Adjuvant Aflibercept for Metastatic Colorectal Cancer

There are over 1.2 million new cases of colorectal cancer and 600,000 deaths worldwide. The
liver is the dominant site of metastases. Approximately 20-25% of patients with advanced
colorectal cancer will be candidates for resection/ablation of all sites of metastatic
disease.1 Unfortunately, despite resection/ablation of all metastatic sites only about 20% of
these patients are ultimately cured.1 An effective adjuvant agent would prevent tumor
recurrence.

Aflibercept and bevacizumab are effective when combined with FOLFIRI for metastatic colon
cancer. Neither has been tested in a randomized study in the adjuvant setting for patients
with resected metastatic disease. Since aflibercept more effectively inhibits all forms of
VEGF including VEGF-A, VEGF-B and PIGF, in striking contrast to bevacizumab which inhibits
only VEGF-A, aflibercept likely will be more effective than bevacizumab as a single agent in
the adjuvant metastatic setting. Therefore, we propose a randomized study of adjuvant
aflibercept for patients metastatic colorectal cancer who have received 10-12 cycles of
perioperative FOLFOX and have had had a complete response to all sites of metastases after
chemotherapy and local modalities such as surgical resection or ablation. SBRT may also be
used to produce a complete response in a metastatic site not easily amenable to surgery or
ablation. Only patients with very high risk of recurrence, defined as 3 or more metastatic
sites, will be included in this study.

Inclusion Criteria:

3.1.1 First-line treatment of metastatic colorectal cancer with 3 or more metastases
3.1.2At least 10 cycles of combination therapy with an oxaliplatin or irinotecan based
regimen per institutional preference (patients may receive 6 cycles, go to surgery, then
complete 4 cycles, they may complete all 10 (or more) prior to surgery, or receive any
combination as long as they receive at least 10 cycles. ) 3.1.3 Resection or ablation of
all metastatic sites that have not achieved complete response with perioperative therapy
(regimen). The sequencing of resection, ablation, and 10-12 cycles of combination therapy
(regimen) with an oxaliplatin or irinotecan based regimen may be performed according to
standard institutional procedure.

3.1.4 Patients achieving a complete response in a metastatic site by stereotactic body
radiation are eligible if the site was not easily accessible by surgery or ablation and a
complete response was achieved.

3.1.5 No severe, uncontrolled concurrent illness that would interfere with protocol
therapy.

3.1.6 No known CNS disease 3.1.7 ECOG Performance Status 0-2 3.1.8 No chemotherapy or
radiation therapy within last 3 weeks 3.1.9 For patients who had 3 months of perioperative
therapy (regimen), then surgery, then 3 months of therapy (regimen), patients must be off
therapy for no more than 8 weeks prior to randomization. For patients who had all their
therapy and then surgery, they must be no more than 8 weeks from surgery prior to
randomization.

3.1.10 No concurrent anticancer therapy. 3.1.11 Absolute neutrophil count ≥ 1,500/uL, Hgb >
9.0 g/dl, platelet ≥ 100,000/uL.

3.1.12 Total bilirubin ≤ 1.5x upper limit of normal (ULN) and AST or ALT ≤ 5x ULN; 3.1.13
Creatinine < 1.5 x ULN 3.1.14 Life expectancy of at least 12 weeks. 3.1.15 Age ≥ 18 years
3.1.16 Women of childbearing potential must have a negative pregnancy test. 3.1.17 Men and
women of childbearing potential must be willing to consent to using effective contraception
while on treatment and for at least 3 months thereafter.

3.1.18 Voluntary written informed consent.

Exclusion Criteria:

3.2.1 Residual metastatic disease after resection/ablation 3.2.2 Clinically significant
cardiac disease (e.g., uncontrolled hypertension [blood pressure of >160/90 mmHg on
medication], history of myocardial infarction within 6 months,), New York Heart Association
(NYHA) Class II or greater congestive heart failure within 6 months, unstable arrhythmia.
Patients with an atrial arrhythmia must have this condition well controlled on stable
medication. Patients with current or recent (within 6 months) unstable angina are also not
eligible. Documentation of cardiac medical history to be provided.

3.2.3 Significant bleeding diathesis or coagulopathy 3.2.4 History of cerebral aneurysms or
cerebral arteriovenous malformations. 3.2.5 Patients with recent (within 12 months)
arterial thromboembolic events, including transient ischemic attack (TIA), cerebrovascular
accident (CVA), or clinically significant peripheral artery disease should also be
excluded.

3.2.6 Patients with a history of a gastrointestinal fistula or perforation. 3.2.7 Women who
are breast-feeding. 3.2.8 Patients who have undergone major surgery, chemotherapy, or
radiotherapy within the last 3 weeks.

3.2.9 Patients on concurrent anticancer therapy.