Combination Chemotherapy Plus Bevacizumab With or Without Oxaliplatin in Treating Older Patients With Metastatic Colorectal Cancer

OBJECTIVES:

Primary

- To compare the progression-free survival (PFS) of elderly patients with metastatic
colorectal carcinoma who are randomized to receive fluoropyrimidine-based therapy plus
bevacizumab, with or without oxaliplatin.

Secondary

- In a prospectively planned pooled analysis with a similar trial to be conducted by the
Japanese Clinical Oncology Group (JCOG), evaluate and compare the overall survival (OS)
of elderly patients with metastatic colorectal carcinoma who are randomized to receive
fluoropyrimidine-based therapy plus bevacizumab, with or without oxaliplatin.

- To assess and compare response rates and adverse events of elderly patients with
metastatic colorectal carcinoma randomized to receive fluoropyrimidine-based therapy
plus bevacizumab, with or without oxaliplatin.

Tertiary (correlative)

- To evaluate the quality of life (QoL) in elderly patients with metastatic colorectal
carcinoma randomized to receive fluoropyrimidine-based therapy plus bevacizumab, with
or without oxaliplatin.

- To determine whether a geriatric/frailty assessment predicts overall ≥ grade 3 toxicity
to chemotherapy and is associated with PFS, OS, overall QoL, hospitalization, dose
modification (delay or reduction), or discontinuation of chemotherapy due to toxicity,
morbidity, or mortality in elderly patients with metastatic colorectal cancer
randomized to receive fluoropyrimidine-based therapy plus bevacizumab, with or without
oxaliplatin.

- Determine whether a geriatric/frailty assessment tool can identify a subgroup of
elderly patients who benefit from oxaliplatin-based chemotherapy as first-line
treatment of metastatic colorectal carcinoma.

- To analyze relevant pharmacogenetic markers in tissue and blood that may predict
toxicity and/or tumor response in elderly patients with metastatic colorectal carcinoma
randomized to receive fluoropyrimidine-based therapy plus bevacizumab, with or without
oxaliplatin.

- To evaluate the association of tissue-based biomarkers (e.g., KRAS and BRAF status) and
outcome in elderly patients with metastatic colorectal carcinoma randomized to receive
fluoropyrimidine-based therapy plus bevacizumab, with or without oxaliplatin.

- To analyze pharmacokinetics and circulating biomarkers prior to and during therapy and
to assess these alterations with outcome in elderly patients with metastatic colorectal
carcinoma randomized to receive fluoropyrimidine-based therapy plus bevacizumab, with
or without oxaliplatin.

OUTLINE: This is a multicenter study. Patients are stratified according to age (≥ 85 years
vs 80-84 years vs 75-79 years vs 70-74 years), ECOG performance status (0-1 vs 2), and
number of metastatic sites (1 vs > 1). Patients are randomized to 1 of 2 treatment arms.

- Arm A: Patients are assigned to 1 of 2 treatment groups based on physician decision for
fluoropyrimidine.

- Arm A1: Patients receive fluorouracil IV over 46-48 hours, leucovorin calcium IV
over 2 hours, and bevacizumab IV over 10-90 minutes on day 1. Courses repeat every
14 days in the absence of disease progression or unacceptable toxicity.

- Arm A2: Patients receive capecitabine orally (PO) twice daily on days 1-14 and
bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 21 days in the
absence of disease progression or unacceptable toxicity.

- Arm B: Patients are assigned to 1 of 2 treatment groups based on physician decision for
fluoropyrimidine.

- Arm B1: Patients receive mFOLFOX7 comprising oxaliplatin IV over 2 hours,
leucovorin calcium IV over 2 hours, and fluorouracil IV over 46-48 hours on day 1.
Patients also receive bevacizumab IV over 10-90 minutes on day 1. Courses repeat
every 14 days in the absence of disease progression or unacceptable toxicity.

- Arm B2: Patients receive XELOX comprising oxaliplatin IV over 2 hours on day 1 and
capecitabine PO twice daily on days 1-14. Patients also receive bevacizumab IV
over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of
disease progression or unacceptable toxicity.

Patients may undergo blood and tissue sample collection at baseline and additional blood
sample collection during and after study for correlative biomarker, pharmacogenetic, and
pharmacological research studies.

Patients undergo neurotoxicity, quality of life, and geriatric/frailty assessments at
baseline and periodically during and after study treatment.

After completion of study treatment, patients are followed up periodically for 5 years.

