Phase II Study of Alternating Sunitinib and Temsirolimus

Study Overview
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Brief Summary
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In the past 5 years, treatment for metastatic Renal Cell Carcinoma (mRCC) has focused on agents directed at blocking tumor and vascular growth pathways. Sunitinib blocks the vascular endothelial growth factor receptor (VEGFr) and temsirolimus is an inhibitor of mammalian target of rapamycin (mTOR). Both sunitinib and temsirolimus are FDA approved agents for mRCC. When agents like these are given together, the toxicity increases but they can be given safely, at full doses, sequentially. We hypothesize that alternating these agents will double the progression free survival (PFS) of the agents when given sequentially.

Detailed Description
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SUMMARY: Alternating Targeted Therapy in Patients with Metastatic Renal Cell Carcinoma: A Phase II Study of Alternating Sunitinib and Temsirolimus Patients with measurable metastatic renal cell carcinoma (any histology) are eligible. All patients will be treated as outlined below with sunitinib alternating with temsirolimus. Patients will be treated continuously, until evidence of progression of disease, or for up to two cycles following disappearance of all disease. A cycle is defined as: Sunitinib 50mg by mouth daily for 4 weeks followed by a two week rest Temsirolimus 25mg IV weekly for 4 weeks followed by a two week rest

Official Title
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Alternating Targeted Therapy in Patients With Metastatic Renal Cell Carcinoma: A Phase II Study of Alternating Sunitinib and Temsirolimus

Conditions
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Metastatic Renal Cell Carcinoma

Intervention / Treatment
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* Drug: Sunitinib
* Drug: Temsirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Histologically confirmed metastatic renal cell cancer with evaluable disease. Patients must be at least 2 weeks from their last immunotherapy, surgery or chemotherapy (6 weeks for nitrosureas) and recovered from all ill effects. Karnofsky Performance Status ≥60% Life expectancy ≥ twelve weeks Adequate end organ function: Cardiac Left ventricular ejection fraction (LVEF) ≥lower limit of institutional normal (LLN) as assessed by echocardiography (ECHO) . The same modality used at baseline must be applied for subsequent evaluations. Women should not be lactating and, if of childbearing age, have a negative pregnancy test within two weeks of entry to the study and practicing acceptable forms of birth control Appropriate Contraception in both sexes The patient must be competent and signed informed consent. EXCLUSION CRITERIA Concomitant second malignancy except for non-melanoma skin cancer, and non-invasive cancer such as cervical CIS, superficial bladder cancer without local recurrence, breast CIS. In patients with a prior history of invasive malignancy, less than five years in complete remission. Have evidence of significant co-morbid illness such as uncontrolled diabetes, hypertension or active infection that would preclude treatment on this regimen. Prior treatment with either sunitinib or temsirolimus Clinically significant gastrointestinal abnormalities 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 (NYHA) History of cerebrovascular accident (CVA) including transient ischemic attack (TIA) within the past 12 months. History of pulmonary embolism or untreated deep venous thrombosis (DVT)within the past 6 months. Note: Subjects with recent DVT who have been treated with therapeutic anticoagulating agents for at least 6 weeks are eligible. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥150 or diastolic blood pressure (DBP) of ≥ 90. Note: 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 diathesis Hemoptysis 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 subject's safety, obtaining informed consent or compliance to the study. Is now undergoing and/or has undergone in the 14 days immediately prior to first dose of study drug any minor surgeries (i.e. skin biopsy, tooth extraction, etc.) and recovered from all ill effects. 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 sunitinib or temsirolimus. Untreated brain metastasis. (Brain metastases that are stable based on radiographic evidence 4 weeks after radiation and/or surgery are permitted).

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alternating Sunitinib and Temsirolimus<br>A cycle is defined as: Sunitinib 50mg by mouth daily for 4 weeks followed by a two week rest Temsirolimus 25mg IV weekly for 4 weeks followed by a two week rest | Drug: Sunitinib<br>* Sunitinib 50mg by mouth daily for 4 weeks followed by a two week rest<br>* Other names: Sutent;Drug: Temsirolimus<br>* Temsirolimus 25mg IV weekly for 4 weeks followed by a two week rest<br>* Other names: TORISEL®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | To determine the time to disease progression in metastatic renal cell carcinoma patients treated with alternating targeted therapy. This time interval constitutes the metric progression free survival time. | From the date of randomization until the first documented disease progression or date of death from any cause, evaluated every 12 weeks throughout duration of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Response Rate as Measured by Best Response Achieved | To be assigned a status of partial response or complete response, changes in tumor measurements must be confirmed by repeat assessments that should be performed no less than 4 weeks after the criteria for response are first met. In the case of stable disease, follow-up measurements must have met the stable disease criteria at least once after study entry at a minimum interval (in general, not less than 6-8 weeks) that is defined in the study protocol. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT/MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR | Every 12 weeks from randomization until progression, estimated time frame is 18 months | 
| To Characterize the Toxicity Profile | The toxicity profile will be characterized by observations of AEs and SAEs graded by the CTCAE criteria v4.0. | Throughout the duration of the patient remaining on study treatment which was a median time of 8 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic Renal Cell Carcinoma, sunitinib, alternating, temsirolimus