Cetuximab and/or Dasatinib in Patients With Colorectal Cancer and Liver Metastases That Can Be Removed by Surgery

This study has been terminated.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00835679
First received: February 3, 2009
Last updated: May 7, 2014
Last verified: January 2013
  Purpose

This phase 0 trial is studying whether 2 weeks of cetuximab and dasatinib will change tumor cells in patients with colorectal cancer and liver metastases that can be removed by surgery. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Dasatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.


Condition Intervention Phase
Liver Metastases
Mucinous Adenocarcinoma of the Colon
Mucinous Adenocarcinoma of the Rectum
Recurrent Colon Cancer
Recurrent Rectal Cancer
Signet Ring Adenocarcinoma of the Colon
Signet Ring Adenocarcinoma of the Rectum
Stage IV Colon Cancer
Stage IV Rectal Cancer
Biological: cetuximab
Drug: dasatinib
Procedure: therapeutic conventional surgery
Other: laboratory biomarker analysis
Phase 0

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: A Preoperative Biological Trial of Cetuximab, Dasatinib or the Combination in Colorectal Cancer Patients With Resectable Liver Metastases

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Patients With a Biologic Response [ Time Frame: on baseline and preoperatively on day of surgery (day 15) ] [ Designated as safety issue: No ]
    Patients who experienced a pre-to-post treatment reduction of at least 1 scoring level from baseline on preoperative-day 15 in at least 1 biomarker of the pathway being inhibited: epidermal growth factor (EGFR) for Cohort B, sarcoma (Src) for Cohort C, and both EGFR and Src for Cohort D. Blood for these biomarkers will be taken on day of baseline and pre-operatively on day 15. Determined by 0-4-scale scoring with score determined by percentage of tumor cells positively stained for pathway in question: minimum 0 (0%), 1 (1-24%), 2 (25-49%), 3 (50-74%), and maximum 4 (75-100%).


Secondary Outcome Measures:
  • Patients With Reduction of Biomarkers in Tumor Tissue [ Time Frame: study entry to day 15 ] [ Designated as safety issue: No ]
    Patients with pre-to-post treatment reduction at least 1 scoring level from baseline on preoperative-day 15 in at least 1 biomarker: total & phi-EGFR, phi-MAPK, phi-Akt, Ki67, phi-FAK, phi-paxillin, phi-Src, capase 3. Determined by 0-4-scale scoring with score determined by percentage of tumor cells positively stained for biomarker in question: minimum 0 (0%), 1 (1-24%), 2 (25-49%), 3 (50-74%), and maximum 4 (75-100%)

  • Number of Patients With the Given Severity of Adverse Event Within a Specified Duration [ Time Frame: weekly to day 15, and at followup on day 30 ] [ Designated as safety issue: Yes ]
    Number of patients with each grade of adverse event (AE) during the specified timeframe using the Common Terminology Criteria for AEs guide, grades 1-5 with one being mild, five is death.

  • Number of Patients With the Given Severity of Post-operative Complications Within the Specified Duration [ Time Frame: From day 15 (day of surgery) to 30 days after surgery ] [ Designated as safety issue: Yes ]

Enrollment: 9
Study Start Date: December 2009
Study Completion Date: August 2011
Primary Completion Date: February 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort A (no systemic neoadjuvant therapy)
Patients receive no systemic neoadjuvant therapy between enrollment and the time of definitive surgical resection of liver metastases. Liver biopsies were performed at surgery since this cohort received no systemic therapy.
Procedure: therapeutic conventional surgery
Undergo surgery
Other: laboratory biomarker analysis
Correlative studies
Experimental: Cohort B (cetuximab)
Patients receive 400 mg/m^2 cetuximab IV over 120 minutes on day 1 and 250 mg/m^2 cetuximab IV over 60-120 minutes on day 8. Definitive surgical resection of liver metastases will take place on day 15.
Biological: cetuximab
Given IV
Other Names:
  • C225
  • C225 monoclonal antibody
  • IMC-C225
  • MOAB C225
  • monoclonal antibody C225
Procedure: therapeutic conventional surgery
Undergo surgery
Other: laboratory biomarker analysis
Correlative studies
Experimental: Cohort C (dasatinib)
Patients receive dasatinib 100 mg orally once daily on days 1-14. Definitive surgical resection of liver metastases will take place on day 15.
Drug: dasatinib
Given orally
Other Names:
  • BMS-354825
  • Sprycel
Procedure: therapeutic conventional surgery
Undergo surgery
Other: laboratory biomarker analysis
Correlative studies
Experimental: Cohort D (cetuximab, dasatinib)
Patients receive 400 mg/m^2 cetuximab IV over 120 minutes on day 1 and 250 mg/m^2 cetuximab IV over 60-120 minutes on day 8 AND dasatinib 100 mg orally once daily on days 1-14. Definitive surgical resection of liver metastases will take place on day 15.
Biological: cetuximab
Given IV
Other Names:
  • C225
  • C225 monoclonal antibody
  • IMC-C225
  • MOAB C225
  • monoclonal antibody C225
Drug: dasatinib
Given orally
Other Names:
  • BMS-354825
  • Sprycel
Procedure: therapeutic conventional surgery
Undergo surgery
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the biological effects of cetuximab, dasatinib, or the combination on epidermal growth factor receptor (EGFR)- and Src-signaling pathways in resected colorectal cancer liver metastases.

