OXC4P1-105: A Phase I Study of the Safety, Tolerability, and Antitumor Activity of Escalating Doses of Combretastatin A4 Phosphate Given in Combination With Bevacizumab to Subjects With Advanced Solid Tumors
1. Histopathologically or cytologically confirmed malignant solid tumors that have
failed standard therapy or for which no life prolonging treatment exists
2. Measurable disease as defined by the Response Evaluation Criteria in Solid Tumors
3. At least 4 weeks since any prior immunotherapy, chemotherapy or radiation therapy
prior to first dose of study drug (six weeks for therapy known to be associated with
delayed toxicity such as nitrosoureas or mitomycin-C)
4. Age > or = to 18 years old
5. Adequate bone marrow function:
1. absolute granulocyte count (neutrophils and bands) > or = to 1500 cells/mm3;
2. platelet count > or = to 100,000 cells/mm3;
3. hemoglobin > or = to 9 g/dL.
6. Adequate renal function (glomerular filtration calculated by Cockcroft/Gault formula
or measure urine creatinine clearance > or = to 50 mL/minute)
7. Adequate hepatic function:
1. bilirubin less than or = to 1.5 mg/dL;
2. aspartate transaminase (AST) and alanine transaminase (ALT) less than or = to
2.5 times the institutional upper limit of normal (ULN) (or less than or = to 5
times ULN if liver metastases are present).
8. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
9. Life expectancy of > or = to 12 weeks
10. Written, signed, dated, and witnessed (if applicable as per International Conference
on Harmonization [ICH] guidelines) Independent Ethics Committee (IEC) approved
informed consent form before any study specific screening procedures are performed
11. Fertile subjects must abstain from sexual intercourse or use effective birth control.
12. All women of child bearing potential (WOCBP) must have a negative serum pregnancy
test within 72 hours of first dose.
1. Contraindications, allergies or sensitivity to the use of the study medications or
any other products required for participation in this study (i.e. contrast agents)
2. Presence of central nervous system (CNS) metastases
3. Diagnosed squamous non-small cell lung cancer (NSCLC)
4. History of gastrointestinal perforations
5. Surgery within 28 days of screening visit or a surgical incision that is not fully
healed. Any surgery planned during the study period.
6. Proteinuria >1 g/24 hours by 24 hour urine collection (perform 24 hour urine
collection if > 1+ on dipstick)
7. Recent hemoptysis (occurrence within the past 3 months)
8. Prior therapy with CA4P or bevacizumab, or other agents which target vascular
endothelial growth factor (VEGF) or VEGFR signaling such as Sorafenib and Sutent
9. Prior radiation involving > 30% of the bone marrow
10. Radical radiotherapy to the thorax or abdomen at any time or post-operative radical
radiotherapy to the pelvis. Palliative radiotherapy treatments are acceptable.
Subjects with rectal primaries who have received pre-operative pelvic radiotherapy or
chemoradiation are eligible if the small bowel was mobile and not stuck to the tumor.
11. Active autoimmune disorder(s)
12. Immunocompromised, including subjects known to be human immunodeficiency virus (HIV)
13. Active infection requiring antibiotic therapy or any other serious intercurrent
14. History of angina (stable or severe, even if controlled with medications), myocardial
infarction, congestive heart failure (CHF), non-controlled atrial arrhythmias or
clinically significant arrhythmias including conduction abnormality, nodal junctional
arrhythmias and dysrhythmias, sinus bradycardia or tachycardia, supraventricular
arrhythmias, atrial fibrillation or flutter, syncope or vasovagal episodes
15. Electrocardiogram (ECG) with evidence of prior myocardial infarction (e.g.,
significant Q waves), QTc > 450 msec or other clinically significant abnormalities
16. Taking any drug(s) known to prolong the QTc interval, which cannot be interrupted for
at least four days during each treatment cycle.
17. Known significant heart wall abnormality or heart muscle damage as evidenced on
multiple-gated acquisition (MUGA) scan or echocardiogram (this is not a required
18. Uncontrolled hypertension (defined as blood pressure consistently greater than
150/100 irrespective of medication). Or controlled hypertension requiring use of > 2
classes of anti-hypertensives.
19. Uncontrolled hypokalemia and/or hypomagnesemia
20. Symptomatic peripheral vascular disease or cerebrovascular disease
21. Psychiatric disorders or other conditions rendering subjects incapable of complying
with the requirements of the protocol
22. Receiving concurrent hormonal therapy with the exception of gonadotropin-releasing
hormone (GnRH) agonists in subjects with hormone refractory prostate cancer, hormone
replacement therapy (HRT), oral contraceptives, and megestrol acetate used for
23. Receiving anticoagulation with warfarin, heparin or low molecular weight heparin
other than low dose (1 mg) warfarin for maintenance of central line patency
24. Women who are currently pregnant, nursing, or planning a pregnancy; or women who have
a positive pregnancy test.
25. Receiving concurrent antineoplastic therapy (radiation therapy, cytotoxic or biologic
26. Participation in an investigational drug or device trial within 30 days of entering