treatment until disease progression, death, unacceptable adverse event, withdrawal of consent, or physician decision. Participants who withdrew due to an adverse event or disease progression were followed for survival.
OG001	Pazopanib 800 mg	Participants received pazopanib 800 milligrams (mg) orally once a day at approximately the same time each day, either 1 hour before a meal or 2 hours after a meal. The tablets were to be swallowed whole and were not to be crushed or broken. Participants received study treatment until disease progression, death, unacceptable adverse event, withdrawal of consent, or physician decision. Participants who withdrew due to an adverse event or disease progression were followed for survival.

Units	Counts
Participants	OG0009 OG00111

Title

Denominators

Categories

Title	Measurements
	OG00010.3(5.3 to NA)There were too few events of progression/death to calculate the upper limit (UL) of the confidence interval (CI). OG00112.7(6.0 to NA)There were too few events of progression/death to calculate the upper limit (UL) of the confidence interval (CI).

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001						Hazard Ratio (HR)	0.92			2-Sided	90	0.32	2.65			HRs were estimated using the Pike estimator. The hazard ratio and p-value from the stratified log-rank test were adjusted for disease stage at Baseline only, due to sparse data.	No	Superiority or Other

Secondary

Overall Survival

Overall survival is defined as the interval between the date of randomization and the date of death from any cause.

The study size (20 participants) and follow up were not adequate to assess overall survival. Participants who had not died at the time of the cut-off for the analysis were to be censored at the date the particpant was last known to be alive.

Posted

From randomization until disease progression or death (up to Study Week 78)

ID	Title	Description
OG000	Pemetrexed 500 mg/m^2	Participants received an intravenous (IV) infusion of pemetrexed (500 mg per meters squared [mg/m^2]) over 10 minutes on Day 1 of each 21-day cycle. Participants received study treatment until disease progression, death, unacceptable adverse event, withdrawal of consent, or physician decision. Participants who withdrew due to an adverse event or disease progression were followed for survival.
OG001	Pazopanib 800 mg	Participants received pazopanib 800 milligrams (mg) orally once a day at approximately the same time each day, either 1 hour before a meal or 2 hours after a meal. The tablets were to be swallowed whole and were not to be crushed or broken. Participants received study treatment until disease progression, death, unacceptable adverse event, withdrawal of consent, or physician decision. Participants who withdrew due to an adverse event or disease progression were followed for survival.

Secondary

Number of Participants (Par.) With the Indicated Best Overall Response

A par. was defined as a responder if s/he sustained a CR (The disappearance of all target lesions. Any pathological lymph node must be less than 10 millimeters [mm] in the short axis) or PR (At least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters) that was confirmed after >=28 days. Response was evaluated by an investigator per RECIST, version 1.1. A par. without a post-Baseline assessment was considered a non-responder. Stable disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD; at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started). To qualify as a best response of SD, a response of SD had to be observed >=12 weeks after randomization. A par. who was not evaluable had no scans at all or did not have a confirmatory scan.

ITT Population

Posted

Number

participants

From randomization until the time of the first documented evidence of a confirmed complete response (CR) or partial response (PR) (average of 10 weeks)

ID	Title	Description
OG000	Pemetrexed 500 mg/m^2	Participants received an intravenous (IV) infusion of pemetrexed (500 mg per meters squared [mg/m^2]) over 10 minutes on Day 1 of each 21-day cycle. Participants received study treatment until disease progression, death, unacceptable adverse event, withdrawal of consent, or physician decision. Participants who withdrew due to an adverse event or disease progression were followed for survival.

Secondary

Number of Participants With Any Non-serious On-therapy Adverse Event (AE: Occurring in >=5% Participants in Any Treatment Arm) and Serious Adverse Event (SAE)

An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered to be related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or results in a congenital anomaly/birth defect. In addition, all Grade 4 laboratory abnormalities and other medically important events that require medical or surgical intervention to prevent one of the outcomes listed previously are considered to be SAEs. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs.

Safety Population: all participants who were randomized and took at least one dose of study medication. This population was based on the actual treatment received, if it differed from that to which the participant was randomized.

Posted

Number

participants

From the time the first dose of study treatment was administered until 28 days following discontinuation of study treatment regardless of initiation of a new cancer therapy or transfer to hospice (up to Study Week 55)

ID	Title	Description
OG000	Pemetrexed 500 mg/m^2	Participants received an intravenous (IV) infusion of pemetrexed (500 mg per meters squared [mg/m^2]) over 10 minutes on Day 1 of each 21-day cycle. Participants received study treatment until disease progression, death, unacceptable adverse event, withdrawal of consent, or physician decision. Participants who withdrew due to an adverse event or disease progression were followed for survival.

Secondary

Time on Study Treatment (Pazopanib), as a Measure of Extent of Exposure

Time on study treatment, as a measure of extent of exposure, was assessed in all participants who received pazopanib. Time on study treatment was not measured in participants receiving pemetrexed. For these participants, extent of exposure was measured as the mean number of dosing cycles and dose intensity. See the outcome measures entitled "Mean number of dosing cycles, as a measure of extent of exposure" and "Average dose of pemetrexed for all cycles, as a measure of extent of exposure," respectively, for pemetrexed data.

Safety Population

Posted

Mean

Standard Deviation

months

From the first day to the last day of treatment (average of 8 weeks)

ID	Title	Description
OG000	Pemetrexed 500 mg/m^2	Participants received an intravenous (IV) infusion of pemetrexed (500 mg per meters squared [mg/m^2]) over 10 minutes on Day 1 of each 21-day cycle. Participants received study treatment until disease progression, death, unacceptable adverse event, withdrawal of consent, or physician decision. Participants who withdrew due to an adverse event or disease progression were followed for survival.
OG001	Pazopanib 800 mg	Participants received pazopanib 800 milligrams (mg) orally once a day at approximately the same time each day, either 1 hour before a meal or 2 hours after a meal. The tablets were to be swallowed whole and were not to be crushed or broken. Participants received study treatment until disease progression, death, unacceptable adverse event, withdrawal of consent, or physician decision. Participants who withdrew due to an adverse event or disease progression were followed for survival.

Secondary

Mean Daily Dose, as a Measure of Extent of Exposure

Mean daily dose, as a measure of extent of exposure, was assessed in all participants who received pazopanib. Mean daily dose was not measured in participants receiving pemetrexed. For these participants, extent of exposure was measured as the mean number of dosing cycles and dose intensity. See the outcome measures entitled "Mean number of dosing cycles, as a measure of extent of exposure" and "Average dose of pemetrexed for all cycles, as a measure of extent of exposure," respectively, for pemetrexed data.

Safety Population

Posted

Mean

Standard Deviation

milligrams

From the first day to the last day of treatment (average of 8 weeks)

ID	Title	Description
OG000	Pemetrexed 500 mg/m^2	Participants received an intravenous (IV) infusion of pemetrexed (500 mg per meters squared [mg/m^2]) over 10 minutes on Day 1 of each 21-day cycle. Participants received study treatment until disease progression, death, unacceptable adverse event, withdrawal of consent, or physician decision. Participants who withdrew due to an adverse event or disease progression were followed for survival.
OG001	Pazopanib 800 mg	Participants received pazopanib 800 milligrams (mg) orally once a day at approximately the same time each day, either 1 hour before a meal or 2 hours after a meal. The tablets were to be swallowed whole and were not to be crushed or broken. Participants received study treatment until disease progression, death, unacceptable adverse event, withdrawal of consent, or physician decision. Participants who withdrew due to an adverse event or disease progression were followed for survival.

Secondary

Mean Number of Pemetrexed Dosing Cycles, as a Measure of Extent of Exposure

Duration of therapy/time on study treatment, measured as the mean number of pemetrexed dosing cycles as a measure of extent of exposure, was assessed in all participants who received pemetrexed. The mean number of dosing cycles was not measured in participants receiving pazopanib. For these participants, extent of exposure was measured as the time on study treatment and mean daily dose. See the outcome measures entitled "Time on study treatment (pazopanib), as a measure of extent of exposure" and "Mean daily dose, as a measure of extent of exposure," respectively, for pazopanib data.

Safety Population

Posted

Mean

Standard Deviation

number of cycles

From the time the first dose of study treatment was administered until discontinuation of the study or death (average of 16 weeks)

ID	Title	Description
OG000	Pemetrexed 500 mg/m^2	Participants received an intravenous (IV) infusion of pemetrexed (500 mg per meters squared [mg/m^2]) over 10 minutes on Day 1 of each 21-day cycle. Participants received study treatment until disease progression, death, unacceptable adverse event, withdrawal of consent, or physician decision. Participants who withdrew due to an adverse event or disease progression were followed for survival.
OG001	Pazopanib 800 mg	Participants received pazopanib 800 milligrams (mg) orally once a day at approximately the same time each day, either 1 hour before a meal or 2 hours after a meal. The tablets were to be swallowed whole and were not to be crushed or broken. Participants received study treatment until disease progression, death, unacceptable adverse event, withdrawal of consent, or physician decision. Participants who withdrew due to an adverse event or disease progression were followed for survival.

Secondary

Average Dose of Pemetrexed for All Cycles, as a Measure of Extent of Exposure

The average dose of pemetrexed for all cycles, as a measure of extent of exposure, was assessed in all participants who received pemetrexed. The average dose was not measured in participants receiving pazopanib. For these participants, extent of exposure was measured as the time on study treatment and mean daily dose. See the outcome measures entitled "Time on study treatment (pazopanib), as a measure of extent of exposure" and "Mean daily dose, as a measure of extent of exposure," respectively, for pazopanib data.

Safety Population

Posted

Mean

Standard Deviation

milligrams per meters squared (m^2)

From the time the first dose of study treatment was administered until discontinuation of the study or death (average of 16 weeks)

ID	Title	Description
OG000	Pemetrexed 500 mg/m^2	Participants received an intravenous (IV) infusion of pemetrexed (500 mg per meters squared [mg/m^2]) over 10 minutes on Day 1 of each 21-day cycle. Participants received study treatment until disease progression, death, unacceptable adverse event, withdrawal of consent, or physician decision. Participants who withdrew due to an adverse event or disease progression were followed for survival.
OG001	Pazopanib 800 mg	Participants received pazopanib 800 milligrams (mg) orally once a day at approximately the same time each day, either 1 hour before a meal or 2 hours after a meal. The tablets were to be swallowed whole and were not to be crushed or broken. Participants received study treatment until disease progression, death, unacceptable adverse event, withdrawal of consent, or physician decision. Participants who withdrew due to an adverse event or disease progression were followed for survival.

Secondary

Number of Participants With Any AE (Serious or Non-serious) Leading to Withdrawal From Study Treatment

An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or results in a congenital anomaly/birth defect. In addition, all Grade 4 laboratory abnormalities and other medically important events that require medical or surgical intervention to prevent one of the outcomes listed previously are considered to be SAEs. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs. A participant cold have been withdrawn fom study treatment due to an SAE or AE.

Safety Population

Posted

Number

participants

From the time the first dose of study treatment was administered until withdrawal from study treatment (up to Study Week 55)

ID	Title	Description
OG000	Pemetrexed 500 mg/m^2	Participants received an intravenous (IV) infusion of pemetrexed (500 mg per meters squared [mg/m^2]) over 10 minutes on Day 1 of each 21-day cycle. Participants received study treatment until disease progression, death, unacceptable adverse event, withdrawal of consent, or physician decision. Participants who withdrew due to an adverse event or disease progression were followed for survival.
OG001

Secondary

Number of Participants With Any On-therapy AE (Serious or Non-serious) Leading to Dose Reductions (DRs) or Interruptions/Delays in the Study

An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or results in a congenital anomaly/birth defect. In addition, all Grade 4 laboratory abnormalities and other medically important events that require medical or surgical intervention to prevent one of the outcomes listed previously are considered to be SAEs. Refer to the general Adverse AE/SAE module for a complete list of AEs/SAEs. Management of AEs may require DRs/interruptions in study treatment. If necessary, the pazopanib dose should be reduced stepwise by 200 mg at each step. DRs for pemetrexed were 50-75% of prior dose based on the toxicity leading to DR.

Safety Population

Posted

Number

participants

From the time the first dose of study treatment was administered until discontinuation of treatment (up to Study Week 55)

ID	Title	Description
OG000	Pemetrexed 500 mg/m^2	Participants received an intravenous (IV) infusion of pemetrexed (500 mg per meters squared [mg/m^2]) over 10 minutes on Day 1 of each 21-day cycle. Participants received study treatment until disease progression, death, unacceptable adverse event, withdrawal of consent, or physician decision. Participants who withdrew due to an adverse event or disease progression were followed for survival.

Secondary

Number of Participants With the Indicated Worst-case Change From Baseline in Blood Pressure

Systolic and diastolic blood pressure (BP) were measured. Categories correspond to the following Common Terminology Criteria for Adverse Events (CTCAE) grades: normal, <120/80 millimeters of mercury (mmHg); prehypertension, 120-139/80-89 mmHg, warranting intervention in participants with high risk; stage I hypertension, 140-159/90-99 mmHg, warranting intervention; and stage II hypertension >/=160/100, warranting immediate attentive intervention to prevent acute symptoms. An increase is defined as an increase in CTCAE grade relative to Baseline grade. Participants with a missing Baseline value were assumed to have a Baseline value of <120 for systolic BP (SBP) and <80 for diastolic BP (DBP).

