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

• Sponsor: George Albert Fisher (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00226941
• Collaborator: Bristol-Myers Squibb (Industry)
• Enrollment: 23
• Location: 1
• Arms: 4
• Duration (Months): 56
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief 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)

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

Condition or Disease	Intervention/Treatment	Phase
Rectal Cancer; Colo-rectal Cancer	Drug: Cetuximab; Drug: Oxaliplatin; Drug: Capecitabine; Radiation: Radiotherapy; Drug: Diphenhydramine hydrochloride (HCl)	Phase 1/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

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Sequential design for 4 dose combinations (arms) through phase 1Sequential design for 4 dose combinations (arms) through phase 1
• Masking: None (Open Label)
• Primary Purpose: 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
• Study Start Date: Jun 1, 2004
• Actual Primary Completion Date: Mar 1, 2008
• Actual Study Completion Date: Feb 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100 Cetuximab 250 mg/m² / week Capecitabine 800 mg/m² Radiotherapy (XRT) Oxaliplatin 100 mg/m², Days 2 and 23	Drug: Cetuximab; 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); Other Names: Erbitux C225 IMC-C225 ; Drug: Oxaliplatin; Oxaliplatin is a cancer medication used to treat colorectal cancer, and is administered on Days 2 and 23.; Other Names: Eloxatin ; Drug: Capecitabine; Capecitabine is a cancer medication, and is administered based on m² of body surface area (BSA) delivered in equivalent morning and evening doses; Other Names: Xeloda ; Radiation: Radiotherapy; Radiotherapy is administered on weekdays in 180 centigray fractions ("doses"), for 28 total fractions delivering a total dose of 5040 centigray (cGy); Other Names: XRT ; Drug: Diphenhydramine hydrochloride (HCl); Diphenhydramine HCl 50 mg (or equivalent) is administered as a per-medication for cetuximab; Other Names: Benadryl Unisom Sominex
Experimental: Group 2 - Cetuximab + Capecitabine-700 + XRT + Oxaliplatin-85 Cetuximab 250 mg/m² / week Capecitabine 700 mg/m² Radiotherapy (XRT) Oxaliplatin 85 mg/m², Days 2 and 23	Drug: Cetuximab; 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); Other Names: Erbitux C225 IMC-C225 ; Drug: Oxaliplatin; Oxaliplatin is a cancer medication used to treat colorectal cancer, and is administered on Days 2 and 23.; Other Names: Eloxatin ; Drug: Capecitabine; Capecitabine is a cancer medication, and is administered based on m² of body surface area (BSA) delivered in equivalent morning and evening doses; Other Names: Xeloda ; Radiation: Radiotherapy; Radiotherapy is administered on weekdays in 180 centigray fractions ("doses"), for 28 total fractions delivering a total dose of 5040 centigray (cGy); Other Names: XRT ; Drug: Diphenhydramine hydrochloride (HCl); Diphenhydramine HCl 50 mg (or equivalent) is administered as a per-medication for cetuximab; Other Names: Benadryl Unisom Sominex
Experimental: Group A - Cetuximab + Capecitabine-800 + XRT Cetuximab 250 mg/m² / week Capecitabine 800 mg/m² Radiotherapy (XRT)	Drug: Cetuximab; 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); Other Names: Erbitux C225 IMC-C225 ; Drug: Capecitabine; Capecitabine is a cancer medication, and is administered based on m² of body surface area (BSA) delivered in equivalent morning and evening doses; Other Names: Xeloda ; Radiation: Radiotherapy; Radiotherapy is administered on weekdays in 180 centigray fractions ("doses"), for 28 total fractions delivering a total dose of 5040 centigray (cGy); Other Names: XRT ; Drug: Diphenhydramine hydrochloride (HCl); Diphenhydramine HCl 50 mg (or equivalent) is administered as a per-medication for cetuximab; Other Names: Benadryl Unisom Sominex
Experimental: Group B - Cetuximab + Capecitabine-1000 + XRT Cetuximab 250 mg/m² / week Capecitabine 1000 mg/m² Radiotherapy (XRT)	Drug: Cetuximab; 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); Other Names: Erbitux C225 IMC-C225 ; Drug: Capecitabine; Capecitabine is a cancer medication, and is administered based on m² of body surface area (BSA) delivered in equivalent morning and evening doses; Other Names: Xeloda ; Radiation: Radiotherapy; Radiotherapy is administered on weekdays in 180 centigray fractions ("doses"), for 28 total fractions delivering a total dose of 5040 centigray (cGy); Other Names: XRT ; Drug: Diphenhydramine hydrochloride (HCl); Diphenhydramine HCl 50 mg (or equivalent) is administered as a per-medication for cetuximab; Other Names: Benadryl Unisom Sominex

