| Exclusion Criteria: | 1) Prior CT-322 therapy.
2) Prior grade 3 or greater toxicity to or failure of irinotecan therapy.
3) Prior treatment with VEGF or VEGFR inhibitors (including but not limited to bevacizumab PTK-787, sorafenib , sunitinib , AZD2171, VEGF Trap, etc.) or vascular targeting/disrupting agents.
4) Prior treatment with stereotactic radiosurgery, brachytherapy, or a surgically created resection cavity to support other anatomically localized therapies.
5) Concurrent severe and/or uncontrolled medical disease that could compromise participation in the study such as: a) Pleural or pericardial effusion of any grade; b) Uncontrolled diabetes (defined as HbA1c > 8.5% or fasting serum glucose persistently >200 mg/dL); c) Uncontrolled hypertension (defined as systolic blood pressure >140 mmHg or diastolic pressure >90 mmHg, despite optimal medical management); d) Active clinically serious infection >CTCAE grade 2;
6) (Continued from # 5) e) History of clinically significant bleeding diathesis or coagulopathy including platelet function disorder (e.g., known von Willebrand disease) or acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies); f) Ongoing or recent (</=3 months) significant gastrointestinal bleeding; g) Serious non-healing wound, ulcer, or bone fracture; or h) Glomerulonephritis.
7) Excessive risk of bleeding as defined by stroke within the prior 12 months, history of CNS (other than stable, grade 1; see below) or intraocular bleed, or septic endocarditis.
8) Females who are pregnant or breast feeding. a) Female patients of childbearing potential must have a negative serum pregnancy test (sensitivity </=25 IU human chorionic gonadotropin per liter) within 72 hours prior to administration of study treatment; b) Female patients of childbearing potential are those who are not either surgically sterile (having undergone hysterectomy and/or bilateral salpingooophorectomy) or at least 50 years old and have had no menses for at least 24 months.
9) Adults of reproductive potential not employing an effective method of birth control and agreeing to continue to do so until at least 4 weeks after the last dose of study drug administration.
10) Has experienced any of the following procedures or conditions in the preceding 12 months: a) Coronary artery bypass graft, angioplasty, vascular stenting, myocardial infarction, unstable angina; b) Symptomatic congestive heart failure (New York Heart Association >/=class II). c) Any patient with a history of prior cardiotoxic chemotherapy exposure or thoracic irradiation must have medical monitor approval prior to enrollment.
11) Thrombotic or embolic cerebrovascular accident including transient ischemic attacks within the past 12 months. Patients with conditions that would not permit, in the judgment of the investigator, the safe discontinuation of medications such as clopidogrel, ticlopidine, dipyridamole, and other anti-platelet agents may not enroll in the study. Patients with conditions that would not permit, in the judgment of the investigator, the safe discontinuation of acetylsalicylic acid in doses >325 mg/day, or a reduction to doses </=325 mg/day, may not enroll in the study.
12) Any grade of intraparenchymal CNS hemorrhage. Exceptions include: a) Grade 1 intraparenchymal hemorrhage in the immediate post-operative period, or b) Grade 1 intraparenchymal hemorrhage that has been stable (no significant change on 2 consecutive MRI scans at least 4 weeks apart) or improved.
13) Current enrollment in another therapeutic clinical trial involving ongoing therapy.
14) Major surgery, open biopsy, or significant traumatic injury within 4 weeks of first dose of study drug.
15) Known human immunodeficiency virus infection or active hepatitis B or C.
16) Prior malignancy within the previous 3 years, except basal cell skin cancer or a cervical carcinoma in situ or if the other primary malignancy is not currently clinically significant or requiring active intervention.
17) Requiring full therapeutic anti-coagulation with either oral or injectable anticoagulants.
18) Hypokalemia or hypomagnesemia that cannot be corrected.
19) Patients taking St. John's wort within 14 days or ketoconazole within 7 days prior to Day 1 of first treatment cycle (as this is an open-label study, St. John's wort and ketoconazole will be allowed for patients who are subsequently randomly assigned to CT-322 without concurrent irinotecan if consistent with their other medication requirements as determined by the investigator).
20) Has any other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that could increase the risks associated with study participation or study drug administration or could interfere with the interpretation of the study results and, in the judgment of the investigator, would make the patient inappropriate for entry in this study.
21) Currently taking anti-platelet agents: Clopidogrel, ticlopidine, dipyridamole (Persantine®), Aspirin. |