The primary objective of this study is to determine the recommended Phase II dose for the
combination of ABT-510 plus bevacizumab in patients with advanced solid tumors and to
evaluate dose limiting toxicities and non-dose limiting toxicities of this combination. The
secondary objectives are to collect preliminary data on the effect of the combination of
ABT-510 plus bevacizumab versus each agent individually on dermal wound angiogenesis in a
skin biopsy and to collect preliminary data on the clinical activity of this combination
(tumor response rate, progression-free survival, rate of stable disease > 6 months).
ABT-510: In the early 1990s, thrombospondin (TSP-1) was first recognized as an endogenously
produced inhibitor of angiogenesis. Since then, thrombospondin has been shown to inhibit
neovascularization and tumorigenesis in numerous mouse models. Its anti- angiogenesis
properties have been localized to its N-terminal region. Although smaller fragments of this
region retain some of thrombospondin's anti-angiogenesis properties, researchers have
discovered that specific amino acid substitutions can greatly enhance these properties. From
these efforts, ABT-510, a nine-amino acid synthetic peptide has emerged as a novel
anti-angiogenesis agent. The peptide is soluble and stable in water and is administered
parenterally as an acetate salt in 5% dextrose solution for clinical use.
ABT-510 has been evaluated in three Phase I studies: one single-dose study in healthy
volunteers and two studies in cancer patients. Doses ranging from 10 mg to 260 mg have been
evaluated as IV infusions (30-minute), subcutaneous bolus injections, or 24-hour
subcutaneous infusions. Overall, ABT-510 has been well tolerated. A preliminary review of
the 103 case report forms collected to date identified a total of 1306 adverse events.
Ninety-one percent (1195/1306) of these events were considered to be mild or moderate in
nature. Eighty-one percent (1052/1306) of these events were reported as not related to or
probably not related to ABT-510. The most common adverse events, occurring in >10% of the
patients, include injection site reaction, asthenia, abdominal pain, nausea, anorexia, pain,
headache, vomiting, diarrhea, dyspnea, constipation, cough increased, back pain, peripheral
edema, dizziness, insomnia, anemia, fever, sweating, chest pain, and rash.
Bevacizumab (Avastin) is a recombinant, humanized, monoclonal antibody directed against
vascular endothelial growth factor (VEGF). This antibody blocks binding of the ligand VEGF
with its receptor. VEGF is known to play a pivotal role in tumor angiogenesis and is a
significant mitogenic stimulus for arterial, venous, and lymphatic endothelial cells. It can
induce vascular permeability essential for extracellular remodeling and can serve as an
endothelial cell survival factor. Phase III studies in 1st line colorectal cancer, 2nd line
colorectal cancer, 1st line breast cancer, and 1st line non-small cell lung cancer have all
demonstrated clinical benefit in terms of overall survival, progression free survival, and
tumor response [Refs.. HH NEJM, A Sandler ASCO2005, L Miller ASCO 2005]. Efficacy has also
been noted in phase II studies of renal cell, ovarian, glioma, and other tumor types. Side
effects of bevacizumab include approximately 10-20% rate of hypertension requiring
anti-hypertensives, uncommon aterial thromboembolilc events (myocardial infarction,
unstable angina, cerebrovascular events, transient ischemic attacks, etc) with background
rates increased from approximately 1-2% to 2-4%, and an approximately 1-2% risk of GI
Aside from this pivotal phase III colorectal cancer study, the dose of bevacizumab used for
all other clinical trials has been 10mg/kg biweekly. A dose of bevacizumab at 10 mg/kg will
be used in this study because it is consistent with the dosing used in most ongoing and
planned bevacizumab studies and it has been shown, when compared to lower doses, to have
comparable or improved activity.
Based on available data, it is a reasonable hypothesis that the combination of ABT-510 and
bevacizumab will be a safe and potentially efficacious anti-angiogenesis strategy for the
treatment of adult solid tumors. This combination may have utility directly or may prove
useful when subsequently combined with other anti-angiogenic agents or standard chemotherapy
regimens. An important aspect of this proposed study will be the inclusion of a clinical
dermal wound angiogenesis assay which will help quantify and characterize the
anti-angiogenic contribution of each agent in this combination. Therefore, this study is
meant to provide important safety information on this combination, but also insight into the
additive mechanistic effects of two agents with different mechanisms of action.
- 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
- Ability to understand and the willingness to sign a written informed consent
- 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
- 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.