Combination Chemotherapy and Bevacizumab With or Without PRI-724 in Treating Patients With Newly Diagnosed Metastatic Colorectal Cancer

PRIMARY OBJECTIVES:

I. Determine the progression‐free survival in patients with newly diagnosed metastatic
colorectal cancer treated with modified fluorouracil, leucovorin calcium, and oxaliplatin 6
(mFOLFOX6)/bevacizumab and PRI‐724 vs. mFOLFOX6/bevacizumab alone.

SECONDARY OBJECTIVES:

I. Overall survival, defined as period from time of randomization to death. II. Response
rate. III. Determine the incidence and severity of adverse events of PRI‐724 administered as
a 7‐day continuous infusion in patients treated with mFOLFOX6/bevacizumab and PRI‐724.

IV. Determine messenger ribonucleic acid (mRNA) expression levels of genes involved in the
Wnt pathway (i.e. survivin) by reverse transcriptase‐polymerase chain reaction (RT‐PCR) in
patients treated with mFOLFOX6/bevacizumab and PRI‐724 vs. mFOLFOX6/bevacizumab alone both
in circulating tumor cells (CTCs) and tumor biopsy specimens.

V. Determine if CTC survivin and stem cell marker expression is consistent and congruent
with expression in tumor specimens.

TERTIARY OBJECTIVES:

I. Determine if a correlation exists between Kirsten rat sarcoma viral oncogene homolog
(KRAS)/ B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutation status and
intratumoral gene expression of the following Wnt related biomarkers: survivin, vascular
endothelial growth factor (VEGF), epidermal growth factor (EGF), epidermal growth factor
receptor (EGFR), S100 calcium binding protein A4 (S100A4), EPH receptor B2 (EphB2),
connexin43, cyclinD1 in patients treated with mFOLFOX6/bevacizumab and PRI‐724 vs.
mFOLFOX6/bevacizumab alone.

II. Determine the mutational spectrum in colon cancer tissues. III. Determine single
nucleotide polymorphism (SNP) profiles in normal and colon cancer tissues.

IV. Determine and describe tumor heterogeneity in colon cancer tissue prior to and during
treatment with PRI‐724.

V. Determine gene expression signatures, micro RNA (miRNA) signatures, and deoxyribonucleic
acid (DNA) methylation signatures as potential predictive and prognostic markers.

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

ARM I: Patients receive CBP/beta-catenin antagonist PRI-724 intravenously (IV) continuously
on days 1-7, bevacizumab IV over 30 minutes, leucovorin calcium IV over 2 hours, oxaliplatin
IV over 2 hours, and fluorouracil IV over 46 hours on day 8. Courses repeat every 14 days in
the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive bevacizumab, leucovorin calcium, oxaliplatin, and fluorouracil as
in Arm I. Courses repeat every 14 days in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3
months.

Inclusion Criteria:

- Histologically confirmed stage IV colorectal adenocarcinoma without any prior
systemic treatment

- Signed informed consent prior to initiation of any study‐specific procedure or
treatment, including consent to provide blood samples for correlative studies and to
obtain a tumor biopsy during the study

- Representative tumor tissue specimens (paraffin block preferred)

- Eastern Cooperative Oncology Group (ECOG) performance status of 0‐1

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

- Leukocytes >= 3,000 per mm^3

- Absolute neutrophil count >= 1,500 per mm^3

- Platelet count >= 100,000 per mm^3

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

- Serum creatinine value < upper limit of normal (ULN) or creatinine clearance of >= 60
mL/min according to Cockgroft‐Gault formula

- 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

- Serum total bilirubin < 1.5 mg/dL

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x ULN (< 5 x
ULN if there is evidence of hepatic involvement by malignant disease)

- 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,
nonhormonal 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 3 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 72 hours prior to administration of
any treatment

- 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

- Patients with treated brain metastases are eligible for study participation; patients
may not receive ongoing treatment with steroids at screening; anticonvulsants (at
stable dose) are allowed; treatment for brain metastases may be whole‐brain
radiotherapy, radiosurgery, neurosurgery, or a combination as deemed appropriate by
the treating physician; radiotherapy and stereotactic radiosurgery must be completed
at least 28 days prior to randomization

- Archival tumor tissue sample (i.e., representative tumor tissue specimen in paraffin
block [preferred] or at least 20 unstained slides) must be requested and available
prior to study entry

- Patients must have biopsiable tumor and agree to study biopsy

Exclusion Criteria:

- Any prior systemic treatment for metastatic colorectal cancer

- Known hypersensitivity to any of the components of PRI‐724, fluorouracil (5‐FU),
oxaliplatin or bevacizumab

- Adjuvant systemic treatment for colorectal cancer within last 12 months

- Radiotherapy to any site for any reason within 28 days prior to treatment

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Sensory peripheral neuropathy > Common Terminology Criteria for Adverse Events
(CTCAE) grade 1

- Corrected QT (QTc) interval > 470 msec (females) or > 450 msec (males)

- Active hepatitis B, hepatitis C

- 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

- Surgery (including open biopsy), significant traumatic injury within 28 days prior to
randomization, or anticipation of the need for major surgery during study treatment

- 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] > 150mmHg,
diastolic blood pressure [DBP] > 100mg Hg)

- Renal insufficiency requiring dialysis

- 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

- Minor surgery, including insertion of an indwelling catheter, within 24 hours prior
to the first bevacizumab infusion

- Current or recent (within 10 days prior to first dose of bevacizumab) use of aspirin
(> 325 mg/day); prophylactic and therapeutic use of anticoagulants is allowed, e.g.,
warfarin (1 mg once daily [QD]) for catheter prophylaxis and prophylactic low
molecular weight heparin (i.e., enoxaparin [40 mg QD])

- Clinically significant (i.e., active) cardiovascular disease (e.g., cerebrovascular
accident or myocardial infarction [MI] within 6 months prior to randomization),
unstable angina, congestive heart failure (CHF) (New York Heart Association [NYHA]
class >= NII), or serious cardiac arrhythmia that is uncontrolled by medication or
may interfere with administration of study treatment