Efficacy and Safety of Pazopanib Monotherapy After First-line Chemotherapy in Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Asian Women

A Study to Evaluate Efficacy and Safety of Pazopanib Monotherapy in Asian Women Who Have Not Progressed After First-line Chemotherapy for Advanced Ovarian, Fallopian Tube or Primary Peritoneal Carcinoma - An Extension Study to VEG110655

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01227928

Enrollment

145

Registered

2010-10-25

Start date

2010-09-30

Completion date

2014-01-31

Last updated

2015-03-03

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Neoplasms, Ovarian

Keywords

tyrosine kinase inhibitors, Primary Peritoneal Carcinoma, primary peritoneal cancer, ovarian cancer, Fallopian Tube Cancer, gynecologic cancer, anti-angiogenesis, pazopanib

Brief summary

This is a study to determine whether therapy with pazopanib is effective and safe in Asian women with epithelial ovarian, fallopian tube or primary peritoneal cancer whose cancer has not progressed on first-line chemotherapy.

Detailed description

This study is an extension study to the VEG110655 study. The parent study, VEG110655, was designed to evaluate whether pazopanib 800 mg daily for 52 weeks will prolong progression free survival (PFS) in women diagnosed with ovarian, fallopian tube or primary peritoneal cancer. These women will have obtained stable disease, a complete remission, or a partial remission after debulking surgery and at least five cycles of chemotherapy (taxane/platinum). This extension study will evaluate safety and efficacy outcomes of pazopanib monotherapy and placebo in an Asian population with the same indication as the parent study.

Interventions

DRUGPazopanib

Pazopanib 800 mg daily for 24 months

DRUGPlacebo comparator

Placebo 800 mg daily for 24 months

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

FEMALE

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* written informed consent * At least 18 years old. * Histologically confirmed, International Federation of Gynecology and Obstetrics (FIGO) stage II-IV epithelial ovarian, fallopian tube or primary peritoneal carcinoma that was treated with surgical debulking and at least five cycles of platinum-taxane doublet chemotherapy. * Study randomization at least 3 weeks and not more than 12 weeks from the date of the last chemotherapy dose, and all major toxicities from the previous chemotherapy must have resolved. * No evidence of disease progression * Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2 * Able to swallow and retain oral medication. * Adequate hematologic, hepatic, and renal system function as follows: Hematologic * Absolute neutrophil count (ANC) at least 1.5 X 10\^9/L * Hemoglobin at least 9 g/dL (or 5.59 mmol/L) * Platelets at least 100 X 10\^9/L * Prothrombin time (PT) or international normalized ratio (INR) up to 1.2 X ULN * Activated partial thromboplastin time (aPTT) up to 1.2 X ULN Hepatic * Total bilirubin up to 1.5 X ULN * AST and ALT up to 2.5 X ULN Renal * Serum creatinine up to 1.5 mg/dL Or, if greater than 1.5 mg/dL: Calculated creatinine clearance at least 50 mL/min Urine Protein * Urine protein is 0, trace, or +1 determined by dipstick urinalysis, or \< 1.0 gram determined by 24-hour urine protein analysis. * Non-childbearing potential (i.e., physiologically incapable of becoming pregnant) OR childbearing potential, and agrees to use adequate contraception.

Exclusion criteria

* Either (a) bulky disease, or (b) any residual disease which in the opinion of the investigator will need imminent second-line therapy * Synchronous primary endometrial carcinoma, or a past history of primary endometrial carcinoma, are excluded unless certain conditions are met. * Clinically significant gastrointestinal abnormalities * Prolongation of corrected QT interval (QTc) \> 480 msecs * History of any one or more cardiovascular conditions within the past 6 months prior to randomization * Poorly controlled hypertension * History of cerebrovascular accident (including transient ischemic attacks), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months prior to randomization * Major surgery (including interval debulking) or trauma within 28 days, or minor surgical procedures within 7 days, prior to randomization, or has any non-healing wound, fracture, or ulcer. * Evidence of active bleeding or bleeding diathesis. * Hemoptysis within 6 weeks prior to randomization. * Endobronchial metastases. * Serious and/or unstable pre-existing medical (e.g., uncontrolled infection), psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures. * Investigational or anti-VEGF anticancer therapy prior to study randomization. * Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib. * Prior or concurrent invasive malignancies that currently or within the last 5 years show/ed activity of disease (except ovarian, fallopian tube, or peritoneal cancer, or concurrent endometrial cancer FIGO stages IA/B)

Design outcomes

Primary

Measure	Time frame	Description
Progression-free Survival (PFS)	From randomization until evidence of progressive disease or death, whichever occurred first (average of 15.2 months)	PFS is defined as the time interval between randomization and evidence of progressive disease (PD), as assessed by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, or death, whichever occurred first. A visit-based analysis approach to determine participants' dates of progression was applied in the analysis method. PD is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as a reference, the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Participants who were alive and had not progressed at the time of analysis were censored at the date associated with the last visit with adequate assessment.

