Efficacy and Safety of Pazopanib Monotherapy After First Line Chemotherapy in Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Study Overview
=================
Brief Summary
-----------------
This was a study to determine whether therapy with pazopanib was effective and safe in women with epithelial ovarian, fallopian tube, or primary peritoneal cancer whose cancer had not progressed on first line chemotherapy.

Detailed Description
-----------------
This was a randomized, two-arm, placebo controlled, double-blind, multicenter, intergroup Phase III study in women with non-bulky FIGO (International Federation of Gynecology and Obstetrics) Stage II - IV ovarian, fallopian tube, or primary peritoneal cancer that had not progressed (i.e., complete response (CR), partial response (PR), stable disease (SD) after completing their first-line chemotherapy for advanced ovarian cancer. Approximately 900 subjects were to be enrolled into the study. Study was closed following 3rd overall survival (OS) interim analysis as planned per protocol, which confirmed futility.

Official Title
-----------------
A Phase III Study to Evaluate the Efficacy and Safety of Pazopanib Monotherapy Versus Placebo in Women Who Have Not Progressed After First Line Chemotherapy for Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Conditions
-----------------
Ovarian Cancer

Intervention / Treatment
-----------------
* Drug: Pazopanib
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: written informed consent At least 18 years old. Histologically confirmed, 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 ECOG status of 0 or 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 Cardiac angioplasty or stenting Myocardial infarction Unstable angina Symptomatic peripheral vascular disease Class III or IV congestive heart failure 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 Invasive malignancies that showed activity of disease within 5 years prior to randomization

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>matched placebo tablet administered orally once daily for up to 24 months | Drug: Placebo<br>* Matching placebo 800 mg tablet daily, for 104 weeks (24 months).<br>|
| Experimental: Pazopanib<br>Pazopanib tablet administered orally at 800 mg once daily for up to 24 months | Drug: Pazopanib<br>* Pazopanib 800 mg tablet daily for 104 weeks (24 months)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Investigator-assessed Progression-free Survival (PFS) | PFS is the interval between the date of randomization and the date of progression, defined by Response Evaluation Criteria in Solid Tumors (RECIST), or death due to any cause. Per RECIST, for target lesions (TLs), disease progression (PD) is defined as >=20% increase in the sum of the longest diameters (LD) of TLs, taking as a reference, the smallest sum LD recorded since the treatment started or the appearance of >=1 new lesions. For non-target lesions (NTLs), PD is defined as the appearance of >=1 new lesions and/or unequivocal progression of existing NTLs. Participants (par.) who did not progress/die were censored at the date of last adequate assessment (LAA). Par. who started a new anti-cancer therapy (ACT) prior to radiological progression/death were censored at the date of LAA prior to the new ACT. Par. who progressed/died after an extended period (>=12 months) without adequate assessment (AA) were censored at the date of their last visit with AA prior to progression/death. | From the date of randomization until the date of progression or death due to any cause (median time of follow-up was 17.9 months for pazopanib and 12.3 months for placebo) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival - Median | Overall surival is defined as the interval between the date of randomization and the date of death due to any cause. For participants who did not die, the time to death was censored at the time of last contact. | From the date of randomization until the date of death due to any cause up to approximately 25 months | 
| Overall Survival: Number of Participants Experiencing Death | Overall surival is defined as the interval between the date of randomization and the date of death due to any cause. For participants who did not die, the time to death was censored at the time of last contact. | From the date of randomization until the date of death due to any cause up to approximately 25 months | 