Outcome Measures

Primary Outcome Measures

1. Dose-limiting Toxicity (DLT) - Number of DLTs by Treatment Group [10 weeks]

   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.

2. Dose-limiting Toxicity (DLT) - Number of Participants Affected [10 weeks]

   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.

Secondary Outcome Measures

1. Pathologic Response Rate [12 to 14 weeks after radiotherapy]

   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.

2. Tumor Downstaging at Surgical Resection [12 to 14 weeks after radiotherapy]

   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.

3. Time-to-Progression (TTP) [5 years]

   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.

4. Overall Survival (OS) [72 months]

   Overall Survival (OS) was assessed as the mean survival from the date of entry on study though 72 months.

5. Survival at 5 Years [5 years]

   Survival at 5 years was assessed as the number of participants alive 5 years after starting treatment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University School of Medicine	Stanford	California	United States	94305

Sponsors and Collaborators

• George Albert Fisher
• Bristol-Myers Squibb

Investigators

• Principal Investigator: George A Fisher, MD, PhD, Stanford University
• Study Chair: Branimir I Sikic, MD, Stanford University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: George Albert Fisher, Professor of Medicine and Colleen Haas Chair in the School of Medicine, Stanford University
• ClinicalTrials.gov Identifier: NCT00226941
• Other Study ID Numbers: IRB-12426; COR0001; 95054
• First Posted: Sep 27, 2005
• Last Update Posted: Dec 8, 2017
• Last Verified: Nov 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Rectal Neoplasms; Diphenhydramine; Promethazine; Capecitabine; Oxaliplatin; Cetuximab

Study Results

Participant Flow

Arm/Group Title	Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100	Group 2 - Cetuximab + Capecitabine-700 + XRT + Oxaliplatin-85	Group A - Cetuximab + Capecitabine-800 + XRT	Group B - Cetuximab + Capecitabine-1000 + XRT
Arm/Group Description	Cetuximab 250 mg/m² / week Capecitabine 800 mg/m² Radiotherapy (XRT) Oxaliplatin 100 mg/m², Days 2 and 23	Cetuximab 250 mg/m² / week Capecitabine 700 mg/m² Radiotherapy (XRT) Oxaliplatin 85mg/m², Days 2 and 23	Cetuximab 250 mg/m² / week Capecitabine 1000 mg/m² Radiotherapy (XRT)	Cetuximab 250 mg/m² / week Capecitabine 1000 mg/m² Radiotherapy (XRT)
Period Title: Overall Study
STARTED	6	6	4	7
COMPLETED	6	6	4	5
NOT COMPLETED	0	0	0	2

Baseline Characteristics

Arm/Group Title	Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100	Group 2 - Cetuximab + Capecitabine-700 + XRT + Oxaliplatin-85	Group A - Cetuximab + Capecitabine-800 + XRT	Group B - Cetuximab + Capecitabine-1000 + XRT	Total
Arm/Group Description	Cetuximab 250 mg/m² / week Capecitabine 800 mg/m² Radiotherapy (XRT) Oxaliplatin 100 mg/m², Days 2 and 23	Cetuximab 250 mg/m² / week Capecitabine 700 mg/m² Radiotherapy (XRT) Oxaliplatin 85 mg/m², Days 2 and 23	Cetuximab 250 mg/m² / week Capecitabine 800 mg/m² Radiotherapy (XRT)	Cetuximab 250 mg/m² / week Capecitabine 1000 mg/m² Radiotherapy (XRT)	Total of all reporting groups
Overall Participants	6	6	4	7	23
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	5 83.3%	6 100%	4 100%	5 71.4%	20 87%
>=65 years	1 16.7%	0 0%	0 0%	2 28.6%	3 13%
Sex: Female, Male (Count of Participants)
Female	1 16.7%	2 33.3%	0 0%	2 28.6%	5 21.7%
Male	5 83.3%	4 66.7%	4 100%	5 71.4%	18 78.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	1 14.3%	1 4.3%
Not Hispanic or Latino	6 100%	6 100%	4 100%	6 85.7%	22 95.7%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	1 16.7%	0 0%	0 0%	1 14.3%	2 8.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%
White	4 66.7%	6 100%	4 100%	5 71.4%	19 82.6%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	1 16.7%	0 0%	0 0%	1 14.3%	2 8.7%
Histology (Count of Participants)
Adenocarcinoid Tumor	0 0%	0 0%	1 25%	4 57.1%	5 21.7%
Adenocarcinoma, Nos	6 100%	6 100%	2 50%	3 42.9%	17 73.9%
Adenosarcoma	0 0%	0 0%	1 25%	0 0%	1 4.3%

Outcome Measures

1. Primary Outcome

Title	Dose-limiting Toxicity (DLT) - Number of DLTs by Treatment Group
Description	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.
Time Frame	10 weeks

Outcome Measure Data

Analysis Population Description

All participants were formally part of the phase 1 portion of this study.

Arm/Group Title	Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100	Group 2 - Cetuximab + Capecitabine-700 + XRT + Oxaliplatin-85	Group A - Cetuximab + Capecitabine-800 + XRT	Group B - Cetuximab + Capecitabine-1000 + XRT
Arm/Group Description	Cetuximab 250 mg/m² / week Capecitabine 800 mg/m² Radiotherapy (XRT) Oxaliplatin 100 mg/m², Days 2 and 23	Cetuximab 250 mg/m² / week Capecitabine 700 mg/m² Radiotherapy (XRT) Oxaliplatin 85 mg/m², Days 2 and 23	Cetuximab 250 mg/m² / week Capecitabine 800 mg/m² Radiotherapy (XRT)	Cetuximab 250 mg/m² / week Capecitabine 1000 mg/m² Radiotherapy (XRT)
Measure Participants	6	6	4	7
Number [DLTs]	10	2	0	0

2. Primary Outcome

Title	Dose-limiting Toxicity (DLT) - Number of Participants Affected
Description	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.
Time Frame	10 weeks

Outcome Measure Data

Analysis Population Description

All participants were formally part of the phase 1 portion of this study.

Arm/Group Title	Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100	Group 2 - Cetuximab + Capecitabine-700 + XRT + Oxaliplatin-85	Group A - Cetuximab + Capecitabine-800 + XRT	Group B - Cetuximab + Capecitabine-1000 + XRT
Arm/Group Description	Cetuximab 250 mg/m² / week Capecitabine 800 mg/m² Radiotherapy (XRT) Oxaliplatin 100 mg/m², Days 2 and 23	Cetuximab 250 mg/m² / week Capecitabine 700 mg/m² Radiotherapy (XRT) Oxaliplatin 85mg/m², Days 2 and 23	Cetuximab 250 mg/m² / week Capecitabine 1000 mg/m² Radiotherapy (XRT)	Cetuximab 250 mg/m² / week Capecitabine 1000 mg/m² Radiotherapy (XRT)
Measure Participants	6	6	4	7
Count of Participants [Participants]	4 66.7%	2 33.3%	0 0%	0 0%

3. Secondary Outcome

Title	Pathologic Response Rate
Description	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.
Time Frame	12 to 14 weeks after radiotherapy

Outcome Measure Data

Analysis Population Description

This outcome is specifically defined per protocol as the phase 2 portion of the study, which did not occur. However, the data for this measure are available from the phase 1 participants (only), and are provided for completeness.

