Biomarker Trial of Everolimus in Patients With Advanced Renal Cell Carcinoma

Study Overview
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Brief Summary
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The purpose of this study is to determine if certain features of tumor specimens sampled prior to therapy can predict for the likelihood of responding to everolimus.

Detailed Description
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Participants will undergo a CT or ultrasound guided biopsy of an accessible tumor lesion before beginning the study medication. Everolimus tablets will be taken orally once a day. Participants will undergo a physical exam and will be asked questions about their general health and specific questions about any problems they might be having. Photographs will be taken of the tumor to assess the response to treatment. This will be done by a CT or MRI scan. Blood tests will be performed every 4 weeks. In addition, blood for research purposes will be done on day 1 of every other cycle. A urine test will be done every 4 weeks.

Official Title
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A Phase II Biomarker Trial of Everolimus in Patients With Advanced Renal Cell Carcinoma

Conditions
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Renal Cell Carcinoma, Renal Cancer

Intervention / Treatment
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* Drug: Everolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have at least one site of disease which in the opinion of the investigator is safely accessible by CT guided biopsy or metastasectomy. Safely accessible metastatic disease will be defined to include those lesions which are palpable with no overlying viscera and are at least 2cm in size. Given the paucity of subcutaneous lesions in RCC, lesions which are felt to be safe to biopsy will also be allowed. These lesions include pleural-based tumors, peripheral liver lesions, kidney lesions and bone lesions with exophytic soft tissue component. As with palpable lesions, these other lesions should be at least 2cm in size with no overlying viscera. At least one measurable site of disease, other than the biopsy site, according to RECIST criterial that has not been previously irradiated. Th the patient has had previous radiation to the marker lesion(s), there must be evidence of progression since the radiation Metastatic renal carcinoma with histologic confirmation by the treating center of either primary or a metastatic lesion. Non-clear cell histologies will be allowed 18 years of age or older Minimum of four weeks since any major surgery, completion of radiation, or completion of all prior systemic anticancer therapy (adequately recovered from the acute toxicities of any prior therapy) ECOG Performance status of 1 or less Adequate bone marrow, liver and renal function as outlined in the protocol Fasting serum cholesterol < 300mg/dL OR < 7.75 mmol/L AND fasting triglycerides < 2.5 x ULN Life expectancy of greater than 6 months Exclusion Criteria: Prior treatment with any investigation drug within the preceding 4 weeks Chronic treatment with systemic steroids or another immunosuppressive agent Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases. Treated brain metastases will be allowed. Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period. Anticonvulsants (stable dose) are allowed. Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS: Gamma Knife, LINAC or equivalent) or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection performed within 3 months prio to day 1 will be excluded. Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study Uncontrolled diabetes mellitus as defined by a fasting serum > 1.5 x ULN A known history of HIV seropositivity. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus Patients with active, bleeding diathesis or on systemic anticoagulation. Aspirin is permitted. Women who are pregnant or breast feeding, or women/men able to conceive and unwilling to practice an effective method of birth control. Patients who have received prior treatment with an mTOR inhibitor. Patients with known hypersensitivity to everolimus or other rapamycins or to its excipients. History of noncompliance to medical regimens

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: Treatment<br>This is a single-arm study. All patients will receive everolimus. | Drug: Everolimus<br>* Tablet form taken orally once a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in Median Progression Free Survival Time Between Favorable and Unfavorable Biomarker Group | The biomarkers of interest are pS6 and pAkt. Expression will be classified as low, intermediate, or high based on a composite score of staining intensity and % of tumor cells staining positive. The difference in progression free survival (PFS) time in the low to high groups is analyzed. PFS is the time from start of treatment to disease progression (PD) or death (estimated by Kaplan Meier method)s. Patients without PD and alive are censored at last date patient is known PD-free. PD is defined by Response Evaluation Criteria In Solid Tumors Criteria 1.1 (RECIST) as follows: >20% increase in the sum of the diameters (SD) of target lesions, referencing the smallest SD on study (including baseline). Must be an increase of >5 mm. New lesions or PD of non-target lesions. Must be represent overall disease status change, not a single lesion increase. Patients with PD at the first on-treatment imaging assessment, will remain on study at investigator discretion until later confirmed. | Follow-up time was up to 39 months from treatment start date. | 
| Median Progression Free Survival | Progression free survival (PFS) is defined as the time from start of treatment to disease progression (PD) or death from any cause as estimated by Kaplan Meier methods. Patients who have not progressed and are alive are censored at the date the patient is known to be progression-free. Progression is defined by Response Evaluation Criteria In Solid Tumors Criteria 1.1 (RECIST) as follows: - >20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (including baseline if it's the smallest). The sum must also demonstrate an increase of >5 mm. OR -Appearance of new lesions and/or unequivocal progression of non-target lesions. It must be representative of overall disease status change, not a single lesion increase. For patients with PD at the first on-treatment imaging assessment, patients will be allowed to remain on study until confirmation at the next assessment at investigator discretion if patient is benefiting from treatment. | Follow-up time was up to 39 months from treatment start date. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response Rate | The best overall response rate is the percentage of participants achieving complete response (CR) or partial response (PR) as the best response recorded on treatment based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. CR and PR must meet the following lesion criteria without having any new lesions as well: Target Lesion: (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Non-Target Lesion: (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). Non-CR/Non-Progressive Disease: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have PR in target lesion. | Evaluated while on treatment. Up to 36 months. | 
| Best Overall Response by PI3K-AKT-MTOR Mutation | Next generation sequencing was used to identify participants with PI3K-AKT-MTOR mutations. Best overall response rate was analyzed with mutant versus wild-type pathways. Please see Best Overall Response Rate for response definition. | Evaluated while on treatment. Up to 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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everolimus