| Progression-free Survival Per Gynecologic Cancer Intergroup (GCIG) Criteria | Progression-free survival by GCIG criteria is defined as the time from the date of randomization to the earliest date of disease progression per GCIG criteria or death due to any cause. Progression is defined according to RECIST but can also be based upon serum CA-125. Progression or recurrence based on serum CA-125 levels are defined on the basis of a progressive serial elevation of serum CA-125, according to the following criteria: (1) participants (par.) with elevated CA-125 pretreatment and normalization of CA-125 must show evidence of CA-125 >=2x the upper normal limit (UNL) on two occasions at least one week apart or; (2) par. with elevated CA-125 pretreatment, which never normalizes, must show evidence of CA-125 >=2x the nadir value on two occasions at least one week apart or; (3) par. with CA-125 in the normal range pretreatment must show evidence of CA-125 >=2x the UNL on two occasions at least one week apart. | From the date of randomization until the date of progression per GCIG criteria or death due to any cause (median time of follow-up was 16.8 months for pazopanib and 11.9 months for placebo) | 
| 3-year Progression-free Survival | 3-year progression-free survival is defined as the percentage of participants who are progression-free at 3 years from randomization. Progression-free survival is defined as the time from the date of randomization to the earliest date of disease progression (defined by RECIST) or death due to any cause. Per RECIST, for target lesions, disease progression (PD) is defined as at least a 20% increase in the sum of the longest diameters (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. For non-target lesions, PD is defined as the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. | Up to 3 years after randomization | 
| Change From Baseline in the European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 Global Health Status Score on Day 1 of Week 13 and Months 7, 10, 13, 16, and 25 | The EORTC QLQ-C30 is a self-reported, 30-item cancer-specific instrument that assesses 15 domains: 5 functional scales (physical, role, emotional, cognitive, and social functioning), 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties), and a global health status, or quality of life. Global health status is assessed using a 7-item Likert scale, ranging from 1 to 7 (poor to excellent). Participants were asked to respond to the following questions using the 7-item Likert scale: How would you rate your overall health during the past week; How would you rate your overall quality of life during the past week? Data are transformed to a scale ranging from 0 to 100. Higher scores represent better functioning (better quality of life). Mean changes from Baseline were calculated via mixed model-repeated measures analysis of covariance (ANCOVA). | Baseline; Week 13; Months 7, 10, 13, 16, and 25 | 
| Change From Baseline in QLQ-OV-28 Module Attitude to Disease/Treatment Functional Score on Day 1 of Week 13 and Months 7, 10, 13, 16, and 25 | The OV (ovarian)-28 module is a 28-item addition to the EORTC QLQ-C30 that focuses on issues specific to ovarian cancer. It assesses attitude to disease/treatment functional symptoms, among others. Participants were asked to indicate the extent to which they experienced attention to disease/treatment functional problems in the week prior to assessment. Participants responded on a scale of 1-4 (1=not at all, 2=a little, 3=quite a bit, 4=very much) to the following questions: How much has your disease been a burden to you?; How much has your treatment been a burden to you?; Were you worried about your future health? Data are transformed to a scale ranging from 0 to 100. Higher scores represent better functioning (better quality of life). Mean changes from Baseline were calculated via mixed model-repeated measures ANCOVA. | Baseline; Week 13; Months 7, 10, 13, 16, and 25 | 
| Change From Baseline in QLQ-OV-28 Module Body Image Functional Score on Day 1 of Week 13 and Months 7, 10, 13, 16, and 25 | The OV-28 module is a 28-item addition to the EORTC QLQ-C30 that focuses on issues specific to ovarian cancer. It assesses body image symptoms, among others. Participants were asked to indicate the extent to which they experienced body image problems in the week prior to assessment. Participants responded on a scale of 1-4 (1=not at all, 2=a little, 3=quite a bit, 4=very much) to the following questions: Have you felt physically less attractive as a result of your disease or treatment?; Have you been dissatisfied with your body? Data are transformed to a scale ranging from 0 to 100. Higher scores represent better functioning (better quality of life). Mean changes from Baseline were calculated via mixed model-repeated measures ANCOVA. | Baseline; Week 13; Months 7, 10, 13, 16, and 25 | 