Arm/Group Title	Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100	Group 2 - Cetuximab + Capecitabine-700 + XRT + Oxaliplatin-85	Group A - Cetuximab + Capecitabine-800 + XRT	Group B - Cetuximab + Capecitabine-1000 + XRT
Arm/Group Description	Cetuximab 250 mg/m² / week Capecitabine 800 mg/m² Radiotherapy (XRT) Oxaliplatin 100 mg/m², Days 2 and 23	Cetuximab 250 mg/m² / week Capecitabine 700 mg/m² Radiotherapy (XRT) Oxaliplatin 85 mg/m², Days 2 and 23	Cetuximab 250 mg/m² / week Capecitabine 800 mg/m² Radiotherapy (XRT)	Cetuximab 250 mg/m² / week Capecitabine 1000 mg/m² Radiotherapy (XRT)
Measure Participants	5	6	4	5
Count of Participants [Participants]	4 66.7%	5 83.3%	3 75%	5 71.4%

4. Secondary Outcome

Title	Tumor Downstaging at Surgical Resection
Description	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.
Time Frame	12 to 14 weeks after radiotherapy

Outcome Measure Data

Analysis Population Description

This outcome is specifically defined per protocol as the phase 2 portion of the study, which did not occur. However, the data for this measure are available from the phase 1 participants (only), and are provided for completeness.

Arm/Group Title	Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100	Group 2 - Cetuximab + Capecitabine-700 + XRT + Oxaliplatin-85	Group A - Cetuximab + Capecitabine-800 + XRT	Group B - Cetuximab + Capecitabine-1000 + XRT
Arm/Group Description	Cetuximab 250 mg/m² / week Capecitabine 700 mg/m² Radiotherapy (XRT) Oxaliplatin 85 mg/m², Days 2 and 23	Cetuximab 250 mg/m² / week Capecitabine 700 mg/m² Radiotherapy (XRT) Oxaliplatin 85 mg/m², Days 2 and 23	Cetuximab 250 mg/m² / week Capecitabine 800 mg/m² Radiotherapy (XRT)	Cetuximab 250 mg/m² / week Capecitabine 1000 mg/m² Radiotherapy (XRT)
Measure Participants	5	6	4	5
Count of Participants [Participants]	4 66.7%	5 83.3%	3 75%	5 71.4%

5. Secondary Outcome

Title	Time-to-Progression (TTP)
Description	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.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

This study was terminated before all patients reached 5 years from the date of surgical resection. Only patients that progressed are reported, and since no patients progressed in Group 2, median and range are not reportable.

Arm/Group Title	Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100	Group 2 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-85	Group A - Cetuximab + Capecitabine-800 + XRT	Group B - Cetuximab + Capecitabine-1000 + XRT
Arm/Group Description	Cetuximab 250 mg/m² / week Capecitabine 800 mg/m² Radiotherapy (XRT) Oxaliplatin 100 mg/m², Days 2 and 23	Cetuximab 250 mg/m² / week Capecitabine 700 mg/m² Radiotherapy (XRT) Oxaliplatin 85 mg/m², Days 2 and 23	Cetuximab 250 mg/m² / week Capecitabine 800 mg/m² Radiotherapy (XRT)	Cetuximab 250 mg/m² / week Capecitabine 1000 mg/m² Radiotherapy (XRT)
Measure Participants	2	0	1	3
Median (Full Range) [years]	1.4	3.0	3.9

6. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall Survival (OS) was assessed as the mean survival from the date of entry on study though 72 months.
Time Frame	72 months

Outcome Measure Data

Analysis Population Description

This outcome is defined per protocol as study phase 2, which did not occur. However, data are provided for phase 1 participants, for completeness. This study was terminated before all patients reached 5 years on study. Some patients are reported as the last known alive date.

