Study of JI-101 in Patients With Advanced Low Grade Endocrine Tumors, Ovarian Cancers or K-RAS Mutant Colon Cancers

• Primary Outcome for Drug Interaction Study [ Time Frame: August 2011 ] [ Designated as safety issue: No ]
  The primary study objective for the Drug Interaction Study is to determine the pharmacokinetic interactions between RAD001 and JI-101
• Primary Outcome for Pharmacodynamic Study [ Time Frame: August 2012 ] [ Designated as safety issue: Yes ]

  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 RECIST Criteria and an assessment of ephrinB4 expression in blood samples.

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 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 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.

• Cancer
• Neuroendocrine
• Ovarian Cancer
• Colon Cancer

• Drug: JI-101
  JI-101 inhibits angiogenesis, and subsequently tumor growth, by inhibiting three receptor tyrosine kinases: VEGF Receptor Type 2 (VEGFR 2), platelet derived growth factor receptor beta (PDGFR β and Ephrin B4 (EphB4). JI-101 selectively inhibits kinases critical for all three stages of tumor angiogenesis.
• Drug: Everolimus
  Everolimus is a signal transduction inhibitor that selectively inhibits mTOR (mammalian target of rapamycin), a key and highly conserved serine-threonine kinase, that is present in all cells and is a central regulator of protein synthesis and ultimately cell growth, cell proliferation, angiogenesis, and cell survival. mTOR is the only currently known target of everolimus (1).
  Other Name: RAD001

• Experimental: Pharmacokinetic Arm
  Patients going on Pharmacokinetic arm will receive JI-101 & Everolimus (4 patients only)
  Interventions:

  • Drug: JI-101
  • Drug: Everolimus
• Experimental: Pharmacodynamic arm
  Patients going on the Pharmacodynamic study will receive JI-101 only.
  Intervention: Drug: 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 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. 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