Secondary

Measure	Time frame	Description
PFS by Gynaecologic Cancer Intergroup (GCIG) Criteria	From randomization to the earliest date of disease progression per GCIG criteria or death due to any cause (average of 15.2 months)	PFS by GCIG criteria is defined as the time from the randomization date to the earliest date of disease progression (PD) per GCIG criteria or death due to any cause. Per GCIG criteria, an objective progression is defined as the earliest event of either tumor progression based on RECIST v1.0 or confirmed CA-125 progression. A participant is counted as Progressed per RECIST if the radiological PD per RECIST occurred prior to or on the same day as CA-125 progression. A participant is counted as Progressed per CA-125 if the radiological PD occurred after CA-125 progression. Per RECIST, PD is defined as at least a 20% increase in the sum of the LD of target lesions, taking as a reference, the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Participants who were alive and had not progressed at the time of analysis were censored at the date associated with the last visit with adequate assessment.
Number of Participants With Any Dose Reduction or Any Dose Interruption	From Week 1 until the end of the treatment period (up to Study Week 108)	Dose interruptions or reductions may have been required following potential drug-related toxicities. As a general rule, if dose reduction of investigational product (IP) was necessary, the dose should have been reduced stepwise by 200 mg at each step, and the participant should have been monitored for 10 to 14 days. If toxicity recurred or worsened during this monitoring time, the IP could have been interrupted and/or the dose of IP further decreased, with continued monitoring for an additional 10 to 14 days, and so on. The cut off for these data was October 12, 2012.
Number of Participants With Any Non-serious Adverse Event (AE) and Any Serious Adverse Event (SAE)	From Week 1 until the end of the treatment period (up to Study Week 108)	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 AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalizaton or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect. See the non-serious AE/SAE module for a list of specific events.
Number of Participants With Any On-therapy AE and Any AE Related to Study Treatment	From Week 1 until the end of the treatment period (up to Study Week 108)	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 AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. On-therapy AEs were those reported from the first day that randomized study drug was received to 28 days after the last dose of randomized study drug, and within 28 days of dose interruption. Relatedness was assessed by the Investigator.
Number of Participants With Any Grade 3 or 4 AE	From Week 1 until the end of the treatment period (up to Study Week 108)	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 AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. The NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 3.0 was used to grade AEs per the following scale to assess severity: Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life-threatening or disabling AE; Grade 5, death related to AE.
Number of Participants With the Indicated On-therapy Grade 3-5 AEs	From Week 1 until the end of the treatment period (up to Study Week 108)	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 AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. On-therapy AEs were those reported from the first day that randomized study drug was received to 28 days after the last dose of randomized study drug, and within 28 days of dose interruption. The NCI-CTCAE Version 3.0 was used to grade AEs per the following scale to assess severity: Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life-threatening or disabling AE; Grade 5, death related to AE. ALT=alanine aminotransferase; AST=aspartate aminotransferase.
Overall Survival	From randomization until death due to any cause (average of 29.4 months)	Overall survival is defined as the time interval from the date of randomization to the date of death due to any cause.
Number of Participants With Any SAE, Any SAE Related to Study Treatment, and Any Fatal SAE	From Week 1 until the end of the treatment period (up to Study Week 108)	An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalizaton or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect. See the non-serious AE/SAE module for a list of specific events. Relatedness was assessed by the Investigator.
Number of Participants With the Indicated Worst-case On-therapy Blood Pressure Shifts From Baseline	From Week 1 until the end of the treatment period (up to Study Week 108)	Systolic blood pressure (SBP) and Diatolic blood pressure (DBP) are measured in millimeters of mercury (mmHg). A participant could have been counted in more than one shift category. Participants who experienced shifts in both SBP and DBP are represented under each individual parameter. A worst-case on-therapy shift is defined as the worst shift that occurred at any time during the treatment period.
Number of Participants With the Indicated Worst-case On-therapy Shift From Baseline in Bazett's Corrected QT Interval (QTc)	From Week 1 until the end of the treatment period (up to Study Week 108)	12-lead ECGs were obtained at the scheduled visits. A worst-case on-therapy shift is defined as the worst shift that occurred at any time during the treatment period. The QTc 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 general, the faster the heart rate the shorter the QTc. If a QTc \>=500 milliseconds (msec) was noted on a scheduled or unscheduled electrocardiogram (ECG), then two additional ECGs should have been obtained within 5 minutes to confirm the abnormality. The average QTc was determined from the three ECG tracings by manual evaluation and was used to determine continued eligibility.
Number of Participants With the Indicated Worst-case On-therapy Hematology Parameter Grade Shifts From Baseline Grade	From Week 1 until the end of the treatment period (up to Study Week 108)	Grade shifts from Baseline were assessed as any grade increase (AGI), increase to Grade (G) 3 (ITG3), and increase to Grade 4 (ITG4). Toxicities were graded according to the National Cancer Institute common toxicity criteria (NCI-Common Toxicity Criteria for Adverse Events), version 4.0. Grade refers to the severity of the toxicity. The CTCAE displays Grades (G) 1 through 5 with unique clinical descriptions of severity for each toxicity based on the following general guideline: G1, mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated; G2, moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL); G3, severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL; G4, Life-threatening consequences; urgent intervention indicated.; G5, death related to AE.
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade	From Week 1 until the end of the treatment period (up to Study Week 108)	Grade shifts from Baseline were assessed as any grade increase (AGI), increase to Grade (G) 3 (ITG3), and increase to Grade 4 (ITG4). Toxicities were graded according to the National Cancer Institute common toxicity criteria (NCI-Common Toxicity Criteria for Adverse Events), version 4.0. Grade refers to the severity of the toxicity. The CTCAE displays Grades (G) 1 through 5 with unique clinical descriptions of severity for each toxicity based on the following general guideline: G1, mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated; G2, moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL); G3, severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL; G4, Life-threatening consequences; urgent intervention indicated.; G5, death related to AE.
Number of Participants With the Indicated Worst-case Eastern Cooperative Oncology Group (ECOG) Performance Status Shifts From Baseline Grades of 0, 1, and 2	From Week 1 until the end of the treatment period (up to Study Week 108)	The ECOG performance status scales and criteria are used by doctors and researchers to assess how a participant's disease is progressing, assess how the disease affects the daily living abilities of the participant, and determine appropriate treatment and prognosis. Grade 0, fully active, able to carry on all pre-disease performance without restriction. Grade 1, restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. Grade 2, ambulatory and capable of all selfcare, but unable to carry out any work activities; up and about more than 50% of waking hours. Grade 3, capable of only limited selfcare; confined to bed or chair more than 50% of waking hours. Grade 4, completely disabled; cannot carry on any selfcare; totally confined to bed or chair. Grade 5, dead.
Number of Participants With AEs Leading to Permanent Discontinuation of Study Treatment, Dose Interruption, and Dose Reduction	From Week 1 until the end of the treatment period (up to Study Week 108)	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 AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. Dose interruptions or reductions may have been required following potential drug-related toxicities. As a general rule, if dose reduction of investigational product (IP) was necessary, the dose should have been reduced stepwise by 200 mg at each step, and the participant should have been monitored for 10 to 14 days. If toxicity recurred or worsened during this monitoring time, the IP could have been interrupted and/or the dose of IP further decreased, with continued monitoring for an additional 10 to 14 days, and so on.