Arm/Group Title	Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100	Group 2 - Cetuximab + Capecitabine-700 + XRT + Oxaliplatin-85	Group A - Cetuximab + Capecitabine-800 + XRT	Group B - Cetuximab + Capecitabine-1000 + XRT
Arm/Group Description	Cetuximab 250 mg/m² / week Capecitabine 800 mg/m² Radiotherapy (XRT) Oxaliplatin 100 mg/m², Days 2 and 23	Cetuximab 250 mg/m² / week Capecitabine 700 mg/m² Radiotherapy (XRT) Oxaliplatin 85 mg/m², Days 2 and 23	Cetuximab 250 mg/m² / week Capecitabine 800 mg/m² Radiotherapy (XRT)	Cetuximab 250 mg/m² / week Capecitabine 1000 mg/m² Radiotherapy (XRT)
Measure Participants	6	6	4	5
Mean (Standard Deviation) [months]	59.7 (0.7)	57.0 (5.8)	54.4 (11.1)	53.7 (11.3)

7. Secondary Outcome

Title	Survival at 5 Years
Description	Survival at 5 years was assessed as the number of participants alive 5 years after starting treatment.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

This outcome is defined per protocol as study phase 2, which did not occur. However, data are available from the phase 1 participants (only), and are provided for completeness. This study was terminated before all patients reached 5 years from study entry. Only patients known to be alive at 5 years are reported.

Arm/Group Title	Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100	Group 2 - Cetuximab + Capecitabine-700 + XRT + Oxaliplatin-85	Group A - Cetuximab + Capecitabine-800 + XRT	Group B - Cetuximab + Capecitabine-800 + XRT
Arm/Group Description	Cetuximab 250 mg/m² / week Capecitabine 800 mg/m² Radiotherapy (XRT) Oxaliplatin 100 mg/m², Days 2 and 23	Cetuximab 250 mg/m² / week Capecitabine 700 mg/m² Radiotherapy (XRT) Oxaliplatin 850 mg/m², Days 2 and 23	Cetuximab 250 mg/m² / week Capecitabine 800 mg/m² Radiotherapy (XRT)	Cetuximab 250 mg/m² / week Capecitabine 1000 mg/m² Radiotherapy (XRT)
Measure Participants	6	6	4	5
Count of Participants [Participants]	5 83.3%	4 66.7%	3 75%	3 42.9%

