A Trial of Maintenance ADAPT Therapy With Capecitabine and Celecoxib in Patients With Metastatic Colorectal Cancer

PRIMARY OBJECTIVES:

I. To determine the rate of complete response 2 years following the initiation of first line
5-FU (fluorouracil) based chemotherapy in patients with initially unresected metastatic
colorectal cancer who are then treated on the activating cancer stem cells (CSCs) from
dormancy and priming them for subsequent targeting (ADAPT) protocol.

SECONDARY OBJECTIVES:

I. To determine overall survival, relapse free survival (if complete response [CR]) based on
intent to treat (ITT) analysis.

II. To determine quality of life while on ADAPT therapy.

III. To determine the effects of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-ras)
mutation status, resection and radiation on response to ADAPT therapy.

OUTLINE:

Patients proceed to surgery, radiation therapy with ADAPT therapy followed by maintenance
ADAPT therapy, or ADAPT therapy. Eligible patients undergo surgical resection at baseline or
upon achievement of resectable disease after radiation therapy.

RADIATION + ADAPT: Patients undergo radiation therapy 5 days per week and receive
capecitabine orally (PO) twice daily (BID) and celecoxib PO BID 5 days per week during
radiation.

ADAPT: Patients receive capecitabine PO BID on days 1-14 and celecoxib PO BID on days 1-21.
Courses repeat every 21 days for up to 3 years in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year,
every 4 months for 2 years, and then every 6 months for 2 years.

Inclusion Criteria:

- Histologically confirmed colorectal cancer

- Evaluable or measurable radiographic evidence of colorectal cancer

- Patients with unresected metastases from colorectal cancer; patients may be either
untreated with chemotherapy or currently receiving first-line 5-FU based chemotherapy
(folinic acid-fluorouracil-irinotecan hydrochloride [FOLFIRI], capecitabine-irinotecan
hydrochloride [CAPIRI], fluorouracil-leucovorin calcium-oxaliplatin [FOLFOX], or
capecitabine-oxaliplatin [CAPOX] with or without bevacizumab) within 10 months of
beginning ADAPT therapy with at least stable disease radiographically; patients who
received prior adjuvant chemotherapy with 5-FU, capecitabine, or FOLFOX are eligible
if adjuvant therapy was completed greater than 6 months ago

- History of histological confirmation for recurrent disease, or if recurrent disease is
not readily accessible to biopsy, must have two consecutive carcinoembryonic antigen
(CEA) or cancer antigen (CA) 19-9 increases, or positron emission tomography (PET)
avidity

- Men and women from all ethnic and racial groups

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Total bilirubin =< 1.5 x the institutional upper-normal limit (IUNL)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])
and/or alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =<
2.5 x IUNL

- Alkaline phosphatase =< 2.5 x IUNL

- Leukocytes >= 3,000/uL

- Absolute neutrophil count >= 1,000/uL

- Platelets >= 100,000/uL

- Women of childbearing potential and all men must agree to use adequate contraception
(hormonal or barrier method of birth control) prior to beginning ADAPT therapy and for
the duration of study participation

- Negative urine pregnancy test for women of childbearing potential

- Must have the ability to understand and the willingness to provide a written informed
consent to participate in the study

Exclusion Criteria:

- History of allergies to sulfonamide, aspirin, any nonsteroidal anti-inflammatory drugs
(NSAIDS), 5-FU or celecoxib

- Prior 5-FU-based adjuvant chemotherapy less than 6 months prior to beginning ADAPT
therapy and any residual neuropathy > grade 2

- Any regular use of cyclooxygenase-2 (COX-2) inhibitors as defined by 2-3 times per
week

- Use of aspirin is NOT an exclusion criterion as long as the daily dose does not exceed
325 mg daily; initiation of ADAPT therapy requires patient to discontinue aspirin for
18 months

- Pregnant or lactating women

- History of significant neurologic or psychiatric disorders, including dementia or
seizures that would impede consent, treatment, or follow up

- Any serious illness or medical condition that could affect participation on trial

- Any uncontrolled congestive heart failure New York Heart Association class III or IV

- Any uncontrolled hypertension, arrhythmia, or active angina pectoris

- Any history of major myocardial infarction, stroke or transient ischemic attack (TIA);
minor acute myocardial infarction (AMI) and patients who have had cardiac bypass free
of symptoms for at least 2 years may be eligible at the discretion of the study chair

- Serious uncontrolled active infection

- Patients with creatinine clearance: < 50 mL/min are excluded from this protocol;
capecitabine is contraindicated in severe renal impairment (clearance < 40 mL/min)

- Inability to swallow oral medications or any medical conditions that may affect
intestinal absorption of the study agent or inability to comply with oral medication

- History of active peptic ulcer disease or major upper gastrointestinal (GI) bleed < 12
months; history of GI bleeding from the colorectal cancer primary is not an exclusion
criterion

- Use of warfarin is not allowed; patient is recommended to switch to low molecular
weight heparin (LMWH) before participating in this study

- Patients with any history of brain or bone metastasis or who have developed
progressive disease on first line 5-FU based therapy

- Current use of systemic steroid medication

- Patients with an obstructive synchronous colorectal tumor requiring up-front surgery
or chemoradiation

- Patients with partial or complete bowel obstruction due to abdominal carcinomatosis