Ziv-Aflibercept in Treating Patients With Metastatic or Unresectable Kidney Cancer

PRIMARY OBJECTIVES:

I. To determine the effect of two different doses of AVE0005 (vascular endothelial growth
factor [VEGF] Trap [ziv-aflibercept]) treatment on the progression-free proportion at 8
weeks in patients with metastatic renal cell carcinoma who had previous treatment with a
tyrosine kinase inhibitor (TKI).

SECONDARY OBJECTIVES:

I. To determine the effect of AVE0005 (VEGF Trap) treatment on objective response rate in
patients with metastatic renal cell carcinoma who have had previous TKI treatment.

II. To describe progression-free survival among patients who undergo dose escalation
following progression on low-dose AVE0005 (VEGF Trap).

III. To evaluate the safety and tolerability of AVE0005 (VEGF Trap) in patients with
metastatic renal cell carcinoma who have had previous treatment with a TKI.

IV. To determine the circulating levels of VEGF AVE0005 (VEGF-Trap) complex and correlate it
with clinical activity.

V. To evaluate the modulation of specific angiogenesis-related protein expression by AVE0005
(VEGF Trap).

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive a higher dose of ziv-aflibercept intervenously (IV) over 1 hour on
day 1.

ARM B: Patients receive a lower dose of ziv-aflibercept IV over 1 hour on day 1.

In both arms, courses repeat every 14 days in the absence of disease progression or
unacceptable toxicity. Patients receiving treatment on Arm I may crossover and receive
treatment on Arm II if disease progression is evident after 4 courses of treatment.

After completion of study treatment, patients are followed every 3 months for 2 years and
then every 6 months for 1 year.

Inclusion Criteria:

- Patient must have histologically confirmed metastatic or unresectable renal cell
carcinoma; disease must be conventional clear cell carcinoma or have a component of
clear cell carcinoma

- Patients with true papillary, sarcomatoid features without any clear cell component,
chromophobe, oncocytoma, collecting duct tumors and transitional cell carcinoma are
NOT eligible

- Patient must have measurable lesions according to the Response Evaluation Criteria In
Solid Tumors (RECIST) criteria; baseline measurements must be performed =< 4 weeks
prior to randomization; all sites of disease, both measurable and nonmeasurable, must
be evaluated =< 4 weeks prior to randomization

- Patient must have evidence of progressive disease following treatment with a tyrosine
kinase inhibitor (TKI) as assessed by the site investigator on the basis of computed
tomography (CT) scans and other appropriate clinical documentation

- Patient must have received at least one prior treatment with a VEGF receptor tyrosine
kinase inhibitor for at least 12 weeks; prior treatment with either temsirolimus or
everolimus is allowed; prior immunotherapy is limited to cytokine therapy with
interleukin 2 and interferon alpha only; no other prior immunotherapy is allowed; no
prior treatment with bevacizumab is allowed

- No prior cellular therapy, vaccine, hormonal or chemotherapy for renal cell carcinoma
is allowed; prior therapy for other cancers is allowable if therapy ended at least 5
years prior to enrollment

- Previous radiotherapy (RT) is permissible provided the measurable disease is outside
the RT port; RT must be completed >= 3 weeks prior to randomization

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Patient must have recovered from any toxic effects of prior radiotherapy or surgical
procedures within 4 weeks prior to randomization

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and
serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3
times upper limit of normal (ULN)

- Total serum bilirubin =< 1.5 times ULN

- Absolute neutrophil count (ANC) >= 1 x 10^9/L

- Platelet count >= 100 x 10^9/L

- Hemoglobin >= 8.0 g/dL

- Serum calcium =< 12.0 mg/dL

- Calculated creatinine clearance (CrCl) >= 60 mL/min, and either proteinuria =< 500
mg/24 hours or urine protein: creatinine ratio (UPCR) =< 1

- International normalized ratio (INR) within normal limits (or =< 1.5 x ULN if on
prophylactic anticoagulation) and activated partial thromboplastin time (aPTT) within
normal limits

- Patients must not have known history of metastatic central nervous system (CNS)
disease

- Female patients MUST NOT be pregnant or breastfeeding; for women of childbearing
potential, a negative serum pregnancy test is required within 1 week prior to
randomization

- Women of childbearing potential and sexually active males must agree to use an
accepted and effective method of contraception while on this study, and for 6 months
after the completion of the study; if a woman becomes pregnant while she is on this
study or within 6 months after the last dose of protocol therapy, she must inform her
treating physician immediately; if a man impregnates a woman while he is on this
study or within 6 months after the last dose of protocol therapy, he must inform his
treating physician immediately

- Patients who have had basal cell skin cancer, squamous cell skin cancer, in situ
cervical cancer, ductal carcinoma in situ of the breast, or lobular carcinoma in situ
of the breast within the past five years are eligible only if treated with curative
intent; patients with other malignancies are eligible only if they have been
continuously disease-free for > 5 years prior to the time of randomization

- Patient must not have any of the following conditions within 24 weeks prior to
randomization: myocardial infarction, severe/unstable angina pectoris,
coronary/peripheral artery bypass graft, New York Heart Association (NYHA) class III
or IV congestive heart failure, cerebrovascular accident or transient ischemic attack

- Patients must not have had a prior pulmonary embolism, deep vein thrombosis, or other
thromboembolic event

- Patient must not have a history of uncontrolled or labile hypertension, with or
without antihypertensive drug treatment, within 12 weeks prior to drug
administration; this is defined as blood pressure > 150/100 mm Hg or systolic blood
pressure > 180 mm Hg on at least 2 repeated determinations on separate days

- Patient must not have known active infection, evidence of bleeding or intratumoral
bleeding, or underlying bleeding disorder

- Patient must not have a known history of hypersensitivity to any Trap agents or
recombinant proteins

- Human immunodeficiency virus (HIV)-positive patients receiving combination
anti-retroviral therapy are excluded from this study