Phase 1/2a Evaluation of AL3818 in Subjects With Recurrent or Metastatic Endometrial, Ovarian or Cervical Cancer (AL3818-US-001)

Exclusion Criteria

• •Subjects who meet any of the following criteria will be excluded from participation in the study:
• •1. Subjects who have received prior treatment with an FGFr inhibitor or antagonist of FGFr. Prior anti-VEGF or anti-angiogenic therapy is allowed in the adjuvant treatment setting Prior anti-VEGF or anti-angiogenic therapy for the treatment of recurrent disease is not allowed.
• •2. Patients who have received prior antiangiogenic therapy, including bevacizumab, sorafenib, sunitinib, in the setting of advanced disease.
• •3. Patients with serious, non-healing wound, ulcer or bone fracture.
• •4. Patients with active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels.
• •5. Patient with history or evidence upon physical examination of CNS disease, including primary brain tumor, seizures not controlled with standard medical therapy, any brain metastases or history of cerebrovascular accident (CVA, stroke) transient ischemic attack (TIA) or subarachnoid hemorrhage within 6 months of the first date of treatment on this study.
• •6. However, patients with metastatic CNS tumors may participate in this trial, if the patient is \> 4 weeks from therapy completion (including radiation and/or surgery), is clinically stable at the time of study entry and is not receiving corticosteroid therapy.
• •7. Patients with proteinuria. Patients discovered to have a urine protein of 1+ on dipstick or ≥ 30 mg/dl at baseline should undergo a 24-hour urine collection, which must be an adequate collection and must demonstrate \< 1000 mg protein/24 hr to allow participation in the study.
• •8. Patients with clinically significant cardiovascular disease; this includes: Uncontrolled hypertension; Myocardial infarction or unstable angina within 6 months prior to registration; New York Heart Association (NYHA) Grade II or greater congestive heart failure (Appendix F); Serious cardiac arrhythmia requiring medication; Grade II or greater peripheral vascular disease (Appendix F).
• •9. Patients who are pregnant or nursing. To date, no fetal studies of AL3818 in animals or humans have been performed. Therefore, AL3818 should not be administered to pregnant women. Subjects will be apprised of the large potential risk to a developing fetus. It is not known whether AL3818 is excreted in human milk. Because many drugs are excreted in human milk, AL3818 should not be administered to nursing women. Women of childbearing potential must agree to use contraceptive measures during study therapy and for at least 3 months after completion of AL3818 therapy. Because many drugs are excreted in human milk.
• •10. Patients with uncontrolled hypokalemia, hypomagnesaemia, and/or hypocalcaemia.
• •11. Hemoptysis within 3 months prior to first scheduled dose of AL3818.
• •12. Patients with acute or chronic liver disease, active hepatitis A or B with known cirrhosis or liver dysfunction.
• •13. Cytotoxic chemotherapy, immunotherapy, or radiotherapy within 4 weeks (6 weeks in cases of mitomycin C, nitrosourea, lomustine) prior to first scheduled dose of AL3818 or a major surgical procedure within 28 days or minor surgical procedure performed within 7 days prior to first scheduled dose of AL3818.
• •14. Concomitant treatment with strong inhibitors or inducers of CYP3A4, CYP2C9 and CYP2C19 who cannot be switched to other alternative medications (See Appendix E).
• •15. Known history of human immunodeficiency virus infection (HIV).
• •16. Subjects with active bacterial infections (other than uncomplicated urinary tract infection) and/or receiving systemic antibiotics.
• •17. Patients with other invasive malignancies, with the exception of non-melanoma skin cancer, who had (or have) any evidence of other cancer present within the last 5 years or whose previous cancer treatment contraindicates this protocol therapy.
• •18. History of non-malignant GI bleeding, gastric stress ulcerations, or peptic ulcer disease within the past 3-months that in the opinion of the investigator may place the patient at risk of side effects on an anti-angiogenesis product.
• •19. History of significant vascular disease (e.g. aortic aneurysm, aortic dissection).
• •20. Intra-abdominal abscess within the last 3 months.
• •21. History of uncontrolled hypertension that is not well managed by medication, as documented by 2 baseline evaluations taken one hour apart with systolic blood pressure \>160 mm or diastolic blood pressure \>90 mm Hg pressure, or that in the opinion of the investigator may place the patient at risk when taking a VEGF inhibitor.
• •22. Pre-existing uncontrolled hypertension as documented by 2 baseline BP readings taken at least one hour apart, defined as systolic bloodpressure (BP) \>160 mm Hg or diastolic BP \> 90 mm Hg pressure.
• •23. QTcF\>470 msec on screening ECG.
• •24. A history of additional risk factors for TdP (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
• •25. The use of concomitant medications that prolong the QT/QTc interval.
• •26. Baseline echocardiogram (within 2 months) with left ventricular ejection fraction (LVEF) \< 50%.
• •27. History of difficulty swallowing, malabsorption, active partial or complete bowel obstruction, or other chronic gastrointestinal disease or condition that may hamper compliance and/or absorption of AL3818.
• •28. History of pancreatitis and/or renal disease that includes histologically confirmed glomerulonephritis, biopsy proven tubulointerstitial nephritis, crystal nephropathy, or other renal insufficiencies.
• •29. Treatment with an investigational agent within the longest time frame of either 5 half- lives or 30 days of initiating study drug.
• •30. Known recreational substance abuse.
• •31. Known hypersensitivity to anti-angiogenic agents.