| Change From Baseline in QLQ-OV-28 Module Peripheral Neuropathy (PN) Symptoms Score at Week 13 and Months 7, 10, 13, 16, and 25 | The OV-28 module is a 28-item addition to the EORTC QLQ-C30 that focuses on issues specific to ovarian cancer. It assesses peripheral neuropathy symptoms, among others. Participants were asked to indicate the extent to which they experienced peripheral neuropathy symptoms or problems in the week prior to assessment. Participants responded on a scale of 1-4 (1=not at all, 2=a little, 3=quite a bit, 4=very much) to the following questions: Did you have tingling hands or feet?; Have you had numbness in your fingers or toes?; Have you felt weak in your arms or legs? Data are transformed to a scale from 0 to 100. Lower scores represent better health (fewer symptoms) for symptom scales. Mean changes from Baseline were calculated via mixed model-repeated measures ANCOVA. | Baseline; Week 13; Months 7, 10, 13, 16, and 25 | 
| Change From Baseline in QLQ-OV-28 Module Abdominal (AB)/Gastrointestinal (GI) Symptoms Score at Week 13 and Months 7, 10, 13, 16, and 25 | The OV-28 module is a 28-item addition to the EORTC QLQ-C30 that focuses on issues specific to ovarian cancer. It assesses AB/GI symptoms, among others. Participants were asked to indicate the extent to which they experienced AB/GI symptoms or problems in the week prior to assessment. Participants responded on a scale of 1-4 (1=not at all, 2=a little, 3=quite a bit, 4=very much) to the following questions: Did you have abdominal pain?; Did you have a bloated feeling in your abdomen/stomach?; Did you have problems with your clothes feeling too tight?; Did you experience any change in bowel habit as a result of your disease or treatment?; Were you troubled by passing wind/gas/flatulence?; Have you felt full too quickly after beginning to eat?; Have you had indigestion/heartburn? Data are transformed to a scale from 0 to 100. Lower scores represent better health (fewer symptoms) for symptom scales. Mean changes from Baseline were calculated via mixed model-repeated measures ANCOVA. | Baseline; Week 13; Months 7, 10, 13, 16, and 25 | 
| Change From Baseline in QLQ-OV-28 Module Hormonal/Menopausal Symptoms Score at Week 13 and Months 7, 10, 13, 16, and 25 | The OV-28 module is a 28-item addition to the EORTC QLQ-C30 that focuses on issues specific to ovarian cancer. It assesses hormonal/menopausal symptoms, among others. Participants were asked to indicate the extent to which they experienced hormonal/menopausal symptoms or problems in the week prior to assessment. Participants responded on a scale of 1-4 (1=not at all, 2=a little, 3=quite a bit, 4=very much) to the following questions: Did you have hot flashes?; Did you have night sweats? Data are transformed to a scale from 0 to 100. Lower scores represent better health (fewer symptoms) for symptom scales. Mean changes from Baseline were calculated via mixed model-repeated measures ANCOVA. | Baseline; Week 13; Months 7, 10, 13, 16, and 25 | 
| Change From Baseline in QLQ-OV-28 Module Sexuality Functional on Day 1 of Week 13 and Months 7, 10, 13, 16, and 25 | The OV-28 module is a 28-item addition to the EORTC QLQ-C30 that focuses on issues specific to ovarian cancer. It assesses sexual functioning symptoms, among others. Participants were asked to indicate the extent to which they experienced sexual functioning problems in the week prior to assessment. Participants responded on a scale of 1-4 (1=not at all, 2=a little, 3=quite a bit, 4=very much) to the following questions: To what extent were you interested in sex?; To what extent were you sexually active?; If sexually active, to what extent was sex enjoyable for you?; If sexually active, did you have a dry vagina during sexual activity? Higher scores represent better functioning (better quality of life). Mean changes from Baseline were calculated via mixed model-repeated measures ANCOVA. Data were not analyzed due to low compliance (<50% at Baseline). | Baseline; Week 13; Months 7, 10, 13, 16, and 25 | 
| Change From Baseline in QLQ-OV-28 Module Other Chemotherapy Side Effects (SE) Symptoms Score at Week 13 and Months 7, 10, 13, 16, and 25 | The OV-28 module is a 28-item addition to the EORTC QLQ-C30 that focuses on issues specific to ovarian cancer. It assesses other chemotherapy SE symptoms, among others. Participants were asked to indicate the extent to which they experienced other chemotherapy SE symptoms/problems in the week prior to assessment. Participants responded on a scale of 1-4 (1=not at all, 2=a little, 3=quite a bit, 4=very much) to the following questions: Have you lost any hair?; If yes, were you upset by the loss of your hair?; Did food/drink taste different from usual?; Did you have aches or pains in your muscles or joints?; Did you have problems with hearing?; Did you urinate frequently?; Have you had skin problems (e.g., itchy, dry)? Data are transformed to a scale from 0 to 100. Lower scores represent better health (fewer symptoms) for symptom scales. Mean changes from Baseline were calculated via mixed model-repeated measures ANCOVA. Data were not analyzed due to low compliance (<50% at Baseline). | Baseline; Week 13; Months 7, 10, 13, 16, and 25 | 
