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

Study Overview
=================
Brief Summary
-----------------
The objectives of this study are to: To assess dose-limiting toxicities (DLTs) of capecitabine +/- oxaliplatin in a combination regimen with capecitabine and radiotherapy (Phase 1) To determine the maximum-tolerated dose (MTD) when capecitabine oxaliplatin in a combination regimen with capecitabine and radiotherapy (Phase 1) To determine the pathologic response rate of cetuximab +/- oxaliplatin in combination with capecitabine and radiotherapy (Phase 2)

Detailed Description
-----------------
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 Assess dose-limiting toxicities (DLTs) and 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.

Official Title
-----------------
A Phase 1-2 Trial of Cetuximab in Combination With Oxaliplatin, Capecitabine, and Radiation Therapy Followed by Surgical Resection for Locally-Advanced Rectal Cancer

Conditions
-----------------
Rectal Cancer, Colo-rectal Cancer

Intervention / Treatment
-----------------
* Drug: Cetuximab
* Drug: Oxaliplatin
* Drug: Capecitabine
* Radiation: Radiotherapy
* Drug: Diphenhydramine hydrochloride (HCl)


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Sequential design for 4 dose combinations (arms) through phase 1
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100<br>Cetuximab 250 mg/m² / week Capecitabine 800 mg/m² Radiotherapy (XRT) Oxaliplatin 100 mg/m², Days 2 and 23 | Drug: Cetuximab<br>* Cetuximab is a chimeric anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody, administered via a intravenous (IV) infusion at 400 mg/m² (initial loading dose) or 250 mg/m² (weekly dose). Dosage is based on m² of body surface area (BSA)<br>* Other names: IMC-C225;Drug: Oxaliplatin<br>* Oxaliplatin is a cancer medication used to treat colorectal cancer, and is administered on Days 2 and 23.<br>* Other names: Eloxatin;Drug: Capecitabine<br>* Capecitabine is a cancer medication, and is administered based on m² of body surface area (BSA) delivered in equivalent morning and evening doses<br>* Other names: Xeloda;Radiation: Radiotherapy<br>* Radiotherapy is administered on weekdays in 180 centigray fractions (doses), for 28 total fractions delivering a total dose of 5040 centigray (cGy)<br>* Other names: XRT;Drug: Diphenhydramine hydrochloride (HCl)<br>* Diphenhydramine HCl 50 mg (or equivalent) is administered as a per-medication for cetuximab<br>* Other names: Sominex;|
| Experimental: Group 2 - Cetuximab + Capecitabine-700 + XRT + Oxaliplatin-85<br>Cetuximab 250 mg/m² / week Capecitabine 700 mg/m² Radiotherapy (XRT) Oxaliplatin 85 mg/m², Days 2 and 23 | Drug: Cetuximab<br>* Cetuximab is a chimeric anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody, administered via a intravenous (IV) infusion at 400 mg/m² (initial loading dose) or 250 mg/m² (weekly dose). Dosage is based on m² of body surface area (BSA)<br>* Other names: IMC-C225;Drug: Oxaliplatin<br>* Oxaliplatin is a cancer medication used to treat colorectal cancer, and is administered on Days 2 and 23.<br>* Other names: Eloxatin;Drug: Capecitabine<br>* Capecitabine is a cancer medication, and is administered based on m² of body surface area (BSA) delivered in equivalent morning and evening doses<br>* Other names: Xeloda;Radiation: Radiotherapy<br>* Radiotherapy is administered on weekdays in 180 centigray fractions (doses), for 28 total fractions delivering a total dose of 5040 centigray (cGy)<br>* Other names: XRT;Drug: Diphenhydramine hydrochloride (HCl)<br>* Diphenhydramine HCl 50 mg (or equivalent) is administered as a per-medication for cetuximab<br>* Other names: Sominex;|
| Experimental: Group A - Cetuximab + Capecitabine-800 + XRT<br>Cetuximab 250 mg/m² / week Capecitabine 800 mg/m² Radiotherapy (XRT) | Drug: Cetuximab<br>* Cetuximab is a chimeric anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody, administered via a intravenous (IV) infusion at 400 mg/m² (initial loading dose) or 250 mg/m² (weekly dose). Dosage is based on m² of body surface area (BSA)<br>* Other names: IMC-C225;Drug: Capecitabine<br>* Capecitabine is a cancer medication, and is administered based on m² of body surface area (BSA) delivered in equivalent morning and evening doses<br>* Other names: Xeloda;Radiation: Radiotherapy<br>* Radiotherapy is administered on weekdays in 180 centigray fractions (doses), for 28 total fractions delivering a total dose of 5040 centigray (cGy)<br>* Other names: XRT;Drug: Diphenhydramine hydrochloride (HCl)<br>* Diphenhydramine HCl 50 mg (or equivalent) is administered as a per-medication for cetuximab<br>* Other names: Sominex;|
