Safety Study of X-82 in Patients With Advanced Solid Tumors

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of advanced solid tumor malignancy that is not responsive to standard therapies or for which there is no effective therapy.
• Eastern Cooperative Group (ECOG) Performance Status score of 0 or 1.
• Life expectancy of at least 12 weeks.
• Ability to swallow and retain oral medication.

• Adequate organ system function, defined as follows:

  • Absolute neutrophil count (ANC) ≥1.5 x 109/L
  • Platelets ≥100 x 109/L
  • Hemoglobin ≥9 g/dL
  • Total bilirubin ≤1.5 times the upper limit of normal (ULN)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 x the upper limit of normal (ULN) if no liver involvement or ≤5 x the upper limit of normal with liver involvement.
  • Creatinine ≤ 1.5 x ULN, OR calculated creatinine clearance ≥ 50 mL/min as calculated by the Cockcroft-Gault method, OR 24-hour measured urine creatinine clearance ≥ 50 mL/min.
• Male patients willing to use adequate contraceptive measures.
• Female patients who are not of child-bearing potential, and female patients of child-bearing potential who agree to use adequate contraceptive measures and who have a negative serum or urine pregnancy test within 24 hours prior to initial trial treatment.
• Patients must have measurable or evaluable disease.
• Patients must be ≥ 18 years of age.
• Patients entering this study must be willing to provide tissue from a previous tumor biopsy (if available) for correlative testing. If tissue is not available, a patient will still be eligible for enrollment into the study.
• Willingness and ability to comply with trial and follow-up procedures.
• Ability to understand the nature of this trial and give written informed consent.

Exclusion Criteria:

• Patients currently receiving cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy [with the exception of LHRH agonists for prostate cancer], surgery and/or tumor embolization).
• Use of an investigational drug within 21 days or 5 half-lives (whichever is shorter) prior to the first dose of X-82. A minimum of 10 days between termination of the investigational drug and administration of X-82 is required. In addition, any drug-related toxicity should have recovered to grade 1 or less.
• Any major surgery, 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 (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.
• Patients with a known allergy or delayed hypersensitivity reaction to drugs chemically related to X-82 (sunitinib, sorafenib or pazopanib) or to the active ingredient of X-82.
• Concomitant use of drugs with a risk of causing prolonged QTc and/or Torsades de Pointes.
• Concomitant use of herbal medications (i.e. St. John's wort, Kava, ephedra (ma huang), ginko biloba) at least 7 days prior to the first dose of study drug and throughout participation in the trial.
• 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 1mg allowed for port line patency permitted). Low molecular weight heparin (LMWH) will be allowed.
• Females who are pregnant or breastfeeding.
• Presence of active gastrointestinal (GI) disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of X-82.
• Decreased left ventricular function at study entry defined as LVEF <50% by either Echocardiogram or MUGA scan.
• Patients who have previously experienced myocardial infarction, severe/unstable angina, coronary/peripheral arterial bypass, symptomatic congestive heart failure (New York Heart Association [NYHA] Class 3 or 4), arterial thrombosis, cerebrovascular accident, or transient ischemia, in the 60 days prior to Day 1 of Cycle 1.
• Patients with inadequately controlled hypertension (defined as BP > 150/100) with or without current antihypertensive medications. Patients with a history of additional risk factors for Torsades de Pointes (e.g. familial long QT syndrome, heart failure, left ventricular hypertrophy, slow heart rate (<45 bpm)).
• Patient with a QTc interval ≥450 msecs. or other significant ECG abnormalities as determined the investigator.
• A serious active infection at the time of treatment, or another serious underlying medical condition that would impair the ability of the patient to receive protocol treatment.
• Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
• Concurrent condition that in the investigator's opinion would jeopardize compliance with the protocol
• Inability or unwillingness to comply with study and/or follow-up procedures outlined in the protocol
• Patients with a history of intolerance to, or significant toxicity with, VEGFR tyrosine kinase inhibitor(s) (TKI).
• Patients entering the expansion after the determination of MTD are limited to previous treatment with one anti-VEGFR TKI