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

This study has been terminated.
(The response rate observed in the phase 1 portion of the study did not merit further evaluation in phase 2 portion of the study.)
Sponsor:
ClinicalTrials.gov Identifier:
NCT00226941
First Posted: September 27, 2005
Last Update Posted: December 8, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
George Albert Fisher, Stanford University
  Purpose

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)

Condition Intervention Phase
Rectal Cancer Colo-rectal Cancer Drug: Cetuximab Drug: Oxaliplatin Drug: Capecitabine Radiation: Radiotherapy Drug: Diphenhydramine hydrochloride (HCl) Phase 1 Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:
Sequential 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

Resource links provided by NLM:


Further study details as provided by George Albert Fisher, Stanford University:

Primary Outcome Measures:
  • Dose-limiting Toxicity (DLT) - Number of DLTs by Treatment Group [ Time Frame: 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.

  • Dose-limiting Toxicity (DLT) - Number of Participants Affected [ Time Frame: 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:
  • Pathologic Response Rate [ Time Frame: 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.

  • Tumor Downstaging at Surgical Resection [ Time Frame: 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.

  • Time-to-Progression (TTP) [ Time Frame: 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.

  • Overall Survival (OS) [ Time Frame: 72 months ]
    Overall Survival (OS) was assessed as the mean survival from the date of entry on study though 72 months.

  • Survival at 5 Years [ Time Frame: 5 years ]
    Survival at 5 years was assessed as the number of participants alive 5 years after starting treatment.


Enrollment: 23
Study Start Date: June 2004
Study Completion Date: February 2009
Primary Completion Date: March 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: XRT
Drug: Diphenhydramine hydrochloride (HCl)
Diphenhydramine HCl 50 mg (or equivalent) is administered as a per-medication for cetuximab
Other Names:
  • Benadryl
  • Unisom
  • Sominex

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.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00226941


Locations
United States, California
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
  More Information

Responsible Party: George Albert Fisher, Professor of Medicine and Colleen Haas Chair in the School of Medicine, Stanford University
ClinicalTrials.gov Identifier: NCT00226941     History of Changes
Other Study ID Numbers: IRB-12426
COR0001 ( Other Identifier: OnCore )
95054 ( Other Identifier: Stanford IRB, historical )
First Submitted: September 8, 2005
First Posted: September 27, 2005
Results First Submitted: July 27, 2017
Results First Posted: December 8, 2017
Last Update Posted: December 8, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
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
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases
Colonic Diseases
Capecitabine
Oxaliplatin
Cetuximab
Diphenhydramine
Promethazine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Anesthetics, Local
Anesthetics
Central Nervous System Depressants
Physiological Effects of Drugs
Sensory System Agents
Peripheral Nervous System Agents
Antiemetics
Autonomic Agents
Gastrointestinal Agents