OUTLINE: This is a multicenter study. Patients are initially enrolled in cohort A. Once cohort A is completed, additional patients are enrolled and randomized to treatment in either cohorts B or C. If a significant biological effect is seen in cohorts B or C, additional patients are enrolled in cohort D.

COHORT A: Patients receive no systemic neoadjuvant therapy between enrollment and the time of definitive surgical resection of liver metastases. Liver biopsies were performed at surgery since this cohort received no systemic therapy.

COHORT B: Patients receive 400 mg/m2 cetuximab intravenously (IV) over 120 minutes on day 1 and 250 mg/m^2 cetuximab IV over 60-120 minutes on day 8. Definitive surgical resection of liver metastases will take place on day 15.

COHORT C: Patients receive dasatinib 100 mg orally once daily on days 1-14. Definitive surgical resection of liver metastases will take place on day 15.

COHORT D: Patients receive 400 mg/m^2 cetuximab IV over 120 minutes on day 1 and 250 mg/m^2 cetuximab IV over 60-120 minutes on day 8 AND dasatinib 100 mg orally once daily on days 1-14. Definitive surgical resection of liver metastases will take place on day 15.

Patients undergo tumor tissue (from initial liver tumor biopsies and liver resection samples), serum, and peripheral blood mononuclear cell sample collection periodically for biomarker analysis via immunohistochemistry (IHC).

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have histologically confirmed adenocarcinoma arising from the large intestine that has metastasized to the liver; liver metastases may be synchronous or metachronous
  • The liver metastases must be considered surgically resectable prior to the initiation of study drugs
  • Prior chemotherapy or chemoradiotherapy for colorectal cancer is allowed provided that toxicities from prior therapy have resolved to Grade 1 or less; no prior anti-EGFR or anti-Src therapy is allowed
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
  • Absolute neutrophil count >= 1.5 x 10^9/L
  • Hemoglobin ≥ 9.0 Gm/dL
  • Platelets >= 100 x 10^9/L
  • Total bilirubin ≤ 1.5 x institutional upper limit of normal (IULN)
  • Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine transaminase (ALT)(serum glutamic pyruvic transaminase [SGPT]) =< 5 x institutional upper limit of normal
  • Creatinine =< 1.5 institutional ULN
  • Women must have a negative pregnancy test; women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
  • Ability to understand and the willingness to sign a written informed consent document
  • Although KRAS status will be evaluated in the tumor, wild type KRAS status is not an eligibility criterion

Exclusion Criteria:

  • Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
  • Patients receiving any other investigational agents
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to cetuximab or dasatinib
  • Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study because of the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with cetuximab or dasatinib, breastfeeding should be discontinued if the mother is treated with cetuximab or dasatinib
  • Patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy; therefore, HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with cetuximab or dasatinib; appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated
  • Patients on potent CYP3A4 inducers and inhibitors
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00835679

Locations
United States, Florida
H. Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, United States, 33612
United States, Tennessee
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Investigators
Principal Investigator: Emily Chan Vanderbilt-Ingram Cancer Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00835679     History of Changes
Other Study ID Numbers: NCI-2013-00014, NCI-2013-00014, VU-VICC-GI-0838, 8069, P30CA068485, 081338, VICC GI 0838, 8069, P30CA068485
Study First Received: February 3, 2009
Results First Received: March 12, 2012
Last Updated: May 7, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Colorectal Neoplasms
Adenocarcinoma
Neoplasm Metastasis
Rectal Neoplasms
Colonic Neoplasms
Liver Neoplasms
Adenocarcinoma, Mucinous
Cystadenocarcinoma
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplastic Processes
Pathologic Processes
Liver Diseases
Neoplasms, Cystic, Mucinous, and Serous
Antibodies
Antibodies, Monoclonal
Cetuximab
Dasatinib
Immunologic Factors

ClinicalTrials.gov processed this record on September 18, 2014