Carcinoma, Renal Cell
Conditions
Keywords
Renal cell carcinoma (RCC), GW786034, Everolimus, Pazopanib, renal cancer, cancer, kidney cancer, hypernephroma, Grawitz tumor, renal adenocarcinoma.
Brief summary
Study to determine the efficacy, safety and tolerability of first-line pazopanib followed by second-line everolimus in metastatic and advanced renal cell carcinoma. Due to changes in the RCC treatment landscape, info gained is no longer clinically relevant to patients. Data collected is deemed sufficient to meet objective.
Detailed description
A non-randomised, open label, single-arm phase II study to evaluate the efficacy and safety of 1st-line pazopanib followed by 2nd-line everolimus in patients with previously untreated advanced or metastatic renal cell carcinoma. Subjects received initial therapy with pazopanib followed, on progression, by 2nd-line therapy with everolimus. Study treatment - sequential treatment with pazopanib followed by everolimus - to continue until disease progression, unacceptable toxicity, withdrawal of consent, or death.
Interventions
DRUGPazopanib followed by everolimus
All patients received Pazopanib (800 mg once daily orally continuous dosing) until disease progression then second line everolimus (10 mg once daily orally continuous dosing)
Sponsors
Novartis Pharmaceuticals
Study design
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age \>=18 years * Histologically confirmed RCC with a clear-cell component * Locally advanced or metastatic RCC * At least one measurable lesion per RECIST 1.1 criteria, as determined by Computer Tomography (CT) Scan or Magnetic Resonance Imaging (MRI) * No systemic therapy for advanced or metastatic RCC prior to enrollment * Karnofsky Performance Status (KPS) ≥70 * Adequate baseline organ function * A female was eligible to enter and participate in this study if she was of: non-childbearing potential, or negative serum pregnancy test with agreement to use adequate contraception during the study * A male with female partner of childbearing potential must have vasectomy/agree to use effective contraception from 2 weeks prior to administration of the 1st dose of study treatment for a period of time after the last dose of study treatment * Able to swallow and retain orally administered medication and must not have clinically significant GI abnormalities that may alter absorption Additional inclusion criteria for starting everolimus: * Disease progression must be within 6 months after stopping pazopanib * At least one measurable lesion at the start of everolimus pe r RECIST 1.1 criteria, as determined by CT or MRI * In case of central nervous system (CNS) progression or metastasis during pazopanib treatment: asymptomatic or neurologically stable, no requirement of steroids to control CNS symptoms, and no requirement of enzyme-inducing anticonvulsants within 4 weeks prior to the start of everolimus
Exclusion criteria
* Lactating female * History of another malignancy (exception: patients disease-free for ≥3 years and patients with completely resected non-melanoma skin cancer or successfully treated in situ carcinoma) * Symptomatic CNS metastases at baseline * Clinically significant gastrointestinal abnormalities * Moderate to severe hepatic impairment (Child Pugh Class C) * Receiving chronic treatment with corticosteroids/other immunosuppressive agents * Active bleeding, bleeding diathesis or on oral anti-vitamin K medication (except low dose coumadin) * Corrected QT interval (QTc) \>480 msec using Bazett's formula * Presence of any severe or uncontrolled medical conditions/infection * Poorly controlled hypertension (defined as systolic blood pressure of \>=140mmHg or diastolic blood pressure of \>=90mmHg) * History of cardiovascular disorders within the last 12 months (e.g. myocardial infraction or unstable angina), history of cerebrovascular events or pulmonary embolism within the last 6 months * Active bleeding or bleeding susceptibility * Known endobronchial lesion and/or lesions infiltrating major pulmonary vessels that increased the risk of pulmonary hemorrhage Additional criteria for exclusion from the second-line everolimus treatment period: \- The subject felt by the investigator to be unsuitable (on the basis of health, compliance, or for any other reason) for inclusion in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) for the Everolimus Treatment Period Using RECIST | Throughout the study period, up to 4 years | Time between the date of first everolimus dose and date of disease progression or death (whichever comes first) in patients treated initially with pazopanib. Disease progression is measured by RECIST (Response Evaluation Criteria in Solid Tumors), which is at least a 20% increase in the sum of the target lesion longest diameters (LDs). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) for the Everolimus Treatment Period Using RECIST | Throughout the study, up to 4 years | Percentage of patients with Complete or Partial Response at any time following the start of second-line everolimus treatment as per RECIST. RECIST Complete Response is defined to be a disappearance of all target lesion(s). RECIST Partial Response is defined to be at least a 30% decrease in the sum of the target lesion LDs. |
| Objective Response Rate (ORR) for the Pazopanib Treatment Period Using RECIST | Throughout the study period, up to 4 years | Percentage of patients with Complete or Partial Response at any time following the start of first-line pazopanib treatment. RECIST Complete Response is defined to be a disappearance of all target lesion(s). RECIST Partial Response is defined to be at least a 30% decrease in the sum of the target lesion LDs. |
| Progression Free Survival (PFS) Rates | 3 months, 6 months | PFS rates 3 and 6 months after date of first dose of second-line everolimus treatment. |
| Overall Survival From the Start (OSS) of Study Treatment | Throughout the study, up to 4 years | Time from first pazopanib dose until death due to any cause in patients who received at least one dose of pazopanib followed by everolimus |
| PFS for the Pazopanib Treatment Period Using RECIST | Throughout the study period, up to 4 years | Time from first pazopanib dose until disease progression or death from any cause (whichever occurred earlier), provided this occurred prior to the start of everolimus and within 6 months of last dose of pazopanib |
| Overall Survival of Everolimus (OSE) | Throughout the study period, up to 4 years | Time from first everolimus dose until death due to any cause |
Countries
Australia, South Korea
Participant flow
Recruitment details
A total of 74 patients were enrolled, all started first-line pazopanib treatment. Of these, 51 discontinued pazopanib and 38 continued to second-line everolimus treatment
Participants by arm
| Arm | Count |
|---|---|
| All Patients All patients were assigned to first-line treatment with pazopanib once daily. Patients who progressed during or within 6 months after stopping pazopanib treatment were eligible to then receive everolimus once daily as second-line treatment. | 74 |
| Total | 74 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Everolimus | Adverse Event | 0 | 6 |
| Everolimus | Disease progression | 0 | 25 |
| Everolimus | Other reason | 0 | 7 |
| Pazopanib | Adverse Event | 19 | 0 |
| Pazopanib | Disease progression | 51 | 0 |
| Pazopanib | Other reason | 4 | 0 |
Baseline characteristics
| Characteristic | All Patients |
|---|---|
| Age, Continuous | 66.0 Years STANDARD_DEVIATION 10.68 |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 74 | 3 / 38 |
| other Total, other adverse events | 73 / 74 | 34 / 38 |
| serious Total, serious adverse events | 47 / 74 | 16 / 38 |
Outcome results
Primary
Progression Free Survival (PFS) for the Everolimus Treatment Period Using RECIST
Time between the date of first everolimus dose and date of disease progression or death (whichever comes first) in patients treated initially with pazopanib. Disease progression is measured by RECIST (Response Evaluation Criteria in Solid Tumors), which is at least a 20% increase in the sum of the target lesion longest diameters (LDs).
Time frame: Throughout the study period, up to 4 years
Population: Intent to treat (ITT) population included all patients who received at least one dose of pazopanib and at least one dose of everolimus.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus | Progression Free Survival (PFS) for the Everolimus Treatment Period Using RECIST | 5.1 months |
Secondary
Objective Response Rate (ORR) for the Everolimus Treatment Period Using RECIST
Percentage of patients with Complete or Partial Response at any time following the start of second-line everolimus treatment as per RECIST. RECIST Complete Response is defined to be a disappearance of all target lesion(s). RECIST Partial Response is defined to be at least a 30% decrease in the sum of the target lesion LDs.
Time frame: Throughout the study, up to 4 years
Population: Intent to treat (ITT) population included all patients who received at least one dose of pazopanib and at least one dose of everolimus.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Everolimus | Objective Response Rate (ORR) for the Everolimus Treatment Period Using RECIST | Complete response | 0.0 Percentages of Participants |
| Everolimus | Objective Response Rate (ORR) for the Everolimus Treatment Period Using RECIST | Partial response | 7.9 Percentages of Participants |
Secondary
Objective Response Rate (ORR) for the Pazopanib Treatment Period Using RECIST
Percentage of patients with Complete or Partial Response at any time following the start of first-line pazopanib treatment. RECIST Complete Response is defined to be a disappearance of all target lesion(s). RECIST Partial Response is defined to be at least a 30% decrease in the sum of the target lesion LDs.
Time frame: Throughout the study period, up to 4 years
Population: Intent to treat (ITT) population included all patients who received at least one dose of pazopanib and at least one dose of everolimus.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Everolimus | Objective Response Rate (ORR) for the Pazopanib Treatment Period Using RECIST | Complete response | 6.8 Percentages of participants |
| Everolimus | Objective Response Rate (ORR) for the Pazopanib Treatment Period Using RECIST | Partial response | 39.2 Percentages of participants |
Secondary
Overall Survival From the Start (OSS) of Study Treatment
Time from first pazopanib dose until death due to any cause in patients who received at least one dose of pazopanib followed by everolimus
Time frame: Throughout the study, up to 4 years
Population: ATS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus | Overall Survival From the Start (OSS) of Study Treatment | 35.7 Months |
Secondary
Overall Survival of Everolimus (OSE)
Time from first everolimus dose until death due to any cause
Time frame: Throughout the study period, up to 4 years
Population: ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus | Overall Survival of Everolimus (OSE) | 15.6 months |
Secondary
PFS for the Pazopanib Treatment Period Using RECIST
Time from first pazopanib dose until disease progression or death from any cause (whichever occurred earlier), provided this occurred prior to the start of everolimus and within 6 months of last dose of pazopanib
Time frame: Throughout the study period, up to 4 years
Population: ATS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus | PFS for the Pazopanib Treatment Period Using RECIST | 11.0 Months |
Secondary
Progression Free Survival (PFS) Rates
PFS rates 3 and 6 months after date of first dose of second-line everolimus treatment.
Time frame: 3 months, 6 months
Population: Intent to treat (ITT) population included all patients who received at least one dose of pazopanib and at least one dose of everolimus.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Everolimus | Progression Free Survival (PFS) Rates | 3 months | 0.737 Survival probability |
| Everolimus | Progression Free Survival (PFS) Rates | 6 months | 0.355 Survival probability |