Carcinoma, Renal Cell
Conditions
Keywords
SUTENT, GW76034, Sunitinib, Renal cell carcinoma, Pazopanib
Brief summary
This was a randomized, open label, parallel group, Phase II study to evaluate the efficacy and safety of pazopanib compared to sunitinib in Asian subjects with advanced renal cell carcinoma (RCC) who have not received prior systemic therapy for advanced or metastatic RCC.
Detailed description
Study VEG113078 is a substudy of Study VEG108844 (NCT00720941). Due to the projected limited enrollment of Asian participants into Study VEG108844, Study VEG113078 was designed to evaluate the efficacy and safety of pazopanib versus sunitinib for the treatment of Asian participants enrolled from selected Far-East Asian countries. The data for Study VEG113078 was pooled at the same time as the main study VEG108844 (NCT00720941). The subjects were centrally randomized in 1:1 ratio to receive open label study medication of either pazopanib 800mg to be administered once daily orally continuous dosing or sunitinib 50mg to be administered in 6-week cycles: 50mg orally daily for 4 weeks followed by 2 weeks off treatment. Subjects were permitted to receive supportive care throughout the study including transfusion of blood and blood products, treatment with antibiotics, anti-emetics, anti-diarrheal agents, analgesics, erythropoietin, or bisphosphonates, when appropriate. The study treatment continued until subjects experience disease progression, unacceptable toxicity, withdraw consent, or death.
Interventions
DRUGPazopanib
800 mg administered once daily orally continuous dosing
DRUGSunitinib
50 mg sunitinib to be administered in 6-week cycle: 50 mg orally daily for 4 weeks followed by 2 weeks off treatment
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent * Diagnosis of renal cell carcinoma with clear-cell component histology. * Received no prior systemic therapy (interleukin-2, interferon-alpha, chemotherapy, bevacizumab, mTOR inhibitor, sunitinib, sorafenib or other VEGF TKI) for advanced or metastatic RCC * Locally advanced or metastatic renal cell carcinoma Measurable disease by CT or MRI * Karnofsky performance scale status of \>=70 * Age \>=18 years * A female is eligible to enter and participate in this study if she is of: non-childbearing or agrees to use adequate contraception. * Adequate organ system function * Total serum calcium concentration \<12.0mg/dL * Left ventricular ejection fraction \>= lower limit of institutional normal
Exclusion criteria
* Pregnant or lactating female (unless agrees to refrain from nursing throughout the treatment period and for 14 days following the last dose of study)-History of another malignancy (unless have been disease-free for 3 years) * History or clinical evidence of central nervous system (CNS) metastases (unless have previously-treated CNS metastases and meet all 3 of the following criteria are: are asymptomatic, have had no evidence of active CNS metastases for \>=6 months prior to enrolment, and have no requirement for steroids or enzyme-inducing anticonvulsants) * Clinically significant gastrointestinal abnormalities including, but not limited to: malabsorption syndrome, major resection of the stomach or small bowel that could affect the absorption of study drug, active peptic ulcer disease, known intraluminal metastatic lesion/s with suspected bleeding, Inflammatory bowel disease, ulcerative colitis, 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 * Presence of uncontrolled infection * Prolongation of corrected QT interval (QTc) \> 480 milliseconds * History of any one or more of the following cardiovascular conditions within the past 12 months: cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery by-pass graft surgery, symptomatic peripheral vascular disease, Class III or IV congestive heart failure, as defined by the New York Heart Association * History of cerebrovascular accident including transient ischemic attack within the past 12 months * History of pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months (unless had recent DVT and have been treated with therapeutic anti-coagulating agents for at least 6 weeks) * Poorly controlled hypertension (defined as systolic blood pressure of \>=150mmHg or diastolic blood pressure of \>=90mmHg). Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry * 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. * Evidence of active bleeding or bleeding susceptibility * Spitting/coughing up blood within 6 weeks of first dose of study drug * Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels * Any serious and/or unstable pre-existing medical, psychiatric, or other conditions that could interfere with patient's safety, obtaining informed consent or compliance to the study * Use any prohibited medications within 14 days of the first dose of study medication * Use of an investigational agent, including an investigational anti-cancer agent, within 28 days or 5 half-lives, whichever is longer, prior to the first dose of study drug * Prior use of an investigational or licensed drug that targets VEGF or VEGF receptors (eg. bevacizumab, sunitinib, sorafenib, etc), or are mTOR inhibitors (eg. temsirolimus, everolimus, etc). * Is now undergoing and/or has undergone in the 14 days immediately prior to first dose of study drug, any cancer therapy (surgery, tumor embolization, chemotherapy, radiation therapy, immunotherapy, biological therapy, or hormonal therapy) * Any ongoing toxicity from prior anti-cancer therapy that is \>Grade 1 and/or that is progressing in severity * Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib or sunitinib
