Cetuximab, Cisplatin, Fluorouracil, and Radiation Therapy in Treating Patients With Anal Cancer

OBJECTIVES:

Primary Objective:

- Determine whether the addition of cetuximab to combined modality therapy (CMT)
comprising cisplatin, fluorouracil, and radiotherapy reduces the local failure rate by ≥
50% at 3 years (compared with historical data) in immunocompetent patients with stage
I-III invasive anal carcinoma.

Secondary Objectives:

- Determine objective response rate (complete and partial), progression-free survival,
colostomy-free survival, and overall survival.

- Determine the overall toxicity of concurrent cisplatin, fluorouracil, and radiation
therapy combined with cetuximab.

Exploratory Objectives:

- Evaluate the effect of cetuximab and CMT on anogenital herpes papilloma virus (HPV)
infection and anal cytology.

- Evaluate whether moderate to strong expression of epidermal growth factor receptor,
Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), and P-Akt (as determined by
immunohistochemistry) is associated with an increased risk of local failure.

OUTLINE: This is a multicenter study with two sequential arms. Arm I was closed to accrual as
of 11/3/2008, and arm II opened to accrual on 8/18/2009. Patients are assigned to 1 of the 2
treatment arms.

- Arm I (closed to accrual as of 11/3/2008): Patients receive cisplatin intravenously (IV)
over 60 minutes on days 1, 29, 57, and 85 and fluorouracil IV continuously over 96 hours
on days 1-4, 29-32, 57-60, and 85-88. Patients also receive cetuximab IV over 120
minutes on day 50 and then IV over 60 minutes on days 57, 64, 71, 78, 85, 92, and 99 and
undergo radiotherapy once daily 5 days a week for 5 weeks, beginning on day 57.

- Arm II (open to accrual on 8/18/2009): Patients receive cetuximab IV over 120 minutes on
day 1 and then IV over 60 minutes on days 8, 15, 22, 29, 36, 43, and 50. Patients also
receive cisplatin IV over 60 minutes on days 8 and 36, fluorouracil IV continuously over
96 hours on days 8-11 and 36-39, and undergo radiotherapy once daily 5 days a week for 5
weeks beginning on day 8.

After completion of study treatment, patients are followed periodically for up to 10 years.

PROJECTED ACCRUAL: A total of 62 patients will be accrued for this study.

INCLUSION CRITERIA:

- Histologically confirmed anal canal or perianal (anal margin) squamous cell carcinoma

- Stage I-IIIB (closed to accrual as of 11/3/2008)

- Stage II (T3, N0 only), IIIA, or IIIB

- Tumors of nonkeratinizing histology, such as basaloid, transitional cell, or
cloacogenic histology, allowed

- No well-differentiated stage I anal margin cancer

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Hemoglobin ≥ 10 g/dL

- Platelet count ≥ 100,000/mm^3

- Absolute neutrophil count > 1,500/mm^3

- Creatinine ≤ 1.5 times upper limit of normal (ULN) OR creatinine clearance > 60 mL/min

- Bilirubin ≤ 2 times ULN

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 times ULN

- Negative pregnancy test

- Fertile patients must use effective contraception during and for ≥ 3 months after
completion of study treatment

- No other malignancies except nonmelanomatous skin cancer

- Prior malignancies must be in remission for ≥ 5 years

- Patients with a known risk factor for human immunodeficiency virus (HIV) infection
must undergo HIV testing within 90 days before study entry AND must be HIV negative by
antibody detection, culture, or quantitative assay of plasma HIV ribonucleic acid
(RNA)

EXCLUSION CRITERIA:

- Presence of the following conditions within the past 6 months:

- Active infection

- Uncontrolled diabetes

- New York Heart Association class II-IV congestive heart failure

- Cerebrovascular accident

- Transient ischemic attack

- Uncontrolled hypertension

- Unstable angina

- Myocardial infarction

- History of rheumatic disorders, irritable bowel syndrome, or inflammatory bowel
disease

- Known HIV positivity

- Known risk factors for HIV infection

- Prior radiotherapy or chemotherapy for this malignancy

- Prior pelvic radiotherapy

- Prior potentially curative surgery (i.e., abdominal or peritoneal resection) for anal
cancer

- Pregnant or nursing