A Phase I Study of ABT-510 in Combination With Bevacizumab in Advanced Solid Tumors

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of advanced solid tumor refractory to standard therapy or for whom there is no standard therapy.
• Patients must not have had radiation therapy, hormonal therapy, biologic therapy or chemotherapy for cancer within the 21 days prior to study Day 1. Patients must not have had major surgery within the 28 days prior to study Day 1 or minor surgical procedures within the 14 days prior to study Day 1.
• Age > 18 years.
• ECOG performance status of 0-1 (see Appendix A).

• Patients must have normal organ and marrow function as defined below:

  • hemoglobin > 9.0g/dL; absolute neutrophil count > 1,500/μl; platelets > 100,000/μl; total bilirubin < 1.5 X upper limit of normal (ULN), AST(SGOT)/ALT(SGPT) < 2.5 X ULN, < 5 X ULN if known hepatic metastases; Urine protein:creatinine ratio < 1.0; creatinine clearance > 50 mL/min/1.73 m2; PT/INR/PTT < 1.2X ULN
• The effect of the investigational drugs on the developing human fetus is not known, but these drugs are likely to be embryo- and feto- toxic. Women of child-bearing potential must agree to use adequate contraception (either surgical sterilization; approved hormonal contraceptives such as birth control pills, Depo-Provera, or Lupron Depot; barrier methods such as condom or diaphragm along with spermicide; or an IUD). Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician and study PI immediately. Patients should be willing to use adequate contraception for three months following discontinuation of study drug.
• The patient is able to self-administer or has a caregiver who can reliably administer subcutaneous injections.
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Patients who have had radiation therapy, hormonal therapy, biologic therapy, or chemotherapy for cancer within the 21 days prior to Day 1 of the study. Patients with prostate cancer who are already receiving androgen deprivation therapy (ie. leuprolide or goserelin) for longer than 3 months may continue on this therapy during the study.
• Patients who have received any other investigational agents within the 28 days prior to Day 1 of the study.
• Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis, the uncertain risk of this regimen on tumor bleeding, and because these patients often develop progressive neurological dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with primary malignancies known to metastasize to the brain (such as lung cancer, breast cancer, renal cell cancer, , sarcoma, carcinoma of unknown primary, melanoma, and head and neck cancers) or patients with symptoms of brain metastases should have a brain MRI within 28 days of enrollment to confirm the absence of CNS metastases. Contrast CT is acceptable for patients who are unable to undergo a brain MRI.
• Patients with poorly controlled or clinically significant atherosclerotic vascular disease including CHF NY Heart Class > 2 (see Appendix B); angina requiring nitrates; MI, CVA, TIA, angioplasty, cardiac or vascular stenting in the past 6 months; or ventricular arrhythmia requiring medication.
• History of intolerance of prior treatment with bevacizumab or ABT-510. Prior treatment with these agents is otherwise permitted.
• Poorly controlled hypertension (> 160/100). Initiation or adjustment of BP medication is permitted prior to study entry provided that patient has 3 consecutive BP readings less than 150/90 mmHg each separated by a minimum of 24 hours. These readings should be collected prior to first skin biopsy.
• History of thrombosis within 3 months prior to enrollment or current use of therapeutic anticoagulation. Prophylactic low-dose anticoagulation for indwelling catheters is permitted; PT/PTT must be within normal limits.
• Use of antiplatelet agents other than aspirin (< 325 mg/day) or standard dose NSAIDs.
• Presence of bleeding diathesis, coagulopathy, or major bleeding event such as an acute GI bleed requiring transfusion or invasive intervention or hemoptysis greater than 1 tablespoon within 6 months prior to Day 1 of the study.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit safety or compliance with study requirements. In addition, patients with non-healing wounds will not be eligible for this study.
• Pregnant women are excluded from this study because the investigational drugs have potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these drugs, breastfeeding should be discontinued if the mother is treated on this study.
• Patients with squamous cell carcinoma of the lung.
• History of intra-abdominal fistula, gastrointestinal perforation or intr-abdominal abscess within 6 months prior to Day 1.