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | From randomization until the earliest date of disease progression or date of death from any cause, assessed up to approximately 24 months (Primary analysis cut-off date = 21-May-2012) at the same time as the main study VEG108844 (NCT00720941). | PFS was defined as the interval between the date of randomization and the earliest date of progressive disease (PD), as defined by the Independent Review Committee (IRC), or death due to any cause. The IRC defined PD per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1. Per RECIST, PD is defined as a \>=20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of \>=1 new lesion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomization until date of death from any cause, assessed up to 40 months (Final OS analysis cut-off date = 30-Sep-2013) at the same time as the main study VEG108844 (NCT00720941). | Overall Survival (OS) was defined as the time (in months) from the date of randomization to the date of death due to any cause. If the patient was not known to have died, then OS was censored. The censoring date was date of the last study visit, or contact, until the cut-off date. The cut-off date was not used for last contact date, unless the patient was seen or contacted on that date. |
| Overall Response Rate (ORR) as Assessed by Independent Review | From randomization until date of radiographic progression, assessed up to approximately 24 months (Primary analysis cut-off date = 21-May-2012) at the same time as the main study VEG108844 (NCT00720941). | Overall Response Rate (ORR) was defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR). ORR was based on RECIST 1.1 response for patients with measurable disease at baseline per central review assessment. |
| Time to Response | From randomization until date of radiographic progression, assessed up to approximately 24 months (Primary analysis cut-off date = 21-May-2012) at the same time as the main study VEG108844 (NCT00720941). | Time to response was defined as the time from the start of treatment until the first documented evidence of CR (the disappearance of all target and non-target lesions) or PR (at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the Baseline sum LD), whichever comes first. CR and PR were evaluated by an independent review per RECIST, Version 1. |
| Duration of Response (DOR) | From the date of the first documented response (CR or PR) to the date of first documented progression, assessed up to approximately 24 months (Primary analysis cut-off date = 21-May-2012) at the same time as the main study VEG108844 (NCT00720941). | DOR was defined as the time from the first documented evidence of response (CR or PR) until the first documented sign of disease progression (a \>=20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of \>=1 new lesion) or death, if sooner. CR=the disappearance of all target and non-target lesions. PR=at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the Baseline sum LD. |
Countries
China, South Korea, Taiwan
Participant flow
Recruitment details
This study was conducted in 58 centers in 4 countries in Asia (China, Korea, Taiwan, and Japan).
Pre-assignment details
Participants were stratified based on Karnofsky Performance Scale scores (70 or 80; 90 or 100), Baseline levels of lactate dehydrogenase (\>1.5 versus \<=1.5 times the upper limit of normal \[ULN\]), and previous nephrectomy (yes versus no) and were randomized in a 1:1 ratio to receive either pazopanib or sunitinib.
Participants by arm
| Arm | Count |
|---|---|
| Pazopanib 800 mg Participants were administered pazopanib 800 milligrams (mg) (2 x 400 mg tablets) orally once daily (OD) continuously. Pazopanib was to be taken at least one hour before or at least two hours after a meal. Study treatment continued until participants experienced disease progression, death, or unacceptable toxicity, or withdrew consent for any other reason. | 188 |
| Sunitinib 50 mg Participants were administered sunitinib 50 mg capsules orally OD in 6-week cycles (4 weeks of treatment, followed by 2 weeks without treatment). Study treatment continued until participants experienced disease progression, death, or unacceptable toxicity, or withdrew consent for any other reason. | 179 |
| Total | 367 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 14 | 6 |
| Overall Study | Physician Decision | 9 | 8 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Transitioned to another mechanism of continuing pazopanib or sunitinib therapy after 30SEP2013 | 4 | 5 |
| Overall Study | Withdrawal by Subject | 10 | 16 |
Baseline characteristics
| Characteristic | Pazopanib 800 mg | Sunitinib 50 mg | Total |
|---|---|---|---|
| Age, Continuous | 57.7 Years STANDARD_DEVIATION 11.51 | 57.6 Years STANDARD_DEVIATION 11.19 | 57.6 Years STANDARD_DEVIATION 11.34 |
| Race/Ethnicity, Customized Asian - Central/South Asian Heritage | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Asian - East Asian Heritage | 154 Participants | 144 Participants | 298 Participants |
| Race/Ethnicity, Customized Asian - Japanese Heritage | 29 Participants | 31 Participants | 60 Participants |
| Race/Ethnicity, Customized Asian - South East Asian Heritage | 3 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Female | 51 Participants | 42 Participants | 93 Participants |
| Sex: Female, Male Male | 137 Participants | 137 Participants | 274 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 7 / 188 | 6 / 179 | 92 / 179 | 80 / 171 |
| other Total, other adverse events | 182 / 186 | 173 / 177 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 76 / 186 | 76 / 177 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Progression-free Survival (PFS)
PFS was defined as the interval between the date of randomization and the earliest date of progressive disease (PD), as defined by the Independent Review Committee (IRC), or death due to any cause. The IRC defined PD per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1. Per RECIST, PD is defined as a \>=20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of \>=1 new lesion.
Time frame: From randomization until the earliest date of disease progression or date of death from any cause, assessed up to approximately 24 months (Primary analysis cut-off date = 21-May-2012) at the same time as the main study VEG108844 (NCT00720941).
