a phase 1-2 trial of cetuximab in combination with oxaliplatin, capecitabine, and radiation therapy followed by surgery for locally-advanced rectal cancer

Conditions: Rectal Cancer; Colo-rectal Cancer

Summary: 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