Safety Population

Posted

Number

participants

From the time of the first dose of study treatment until 28 days following discontinuation of study treatment (up to Study Week 55)

ID	Title	Description
OG000	Pemetrexed 500 mg/m^2	Participants received an intravenous (IV) infusion of pemetrexed (500 mg per meters squared [mg/m^2]) over 10 minutes on Day 1 of each 21-day cycle. Participants received study treatment until disease progression, death, unacceptable adverse event, withdrawal of consent, or physician decision. Participants who withdrew due to an adverse event or disease progression were followed for survival.
OG001	Pazopanib 800 mg

Secondary

Number of Participants With a Increase From Baseline in Bazett's QTc at the Indicated Time Points

The QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. In clinical studies with pazopanib, events of QT prolongation have occurred.

Safety Population

Posted

Number

participants

Baseline; Week 6; Week 15; every 9 weeks in the first 6 months; every 12 weeks in the next 6 months; and, after 1 year, every 6 months (up to Study Week 55)

ID	Title	Description
OG000	Pemetrexed 500 mg/m^2	Participants received an intravenous (IV) infusion of pemetrexed (500 mg per meters squared [mg/m^2]) over 10 minutes on Day 1 of each 21-day cycle. Participants received study treatment until disease progression, death, unacceptable adverse event, withdrawal of consent, or physician decision. Participants who withdrew due to an adverse event or disease progression were followed for survival.
OG001	Pazopanib 800 mg	Participants received pazopanib 800 milligrams (mg) orally once a day at approximately the same time each day, either 1 hour before a meal or 2 hours after a meal. The tablets were to be swallowed whole and were not to be crushed or broken. Participants received study treatment until disease progression, death, unacceptable adverse event, withdrawal of consent, or physician decision. Participants who withdrew due to an adverse event or disease progression were followed for survival.

Secondary

Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Laboratory Parameters

Hematology and clinical chemistry data were summarized according to National Cancer Institutes (NCI) CTCAE grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3, Severe; Grade 4, Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Participants with missing Baseline grades were assumed to have a Baseline grade of 0. Lymphocyte count increased: Grade 3, <500 - 200/millimeters cubed (mm^3); <0.5 - 0.2x 10e9/Liters (L); Grade 4, <200/mm^3; <0.2x 10e9/L. Lymphocyte count decreased: Grade 3, >20000/mm^3; Grade 4, NA. Hyperglycemia; Grade 3, >250 - 500 milligrams per deciliter (mg/dL); >13.9 - 27.8 millimoles per Liter (mmol/L); hospitalization indicated; Grade 4, >500 mg/dL; >27.8 mmol/L; life-threatening consequences. Hypophosphatemia (inorganic phosphorus): Grade 3, <2.0 - 1.0 mg/dL, <0.6 - 0.3 mmol/L; Grade 4, <1.0 mg/dL, <0.3 mmol/L, life-threatening consequences.

Safety Population

Posted

Number

participants

From the time of the first dose of study treatment until 28 days following discontinuation of study treatment (up to Study Week 55)

ID	Title	Description
OG000	Pemetrexed 500 mg/m^2	Participants received an intravenous (IV) infusion of pemetrexed (500 mg per meters squared [mg/m^2]) over 10 minutes on Day 1 of each 21-day cycle. Participants received study treatment until disease progression, death, unacceptable adverse event, withdrawal of consent, or physician decision. Participants who withdrew due to an adverse event or disease progression were followed for survival.

Secondary

Number of Participants With the Indicated Grade Changes From Baseline Grade in Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Alkaline Phosphatase (Alk. Phos.), and Total Bilirubin (TB)

The laboratory parameters AST, ALT, Alk. Phos., and TB were summarized according to NCI CTCAE grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3, Severe; Grade 4, Life-threatening or disabling; Grade 5, Death. Data are presented for any grade increase, increase to Grade 3, and increase to Grade 4. Participants with missing Baseline grades were assumed to have a Baseline grade of 0. AST/ALT: Grade 1, >upper limit of normal (ULN) - 3.0x ULN; Grade 2, >3.0 to 5.0x ULN; Grade 3, >5.0 - 20.0x ULN; Grade 4, >20.0x ULN; Grade 5, not available (NA). Alk. Phos.: Grade 1, >ULN - 2.5x ULN; Grade 2, >2.5 - 5.0x ULN; Grade 3, >5.0 - 20.0x ULN; Grade 4, >20.0x ULN; Grade 5, NA. TB: Grade 1, >ULN - >1.5x ULN; Grade 2, >1.5 - 3.0x ULN; Grade 3, >3.0 - 10.0x ULN; Grade 4, >10.0x ULN; Grade 5, NA.