Population: Intent-to-Treat (ITT) Population. Analysis was based on the assigned randomized treatment, not on the actual treatment received/not received. Participants who had neither progressed nor died were censored at the date of the last adequate tumor assessment at the time of the cut-off.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pazopanib 800 mg | Progression-free Survival (PFS) | 8.4 Months |
| Sunitinib 50 mg | Progression-free Survival (PFS) | 11.1 Months |
95% CI: [0.7658, 1.3542]
Secondary
Duration of Response (DOR)
DOR was defined as the time from the first documented evidence of response (CR or PR) until the first documented sign of disease progression (a \>=20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of \>=1 new lesion) or death, if sooner. CR=the disappearance of all target and non-target lesions. PR=at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the Baseline sum LD.
Time frame: From the date of the first documented response (CR or PR) to the date of first documented progression, assessed up to approximately 24 months (Primary analysis cut-off date = 21-May-2012) at the same time as the main study VEG108844 (NCT00720941).
Population: Intent-to-Treat (ITT) Population. Analysis was based on the assigned randomized treatment, not on the actual treatment received/not received. Only those participants who had either a confirmed CR or PR were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pazopanib 800 mg | Duration of Response (DOR) | 15.2 Months |
| Sunitinib 50 mg | Duration of Response (DOR) | 18.0 Months |
Secondary
Overall Response Rate (ORR) as Assessed by Independent Review
Overall Response Rate (ORR) was defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR). ORR was based on RECIST 1.1 response for patients with measurable disease at baseline per central review assessment.
Time frame: From randomization until date of radiographic progression, assessed up to approximately 24 months (Primary analysis cut-off date = 21-May-2012) at the same time as the main study VEG108844 (NCT00720941).
Population: Intent-to-Treat (ITT) Population. Analysis was based on the assigned randomized treatment, not on the actual treatment received/not received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pazopanib 800 mg | Overall Response Rate (ORR) as Assessed by Independent Review | 36 Percentage of Participants |
| Sunitinib 50 mg | Overall Response Rate (ORR) as Assessed by Independent Review | 21 Percentage of Participants |
Secondary
Overall Survival (OS)
Overall Survival (OS) was defined as the time (in months) from the date of randomization to the date of death due to any cause. If the patient was not known to have died, then OS was censored. The censoring date was date of the last study visit, or contact, until the cut-off date. The cut-off date was not used for last contact date, unless the patient was seen or contacted on that date.
Time frame: From randomization until date of death from any cause, assessed up to 40 months (Final OS analysis cut-off date = 30-Sep-2013) at the same time as the main study VEG108844 (NCT00720941).
Population: Intent-to-Treat (ITT) Population. Analysis was based on the assigned randomized treatment, not on the actual treatment received/not received. Participants who had not died were censored at the date of the last adequate tumor assessment at the time of the cut-off.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pazopanib 800 mg | Overall Survival (OS) | 26.7 Months |
| Sunitinib 50 mg | Overall Survival (OS) | 33.4 Months |
p-value: 0.60495% CI: [0.808, 1.441]Log Rank
Secondary
Time to Response
Time to response was defined as the time from the start of treatment until the first documented evidence of CR (the disappearance of all target and non-target lesions) or PR (at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the Baseline sum LD), whichever comes first. CR and PR were evaluated by an independent review per RECIST, Version 1.
Time frame: From randomization until date of radiographic progression, assessed up to approximately 24 months (Primary analysis cut-off date = 21-May-2012) at the same time as the main study VEG108844 (NCT00720941).
Population: Intent-to-Treat (ITT) Population. Analysis was based on the assigned randomized treatment, not on the actual treatment received/not received. Only those participants who experienced either a confirmed CR or a PR were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pazopanib 800 mg | Time to Response | 11.9 Weeks |
| Sunitinib 50 mg | Time to Response | 17.9 Weeks |
Post Hoc
All Collected Deaths
Pre-treatment deaths were collected from day of participant's informed consent to the day before first dose of study medication. On-treatment deaths were collected from first dose of study medication to 28 days after last dose of study medication (on-treatment), up to approximately 125 months. Deaths were collected in the post treatment survival follow up from 29 days after last dose of study medication until the end of the study, up to approximately 135 months.
Time frame: Pre-treatment deaths: Up to 21 days prior to treatment. On-treatment deaths: Up to 125 months. Post-treatment deaths: up to 135 months.
Population: Intent-to-Treat (ITT) Population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pazopanib 800 mg | All Collected Deaths | Pre-treatment deaths | 0 Participants |
| Pazopanib 800 mg | All Collected Deaths | On-treatment deaths | 7 Participants |
| Pazopanib 800 mg | All Collected Deaths | Post-treatment deaths | 92 Participants |
| Pazopanib 800 mg | All Collected Deaths | All deaths | 99 Participants |
| Sunitinib 50 mg | All Collected Deaths | All deaths | 86 Participants |
| Sunitinib 50 mg | All Collected Deaths | Pre-treatment deaths | 0 Participants |
| Sunitinib 50 mg | All Collected Deaths | Post-treatment deaths | 80 Participants |
| Sunitinib 50 mg | All Collected Deaths | On-treatment deaths | 6 Participants |