Panitumumab and Chemotherapy in Patients With Advanced Colorectal Cancer After Prior Therapy With Bevacizumab

PRIMARY OBJECTIVES:

I. To determine the median progression-free survival in patients treated with leucovorin
calcium, fluorouracil, and irinotecan hydrochloride (FOLFIRI) and panitumumab for K-ras and
NRAS wild-type, metastatic colorectal carcinoma who have already progressed on FOLFIRI +
Bevacizumab.

SECONDARY OBJECTIVES:

I. To determine the frequency and severity of toxicities of the regimens. II. To determine
overall response rate. III. To determine the median overall survival and the overall survival
rate at 1 year.

OUTLINE:

Patients receive panitumumab intravenously (IV) over 60-90 minutes, leucovorin calcium IV
over 90 minutes, fluorouracil IV continuously over 46 hours, and irinotecan hydrochloride IV
over 90 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease
progression or unacceptable toxicity.

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

Inclusion Criteria:

- Patients with advanced adenocarcinoma of the colon or rectum not curable with surgery
or radiotherapy and have been previously treated for their disease with FOLFIRI plus
bevacizumab in the first line metastatic setting; patients will only be eligible if
their last line of therapy prior to enrolling onto the study was FOLFIRI and
bevacizumab received no more than 6 months prior to enrolling in this study; they
should have been treated with FOLFIRI plus bevacizumab until disease progression is
radiographically documented

- Patients' tumors will need to tested for the K-RAS and N-RAS mutation status; only
those patients with wild-type or unmutated K-RAS and N-RAS oncogene are eligible to
participate in this study

- Provide written informed consent prior to study-specific screening procedures, with
the understanding that the patient has the right to withdraw from the study at any
time, without prejudice

- Prior cetuximab is allowed in the adjuvant but not in the metastatic setting, but must
have been completed at least 6 months before starting this trial

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1

- Life expectancy greater than 12 weeks

- No active brain metastasis; previously surgically treated or irradiated lesions are
allowed if not clinically active

- Has a negative serum pregnancy test within 7 days prior to registration (female
patients of childbearing potential)

- Ability to understand and willingness to sign a written informed consent

- No history of severe reactions to fluorouracil (5-FU), irinotecan (irinotecan
hydrochloride), or a monoclonal antibody

- Leukocytes >= 3000/uL

- Absolute neutrophil count >= 1500/uL

- Platelets >= 100,000/uL

- Hemoglobin >= 9 mg/dL

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

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 X ULN (or < 5 x
ULN with liver metastases)

- Creatinine clearance (CrCl) >= 30 ml/min (Cockroft-Gault equation)

- Magnesium >= lower limit of normal

- Measurable disease is required according to Response Evaluation Criteria in Solid
Tumors (RECIST) 1.1 criteria

- The effects of Panitumumab on the developing human fetus are unknown; for this reason
and because monoclonal antibodies as well as other therapeutic agents used in this
trial are known to be teratogenic, women of child-bearing potential and men must agree
to use adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry and for the duration of study participation and up to
6 months after completing therapy; should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her treating physician
immediately

Exclusion Criteria:

- Pregnant or lactating women; women of childbearing potential with either a positive or
no pregnancy test at baseline; woman or men of childbearing potential not using a
reliable and appropriate contraceptive method; (postmenopausal woman must have been
amenorrheic for at least 12 months to be considered of non-childbearing potential)

- Sexually active males unwilling to practice contraception during the study and 6
months beyond

- Uncontrolled intercurrent illness including but not limited to clinically significant
cardiac disease not well controlled with medication (e.g. congestive heart failure,
symptomatic coronary artery disease and cardiac arrhythmias) or myocardial infarction
within the last 12 months, and serious concurrent infections

- History of interstitial lung disease (eg, pneumonitis or pulmonary fibrosis) or
evidence of interstitial lung disease on baseline chest computed tomography (CT) scan

- KRAS or NRAS mutant tumors

- Active inflammatory bowel disease or other bowel disease causing chronic diarrhea
(defined as >= Common Toxicity Criteria [CTC] grade 2 [Common Terminology Criteria for
Adverse Events (CTCAE) version 4.0])

- Clinically significant cardiovascular disease (including myocardial infarction,
unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac
arrhythmia) =< 1 year

- Bevacizumab within the last 4 weeks before starting treatment on trial

- Patient is more than 6 months since the last dose of FOLFIRI

- Patients who have required toxicity related dose reductions of no less than 50% of the
original dose of infusional 5-FU and/or irinotecan during the administration of
FOLFIRI + bevacizumab

- Prior exposure to panitumumab in any setting

- Prior exposure to cetuximab in the metastatic (stage IV) setting

- Radiotherapy =< 14 days prior to enrollment; patients must have recovered from all
radiotherapy-related toxicities

- Prior unanticipated severe reaction to fluoropyrimidine therapy, or known sensitivity
to 5-fluorouracil, leucovorin (leucovorin calcium), irinotecan, or panitumumab

- Treatment for other carcinomas within the last three years, except cured non-melanoma
skin and treated in-situ cervical cancer

- Participation in any investigational drug study within 4 weeks preceding the start of
study treatment

- Other serious uncontrolled medical conditions that the investigator feels might
compromise study participation

- Major surgery within 4 weeks of the start of study treatment, without complete
recovery

- Unwillingness to give written informed consent

- Unwillingness to participate or inability to comply with the protocol for the duration
of the study

- Patients with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome
(AIDS) and those severely immunocompromised will be excluded; however, no patients
will be tested for HIV