A Phase 1-2 Trial of Cetuximab in Combination With Oxaliplatin, Capecitabine, and Radiation Therapy Followed by Surgery for Locally-advanced Rectal Cancer

The objectives of this study are to:

1. To assess dose-limiting toxicities (DLTs) of capecitabine +/- oxaliplatin in a combination regimen with capecitabine and radiotherapy (Phase 1)
2. To determine the maximum-tolerated dose (MTD) when capecitabine

   * oxaliplatin in a combination regimen with capecitabine and radiotherapy (Phase 1)
3. To determine the pathologic response rate of cetuximab +/- oxaliplatin in combination with capecitabine and radiotherapy (Phase 2)

Part of the treatment plan for this study is surgical removal of the tumor that is planned to occur 6 to 8 weeks after completion of radiotherapy (XRT). This study consists of 2 distinct phases (Phase 1 and Phase 2).

In Phase 1, the objectives are to

1. Assess dose-limiting toxicities (DLTs) and
2. Determine a maximum-tolerated dose (MTD)

The Phase 1 endpoints are assessed on an initial cohort of patients after the completion of the chemo-radiotherapy regimen at defined timepoints that precede surgery.

Phase 2 is the efficacy assessment portion of this study. In Phase 2, the objective is to accrue an expansion cohort. Efficacy assessments for phase 2 are to be assessed across all study participants at the time of, or after, surgery, as measured by the pathologic response rate; downstaging; and survival at 5 years from the start of treatment.

Eligibility Criteria:
INCLUSION CRITERIA

* Histologically-confirmed adenocarcinoma of the rectum. Clinical stages T3; T4; or N1 as determined by endoscopic ultrasound; or a rectal CT or MRI scan are eligible, including T3 N0; T3 N1; T4 N0; T4 N1; T1-4 N1. Rectal cancers are defined as those whose distal border extends to within 12 cm of the anal verge.
* Age ≥ 18
* Karnofsky performance status (KPS) ≥ 70
* Leukocyte count \> 3,500 x 10e6/µL
* Platelet count \> 100,000/µL
* Serum glutamic-oxaloacetic transaminase (SGOT) \< 2.5 x institutional upper limits of normal (ULN)
* Serum glutamic-pyruvic transaminase (SGPT) \< 2.5 x ULN
* Alkaline phosphatase \< 2.5 x ULN
* Total bilirubin \< 1.5x ULN
* Creatinine:

  * Within normal institutional limits
  * OR
  * Creatinine clearance \> 60 mL/min/1.73 m2 (if serum creatinine levels above institutional normal)
* Ability to swallow pills without difficulty
* Women of child-bearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG), within 72 hours prior to the start of study medication
* Women of child-bearing potential must be using an adequate method of contraception to avoid pregnancy throughout the treatment

EXCLUSION CRITERIA

* Metastatic (M1) or stage IV disease
* Prior history of treatment with cetuximab or other therapy targeting EGFR
* Prior history of anti-cancer murine monoclonal antibody therapy
* Prior pelvic or whole abdominal radiotherapy
* 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
* Patients with a concurrent malignancy or previous malignancy within 5 years of screening will be excluded from this study (EXCEPTION: concurrent or previous non-melanoma skin cancer, hematolymphoid malignancy or carcinoma in-situ of the cervix may be allowed at the investigator's discretion)
* Inability to sign written consent
* Pregnant or breastfeeding
* Unwilling or unable to use effective contraception in self or partner for the entire study period and for up to 4 weeks after the study