Pazopanib Versus Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma

Phase 3CompletedNCT00720941

Novartis Pharmaceuticals1,110 enrolled

Overview

This was a randomized, open-label, parallel group Phase III non inferiority study to evaluate the efficacy and safety of pazopanib compared with sunitinib in subjects with advanced renal cell carcinoma (RCC) who had not received prior systemic therapy for advanced or metastatic RCC.

Approximately 876 eligible subjects (approximately 438 per treatment arm) were planned to be enrolled over the course of the study. However, due to higher than expected withdrawal rates and discordance rates between independent review committee (IRC) and investigator assessments of progression, the protocol was amended (Protocol Amendment 4) to increase the number of subjects to approximately 1100 total by including all subjects enrolled in CPZP034A2301 (hereafter referred as Study A2301) and CPZP034A2201 (a sub study of CPZP034A2301, hereafter referred as Study A2201 with NCT01147822). The subjects were centrally randomized in 1:1 ratio to receive either 800mg pazopanib to be administered once daily orally continuous dosing or 50mg sunitinib 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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

1,110

Conditions

Carcinoma, Renal Cell

Interventions

PazopanibDRUG

800 mg administered once daily orally continuous dosing

SunitinibDRUG

50 mg sunitinib to be administered in 6-week cycles: 50mg orally daily for 4 weeks followed by 2 weeks off treatment

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (227)

Outcomes

Primary Outcomes

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 39 months

Secondary Outcomes

Overall Survival

Overall survival was defined as the time from randomization until death due to any cause.

Time frame: From randomization until date of death from any cause, assessed up to approximately 62 months

Overall Response Rate (ORR) as Assessed by Independent Review

The number of participants with evidence of Complete Response (CR) (the disappearance of all target and non-target lesions), Partial Response (PR) (at least a 30% decrease in the sum of the longest diameters \[LD\] of target lesions, taking as a reference the Baseline sum LD), Stable Disease (small changes that do not meet previously given criteria, taking as reference the smallest sum LD since the treatment started), or Progressive Disease (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) was evaluated by an independent review per RECIST, Version 1.

Time frame: From randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 39 months

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.

Data from ClinicalTrials.gov

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Novartis Investigative Site

Huntsville, Alabama, United States

Novartis Investigative Site

Tucson, Arizona, United States

Novartis Investigative Site

Little Rock, Arkansas, United States

Novartis Investigative Site

Beverly Hills, California, United States

Novartis Investigative Site

Escondido, California, United States

Novartis Investigative Site

Fresno, California, United States

Novartis Investigative Site

Greenbrae, California, United States

Novartis Investigative Site

Hayward, California, United States

Novartis Investigative Site

La Jolla, California, United States

Novartis Investigative Site

Los Angeles, California, United States

...and 217 more locations

Time frame: From randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 39 months

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 or death due to any cause, assessed up to approximately 39 months

Number of Participants With Adverse Events

The distribution of adverse events was done via the analysis of frequencies for Adverse Event (AEs) and Serious Adverse Event (SAEs), through the monitoring of relevant clinical and laboratory safety parameters.

Time frame: From study treatment start date till 28 days safety follow-up, assessed up to approximately 152 months

Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale Scores at Day 28 of Cycles 1-4

FACIT Fatigue Subscale is a short, 13-item, easy to administer tool that measures an individual's level of fatigue during their usual daily activities over the past week. The level of fatigue is measured on a four point Likert scale (4 = not at all fatigued to 0 = very much fatigued). The total score range is from 0-52. The higher the score, the lower the fatigue level.