RAD001 (Everolimus) and Pasireotide (SOM230) LAR in Patients With Advanced Uveal Melanoma

Study Overview
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Brief Summary
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The purpose of this study is to find out what effects, good and/or bad, the drugs everolimus and pasireotide have on the patient and on melanoma. Pasireotide is also called SOM-230. Pasireotide is an experimental drug and is not approved by the Food and Drug Administration. Everolimus is also called RAD001. Everolimus is approved for use in the U.S. for kidney cancer. Everolimus is not approved for treatment of melanomas, but early studies show that it may help some patients with melanoma.

Official Title
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A Phase II Study of RAD001 (Everolimus) and Pasireotide (SOM230) LAR in Patients With Advanced Uveal Melanoma

Conditions
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Uveal Melanoma

Intervention / Treatment
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* Drug: RAD001 (Everolimus) and Pasireotide (SOM230) LAR


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed metastatic uveal melanoma. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as > or = to 20 mm with conventional techniques or as > or = to 10 mm with spiral CT scan. Patients may have had any number of prior therapies, but cannot have previously been treated with a somatostatin analogue or an mTOR inhibitor. At least 3 weeks must have elapsed since the last dose of systemic therapy. At least 6 weeks must have elapsed if the last regimen included BCNU or mitomycin C. At least 3 months must have elapsed if the last regimen included an anti-CTLA4 antibody. If the last regimen included an anti-CTLA4 antibody, radiographic disease progression since this therapy must be documented. Age > or = to 18 years. Because no dosing or adverse event data are currently available on the use of RAD001 and SOM230 in patients <18 years of age, children are excluded from this study but will be eligible for future pediatric trials, if applicable. Life expectancy of greater than 3 months. ECOG performance status 0 or 1. Patients must have normal organ and marrow function as defined below: leukocytes > or = to 3,000/mcL absolute neutrophil count > or = to 1,500/mcL platelets > or = to 100,000/mcL hemoglobin > or = to 9.0 g/dL not requiring transfusions within the past 2 weeks total bilirubin < 1.5 X institutional upper limit of normal AST(SGOT)/ALT(SGPT) ≤ 2.5 X institutional upper limit of normal Creatinine ≤ 1.5 X institutional upper limit of normal or creatinine clearance less than 60 ml/min Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5 x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication. INR ≤1.5. (Anticoagulation is allowed if target INR ≤ 1.5 on a stable dose of warfarin or on a stable dose of LMW heparin for >2 weeks at time of study initiation). Women of childbearing potential must have a negative serum pregnancy test within 14 days of the administration of the first study treatment. Women must not be lactating. Both men and women of childbearing potential must be advised of the importance of using effective birth control measures during the course of the study. Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are therefore not considered effective for this study. Ability to understand and the willingness to sign a written informed consent document. Evidence of disease progression, as determined by the investigator. Exclusion Criteria: Patients may not be receiving any other investigational agents. Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases. Treated brain metastases must have been stable for at least 2 months. History of allergic reactions attributed to compounds of similar chemical or biologic composition to RAD001 or SOM230. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or bleeding, severely impaired lung function, or psychiatric illness/social situations that would limit compliance with study requirements. Pregnant women are excluded from this study because RAD001 and SOM230 are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants, breast-feeding should be discontinued. Patients with the presence of active or suspected acute or chronic uncontrolled infection or with a history of immunocompromise, including a positive HIV test result (ELISA and Western blot). The safety of a potentially immunosuppressive drug like everolimus is not proven in patients with HIV. HBV DNA and HCV RNA PCR testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection (see Section 8.0 and hepatitis B/C risk factor screening form. Baseline QTc > 450 ms. Patients with risk factors for torsades de pointes, including uncorrected hypokalemia, uncorrected hypomagnesemia, family history of long QT syndrome, clinically significant/symptomatic bradycardia, high-grade AV block, autonomic neuropathy (including that caused by diabetes or Parkinson's disease, uncontrolled hypothyroidism, cirrhosis, or the use of concomitant medications known to prolong the QT interval. Patients with a history of syncope, family history of idiopathic sudden death, a history of sustained or clinically significant cardiac arrhythmias, symptomatic congestive heart failure (NYHA Class III or IV), unstable angina pectoris, sustained ventricular tachycardia, ventricular fibrillation, advanced heart block, or a history of acute myocardial infarction within the six months preceding enrollment . No concomitant anti-cancer chemotherapy or other systemic drugs. Palliative radiation therapy will be allowed as long as the patient meets all other eligibility criteria. Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g. inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption. Chronic treatment with systemic steroids or another immunosuppressive agent. Patients should not receive immunization with attenuated live vaccines during study period or within 1 week of study entry. Close contact with those who have received attenuated live vaccines should be avoided during treatment with RAD001. Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines. Patients with prior or concurrent malignancy except for the following: adequately treated basal cell or squamous cell skin cancer, or other adequately treated in situ cancer, or any other cancer from which the patient has been disease free for five years. Patients with a fasting plasma glucose > 1.5 ULN. Note: At the principle investigator's discretion, non-eligible patients can be re-screened after adequate medical therapy has been instituted. Patients with symptomatic cholelithiasis. Patients who have a history of alcohol or drug abuse in the 6 month period prior to receiving treatment with pasireotide or RAD001. History of liver disease, such as cirrhosis or chronic active hepatitis B and C. Presence of Hepatitis B surface antigen (HbsAg). Presence of Hepatitis C antibody test (anti-HCV). History of, or current alcohol misuse/abuse within the past 12 months. Known gallbladder or bile duct disease, acute or chronic pancreatitis.

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: RAD001 and pasireotide LAR<br>This study will be an open-label, single-arm, phase II study of RAD001 and pasireotide LAR. | Drug: RAD001 (Everolimus) and Pasireotide (SOM230) LAR<br>* Patients will be treated with SOM-230 (pasireotide) LAR 60mg IM once every 28 days and with RAD001 (Everolimus) 10mg PO daily. Each cycle is 28 days. An optional biopsy may be requested required after weeks of therapy. The biopsy may be performed between days 28 and 42.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Complete Response (CR) | For patients with metastatic uveal melanoma treated with RAD001 and pasireotide LAR. | at 16 weeks | 
| Number of Participants With Partial Response (PR) | For patients with metastatic uveal melanoma treated with RAD001 and pasireotide LAR. | at 16 weeks | 
| Number of Participants With Stable Disease (SD) | For patients with metastatic uveal melanoma treated with RAD001 and pasireotide LAR. | at 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression Free Survival(PFS) |  | Up to 3 years | 
| Safety and Toxicity in This Patient Population. | Safety assessments will consist of monitoring and recording all adverse events, including serious adverse events, the regular monitoring of hematology (including glycosylated hemoglobin and coagulation parameters), blood chemistry (including fasting glucose, thyroid function tests, GH, IGF-1 and prolactin), urinalysis, regular monitoring of vital signs, echocardiography, ECGs, and body weight. Toxicity will be assessed using the NCI-CTC for Adverse Events, version 4.0 (CTCAEv4.0, | 16 weeks | 
| Median Overall Survival (OS) |  | Up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PASIREOTIDE (SOM230), RAD001 (EVEROLIMUS), eye, 10-123