Study of JI-101 in Patients With Advanced Low Grade Endocrine Tumors, Ovarian Cancers or K-RAS Mutant Colon Cancers
Study of JI-101 in Patients With Advanced Low Grade Endocrine Tumors, Ovarian Cancers or K-RAS Mutant Colon Cancers
The study consists of two parts: Drug Interaction (Pharmacokinetic) Phase and Pharmacodynamic
 Phase

 The primary study objective for the Drug Interaction Study is to determine the
 pharmacokinetic interactions between RAD001 and JI-101.

 The primary study objective for the Pharmacodynamic Study is progression-free survival at 2
 moths, evaluated separately in each of the three cohorts.

 These will include a determination of tumor response using Response Evaluation Criteria in
 Solid Tumors (RECIST) Criteria and an assessment of ephrinB4 expression in blood samples.

 Secondary objectives are to determine safety and tolerability of JI-101. The investigational
 products are everolimus (42-O-(2-hydroxyethyl) rapamycin) and JI-101
 (1-[1-(2-amino-pyridin-4-ylmethyl)-1H-indol-4-yl]-3-(5-bromo-2 methoxy-phenyl)-urea)

 Eligible patients meeting all study entry criteria will be enrolled in the study. For the
 Drug Interaction study, patients with solid tumors will receive a single dose (10 mg) of
 Everolimus by mouth on Day 1 and Day 8 and JI-101 capsules (200 mg) by mouth on Day 8 and Day
 15. For the Pharmacodynamic Study, all patients will receive JI-101 capsules by mouth (200 mg
 BID) for 28 day treatment cycles.
This is a multi-center, non-randomized, open-label study to evaluate the safety and efficacy
 of RAD001 and JI-101 in patients with solid tumors.

 Patients will complete all Screening evaluations within 21 days of Study Cycle 1Day 1. All
 patients will provide written Informed consent and Health Insurance Portability and
 Accountability Act (HIPAA) authorization before any procedures or assessments are initiated
 for the purposes of the protocol.

 For the Drug Interaction Study, Everolimus will be administered to eligible patients at Cycle
 1 Day 1 and blood will be drawn for pharmacokinetic analyses prior to dosing and at 0.5, 1,
 2, 4, 6, 8, 10, and 24 hours after dosing. On Day 8, Everolimus and JI-101 will be
 administered and blood will be drawn for pharmacokinetic analyses prior to dosing and at 0.5,
 1, 2, 4, 6, 8, 10, and 24 hours after dosing. On Day 15, JI-101 will be administered and
 blood will be drawn for pharmacokinetic analyses prior to dosing and at 0.5, 1, 2, 4, 6, 8,
 10, and 24 hours after dosing. Patients will continue to receive JI-101(200 mg BID) for 28
 day treatment cycles. Patients in the Drug Interaction Study will also receive CT scans prior
 to screening and every 2 treatment cycles.

 For the Pharmacodynamic Study, JI-101 will be dispensed to eligible patients at Cycle 1 Day
 1. JI-101 will be administered (200 mg BID) for 28 day treatment cycles. PET and CT scans
 will be performed prior to commencing treatment if it is standard of care. A CT scan will be
 performed otherwise. Patients will return to the study site every 2 cycles to complete safety
 assessments with radiologic tumor assessments (CT and/or PET). Adverse events will be
 monitored following the first administration of investigational product for the duration of
 the patient's participation in this study. Archival tissue will be collected for detection of
 mutations in relevant pathways and development of assays to study modulation of pathways that
 are targeted by JI-101.
Inclusion Criteria:

 1. Male or female, ≥18 years of age

 2. For the Pharmacokinetic Drug Interaction Study: Histologically or cytologically
 confirmed advanced solid tumors that are refractory to all standard of care therapy or
 for whom no standard therapy is available, or for whom other standard therapies the
 patient has denied. For the Pharmacodynamic Study: Histologically or cytologically
 confirmed metastatic/advanced ovarian carcinoma or metastatic/advanced KRAS mutant
 colorectal cancer or metastatic/advanced Head and neck squamous cell cancer (HNSCC)
 that are refractory to all standard therapies therapy or for whom no standard therapy
 is available, or for whom other standard therapies the patient has denied.

 3. At least one measurable tumor as defined by RECIST

 4. Minimum of 4 weeks since any major surgery, completion of radiation, or completion of
 all prior systemic anticancer therapy

 5. Eastern Cooperative Oncology Group (ECOG) of 0 to 2

 6. Organ &marrow function as defined in the protocol.

 7. No evidence of preexisting uncontrolled hypertension as documented by two baseline
 blood pressure readings taken at least 1 hour apart

 8. Clinically euthyroid

 9. Normal range cardiac function

 10. For female patients of child-bearing potential, a negative serum pregnancy test at
 Screening.

 11. Current use of an acceptable form of double-barrier birth control

 12. Have provided written informed consent

 Exclusion Criteria:

 1. Known brain or other central nervous system metastases metastases that are not stable
 for 3 months or longer

 2. Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other
 gastrointestinal conditions with increased risk of perforation.

 3. Major surgery, radiotherapy, chemotherapy, or cytokine therapy within 28 days of Study
 Day 0;

 4. History of intratumoral bleeding or evidence of bleeding diathesis or coagulopathy

 5. Female patients who are pregnant, planning a pregnancy, or who are breastfeeding

 6. Known allergy or hypersensitivity to JI-101 or everolimus or any component of the
 investigational products

 7. Use of an investigational drug/device/biologic within 28 days of Study Day 0

 8. Current drug or alcohol abuse or history of drug or alcohol abuse within the past two
 years

 9. Known history of or serologic positivity for the Hepatitis B Virus (HBV), or the
 Hepatitis C Virus (HCV), or for the human immunodeficiency virus (HIV)

 10. History of cardiac abnormalities

 11. Gastrointestinal (GI) abnormalities

 12. Use of concomitant medications that prolong the QT/QTc interval within 14 days prior
 to Study Day 0

 13. History of cerebrovascular accident including transient ischemic attack within the
 past 6 months

 14. History of pulmonary embolism or deep vein thrombosis within the past 6 months

 15. History of significant retinopathy or any progressive eye disease that could lead to
 severe loss of visual acuity or visual field loss during the study period

 16. Treatment with heparin or heparin analogs

 17. Inability or unwillingness to meet the requirements of the study

 18. Other current active malignancy or history of malignancy within the past five years,
 except for cervical carcinoma in situ, basal cell carcinoma that has been surgically
 removed, or prostate cancer that is being managed with watchful waiting.

 19. Any clinically significant abnormal finding at screening that the investigator judges
 would interfere with study participation