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Cetuximab, 5-FU and Radiation as Neoadjuvant Therapy for Patients With Locally Advanced Rectal Cancer

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ClinicalTrials.gov Identifier: NCT00611858
Recruitment Status : Terminated (Slow accrual)
First Posted : February 11, 2008
Results First Posted : November 14, 2018
Last Update Posted : November 14, 2018
Sponsor:
Collaborators:
Massachusetts General Hospital
Beth Israel Deaconess Medical Center
Brigham and Women's Hospital
Bristol-Myers Squibb
Information provided by (Responsible Party):
Jeffrey A. Meyerhardt, MD, Dana-Farber Cancer Institute

Brief Summary:
The standard treatment for rectal cancer is to receive the chemotherapeutic drug 5-fluorouracil (5-FU) with radiation therapy before having surgery to remove the rectal cancer. This is known as neoadjuvant chemoradiotherapy. The purpose of this research study is to determine if Cetuximab improves the benefits of neoadjuvant chemoradiotherapy when given with 5-FU and radiation therapy.

Condition or disease Intervention/treatment Phase
Rectal Cancer Drug: Cetuximab Drug: 5-Fluorouracil Radiation: Radiation Phase 2

Detailed Description:

The epidermal growth factor receptor (EGFR) present in normal and tumor cells is involved in signaling pathways affecting cellular growth, differentiation, proliferation and programmed cell death. Overexpression of EGFR has been associated with poorer prognosis in colorectal cancer. Cetuximab targets and blocks EGFR and has been shown to be safe and effective in treating colorectal cancer and head and neck cancers.

The primary hypothesis is that cetuximab in combination with standard 5-FU and radiation as neoadjuvant therapy would improve pathological complete response (pCR) compared to the historical rate (30% versus 10%). The regimen would be considered promising if 5 or more of 25 evaluable participants achieve pCR. The probability of observing this outcome is 0.91 and 0.10 if the true pCR rate is 30% and 10%, respectively.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 13 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study of Cetuximab, 5-FU and Radiation as Neoadjuvant Therapy for Patients With Locally Advanced Rectal Cancer
Study Start Date : January 2008
Actual Primary Completion Date : December 2012
Actual Study Completion Date : September 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cetuximab, 5-FU and Radiation

Cetuximab: Participants first receive cetuximab at the initial dose of 400 mg/m2 intravenously (IV) administered over 120 minutes, followed by weekly infusions at 250 mg/m2 over 60 minutes. Cetuximab is given as single agent during the first 3 weeks on study and then in combination with 5-FU and radiation.

Radiation: Radiation therapy given as standard of care is initiated after the 3rd dose of cetuximab with a total dose of 50.4 Gray (Gy) in 28 fractions over approximately 5.5 weeks.

5-FU: Participants receive 5-Fluorouracil (5-FU) continuous infusion through central venous access at 225 mg/m2/day given 7 days a week starting day 1 of radiation (no later than 3 days) and lasting the duration of radiation therapy.

Duration of neoadjuvant therapy is estimated to be 9 weeks. Surgery follows at week 13-17. Sigmoidoscopy is performed for biopsy prior to the 1st dose and after 3rd dose of cetuximab before the initiation of radiation and/or 5-FU.

Drug: Cetuximab
Other Name: Erbitux

Drug: 5-Fluorouracil
Other Name: 5-FU

Radiation: Radiation
Other Name: External Beam Radiation Therapy




Primary Outcome Measures :
  1. Pathological Complete Response Rate [ Time Frame: Disease is assessed at the time of surgery which in this study cohort occurred up to 24 weeks from date of registration. ]
    Pathological complete response (pCR) rate is the percentage of participants who achieve pCR defined as no evidence of tumor cells in the surgical specimen including the lymph nodes (down-staging to pathological T0, N0 after planned neoadjuvant therapy).


Secondary Outcome Measures :
  1. Local Recurrence Rate [ Time Frame: CT scans for surveillance recommended yearly x 3 years from date of surgery with additional scanning at discretion of treating oncologist. Mean follow-up for this study cohort was 4.4 years from study entry, up to 7.9 years. ]
    Local recurrence rate is the percentage of participants experiencing recurrence within the pelvis.