Countries

China, Hong Kong, South Korea, Taiwan

Participant flow

Participants by arm

Arm	Count
Placebo Participants received matching placebo administered orally once daily for up to 24 months.	72
Pazopanib 800 Milligrams Participants received pazopanib 800 milligrams administered orally once daily for up to 24 months.	73
Total	145

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Death	14	12
Overall Study	Lost to Follow-up	4	2
Overall Study	Withdrawal by Subject	4	3

Baseline characteristics

Characteristic	Placebo	Pazopanib 800 Milligrams	Total
Age, Continuous	54.1 Years STANDARD_DEVIATION 10.46	51.7 Years STANDARD_DEVIATION 9.62	52.9 Years STANDARD_DEVIATION 10.09
Race/Ethnicity, Customized Asian	72 participants	73 participants	145 participants
Sex: Female, Male Female	72 Participants	73 Participants	145 Participants
Sex: Female, Male Male	0 Participants	0 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	59 / 72	72 / 72
serious Total, serious adverse events	4 / 72	7 / 72

Outcome results

Primary

Progression-free Survival (PFS)

PFS is defined as the time interval between randomization and evidence of progressive disease (PD), as assessed by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, or death, whichever occurred first. A visit-based analysis approach to determine participants' dates of progression was applied in the analysis method. PD is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as a reference, the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Participants who were alive and had not progressed at the time of analysis were censored at the date associated with the last visit with adequate assessment.

Time frame: From randomization until evidence of progressive disease or death, whichever occurred first (average of 15.2 months)

Population: Intent-to-Treat (ITT) Population: all randomized participants who were not screen failures. Participants who were screen failures and randomized by mistake, but who did not receive study treatment, were not included. The treatment assignment in the ITT Population was based on the randomized treatment. The data cut off was October 12, 2012.

Arm	Measure	Value (MEDIAN)
Placebo	Progression-free Survival (PFS)	18.1 months
Pazopanib 800 Milligrams	Progression-free Survival (PFS)	18.1 months

95% CI: [0.595, 1.626]

Secondary

Number of Participants With AEs Leading to Permanent Discontinuation of Study Treatment, Dose Interruption, and Dose Reduction

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 AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. Dose interruptions or reductions may have been required following potential drug-related toxicities. As a general rule, if dose reduction of investigational product (IP) was necessary, the dose should have been reduced stepwise by 200 mg at each step, and the participant should have been monitored for 10 to 14 days. If toxicity recurred or worsened during this monitoring time, the IP could have been interrupted and/or the dose of IP further decreased, with continued monitoring for an additional 10 to 14 days, and so on.