| Change From Baseline in the EuroQOL EQ-5D (Five Dimensions) Thermometer Score at Week 13 and Months 7, 10, 13, 16, and 25 | The EuroQol (EQ-5D) questionnaire is a 2-page, generic, preference-based quality of life measure comprised of a 5-item health status measure and a visual analogue scale (VAS) and is used to generate two scores: the utility score and the thermometer score The thermometer score is based on a vertical VAS. The VAS is designed like a thermometer scale on which the best health state the participant can imagine is referenced at 100, and the worst health state the participant can imagine is marked by 0. Based on how good or bad the current health state is, the participant is asked to draw a line across the thermometer scale. For example, a line drawn across 46 on the scale of 0 to 100 would be coded 46. A negative adjusted mean change from Baseline represents a worsening of quality of life. Mean changes from Baseline were calculated via mixed model-repeated measures ANCOVA. | Baseline; Week 13; Months 7, 10, 13, 16, and 25 | 
| Change From Baseline in the EQ-5D (Five Dimensions) Utility Score at Week 13 and Months 7, 10, 13, 16, and 25 | The EQ-5D utility score captures health status across five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety and/or depression. Participants indicated the level of perceived problems in each of the five dimensions on three levels: 1, no problems; 2, some problems; 3, an extreme problem. Unique health states were defined by combining response levels from each of the five dimensions. For example, state 11111 indicates no problem on any of the five dimensions, whereas state 11223 indicates no problems with mobility or self-care; some problems with performing usual activities, moderate pain/discomfort; and extreme anxiety/depression. Responses are typically converted into health utilities or valuations on a scale ranging from 0 (worst health) to 1 (perfect health). A negative adjusted mean change from Baseline represents a worsening of quality of life. Mean changes from Baseline were calculated via mixed model-repeated measures ANCOVA. | Baseline; Week 13; Months 7, 10, 13, 16, and 25 | 
| Number of Participants With the Indicated Grade 2, 3, and 4 On-therapy Adverse Events Occurring in >=10% of Participants in Either Treatment Arm | An AE is 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. AEs were graded according to the Common Terminiology Criteria for Adverse Events (CTCAE), Version 4.0. Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life threatening; Grade 5, death. | From the date of the first dose of study drug to the date of the last dose plus 28 days (average of 9.8 months for pazopanib and 12.6 months for placebo) | 
| Number of Participants With the Indicated On-therapy Hematology Grade Shifts From Baseline Grade | Hematology toxicities were graded according to the Common Terminiology Criteria for Adverse Events (CTCAE), Version 4.0. Grade refers to the severity of the toxicity. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each toxicity based on this general guideline: Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life threatening; Grade 5, death. Participants with a missing Baseline grade were assumed to have a Baseline grade of 0. WBC=White blood cell. | From the date of the first dose of study drug to the date of the last dose plus 28 days (average of 9.8 months for pazopanib and 12.6 months for placebo) | 
| Number of Participants With the Indicated On-therapy Chemistry Grade Shifts From Baseline Grade | Hematology toxicities were graded according to the Common Terminiology Criteria for Adverse Events (CTCAE), Version 4.0. Grade refers to the severity of the toxicity. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each toxicity based on this general guideline: Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life threatening; Grade 5, death. Participants with a missing Baseline grade were assumed to have a Baseline grade of 0. | From the date of the first dose of study drug to the date of the last dose plus 28 days (average of 9.8 months for pazopanib and 12.6 months for placebo) | 
| Number of Participants With the Indicated Treatment-emergent Thyroid-stimulating Hormone (TSH) Elevations Above 5 Million Units Per Liter (MU/L) | Participants were assessed for thyroid function abnormalities. Clinical hypothyroidism is defined as 5 <TSH <=10 MU/L and T4 <lower limit of normal (LLN). | From the date of the first dose of study drug to the date of the last dose plus 28 days (average of 9.8 months for pazopanib and 12.6 months for placebo) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
fallopian tube cancer, pazopanib, anti-angiogenesis, ovarian cancer, primary peritoneal cancer, tyrosine kinase inhibitors, gynecologic cancer