Rotating Pazopanib and Everolimus to Avoid Resistance

Study Overview
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Brief Summary
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In this study will be examined whether alternating treatment between two classes of drugs (TKI's and m-TOR inhibitors) postpones or prevents drug resistance in patients with renal cancer.

Detailed Description
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Current practice is to treat with VEGFR-TKI or mTOR inhibitors until progression and then continue with the next active agent. From a biological perspective, TKI's will most likely activate compensatory pathways which, may ultimately lead to the development of resistance. Recent studies suggest that resistance to treatment with TKI may be reversible after stopping treatment. There is therefore a rationale to alternate treatment to prevent or delay the occurrence of resistance. Our hypothesis is that alternating active agents in clear cell renal carcinoma (ccRCC) may reduce side effects, improve tolerability and compliance of treatment and prolong progression free survival and overall survival compared to the standard of care.

Official Title
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A Randomized Phase II Study to Explore the Efficacy and Feasibility of Upfront Bi-monthly Rotations Between Everolimus and Pazopanib in Patients With Advanced or Metastatic Clear Cell Renal Cancer

Conditions
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Clear Cell Renal Carcinoma

Intervention / Treatment
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* Drug: Pazopanib
* Drug: Everolimus
* Drug: Pazopanib
* Drug: Everolimus
* Drug: Everolimus
* Drug: Pazopanib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must provide written informed consent prior to performance of study-specific procedures or assessments, and must be willing to comply with treatment and follow-up. Age ≥ 18 years. Histologically confirmed diagnosis of progressive metastatic clear cell renal cell cancer defined as >10% of the tumor cells having the clear cell phenotype. Locally advanced (defined as disease not amenable to curative surgery or radiation therapy) or metastatic RCC (equivalent to Stage IV RCC according to AJCC staging). Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Measurable disease. No prior systemic anti-cancer treatment against clear cell renal carcinoma. Adequate organ system function. Non-childbearing potential. Exclusion Criteria: Prior malignancy. History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis. Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding. Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product. Presence of uncontrolled infection. Known past or present infection with Hepatitis B virus (HBV), Hepatitis C virus (HCV) or Human Immunodeficiency Virus (HIV). 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 Stable or unstable angina pectoris. 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 ≥160 mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg]. History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months. Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any nonhealing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major). Evidence of active bleeding or bleeding diathesis. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels. Hemoptysis in excess of 2.5 mL (or one half teaspoon) within 8 weeks of first dose of study drug. Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures. Unable or unwilling to discontinue use of prohibited medications or modify the dosing of interacting drugs for at least 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of study drug and for the duration of the study. Pregnant or lactating female. Treatment with any of the following anti-cancer therapies: Radiation therapy, surgery or tumor embolization within 14 days prior to the first dose of Pazopanib OR Chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal therapy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alternating regimen<br>In the experimental arm (Arm A) alternating treatment will consist of 8 weeks of Pazopanib 800 mg qd alternated by 8 weeks of Everolimus 10 mg qd until first progression(PD per RECIST 1.1)followed thereafter by Pazopanib (when PD after 8 weeks of Everolimus)or Everolimus (when PD after 8 weeks of Pazopanib) monotherapy until second progression. | Drug: Pazopanib<br>* tablet 800mg qd, alternating schedule: 8 weeks Pazopanib, 8 weeks Everolimus<br>* Other names: L01XE11;Drug: Everolimus<br>* tablet 10mg qd, alternating schedule: 8 weeks Pazopanib, 8 weeks Everolimus<br>* Other names: L01XE10;Drug: Everolimus<br>* Everolimus 10mg qd monotherapy until second progression (PD per RECIST 1.1)when first progression after 8 weeks of Pazopanib in alternating regimen<br>* Other names: L01XE10;Drug: Pazopanib<br>* Pazopanib 800mg qd monotherapy until second progression (PD per RECIST 1.1) when first progression after 8 weeks of Everolimus in alternating regimen<br>* Other names: L01XE11;|
| Active Comparator: Sequential treatment<br>The comparative arm (Arm B) will be the standard regimen of Pazopanib (800 mg qd continuously) until progression, followed thereafter by Everolimus (10 mg qd continuously) until progression. | Drug: Pazopanib<br>* Tablet 800mg qd til progression<br>* Other names: L01XE11;Drug: Everolimus<br>* tablet 10 mg qd til progression<br>* Other names: L01XE10;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival |  | Randomization until earliest date of disease progression (according RECIST 1.1 criteria) or death, an expected average of one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to second progression | Time between first progression and second progression (PD) per RECIST 1.1 on Everolimus monotherapy (when PD after 8 weeks Pazopanib) or Pazopanib monotherapy (when PD after 8 weeks Everolimus) as second line treatment in experimental arm and time to progressive disease on Everolimus as second line treatment in comparative arm. | Time between first and second progression, an expected average of five months | 
| Change in Quality of life assessed by the FKSI-DRS and EORTC QLQ-C30 questionnaires compared to baseline | Quality of life will be assessed bi-monthly by using the FACT Kidney Symptom Index (FKSI)-Disease Related Symptom (DRS)and the EORTC QLQ-C30 questionnaire. The symptoms covered by the FKSI-DRS include fatigue, pain, weight loss, dyspnea, cough, fever and hematuria. The EORTC QLQ-C30 questionnaire evaluates five functional scales (physical, role, emotional, social and cognitive functioning), three symptom scales (fatigue, pain, nausea, and vomiting), a global health status/QoL scale, and six single items (dyspnea, diarrhea, constipation, anorexia, insomnia and financial impact). | From randomization until one month after ceasing study medication, an expected average of 18 months | 
| Toxicity reported as number/percentage of patients with adverse events | Adverse events will be reported according Criteria for Adverse Events v4.0 (NCI CTCAE v4) | From randomization until one month after ceasing study medication, an expected average of 18 months | 
| Overall survival |  | Time between randomization and death, an estimated average of 2-5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renal carcinoma, Resistance, Reversible, Translational