Ziv-Aflibercept Followed by Ziv-Aflibercept, Fluorouracil, and Leucovorin Calcium in Treating Patients With Stage IV Colorectal Cancer

PRIMARY OBJECTIVES:

I. To determine the progression‐free survival during the first phase of the study (PFS1) in
patients with metastatic colorectal cancer treated with single agent ziv‐aflibercept after
progressing on leucovorin calcium, fluorouracil, oxaliplatin (FOLFOX) and leucovorin
calcium, fluorouracil, irinotecan hydrochloride (FOLFIRI) with bevacizumab +/‐ cetuximab or
panitumumab.

II. To determine the progression‐free survival (PFS2) in patients with metastatic colorectal
cancer treated with ziv‐aflibercept and 5‐fluorouracil (fluorouracil), after progressing on
ziv‐aflibercept alone.

SECONDARY OBJECTIVES:

I. Overall survival. II. Response rate. III. Incidence and nature of adverse events. IV.
Growth modulation index (ratio of PFS2/PFS1).

TERTIARY OBJECTIVES:

I. To determine relevant biomarkers which can distinguish patients with a progression free
survival greater than 3 months on single agent ziv‐aflibercept (tumor vascular endothelial
growth factor [VEGF], vascular endothelial growth factor receptor [VEGFR]1 and 2, baseline
plasma phosphatidylinositol glycan anchor biosynthesis, class F [PlGF]).

II. Plasma levels of VEGF‐A, B, C, D, intercellular adhesion molecule 1 (ICAM), chemokine
(C-X-C motif) ligand 1 (melanoma growth stimulating activity, alpha) (Gro alpha), hepatocyte
growth factor (HGF), stem cell growth factor beta (SCGF beta) prior to treatment and with
each cycle of therapy.

III. Single nucleotide polymorphisms (SNPs) of VEGFA, VEGFR1 & 2 & 3, interleukin (IL)8,
angiopoietin-2 (Ang2), IL‐6, ICAM, PlGF, neuropilin (NRP)1 & 2, chemokine (C-X-C motif)
receptor 2 (CXCR2) and others in the angiogenic pathway.

IV. Tumor messenger ribonucleic acid (mRNA) expression levels of VEGF B, C, D, VEGFR 3; NRP
1, 2, and VEGF isoforms on biopsy specimens taken at trial initiation and upon disease
progression and addition of 5‐FU.

V. Correlation of biomarkers with toxicity of ziv‐aflibercept alone and with 5‐FU.

OUTLINE:

PHASE I: Patients receive ziv‐aflibercept intravenously (IV) over 1 hour on day 1. Courses
repeat every 14 days in the absence of disease progression or unacceptable toxicity. At the
time of progression, patients proceed to Phase II.

PHASE II: Patients receive ziv‐aflibercept IV over 1 hour, leucovorin calcium IV over 1
minute, and fluorouracil IV over 46 hours on day 1. Courses repeat every 14 days in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Inclusion Criteria:

- Histologically confirmed stage IV colorectal adenocarcinoma previously treated with
FOLFOX and FOLFIRI and bevacizumab, receipt of cetuximab or panitumumab is not
required, and has shown progression or intolerant of both oxaliplatin and
irinotecan‐based regimens; baseline tumor assessments must be done within 28 days of
starting treatment

- Patients must have lesions that can be easily biopsied

- Representative tumor tissue specimens (paraffin block preferred)

- Signed informed consent prior to initiation of any study‐specific procedure or
treatment, including agreement to two biopsies during the study

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

- Able to comply with the protocol, including tissue and blood sampling

- Leukocytes >= 3,000 per mm^3

- Absolute neutrophil count >= 1,000 per mm^3

- Platelet count >= 75,000 per mm^3

- Hemoglobin >= 9 g/dL (may be transfused to maintain or exceed this level)

- Creatinine clearance according to the Cockcroft and Gault formula of >= 50 mL/min

- Urine for proteinuria should be < 2 +; patients discovered to have >= 2 + proteinuria
on dipstick urinalysis at baseline should undergo a 24‐hour urine collection and must
demonstrate < 1 g of protein in 24 hours

- Total bilirubin < 1.5 x upper limit of normal (ULN)

- Aspartate aminotransferase and alanine aminotransferase < 2.5 x ULN

- International normalized ratio =< 1.5 and activated prothrombin time =< 1.5 x ULN for
patients not receiving anti‐coagulation therapy

- The use of full‐dose oral or parenteral anticoagulants is permitted as long as the
international normalized ratio (INR) or activated partial thromboplastin time (aPTT)
is within therapeutic limits (according to the medical standard of the enrolling
institution), and the patient has been on a stable dose of anticoagulants for at
least two weeks prior to the first study treatment

- Female patients should not be pregnant or breast‐feeding

- A female of child‐bearing potential is any woman (regardless of sexual
orientation, having undergone a tubal ligation, or remaining celibate by choice)
who meets the following criteria:

- Has not undergone hysterectomy or bilateral oophorectomy; OR

- Has not been naturally postmenopausal for at least 12 consecutive months
(i.e. has had menses at any time in the preceding 12 months)

- Female patients with childbearing potential should agree to use effective,
non‐hormonal means of contraception (intrauterine contraceptive device, barrier
method of contraception in conjunction with spermicidal jelly or surgically
sterile) during the study and for a period of at least 6 months following the
last administration of study drug

- Female patients with an intact uterus (unless amenorrheic for the last 24
months) must have a negative serum pregnancy test within 7 days prior to
randomization into the study

- Male patients must agree to use effective contraception during the study and for a
period of at least 6 months following the last administration of study drugs, even if
they have been surgically sterilized

Exclusion Criteria:

- Any prior systemic treatment with targeted antiangiogenic agents except for
bevacizumab; receipt of cetuximab or panitumumab is not an exclusion criteria

- Radiotherapy to any site for any reason within 14 days prior to treatment

- Uncontrolled intercurrent illness including, but not limited to

- Any of the following within 6 months prior to inclusion: myocardial infarction,
severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New
York Heart Association (NYHA) class III or IV congestive heart failure, stroke
or transient ischemic attack

- Any of the following within 3 months prior to inclusion: grade 3-4
gastrointestinal bleeding/hemorrhage (unless due to resected tumor), treatment
resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious or
inflammatory bowel disease, diverticulitis, pulmonary embolism or other
uncontrolled thromboembolic event

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to agents used in the study

- History of arterial thromboembolic events

- History of abdominal fistula formation, gastrointestinal perforation, or abdominal
abscess within six months

- History or evidence of inherited bleeding diathesis or coagulopathy with a risk of
bleeding

- Patients must not be pregnant or nursing

- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
before start of study drug

- Any hemorrhage or bleeding event >= CTCAE grade 3 within 4 weeks prior to the start
of study medication

- Non‐healing wound, ulcer, or bone fracture

- Inadequately controlled hypertension (systolic blood pressure [SBP] > 150 mmHg,
diastolic blood pressure [DBP] > 100 mg Hg)

- Known positivity for human immunodeficiency virus (HIV)

- Malignancies other than colorectal adenocarcinoma within 5 years prior to treatment,
except for adequately treated carcinoma in situ of the cervix, basal or squamous cell
skin cancer, localized prostate cancer treated surgically with curative intent, and
ductal carcinoma in situ treated surgically with curative intent

- Clinically detectable (by physical exam) third‐space fluid collections (e.g. ascites
or pleural effusion) that cannot be controlled by drainage or other procedures prior
to study entry

- Treatment with any other investigational agent, or participation in another
investigational drug trial within 28 days prior to randomization

- Patients can withdraw consent anytime during the study