Adverse Events

Time Frame	5 years
Arm/Group Title	Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100		Group 2 - Cetuximab + Capecitabine-700 + XRT + Oxaliplatin-85		Group A - Cetuximab + Capecitabine-800 + XRT		Group B - Cetuximab + Capecitabine-1000 + XRT
Arm/Group Description	Cetuximab 250 mg/m² / week Capecitabine 800 mg/m² Radiotherapy (XRT) Oxaliplatin 100 mg/m², Days 2 and 23		Cetuximab 250 mg/m² / week Capecitabine 700 mg/m² Radiotherapy (XRT) Oxaliplatin 85 mg/m², Days 2 and 23		Cetuximab 250 mg/m² / week Capecitabine 800 mg/m² Radiotherapy (XRT)		Cetuximab 250 mg/m² / week Capecitabine 1000 mg/m² Radiotherapy (XRT)
All Cause Mortality
	Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100		Group 2 - Cetuximab + Capecitabine-700 + XRT + Oxaliplatin-85		Group A - Cetuximab + Capecitabine-800 + XRT		Group B - Cetuximab + Capecitabine-1000 + XRT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/6 (16.7%)		1/6 (16.7%)		0/4 (0%)		0/7 (0%)
Serious Adverse Events
	Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100		Group 2 - Cetuximab + Capecitabine-700 + XRT + Oxaliplatin-85		Group A - Cetuximab + Capecitabine-800 + XRT		Group B - Cetuximab + Capecitabine-1000 + XRT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		6/6 (100%)		3/4 (75%)		7/7 (100%)
Gastrointestinal disorders
Small bowel obstruction-Ileus	0/6 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	1/7 (14.3%)	1
Anorexia	3/6 (50%)	4	1/6 (16.7%)	1	2/4 (50%)	2	1/7 (14.3%)	1
Dehydration	3/6 (50%)	3	2/6 (33.3%)	2	0/4 (0%)	0	1/7 (14.3%)	1
Diarrhea	5/6 (83.3%)	8	2/6 (33.3%)	7	0/4 (0%)	0	5/7 (71.4%)	12
Vomiting	3/6 (50%)	4	2/6 (33.3%)	2	0/4 (0%)	0	1/7 (14.3%)	1
Infections and infestations
Urinary Tract Infection	1/6 (16.7%)	1	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Respiratory, thoracic and mediastinal disorders
Decrease in lung volumes with increased bibasilar atelectasis	0/6 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	1/7 (14.3%)	1
Nausea	6/6 (100%)	11	1/6 (16.7%)	2	1/4 (25%)	1	2/7 (28.6%)	2
Other (Not Including Serious) Adverse Events
	Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100		Group 2 - Cetuximab + Capecitabine-700 + XRT + Oxaliplatin-85		Group A - Cetuximab + Capecitabine-800 + XRT		Group B - Cetuximab + Capecitabine-1000 + XRT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		6/6 (100%)		4/4 (100%)		7/7 (100%)
Blood and lymphatic system disorders
Hemorrhage in rectum	3/6 (50%)	3	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Hypokalemia	0/6 (0%)	0	1/6 (16.7%)	1	1/4 (25%)	1	1/7 (14.3%)	1
Hematocrit decreased	1/6 (16.7%)	1	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Neutropenia	1/6 (16.7%)	1	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Cardiac disorders
Hypertension	1/6 (16.7%)	1	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Tachycardia	1/6 (16.7%)	2	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Ear and labyrinth disorders
Pain, middle ear	0/6 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	1/7 (14.3%)	1
Endocrine disorders
Hypomagnesemia	0/6 (0%)	0	0/6 (0%)	0	1/4 (25%)	1	1/7 (14.3%)	1
Eye disorders
Dry eye syndrome	0/6 (0%)	0	0/6 (0%)	0	1/4 (25%)	1	0/7 (0%)	0
Gastrointestinal disorders
Abdominal cramping	1/6 (16.7%)	1	0/6 (0%)	0	0/4 (0%)	0	1/7 (14.3%)	1
Abdominal pain	0/6 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	2/7 (28.6%)	2