Safety Population

Posted

Number

participants

From the time of the first dose of study treatment until 28 days following discontinuation of study treatment (up to Study Week 55)

ID	Title	Description
OG000	Pemetrexed 500 mg/m^2	Participants received an intravenous (IV) infusion of pemetrexed (500 mg per meters squared [mg/m^2]) over 10 minutes on Day 1 of each 21-day cycle. Participants received study treatment until disease progression, death, unacceptable adverse event, withdrawal of consent, or physician decision. Participants who withdrew due to an adverse event or disease progression were followed for survival.

Secondary

Number of Participants With the Indicated Changes From Baseline Value in Lactate Dehydrogenase (LDH)

Change from Baseline in the laboratory parameter LDH was assessed as "decrease to low," "change to normal" of "no change," and "increase to high." Participants with missing Baseline values were assumed to have a normal Baseline value. There is no standard normal range for LDH.

Safety Population

Posted

Number

participants

From the time of the first dose of study treatment until 28 days following discontinuation of study treatment (up to Study Week 55)

ID	Title	Description
OG000	Pemetrexed 500 mg/m^2	Participants received an intravenous (IV) infusion of pemetrexed (500 mg per meters squared [mg/m^2]) over 10 minutes on Day 1 of each 21-day cycle. Participants received study treatment until disease progression, death, unacceptable adverse event, withdrawal of consent, or physician decision. Participants who withdrew due to an adverse event or disease progression were followed for survival.
OG001	Pazopanib 800 mg	Participants received pazopanib 800 milligrams (mg) orally once a day at approximately the same time each day, either 1 hour before a meal or 2 hours after a meal. The tablets were to be swallowed whole and were not to be crushed or broken. Participants received study treatment until disease progression, death, unacceptable adverse event, withdrawal of consent, or physician decision. Participants who withdrew due to an adverse event or disease progression were followed for survival.

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Fatigue	General disorders	MedDRA	Systematic Assessment	EG0003 affected9 at risk EG0013 affected10 at risk
Nausea	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0002 affected9 at risk EG0013 affected10 at risk
Alanine aminotransferase increased	Investigations	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0013 affected10 at risk
Aspartate aminotransferase increased	Investigations	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0013 affected10 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0013 affected10 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0002 affected9 at risk EG0012 affected10 at risk
Headache	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0012 affected10 at risk
Hypertension	Vascular disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0012 affected10 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0012 affected10 at risk
Palmar-plantar erythrodysaesthesia syndrome	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0012 affected10 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0002 affected9 at risk EG0011 affected10 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0002 affected9 at risk EG0011 affected10 at risk
Constipation	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0011 affected10 at risk
Dehydration	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0011 affected10 at risk
Dysphonia	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0011 affected10 at risk
Hypokalaemia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0011 affected10 at risk
Leukopenia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0011 affected10 at risk
Abdominal tenderness	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0011 affected10 at risk
Asthenia	General disorders	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0011 affected10 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0011 affected10 at risk
Blood alkaline phosphatase increased	Investigations	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0011 affected10 at risk
Blood lactate dehydrogenase increased	Investigations	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0011 affected10 at risk
Colitis	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0011 affected10 at risk
Contusion	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0011 affected10 at risk
Diverticulum	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0011 affected10 at risk
Dry skin	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0011 affected10 at risk
Dysgeusia	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0011 affected10 at risk
Dysuria	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0011 affected10 at risk
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0011 affected10 at risk
Flatulence	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0011 affected10 at risk
Hepatic enzyme increased	Investigations	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0011 affected10 at risk
Influenza like illness	General disorders	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0011 affected10 at risk
Insomnia	Psychiatric disorders	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0011 affected10 at risk
Joint stiffness	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0011 affected10 at risk
Musculoskeletal chest pain	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0011 affected10 at risk
Neutropenia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0011 affected10 at risk
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0011 affected10 at risk
Sinus congestion	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0011 affected10 at risk
Sneezing	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0011 affected10 at risk
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0011 affected10 at risk
Transaminases increased	Investigations	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0011 affected10 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0011 affected10 at risk
Upper-airway cough syndrome	Infections and infestations	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0011 affected10 at risk
Viral upper respiratory tract infection	Infections and infestations	MedDRA	Systematic Assessment	EG0000 affected9 at risk EG0011 affected10 at risk
Anaemia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0002 affected9 at risk EG0010 affected10 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0002 affected9 at risk EG0010 affected10 at risk
Chills	General disorders	MedDRA	Systematic Assessment	EG0002 affected9 at risk EG0010 affected10 at risk
Hypoaesthesia	Nervous system disorders	MedDRA	Systematic Assessment	EG0002 affected9 at risk EG0010 affected10 at risk
Pyrexia	General disorders	MedDRA	Systematic Assessment	EG0002 affected9 at risk EG0010 affected10 at risk
Vomiting	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0002 affected9 at risk EG0010 affected10 at risk
Abdominal pain upper	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Arthritis	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Arthropod bite	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Bronchitis	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Chest discomfort	General disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Dermatitis allergic	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Dizziness postural	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Dry mouth	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Dyspnoea exertional	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Eye irritation	Eye disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Flushing	Vascular disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Fungal skin infection	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Glossodynia	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Haematochezia	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Hypomagnesaemia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Laryngitis	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Malaise	General disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Mood altered	Psychiatric disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Musculoskeletal discomfort	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Neck pain	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Night sweats	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Oesophageal spasm	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Oral pain	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Palpitations	Cardiac disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Paraesthesia	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Pelvic pain	Reproductive system and breast disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Pollakiuria	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Productive cough	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Rash	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Rash macular	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Respiratory tract infection	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Spinal pain	General disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Stomatitis	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk
Wheezing	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0001 affected9 at risk EG0010 affected10 at risk

ID	Term
D055752	Small Cell Lung Carcinoma
D002289	Carcinoma, Non-Small-Cell Lung

ID	Term
D002283	Carcinoma, Bronchogenic
D001984	Bronchial Neoplasms
D008175	Lung Neoplasms
D012142	Respiratory Tract Neoplasms
D013899	Thoracic Neoplasms
D009371	Neoplasms by Site
D009369	Neoplasms
D008171	Lung Diseases
D012140	Respiratory Tract Diseases

ID	Term
D006147	Guanine
D007042	Hypoxanthines
D011688	Purinones
D011687	Purines
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring
D006571	Heterocyclic Compounds
D005971	Glutamates
D024342	Amino Acids, Acidic
D000596	Amino Acids
D000602	Amino Acids, Peptides, and Proteins
D000600	Amino Acids, Dicarboxylic

ID	Title	Description
BG000	Pemetrexed 500 mg/m^2	Participants received an intravenous (IV) infusion of pemetrexed (500 mg per meters squared [mg/m^2]) over 10 minutes on Day 1 of each 21-day cycle. Participants received study treatment until disease progression, death, unacceptable adverse event, withdrawal of consent, or physician decision. Participants who withdrew due to an adverse event or disease progression were followed for survival.
BG001	Pazopanib 800 mg	Participants received pazopanib 800 milligrams (mg) orally once a day at approximately the same time each day, either 1 hour before a meal or 2 hours after a meal. The tablets were to be swallowed whole and were not to be crushed or broken. Participants received study treatment until disease progression, death, unacceptable adverse event, withdrawal of consent, or physician decision. Participants who withdrew due to an adverse event or disease progression were followed for survival.
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Pemetrexed 500 mg/m^2	Participants received an intravenous (IV) infusion of pemetrexed (500 mg per meters squared [mg/m^2]) over 10 minutes on Day 1 of each 21-day cycle. Participants received study treatment until disease progression, death, unacceptable adverse event, withdrawal of consent, or physician decision. Participants who withdrew due to an adverse event or disease progression were followed for survival.			2	9	9	9
EG001	Pazopanib 800 mg	Participants received pazopanib 800 milligrams (mg) orally once a day at approximately the same time each day, either 1 hour before a meal or 2 hours after a meal. The tablets were to be swallowed whole and were not to be crushed or broken. Participants received study treatment until disease progression, death, unacceptable adverse event, withdrawal of consent, or physician decision. Participants who withdrew due to an adverse event or disease progression were followed for survival.			2	10	9	10