A Phase 1/2, Open-Label, Dose-Escalation Study of JI-101, in Patients With Advanced Solid Tumors

The purpose of this study, the first clinical trial of JI-101, is to determine the maximum tolerated dose of JI-101 when given orally to patients with solid tumors. Safety, tolerability, pharmacokinetics, pharmacodynamics, and the effects of the drug on tumor metabolism will also be studied. JI-101 is an inhibitor of new blood vessel growth that may provide benefit to patients with solid tumors that have failed standard therapeutic regimens.

JI-101 is a compound being developed for the treatment of patients with solid tumors; specifically patients for which no approved therapy or standard of care is available or have solid tumors and have failed standard of care therapy. JI-101 is an inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor beta (PDGFRβ), and EphB4 receptor, each of which plays an important role in driving vascularization (angiogenesis and vasculogenesis) during normal development and tumorigenesis. JI-101 inhibits the growth of new blood vessels, which in turn, may slow or prevent the growth of tumors. The purpose of this open label study is to treat patients with advanced solid tumors, with increasing doses of JI-101, thereby providing information about the maximum tolerated dose (MTD). The study will also examine safety, tolerability, pharmacokinetics, pharmacodynamics, and may evaluate the effects of the drug on tumor metabolism. During this dose-escalation study, at least two patients will be dosed at each dose level (cohort). The patients must complete 21 days of dosing and safety results will be reviewed prior to any patients being assigned the next higher dose level. A continuous reassessment method will be utilized to escalate JI-101 doses between cohorts. Doses will be increased, with an anticipated high dose of 800mg per day. If the MTD is not reached, an optimal biologic dose (OBD) will be determined based on the highest doses that are tolerable with acceptable efficacy. The cohort at MTD or OBD will be expanded to include up to 30 patients with solid tumors to further explore the safety and tolerability of orally-administered JI-101.

Eligibility Criteria:
Inclusion Criteria:

* Be 18 years of age or greater at the time of consent.
* Have solid tumors for which no approved therapy or standard of care is available or have solid tumors and have failed standard-of-care therapy.
* Have life expectancy of greater than 3 months.
* Have Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
* Have organ and marrow function as defined below:

  * absolute neutrophil count ≥ 1.5 x 10\^9 cells/L
  * hemoglobin ≥ 9.0 g/dL
  * platelets ≥ 75 x 10\^9 cells/L
  * total bilirubin ≤ 1.5 x upper limit of normal (ULN)
  * AST(SGOT)/ALT(SGPT) ≤ 2.5 x ULN (≤ 5 x ULN for liver metastases)
  * serum creatinine \< 1.5 x ULN
  * \< 500 mg urinary protein/24 hours or dipstick \< 2+
* No evidence of preexisting uncontrolled hypertension as documented by two baseline blood pressure readings taken at least 1 hour apart (the baseline systolic blood pressure readings must be \<140 mm Hg, and the baseline diastolic blood pressure readings must be \<90 mm Hg. Patients whose hypertension is controlled by antihypertensive therapies are eligible)
* Have no clinically significant disease that poses a risk to the patient and/or would interfere with study evaluations or procedures.
* Have within normal range cardiac function as measured by twelve-lead electrocardiogram at Screening.
* Be clinically euthyroid.
* If female, must be postmenopausal (at least 1 year from last menses), or surgically sterile, or if a female patient of childbearing potential they must agree to use acceptable methods of birth control, which include local double-barrier contraceptive methods, such as cervical diaphragm plus spermicide, female condom plus spermicide, or a non-hormonal intrauterine device (IUD) plus spermicide, or systemic contraceptive methods, such as oral, injectable, transdermal or implantable hormonal contraceptives (including hormone-containing IUDs) during the study period, and for 30 days after the last dose of study drug. Female patients of childbearing potential must have a negative serum pregnancy test within the 3 days before the first study drug administration. Male patients must be surgically sterile or also agree to use acceptable methods of birth control with their female partners, and this may include use of a male condom plus spermicide. If the subject is practicing abstinence at the time of Screening, he/she must agree to use a double-barrier contraceptive method if he/she becomes sexually active.
* Be able to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

* Be pregnant or breastfeeding.
* Have a known history of human immunodeficiency virus (HIV) infection because the effect of JI-101 on immunosuppression and drug interactions with anti-retroviral medications is unknown.
* Have participated in an investigational drug/device/biologic study within 30 days (or within 5 half-lives of the treatment, whichever is longer) before Visit 1 or who are currently participating in another investigational drug/device/biologic study. Participation in non-interventional or observational studies is allowed.
* Have a history of cardiac abnormalities including: abnormal and clinically relevant ECGs; frequent palpitations or syncopal episodes; heart failure; hypokalemia; stroke; family history of Long QT Syndrome; acute myocardial infarction or ventricular tachyarrhythmia within the previous 12 months.
* Have used concomitant medications that prolong the QT/QTc interval within 14 days prior to Day 1.
* Have a 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.
* Have had therapeutic reanticoagulation with heparin or heparin analogs (low molecular weight heparins) or warfarin within the past 4 weeks. Low dose warfarin (1 to 2 mg/day) is allowed for prophylaxis treatment.
* Have had major surgery, radiotherapy, chemotherapy, or cytokine therapy within 4 weeks of treatment initiation. Patients must have recovered to baseline or grade 1 from any clinically significant adverse event experienced during those prior therapies.
* Have gastrointestinal abnormalities including inability to take oral medications, malabsorption syndromes or other clinically significant GI abnormalities that may impair the absorption of JI-101 in the opinion of the Investigator.
* Have uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, unstable angina pectoris, or psychiatric illness/social situations that would pose a risk to patient safety or that would limit compliance with study requirements.
* Have any condition that, in the opinion of the Investigator, would interfere with a patient's ability to perform the required activities of the study or would subject the patient to undue risk.
* Patients with proteinuria (patients with \>2+ protein on urine dipstick) at baseline should undergo a 24-hour urine collection. Results must demonstrate \<500 mg of protein in 24 hours to allow participation in the study)
* Patients with any of the following contraindications to FDG-PET can participate in the study if all of the inclusion criteria and none of the exclusion criteria are met, but these patients are excluded from FDG PET assessments:

  o Inability to remain lying down in PET scanner (for PET portion of the study).
* Absence of at least one metastatic lesion greater than or equal to 2 cm on pre-dose CT (computed tomography) scan or other radiographic imaging as defined by response evaluation criteria in solid tumors (RECIST) criteria.