Anorexia	4/6 (66.7%)	4	1/6 (16.7%)	1	3/4 (75%)	3	2/7 (28.6%)	2
Backache	0/6 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	1/7 (14.3%)	1
Distension	3/6 (50%)	3	1/6 (16.7%)	1	0/4 (0%)	0	0/7 (0%)	0
Bloody stool	0/6 (0%)	0	2/6 (33.3%)	2	1/4 (25%)	1	4/7 (57.1%)	5
Bloody rectum	0/6 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	1/7 (14.3%)	1
Constipation	3/6 (50%)	3	1/6 (16.7%)	2	1/4 (25%)	1	0/7 (0%)	0
Constipation, alternating with diarrhea	0/6 (0%)	0	0/6 (0%)	0	1/4 (25%)	3	0/7 (0%)	0
Diarrhea	5/6 (83.3%)	10	2/6 (33.3%)	7	0/4 (0%)	0	4/7 (57.1%)	11
Diarrhea with cramping	1/6 (16.7%)	1	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Flatus	2/6 (33.3%)	2	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Gastritis	0/6 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	1/7 (14.3%)	1
Hemorrhoids	2/6 (33.3%)	2	2/6 (33.3%)	2	1/4 (25%)	1	0/7 (0%)	0
Nausea	6/6 (100%)	14	1/6 (16.7%)	2	2/4 (50%)	2	2/7 (28.6%)	2
Pain with bowel movements	4/6 (66.7%)	4	0/6 (0%)	0	1/4 (25%)	2	3/7 (42.9%)	3
Vomiting	3/6 (50%)	4	2/6 (33.3%)	2	0/4 (0%)	0	1/7 (14.3%)	1
Pain, umbilical cord protrusion	0/6 (0%)	0	0/6 (0%)	0	1/4 (25%)	1	0/7 (0%)	0
Reflux	0/6 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	1/7 (14.3%)	1
General disorders
Chest tightness	0/6 (0%)	0	0/6 (0%)	0	1/4 (25%)	1	0/7 (0%)	0
Dehydration	2/6 (33.3%)	2	2/6 (33.3%)	2	0/4 (0%)	0	1/7 (14.3%)	1
Migraine	0/6 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	1/7 (14.3%)	1
Weight loss	1/6 (16.7%)	1	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Taste disturbance	0/6 (0%)	0	1/6 (16.7%)	1	0/4 (0%)	0	0/7 (0%)	0
Infection, rectal-anal	3/6 (50%)	3	5/6 (83.3%)	6	2/4 (50%)	2	2/7 (28.6%)	2
Pain	2/6 (33.3%)	2	4/6 (66.7%)	5	1/4 (25%)	1	2/7 (28.6%)	2
Pain (t11-12 level)	1/6 (16.7%)	1	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Immune system disorders
Fatigue	4/6 (66.7%)	7	1/6 (16.7%)	2	2/4 (50%)	2	1/7 (14.3%)	1
Infections and infestations
Pain	1/6 (16.7%)	1	0/6 (0%)	0	1/4 (25%)	1	0/7 (0%)	0
Infection	1/6 (16.7%)	1	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Fever	4/6 (66.7%)	4	0/6 (0%)	0	0/4 (0%)	0	1/7 (14.3%)	1
Candidal infection	0/6 (0%)	0	0/6 (0%)	0	1/4 (25%)	3	0/7 (0%)	0
Flu-like symptoms	0/6 (0%)	0	0/6 (0%)	0	1/4 (25%)	1	0/7 (0%)	0
Low grade fever	1/6 (16.7%)	1	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Infection, urinary track (UTI)	1/6 (16.7%)	2	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Infection, upper respiratory tract	1/6 (16.7%)	1	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Rhinitis	0/6 (0%)	0	1/6 (16.7%)	1	0/4 (0%)	0	0/7 (0%)	0
Injury, poisoning and procedural complications
Pain, groin	2/6 (33.3%)	2	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Injection site reaction	1/6 (16.7%)	1	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Pain, left knee	0/6 (0%)	0	0/6 (0%)	0	1/4 (25%)	1	0/7 (0%)	0
Pain, lower back	1/6 (16.7%)	1	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Investigations
Insomnia	3/6 (50%)	3	0/6 (0%)	0	1/4 (25%)	1	0/7 (0%)	0
Syncope	1/6 (16.7%)	1	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Musculoskeletal and connective tissue disorders
Bilateral jaw pain	1/6 (16.7%)	1	0/6 (0%)	0	1/4 (25%)	1	0/7 (0%)	0
Body aches	1/6 (16.7%)	1	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Cramping	0/6 (0%)	0	1/6 (16.7%)	1	0/4 (0%)	0	2/7 (28.6%)	2