| Experimental: Group B - Cetuximab + Capecitabine-1000 + XRT<br>Cetuximab 250 mg/m² / week Capecitabine 1000 mg/m² Radiotherapy (XRT) | Drug: Cetuximab<br>* Cetuximab is a chimeric anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody, administered via a intravenous (IV) infusion at 400 mg/m² (initial loading dose) or 250 mg/m² (weekly dose). Dosage is based on m² of body surface area (BSA)<br>* Other names: IMC-C225;Drug: Capecitabine<br>* Capecitabine is a cancer medication, and is administered based on m² of body surface area (BSA) delivered in equivalent morning and evening doses<br>* Other names: Xeloda;Radiation: Radiotherapy<br>* Radiotherapy is administered on weekdays in 180 centigray fractions (doses), for 28 total fractions delivering a total dose of 5040 centigray (cGy)<br>* Other names: XRT;Drug: Diphenhydramine hydrochloride (HCl)<br>* Diphenhydramine HCl 50 mg (or equivalent) is administered as a per-medication for cetuximab<br>* Other names: Sominex;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting Toxicity (DLT) - Number of DLTs by Treatment Group | Dose-limiting Toxicity (DLT) is the measure used to establish overall Maximum-tolerated dose (MTD) of cetuximab + capecitabine + radiotherapy +/- oxaliplatin. MTD is defined as the highest dose level for which participants have a < 30% incidence of dose-limiting toxicity (DLT). The outcome is expressed as the number of DLTs by treatment group. | 10 weeks | 
| Dose-limiting Toxicity (DLT) - Number of Participants Affected | Dose-limiting Toxicity (DLT) is the measure used to establish overall Maximum-tolerated dose (MTD) of cetuximab + capecitabine + radiotherapy +/- oxaliplatin. MTD is defined as the highest dose level for which participants have a < 30% incidence of dose-limiting toxicity (DLT). The outcome is expressed as the number of participants experiencing a DLT. | 10 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic Response Rate | After treatment with capecitabine, cetuximab, radiotherapy, and oxaliplatin, the pathologic response rate was assessed based on the excised tumor taken at the time of surgical resection. Pathologic response rate was determined as the number and proportion of participants who experienced either downstaging of their disease, or complete response (CR, no detectable disease). A participant will be considered to have downstaging of the tumor as a result of the neoadjuvant therapy when the primary tumor (T) stage by pathology isless than the T stage by clinical (endoscopic) evaluation, or when the regional lymph node (N) tumor stage by pathology is less than the N stage by clinical (endoscopic) evaluation. | 12 to 14 weeks after radiotherapy | 
| Tumor Downstaging at Surgical Resection | Downstaging means a reduction from the stage of disease observed at baseline to the stage of disease after treatment with cetuximab, radiotherapy, oxaliplatin, and capecitabine, as determined at the time of surgical removal of the tumor. Downstaging may be observed as improvements in tumor staging at the primary site of the tumor; in nearby (regional) lymph nodes; or in metastatic disease beyond the regional lymph nodes. This outcome specifically does not include participants that achieved a complete response, nor those that experienced no response or disease progression. | 12 to 14 weeks after radiotherapy | 
| Time-to-Progression (TTP) | Time-to-progression was assessed as the time from the date of surgical resection to the appearance of either local disease recurrence or distant metastases by any modality (eg, clinical exam, endoscopy, radiographic imaging). All relapses were to be confirmed by biopsy and pathology review. | 5 years | 
| Overall Survival (OS) | Overall Survival (OS) was assessed as the mean survival from the date of entry on study though 72 months. | 72 months | 
| Survival at 5 Years | Survival at 5 years was assessed as the number of participants alive 5 years after starting treatment. | 5 years |