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

• Response rate [ Time Frame: Not Provided ] [ Designated as safety issue: No ]
  A true objective response rate of 10% would be of interest, whereas a true rate of 1% would not.
• Toxicity as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 30 days of the last dose of treatment ] [ Designated as safety issue: Yes ]
  All patients receiving treatment, regardless of eligibility, will be included in the assessment of toxicity. Assuming that all 60 patients per arm receive treatment, the maximum width of a 90% exact binomial confidence interval on the rate of severe toxicities will be no wider than 22.5%.
• Response duration [ Time Frame: From the time that measurement criteria are met for complete or partial response until the first date that recurrent or progressive disease is objectively documented, assessed up to 3 years ] [ Designated as safety issue: No ]
• Overall survival [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]

This randomized phase II trial studies how well ziv-aflibercept works in treating patients with metastatic or unresectable kidney cancer. Ziv-afliberceptmay stop the growth of kidney cancer by blocking blood flow to the tumor.

PRIMARY OBJECTIVES:

I. Compare the effect of two different doses of AVE0005 (vascular endothelial growth factor [VEGF] Trap) 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. 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. Describe progression-free survival among patients who undergo dose escalation after progression on low-dose AVE0005 (VEGF Trap).

III. 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. Determine the circulating levels of VEGF AVE0005 (VEGF-Trap) complex and correlate it with clinical activity.

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

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to prior cytokine therapy (yes vs no) and Memorial Sloan Kettering Cancer Center (MSKCC) risk (low vs medium vs high). Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive a higher dose of VEGF Trap intervenously (IV) over 1 hour on day 1.

ARM B: Patients receive a lower dose of VEGF Trap 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 3 years.

• Clear Cell Renal Cell Carcinoma
• Recurrent Renal Cell Cancer
• Stage III Renal Cell Cancer
• Stage IV Renal Cell Cancer

• Biological: ziv-aflibercept
  Given IV
  Other Names:

  • aflibercept
  • vascular endothelial growth factor trap
  • VEGF Trap
  • Zaltrap
• Other: laboratory biomarker analysis
  Correlative studies

• Experimental: Arm A (angiogenesis therapy)
  Patients receive a higher dose of VEGF Trap IV over 1 hour on day 1.
  Interventions:

  • Biological: ziv-aflibercept
  • Other: laboratory biomarker analysis
• Experimental: Arm B (angiogenesis therapy)
  Patients receive a lower dose of VEGF Trap IV over 1 hour on day 1.
  Interventions:

  • Biological: ziv-aflibercept
  • Other: laboratory biomarker analysis

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 glutamic 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 history of metastatic central nervous system (CNS) disease
• Female patients MUST NOT be pregnant or breastfeeding; due to the unknown teratogenic properties of AVE0005 (AVE0005 (VEGF Trap), its use in pregnant or breastfeeding patients is INADVISABLE; 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
• No 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 because of possible pharmacokinetic interactions with AVE0005 (VEGF Trap)