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

Early Phase 1

Terminated

Conditions: Mucinous Adenocarcinoma of the Rectum
Stage IV Colon Cancer
Liver Metastases
Mucinous Adenocarcinoma of the Colon
Recurrent Colon Cancer
Recurrent Rectal Cancer
Signet Ring Adenocarcinoma of the Colon
Signet Ring Adenocarcinoma of the Rectum
Stage IV Rectal Cancer

Interventions: Procedure: therapeutic conventional surgery
Biological: cetuximab
Drug: dasatinib
Other: laboratory biomarker analysis

Registration Number: NCT00835679

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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.

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).

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 9

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort A (no systemic neoadjuvant therapy)	therapeutic conventional surgery	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 A (no systemic neoadjuvant therapy)	laboratory biomarker analysis	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 (cetuximab)	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.
Cohort B (cetuximab)	therapeutic conventional surgery	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.
Cohort B (cetuximab)	laboratory biomarker analysis	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.
Cohort C (dasatinib)	therapeutic conventional surgery	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 C (dasatinib)	laboratory biomarker analysis	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 (cetuximab, dasatinib)	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 AND dasatinib 100 mg orally once daily on days 1-14. Definitive surgical resection of liver metastases will take place on day 15.
Cohort D (cetuximab, dasatinib)	therapeutic conventional surgery	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.
Cohort D (cetuximab, dasatinib)	laboratory biomarker analysis	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.
Cohort C (dasatinib)	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.
Cohort D (cetuximab, dasatinib)	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.

Primary Outcome Measures

Name	Time	Method
Patients With a Biologic Response	on baseline and preoperatively on day of surgery (day 15)	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

Name	Time	Method
Patients With Reduction of Biomarkers in Tumor Tissue	study entry to day 15	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	weekly to day 15, and at followup on day 30	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	From day 15 (day of surgery) to 30 days after surgery

Trial Locations

Locations (2): H. Lee Moffitt Cancer Center and Research Institute
🇺🇸
Tampa, Florida, United States
Vanderbilt-Ingram Cancer Center
🇺🇸
Nashville, Tennessee, United States