Hand and foot syndrome	2/6 (33.3%)	3	0/6 (0%)	0	0/4 (0%)	0	1/7 (14.3%)	1
Left arm numbness	1/6 (16.7%)	1	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Tingling, fingertips	0/6 (0%)	0	1/6 (16.7%)	1	0/4 (0%)	0	0/7 (0%)	0
Tingling, cheeks	1/6 (16.7%)	1	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Nervous system disorders
Rigors	2/6 (33.3%)	3	0/6 (0%)	0	0/4 (0%)	0	1/7 (14.3%)	1
Neuropathy	0/6 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	1/7 (14.3%)	1
Dizziness	0/6 (0%)	0	1/6 (16.7%)	1	0/4 (0%)	0	1/7 (14.3%)	1
Depression	0/6 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	1/7 (14.3%)	1
Cold sensitivity	2/6 (33.3%)	2	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Headache	2/6 (33.3%)	2	1/6 (16.7%)	1	2/4 (50%)	2	2/7 (28.6%)	2
Lightheadedness	0/6 (0%)	0	0/6 (0%)	0	1/4 (25%)	1	0/7 (0%)	0
Nocturia	0/6 (0%)	0	1/6 (16.7%)	1	0/4 (0%)	0	0/7 (0%)	0
Neuropathy, right arm	2/6 (33.3%)	4	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Renal and urinary disorders
Urinary frequency	1/6 (16.7%)	1	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Elevated alanine aminotransferase (ALT)	2/6 (33.3%)	2	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Elevated aspartate aminotransferase (AST)	2/6 (33.3%)	2	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Abnormal liver function test (LFT)	0/6 (0%)	0	1/6 (16.7%)	1	0/4 (0%)	0	0/7 (0%)	0
Urinary retention	1/6 (16.7%)	1	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Urinary hesitancy	0/6 (0%)	0	0/6 (0%)	0	1/4 (25%)	1	0/7 (0%)	0
Blood in stool, scant	0/6 (0%)	0	0/6 (0%)	0	1/4 (25%)	1	0/7 (0%)	0
Pain, bladder and testes	1/6 (16.7%)	1	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Reproductive system and breast disorders
Libido	0/6 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	1/7 (14.3%)	1
Respiratory, thoracic and mediastinal disorders
Allergic reaction	0/6 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	1/7 (14.3%)	1
Cough	1/6 (16.7%)	2	0/6 (0%)	0	0/4 (0%)	0	1/7 (14.3%)	1
Dyspnea	0/6 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	1/7 (14.3%)	1
Flushing	1/6 (16.7%)	1	1/6 (16.7%)	1	0/4 (0%)	0	0/7 (0%)	0
Pain, throat	0/6 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	1/7 (14.3%)	1
Skin and subcutaneous tissue disorders
Acne	0/6 (0%)	0	1/6 (16.7%)	1	0/4 (0%)	0	0/7 (0%)	0
Edema	1/6 (16.7%)	1	1/6 (16.7%)	1	0/4 (0%)	0	0/7 (0%)	0
Skin cracking	1/6 (16.7%)	1	1/6 (16.7%)	2	0/4 (0%)	0	3/7 (42.9%)	3
Cuticle dryness	1/6 (16.7%)	1	0/6 (0%)	0	0/4 (0%)	0	1/7 (14.3%)	1
Erythema at incision	1/6 (16.7%)	1	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Rash, follicular, chest and back	1/6 (16.7%)	1	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Induration	1/6 (16.7%)	1	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Skin dryness	1/6 (16.7%)	1	0/6 (0%)	0	0/4 (0%)	0	0/7 (0%)	0
Radiation demititis	2/6 (33.3%)	3	0/6 (0%)	0	1/4 (25%)	1	0/7 (0%)	0
Rash	6/6 (100%)	11	6/6 (100%)	10	4/4 (100%)	7	5/7 (71.4%)	12
Psoriasis	0/6 (0%)	0	1/6 (16.7%)	1	0/4 (0%)	0	0/7 (0%)	0

Limitations/Caveats

This trial was halted after the phase 1 portion of enrollment, and before the phase 2 portion accrued. Data reported for phase 2 objectives/outcomes do not include any phase 2 participants, and are only provided for completeness.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.