  2. Complete Resection Rate [ Time Frame: Disease is assessed at the time of surgery which in this study cohort occurred up to 24 weeks from date of registration. ]
    Complete resection rate is the percentage of participants having all gross disease removed by the surgeon at the time of operation.

  3. Distant Recurrence Rate [ Time Frame: CT scans for surveillance recommended yearly x 3 years from date of surgery with additional scanning at discretion of treating oncologist. Mean follow-up for this study cohort was 4.4 years from study entry, up to 7.9 years. ]
    Distant recurrence rate is the percentage of participants experiencing recurrence outside the pelvis.

  4. Incidence of Grade 4 Treatment-Related Toxicity [ Time Frame: Disease is assessed through the time of surgery which in this study cohort occurred up to 24 weeks from date of registration. ]
    All grade 4 adverse events (AE) with treatment attribution of possibly, probably or definite based on NCI Common Toxicity Criteria for Adverse Events version 3 (CTCAEv3) as reported on case report forms were counted. Incidence is the number of patients experiencing at least one treatment-related grade 4 AE of any type during the time of observation.

  5. 1-Year Overall Survival Rate [ Time Frame: Mean follow-up for this study cohort was 4.4 years from study entry, up to 7.9 years. ]
    1-year overall survival is the percentage of participants remaining alive 1 year from study entry.


Other Outcome Measures:
  1. 1-Year Disease-Free Survival Rate [ Time Frame: CT scans for surveillance recommended yearly x 3 years from date of surgery with additional scanning at discretion of treating oncologist. Mean follow-up for this study cohort was 4.4 years from study entry, up to 7.9 years. ]
    Disease-Free Survival Rate is the percentage of participants remaining alive without disease progression.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed adenocarcinoma of the rectum that begins within 15cm of the anal verge as determined by sigmoidoscopy and/or colonoscopy, with no evidence of distant metastatic disease. A complete colonoscopy to the cecum is recommended prior to initiating protocol therapy.
  • Staging with transrectal ultrasound or endorectal coil Magnetic resonance imaging (MRI) to confirm clinical stage of T3 or T4 or lymph node positive rectal adenocarcinoma
  • Tumor is K-ras wildtype by method of choice at respective institution (testing codons 12 and 13)
  • Performance status: Eastern Cooperative Oncology Group Performance Score (ECOG PS) less than or equal to 2
  • 18 years of age or older
  • No evidence of metastatic disease by abdominal/pelvic (Computed tomography) CT and chest imaging
  • Adequate bone marrow, renal,and hepatic function as outlined in protocol
  • All patients will be evaluated by a surgeon and considered a candidate for definitive surgery
  • Coumadin or heparin management for line care of other indications is permitted. The International Normalised Ratio (INR) will be monitored weekly in patients taking coumadin.

Exclusion Criteria:

  • Prior treatment for this malignancy
  • Prior history of pelvic radiation therapy
  • Prior history of 5-FU based or EGFR receptor inhibitor therapy
  • Prior history of an allergic reaction to a monoclonal antibody
  • Uncontrolled serious medical or psychiatric illness
  • Significant history of uncontrolled cardiac disease
  • Sexually active women of childbearing potential must use an effective method of birth control during the course of the study
  • Unwilling to agree to pre and post-cetuximab sigmoidoscopy and biopsy

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): NCT00611858


Locations
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
South Shore Hospital
Weymouth, Massachusetts, United States
United States, Tennessee
Vanderbilt Medical Center
Nashville, Tennessee, United States
Sponsors and Collaborators
Dana-Farber Cancer Institute
Massachusetts General Hospital
Beth Israel Deaconess Medical Center
Brigham and Women's Hospital
Bristol-Myers Squibb
Investigators
Principal Investigator: Jeffrey Meyerhardt, MD, MPH Dana-Farber Cancer Institute

Responsible Party: Jeffrey A. Meyerhardt, MD, Principal Investigator, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT00611858     History of Changes
Other Study ID Numbers: 07-297
BMS CA225302
First Posted: February 11, 2008    Key Record Dates
Results First Posted: November 14, 2018
Last Update Posted: November 14, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Jeffrey A. Meyerhardt, MD, Dana-Farber Cancer Institute:
5-FU
cetuximab
radiation
adenocarcinoma of the rectum
neoadjuvant therapy

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
Cetuximab
Fluorouracil
Antineoplastic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs