Patient Preference Study of Pazopanib Versus Sunitinib in Advanced or Metastatic Kidney Cancer

A Randomised Double-blind Cross-over Patient Preference Study of Pazopanib Versus Sunitinib in Treatment naïve Locally Advanced or Metastatic Renal Cell Carcinoma.

This is a randomised, double-blind, cross-over study of pazopanib versus sunitinib in patients with locally advanced or metastatic renal cell carcinoma (mRCC) who have received no prior systemic therapy for advanced or metastatic RCC. Approximately 160 eligible patients will be stratified based on the ECOG performance status (0 vs. 1) and number of metastatic sites of disease (0 and 1 vs. >=2). The study consists of two treatment periods of 10 weeks with a 2-week wash-out period between the two treatment periods. Patients will receive pazopanib and sunitinib treatment sequentially in a double-blinded fashion. The primary objective of the study is to assess how the tolerability and safety differences between pazopanib and sunitinib translate into patient preference, defined by the patient's stated preference for which drug they may prefer to continue treatment with at end of study. The secondary objectives are to evaluate the reason for patient preference as assessed by a patient preference questionnaire; to evaluate fatigue as assessed by FACIT-Fatigue and quality of life as assessed by EuroQoL EQ-5D; to evaluate dose modifications and time to dose modification; and to evaluate safety.

This is a randomised, double-blind, cross-over study to evaluate the patient preference of pazopanib versus sunitinib in patients with locally advanced or metastatic RCC who have received no prior systemic therapy for advanced or metastatic RCC. Approximately 160 eligible patients will be stratified based on the ECOG performance status (0 vs. 1) and number of metastatic sites of disease (0 and 1 vs. 2+).

The study consists of two 10-weeks treatment periods with a two-week wash-out period between the treatment periods. Patients will receive pazopanib and sunitinib treatment sequentially. At the end of the second treatment period, patient preference and disease assessment are evaluated and the patients are unblinded. Further treatment is at the discretion of the physician. Further treatment with pazopanib is available within the study. Patients requiring other treatments will complete the study at this point.

Patients will be randomized in a 1:1 ratio to receive blinded (overencapsulated) study drug: either 800mg pazopanib orally for 10 weeks followed by 50mg sunitinib orally for 10 weeks or 50mg sunitinib orally for 10 weeks followed by 800mg pazopanib orally for 10 weeks. A two-week washout period will separate the treatment periods (the medical monitor should be consulted if ongoing AEs need to be resolved and the wash-out period needs to be extended). The regimen for sunitinib is 4 weeks of treatment followed by 2 weeks off treatment. To maintain the double-blind during the two weeks off drug for patients on sunitinib ('Treatment Holiday'), patients will be taking matching placebo. No study drug will be taken during the wash-out period in either arm.

Following the two-week wash-out period and disease assessment, all patients are planned to cross over to the second treatment. Patients will be informed of their disease assessment result and any patient that wishes to come off study at this point due to a very significant response, defined as more than a 50% reduction in tumour size (or complete response if non-measurable disease), will have the option to be unblinded to continue with whichever treatment they were on, however each patient case will need to be discussed with the medical monitor prior to unblinding. Patients who were on sunitinib will leave the study and continue treatment outside the study. Patients who were on pazopanib will continue on pazopanib within the pazopanib open-label part of the study. Conversely, should a patient have a very significant response and wish to cross over or complete the study, this must be documented in the patients notes.

Patients crossing over with progressive disease will follow the same visit schedule and assessments and investigators will have the option for these patients to be unblinded or not. The patients' preference will be collected and analysed but will not contribute to the primary, but an exploratory analysis because of the bias caused by progressing on the first treatment. Even if unblinded, patients may continue to receive the second treatment and may receive open label pazopanib after the second treatment within the study if they did not progress on pazopanib.

Patients who withdraw from treatment due to unacceptable toxicity or progression during the first treatment period will cross-over directly to the second treatment following a 2-week wash-out period.

Actual further treatment at the end of the study will be at the discretion of the investigator taking into account both disease assessments results, laboratory results and the patient preference. Choice and rationale for continuing treatment will be documented.

Patients who did not progress on pazopanib and who prefer to continue with pazopanib may continue on pazopanib and will be followed up for safety until the patient comes off pazopanib due to disease progression, toxicity, death or patient choice, which ever is the earliest.

Those patients that may benefit from further treatment with sunitinib for the same reasons as above will receive it off study and will not be followed up, as will patients who receive any other treatment.

Patients are permitted to receive supportive care throughout the study including transfusion of blood and blood products, treatment with antibiotics, anti-emetics, anti-diarrhoeal agents, analgesics, erythropoietin or bisphosphonates, when appropriate. The study treatment will continue until the end of the two treatment periods or unacceptable toxicity or consent withdrawal or death, whichever occurs first.

The patient preference will be ascertained prior to the second disease assessment result being shared with the patient to avoid bias.

Inclusion Criteria:

• Patients must provide written informed consent prior to performance of any study-specific procedures or assessments and must be willing to comply with treatment and follow up. Procedures conducted as part of the patient's routine clinical management (e.g. blood count, imaging study) and obtained prior to signing of informed consent may be utilised for screening or baseline purposes provided these procedures are conducted as specified in the protocol.
• Received no prior systemic therapy (including interleukin-2, interferon-alpha, chemotherapy, bevacizumab, mTOR inhibitor, sunitinib, sorafenib or other VEGF TKI) for advanced or metastatic RCC. Patients who received adjuvant treatment with a cancer vaccine are eligible.
• Locally advanced (defined as disease not amenable to curative surgery or radiation therapy) or metastatic renal cell carcinoma of any histology (equivalent to Stage IV RCC according to AJCC staging). Patients with non-measurable disease are allowed if metastatic disease can be confirmed.
• ECOG PS of 0 or 1
• Age >= 18 years
• A female is eligible to enter and participate in this study if she is of:

Non-childbearing potential (i.e. physiologically incapable of becoming pregnant) Childbearing potential, including any female who has had a negative serum pregnancy test within two weeks prior to the first dose of study treatment, preferably as close to the first dose as possible and agrees to use adequate contraception.

• Adequate organ system functions
• Total serum calcium concentration <12.0mg/dL
• Left ventricular ejection fraction (LVEF) >=lower limit of institutional normal (LLN) as assessed by echocardiography (ECHO) or multigated acquisition (MUGA) scan. The same modality used at baseline must be applied for subsequent evaluations.
• Patient is able to swallow and retain oral tablets

Exclusion Criteria:

• Poor MSKCC risk group
• History of another malignancy. Note: Patients who have had another malignancy and have been disease-free for 3 years or patients with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible.
• History or clinical evidence of central nervous system (CNS) metastases.

Note: Patients who have previously-treated CNS metastases (surgery +/- radiotherapy, radiosurgery, or gamma knife) and meet all 3 of the following criteria are eligible:

• Are asymptomatic,
• Have had no evidence of active CNS metastases for >=6 months prior to enrolment ,
• Have no requirement for steroids or enzyme-inducing anticonvulsants (EIAC).
• Any clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding or affect absorption of investigational product 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
• 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.
• Corrected QT interval (QTc) >480 msecs using Bazett's formula
• History of one or more of the following cardiovascular conditions within the past 6 months:
• Cardiac angioplasty or stenting
• Myocardial infarction
• Unstable angina
• Coronary artery bypass graft surgery
• Symptomatic peripheral vascular disease
• Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA)
• Poorly controlled hypertension (defined as systolic blood pressure (SBP) of > 150mmHg or diastolic blood pressure (DBP) of > 90mmHg) at baseline.

Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. Blood pressure must be re-assessed on two occasions that are separated by a minimum of 1 hour within a visit. The mean SBP/DBP values from each blood pressure assessment must be <=150/90mmHg in order for a patient to be eligible for the study.

- History of cerebrovascular accident (CVA) including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.

Note: Patients with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible.

• 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 (procedures such as catheter placement not considered to be major).
• Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels.
• Evidence of active bleeding or bleeding diathesis.
• Significant haemoptysis within 6 weeks prior to first dose of study drug.
• 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.
• Radiation therapy, surgery or tumour embolisation within 14 days prior to the first dose of study treatment.
• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib or sunitinib.
• Pregnant or lactating female Female patients who are lactating should discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug.