VEGFR/PDGFR Dual Kinase Inhibitor X-82 and Everolimus for Treating Patients With Pancreatic Neuroendocrine Tumors

Inclusion Criteria: Phase I and PK Expansion Cohort Inclusion Criteria * Phase I Patients: Histologic documentation of a solid malignancy and has exhausted available standard medical treatments or has no standard treatments currently available. This includes primary brain tumors. * PK Expansion Patients: Histologic documentation of locally unresectable or metastatic renal cell carcinoma not currently amenable to surgery, radiation, or other therapy with curative intent. * Measurable or nonmeasurable disease per RECIST 1.1 criteria. * ECOG performance status of 0-1 * At least 18 years of age. * Normal bone marrow and organ function as defined below: * Granulocytes ≥ 1,500/mcL * Platelets ≥ 100,000/mcL * Hemoglobin ≥9 g/dL * Creatinine ≤ 1.5 x ULN * Bilirubin ≤ 1.5 x ULN * AST and ALT ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases are present) * Urine protein ≤ 1+ OR urine protein to creatinine ratio ≤ 1; if UPC ratio is \> 1 on urinalysis, then 24-hour urine collection for protein must be obtained and level must be \< 1,000 mg for patient enrollment. * QTcF \< 450 ms. * Normal LVEF. * Recovery from any major or minor surgeries. * Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. * Ability to swallow and retain oral medication. * Able to understand and willing to sign written informed consent document. Phase II Inclusion Criteria * Histologic documentation of well differentiated or moderately differentiated locally unresectable or metastatic pancreatic neuroendocrine tumor from either a primary or metastatic site with documented disease progression ≤ 12 months prior to enrollment whose disease is not currently amenable to surgery, radiation, or other modality therapy with curative intent. If different histologic classification schemes are used, equivalent histologic classifications (for example "grade 1," "low grade," or "intermediate grade") are allowed. There must be histologic documentation of a pancreatic primary site or clinical evidence of a pancreatic neuroendocrine primary tumor as determined by the treating physician. Documentation from a metastatic site is sufficient if there is clinical evidence of a pancreatic primary site. In the case of discordant pathology, patient eligibility will be determined by the PI after review of available records. Patients with neuroendocrine tumors (e.g., gastrinoma, VIPoma) in whom a pancreatic or peripancreatic primary site is strongly suspected are also eligible. * Evidence of measurable disease per RECIST 1.1. Measurable disease is defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 2 cm with conventional techniques or as ≥ 1 cm with spiral CT scan. * There is no limit on the number of prior chemotherapy regimens allowed. Any prior treatment (with the exception of lanreotide or octreotide) must be completed at least 4 weeks prior to initiation of treatment. * Prior treatment with embolization or ablative therapies is allowed if measurable disease remains outside of the treated area or if there is definite progression of the treated lesions. There is no limit on the number of prior procedures. * ECOG performance status of 0-1 * At least 18 years of age. * Normal bone marrow and organ function as defined below: * Granulocytes ≥ 1,500/mcL * Platelets ≥ 100,000/mcL * Hemoglobin ≥9 g/dL * Creatinine ≤ 1.5 x ULN * Bilirubin ≤ 1.5 x ULN * ALT and AST ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases are present) * Urine protein ≤ 1+ OR urine protein to creatinine ratio ≤ 1; if UPC ratio is \> 1 on urinalysis, then 24-hour urine collection for protein must be obtained and level must be \< 1,000 mg for patient enrollment. * QTcF \< 450 ms. * Normal LVEF. * Patients with fasting serum cholesterol \> 300 mg/dL OR \> 7.75 mmol/L AND fasting triglycerides \> 2.5 x ULN should initiate lipid lowering medications. * Recovery from any major or minor surgeries. Patient must be 4 weeks post-major surgery and 2 weeks post-minor surgery. * Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. * Ability to swallow and retain oral medication. * Able to understand and willing to sign written informed consent document. Exclusion Criteria: Phase I and PK Expansion Cohort Exclusion Criteria * Active or severe liver disease (acute or chronic hepatitis, cirrhosis). * Patients currently receiving cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy, surgery and/or tumor embolization). * Receiving any other investigational agent(s) within 21 days or 5 half-lives (whichever is shorter) prior to the first dose of study drug. A minimum of 10 days between termination of the investigational drug and administration of study drug is required. * Any radiotherapy or immunotherapy within the last 3 weeks (limited palliative radiation is allowed ≥2 weeks). Chemotherapy regimens with delayed toxicity within the last 4 weeks (or within the last 6 weeks for prior nitrosourea or mitomycin C). Chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity within the last 2 weeks. * Major surgery within the last 4 weeks; minor surgery within the last 2 weeks. * Immunization with any attenuated live vaccine within 1 week prior to registration. * Concurrent condition resulting in immune compromise, including chronic treatment with corticosteroids or other immunosuppressive agents. * History of allergic reactions attributed to, or intolerance of, or other significant toxicity with, compounds of similar chemical or biologic composition to X-82 or everolimus. * Patients with fasting serum cholesterol \> 300 mg/dL OR \> 7.75 mmol/L AND fasting triglycerides \> 2.5 x ULN who would need to initiate lipid lowering medications. * Concomitant use of drugs with a risk of causing prolonged QTc and/or Torsades de Pointes, or patients with a history of risk factors for Torsades de Pointes (e.g., familial long QT syndrome, heart failure, left ventricular hypertrophy, slow heart rate (\<45 beats per minute)). * Concomitant use of herbal medications (i.e. St. John's wort, Kava, ephedra (ma huang), ginkgo biloba) at least 7 days prior to the first dose of study drug and throughout participation in the trial. * Concomitant use of any drug which is a moderate or strong CYP3A4 inhibitor or strong CYP3A4 inducer. * Patients with known CNS metastases, unless metastases are treated and stable and the patients do not require systemic steroids. * Treatment with therapeutic doses of coumarin-type anticoagulants (maximum daily dose of 1 mg allowed for port line patency permitted). Low molecular weight heparin (LMWH) will be allowed. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, inadequately controlled hypertension, uncontrolled diabetes mellitus, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or cerebrovascular accident or transient ischemic attack within 6 months of starting study drugs, or psychiatric illness/social situations that would limit compliance with study requirements. * Presence of active gastrointestinal (GI) disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of the study drugs. * Inability or unwillingness to comply with study and/or follow-up procedures outlined in the protocol. * Pregnant or breastfeeding. * Known HIV-positivity on combination antiretroviral because of the potential for pharmacokinetic interactions with X-82 or everolimus. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated. Phase II Exclusion Criteria * Poorly differentiated neuroendocrine carcinoma or small cell carcinoma. * Prior treatment with everolimus, other mTOR inhibitors, or anti-VEGF drug (sunitinib, bevacizumab). * Patients currently receiving cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy, surgery and/or tumor embolization). * Major surgery \< 4 weeks from the start of treatment. * Minor surgery \< 2 weeks from the start of treatment. (Insertion of a vascular access device is not considered major or minor surgery.) * Any radiotherapy or immunotherapy within the last 21 days (limited palliative radiation is allowed ≥2 weeks). Chemotherapy regimens with delayed toxicity within the last 4 weeks. Chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity within the last 2 weeks. * Immunization with any attenuated live vaccine within 1 week prior to registration. * Concurrent condition resulting in immune compromise, including chronic treatment with corticosteroids or other immunosuppressive agents. * Concomitant use of drugs with a risk of causing prolonged QTc and/or Torsades de Pointes, or patients with a history of risk factors for Torsades de Pointes (e.g., familial long QT syndrome, heart failure, left ventricular hypertrophy, slow heart rate (\<45 beats per minute)). * Concomitant use of herbal medications (i.e. St. John's wort, Kava, ephedra (ma huang), ginkgo biloba) at least 7 days prior to the first dose of study drug and throughout participation in the trial. * Concomitant use of any drug which is a moderate or strong CYP3A4 inhibitor or strong CYP3A4 inducer. * Active or severe liver disease (acute or chronic hepatitis, cirrhosis). * Positive anti-HBV. HBV seropositive patients (HBsAg positive) are eligible if they are closely monitored for evidence of active HBV infection by HBV DNA testing, and they must agree to receive suppressive therapy with lamivudine or other HBV-suppressive therapy until at least 4 weeks after the last dose of everolimus. Patients who are anti-HCV positive are eligible provided that hepatitis C viral load (hepatitis C RNA) is undetectable. * Clinical evidence of brain metastases or carcinomatous meningitis. * History of GI perforation within 12 months prior to registration or presence of active gastrointestinal (GI) disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of the study drugs. * History of clinically significant bleeding episodes. * Current NYHA class II, III, or IV congestive heart failure (see Appendix C) or symptomatic heart failure within 60 days prior to the start of study drugs. * Symptomatic arterial peripheral vascular disease. * History of aortic aneurysm, aortic dissection, angina, myocardial infarction, stroke, transient ischemic attack, or other arterial thrombotic events within 6 months of registration. Patients on therapeutic non-coumarin anticoagulation are eligible provided that they are on a stable dose of anticoagulants. * Uncontrolled diabetes mellitus or inadequately controlled hypertension. * Receiving any other investigational agent(s) within 21 days or 5 half-lives (whichever is shorter) prior to the first dose of study drug. A minimum of 10 days between termination of the investigational drug and administration of study drug is required. * History of allergic reactions or intolerance of, or other significant toxicity with, attributed to compounds of similar chemical or biologic composition to X-82 or everolimus. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements. * Inability or unwillingness to comply with study and/or follow-up procedures outlined in the protocol * Pregnant or breastfeeding. * Known HIV-positivity on combination antiretroviral because of the potential for pharmacokinetic interactions with X-82 or everolimus. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.