5-FU Based Maintenance Therapy in RAS Wild Type Metastatic Colorectal Cancer After Induction With FOLFOX Plus Panitumumab

PRIMARY OBJECTIVES:

I. To compare the duration of progression free survival 1 (PFS1) in patients with RAS wild
type who have received induction leucovorin calcium, fluorouracil, and oxaliplatin (FOLFOX) +
panitumumab and not progressed at 6 cycles and randomized to maintenance therapy with
fluorouracil (5FU) based therapy with or without panitumumab.

SECONDARY OBJECTIVES:

I. To compare the response rate (RR) in patients with RAS wild type who are randomized to
maintenance therapy with 5FU based therapy to those randomized to 5FU based therapy with
panitumumab.

TERTIARY OBJECTIVES:

I. Progress free survival 2 (PFS2). II. To assess the adverse event (AE) profile and safety
of the proposed treatment in this population.

III. To assess and compare the overall survival (OS) between the two treatment groups.

IV. To compare the quality of life (QOL) as measured by health state index (HIS) between
patients who achieve partial response (PR) versus (vs.) those who progress and those who have
stable disease during the induction phase.

V. To compare the QOL as measured by HSI between the two groups randomized to maintenance
therapy.

VI. To assess the evolution of RAS mutation under treatment during induction phase as well as
maintenance.

VII. To explore relationship between genomic and proteomic alterations of the tumor with
response and PFS to panitumumab.

OUTLINE:

INDUCTION:

Patients receive panitumumab intravenously (IV) over 30-60 minutes, oxaliplatin IV over 2
hours, leucovorin calcium IV, and fluorouracil over 46-48 hours on day 1. Treatment repeats
every 14 days for up to 6 courses in the absence of disease progression or unacceptable
toxicity.

MAINTENANCE: Patients who are not candidates for surgery, have no disease progression, or do
not have complete response after Induction are randomized to 1 of 2 arms.

ARM I: Patients receive panitumumab IV over 30 minutes, leucovorin calcium IV, and
fluorouracil over 46-48 hours on day 1. Courses repeat every 14 days in the absence of
disease progression or unacceptable toxicity.

ARM II: Patients receive capecitabine orally (PO) twice daily (BID) on days 1-21. Courses
repeat every 21 days in the absence of disease progression or unacceptable toxicity.

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

Inclusion Criteria:

- Metastatic or locally advanced (unresectable) colorectal cancer with histological
confirmation of adenocarcinoma (patients with or without measurable disease by imaging
are eligible)

- No prior systemic chemotherapy for metastatic disease; subjects who received adjuvant
therapy with FOLFOX and at the time of recurrence are at least 6 months away from last
chemotherapy are eligible for this study

- At the time of randomization to maintenance therapy only patients who didn't progress
by Response Evaluation Criteria in Solid Tumors (RECIST) criteria are eligible;
patients with complete response (CR) and those who are candidates for resection will
not be eligible for randomization to maintenance therapy, subjects who undergo surgery
potentially have curable disease with defined duration of treatment and use of EGFR in
the adjuvant setting is deemed to be detrimental in these population; likelihood of
achieving CR is low and standard of care in this unique patient population is not well
defined

- Provide written informed consent

- RAS wild‐type tumor

- Negative serum or urine pregnancy test done =< 7 days prior to registration, for women
of childbearing potential only

- Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0 or 1

- Total serum bilirubin =< institutional upper limit of normal (ULN)

- Absolute neutrophil count (ANC) >= 1500/mm^3

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

- Hemoglobin >= 9.0 g/dL (hemoglobin may be supported by transfusion)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN (=< 5
x ULN for subjects with liver involvement of their cancer)

- Creatinine within institutional limits of normal OR creatinine clearance > 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- Magnesium >= lower limit of normal

- Willing to provide tissue and blood samples for mandatory correlative and research
purposes

Exclusion Criteria:

- Patients who are candidates for upfront metastasectomy (defined as those with limited
liver metastatic disease) are not eligible for this study; the candidacy for
resectability can be determined by the treating physician and or local surgeon; in
ambiguous situations, please discuss the case with the principle investigator (PI)

- Known or suspected brain or central nervous system (CNS) metastases

- Active, uncontrolled infection, including hepatitis B, hepatitis C

- Patients with history of interstitial lung disease/pulmonary fibrosis

- Concurrent anti‐cancer therapy, including chemotherapy agents, targeted agents, or
biological agents not otherwise specified in this protocol

- Radiation therapy =< 2 weeks prior to randomization

- Any of the following

- Pregnant or nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception

- Co‐morbid systemic illnesses or other severe concurrent disease, history of any
psychiatric or addictive disorder, or laboratory abnormality, which, in the judgment
of the investigator, would make the patient inappropriate for entry into this study or
interfere significantly with the proper assessment of safety and toxicity of the
prescribed regimens

- Patients known to be human immunodeficiency virus (HIV) positive

- Uncontrolled intercurrent illness whom in the opinion of the investigator, may
increase the risks associated with study participation or study treatment, or may
interfere with the conduct of the study or the interpretation of the study results

- Receiving any other investigational agent, which would be considered as a treatment
for the primary neoplasm

- Other active malignancy =< 3 years prior to registration; exceptions are: nonmelanoma
skin cancer or carcinoma‐in‐situ of the cervix that has been treated

- History of prior malignancy for which patient is receiving other specific treatment
for their cancer

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to study drugs