DISEASE CHARACTERISTICS:

- Patients must have metastatic colorectal cancer that has been histologically or
cytologically confirmed

- Histologic confirmation can be obtained from the primary tumor with appropriate
imaging studies confirming metastatic spread

- No known central nervous system or brain metastasis that are either symptomatic or
untreated

- If a patient has a resection of the metastasis and is no longer symptomatic, the
patient is eligible for the study

- Patients with neurological symptoms must undergo a CT scan/MRI of the brain to
exclude brain metastasis

PATIENT CHARACTERISTICS:

- Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0, 1, or 2

- Life expectancy ≥ 3 months

- Absolute neutrophil count (ANC) ≥ 1,500/mm^3

- Peripheral platelet count (PLT) ≥ 100,000/mm^3

- Hemoglobin (HgB) > 9.0 g/dL

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

- Aspartate transaminase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver
involvement)

- Alkaline phosphatase ≤ 3 x ULN (≤ 5 x ULN for patients with liver involvement)

- Creatinine ≤ 1.5 x ULN

- No calculated creatinine clearance < 60 mL/minute

- NOTE: If calculated creatinine clearance does not meet eligibility requirement,
a 24-hour urine can be collected for a creatinine clearance, and the patient can
be enrolled if measured creatinine clearance ≥ 60 mL/minute.

- INR < 1.5 x ULN unless patients are receiving anti-coagulation therapy

- Patients receiving prophylactic anti-coagulation therapy with an agent such as
warfarin or heparin are allowed to participate if INR ≤ 3.0

- UPC ratio < 1 or urine dipstick < 2+

- NOTE: Urine protein must be screened by urine analysis for urine protein
creatinine (UPC) ratio or by dipstick. For UPC ratio ≥ 1.0 or urine dipstick ≥
2+, 24-hour urine protein must be obtained and the level should be < 1,000 mg.

- No men of childbearing potential who are unwilling to employ adequate contraception
during and for 6 months after the last dose of bevacizumab

- Ability to complete questionnaire(s) by themselves or with assistance

- Willing to provide mandatory blood samples for correlative research purposes

- No co-morbid systemic illnesses or other severe concurrent disease that, in the
judgment of the investigator, would make the patient inappropriate for entry into
this study or interfere significantly with the proper assessment of the safety and
adverse events of the prescribed regimens

- No immunocompromised patients (other than that related to the use of corticosteroids)
including patients known to be HIV positive with CD4 < 100 cells/uL

- No uncontrolled intercurrent illness including, but not limited to:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness/social situations that would limit compliance with study
requirements

- No other active malignancy ≤ 3 years prior to randomization EXCEPT for nonmelanotic
skin cancer or carcinoma-in-situ of the cervix

- No New York Heart Association (NYHA) classification III or IV congestive heart
failure

- No inadequately controlled hypertension (systolic blood pressure of > 150 mm Hg or
diastolic blood pressure > 100 mm Hg on anti-hypertensive medications)

- No significant traumatic injury ≤ 28 days prior to randomization

- No active or recent hemoptysis (≥ ½ teaspoon of bright red blood per episode) ≤ 30
days prior to randomization

- No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess ≤ 6 months prior to randomization

- No serious non-healing wound, active ulcer, or untreated bone fracture

- NOTE: Patients with fractures secondary to metastatic disease are eligible after
appropriate radiotherapy.

- No history of hypertensive crisis or hypertensive encephalopathy

- No patient that has experienced any arterial thromboembolic events including, but not
limited to:

- Myocardial infarction

- Stroke

- Transient ischemic attack (TIA)

- Cerebrovascular accident

- Unstable angina ≤ 6 months prior to randomization

- Congestive heart failure requiring use of ongoing maintenance therapy for
life-threatening ventricular arrhythmias

- No significant vascular disease (e.g., aortic aneurysm, aortic dissection) or recent
peripheral arterial thrombosis ≤ 6 months prior to randomization

- No evidence or history of bleeding diathesis (greater than normal risk of bleeding),
coagulopathy (in the absence of therapeutic anticoagulation), or hemorrhage/bleeding
event > grade 3 ≤ 4 weeks prior to randomization

- No known hypersensitivity to any of the components of 5-fluorouracil/leucovorin,
capecitabine, oxaliplatin, or bevacizumab

- No clinically significant peripheral neuropathy at the time of randomization (defined
in the NCI Common Terminology Criteria for Adverse Events [CTCAE] v4.0 as ≥ grade 2
neurosensory or neuromotor toxicity)

PRIOR CONCURRENT THERAPY:

- No prior chemotherapy, radiation therapy, immunotherapy, or biological therapy for
recurrent or metastatic colorectal cancer

- NOTE: Prior chemotherapy or radiotherapy is permitted if they had been
administered as adjuvant or neoadjuvant therapy and a complete surgical
resection of the original colorectal cancer had been achieved.

- No progressive disease ≤ 12 months of completing oxaliplatin-containing adjuvant
therapy

- No prior radiation to > 30% of the bone marrow at any time

- No major surgical procedures or open biopsy ≤ 28 days prior to randomization or
anticipation of need for elective or planned major surgical procedure during the
course of the study

- No core biopsy or other minor surgical procedures ≤ 7 days prior to randomization

- NOTE: Placement of a vascular access device is allowed.

- If there is a history of prior malignancy, patients must not be receiving other
specific treatment (other than hormonal therapy) for this prior cancer

- Not receiving any other investigational agent which would be considered as a
treatment for the primary neoplasm

- Patients receiving full-dose anticoagulants are eligible provided the patient has
been on a stable dose, for at least 2 weeks, of low molecular weight heparin or
warfarin and has an INR range 2-3

- No aspirin doses > 325 mg daily