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Phase I Study of Cetuximab With RO4929097 in Metastatic Colorectal Cancer | Clinical Trials | Clareo Health

TERMINATEDPHASE1

Phase I Study of Cetuximab With RO4929097 in Metastatic Colorectal Cancer

NCT01198535•National Cancer Institute (NCI)

Summary

The purpose of this study is to determine if a new drug, RO4929097, can work with cetuximab, a drug already approved for colorectal cancer, to help fight the patient's cancer. Cancers arise as a result of abnormal control of gene expression. One of the pathways that gets abnormally regulated in some cancers is the Notch pathway. RO4929097 is an investigational drug that blocks the activation of the Notch pathway. It is hoped that by blocking this abnormal activation, this drug may be helpful in patients with cancer but the investigators do not yet know if that is true. Cetuximab is an antibody against epidermal growth factor receptor and is known to have activity in metastatic colorectal cancer. Recent studies have shown that people with colorectal cancers that contain a mutation in a gene called K-ras do not benefit from receiving cetuximab. It is unknown if adding RO4929097 to cetuximab would benefit patients who have tumors with this mutation.

Detailed Description

PRIMARY OBJECTIVES: I. Determination of the maximum tolerated dose (MTD) of the combination of cetuximab and RO4929097. SECONDARY OBJECTIVES: I. Safety and tolerability of the combination of cetuximab and RO4929097. II. Exploratory analyses of anti-tumor effect with the combination. III. Laboratory correlatives exploring response rate with notch receptors and ligand expression, correlation of response and toxicity profiles to expression of EGFR pathway components, and evaluation of serum and tissue markers of gamma-secretase inhibitor activity. IV. Pharmacokinetic studies. OUTLINE: This is a dose-escalation study of gamma-secretase/Notch signalling pathway inhibitor RO4929097. Phase I dose escalation: In this part of the study, the investigators are trying to find out what is the highest tolerated dose of RO4929097 that can be safely combined with cetuximab. The investigators will be testing two different cetuximab doses. One is the standard dose (Arm A) and one is a little less than the standard dose (Arm B). Everyone will get treated with cetuximab and R04929097 in this part of the study. Phase I dose expansion: In this part of the study, the investigators will take the highest tolerated dose found in the phase I part of the study and test a small number of people with colorectal cancer to see if there is any activity with the combination of drugs. Everyone will get treated with cetuximab and RO4929097 in this part of the study. This part of the study will be restricted to patients whose tumors do not have a mutation in the K-ras gene. RO4929097 is an investigational anti-cancer agent that has not yet been approved by the Food and Drug Administration (FDA) for use in colorectal cancer. Cetuximab is FDA approved for metastatic colorectal cancer. After completion of study treatment, patients are followed up every 3 months.

Eligibility

Age

18 - No limit years

Sex

ALL

Healthy Volunteers

Inclusion Criteria

•Patients must have histologically or cytologically confirmed metastatic colorectal adenocarcinoma
•Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as \>= 20 mm with conventional techniques or as \>= 10 mm with spiral CT scan
•Patients must have received at least one prior therapy for metastatic disease; prior therapy with anti-EGFR antibody is allowed only as long as patient did not require dose reductions of the anti-EGFR antibody because of poor tolerability
•Life expectancy of greater than 3 months
•ECOG performance status =\<2 (Karnofsky \>= 60%)
•Leukocytes \>= 3,000/mcL
•Absolute neutrophil count \>= 1,500/mcL
•Platelets \>= 100,000/mcL
•Hemoglobin \>= 9 g/dL
•Total bilirubin within normal institutional limits if no liver metastases
+17 more criteria

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 to a grade 1 or less from adverse events due to agents administered more than 4 weeks earlier with the exception of alopecia and neuropathy
•Patients may not be receiving any other investigational agents
•Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
•History of allergic reactions attributed to compounds of similar chemical or biologic composition to RO4929097 or other agents (EGFR antibodies) used in the study
•Patients taking medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible
•Preclinical studies indicate that RO4929097 is a substrate of CYP3A4 and inducer of CYP3A4 enzyme activity. Caution should be exercised when dosing RO4929097 concurrently with CYP3A4 substrates, inducers, and/or inhibitors; furthermore, patients who are taking concurrent medications that are strong inducers/inhibitors or substrates of CYP3A4 should be switched to alternative medications to minimize any potential risk; if such patients cannot be switched to alternative medications, they will be ineligible to participate in this study
•Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption; patients must be able to swallow tablets
•Patients with uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia or hypokalemia defined as less than the lower limit of normal for the institution, despite adequate electrolyte supplementation are excluded from this study
•Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, a history of torsades de pointes, significant cardiac arrhythmia other than chronic, stable atrial fibrillation, or psychiatric illness/social situations that would limit compliance with study requirements
•Pregnant women are excluded from this study because RO4929097 is a Notch pathway inhibiting agent with 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 RO4929097, breastfeeding should be discontinued if the mother is treated with RO4929097; these potential risks may also apply to other agents used in this study
+5 more criteria

Locations (1)

Vanderbilt University/Ingram Cancer Center

Nashville, Tennessee, United States

Key Dates

Start Date

September 1, 2010

Primary Completion Date

July 1, 2012

Last Updated

May 18, 2015

Enrollment

ACTUAL participants

Conditions

Colon Mucinous AdenocarcinomaColon Signet Ring Cell AdenocarcinomaRectal Mucinous AdenocarcinomaRectal Signet Ring Cell AdenocarcinomaRecurrent Colon CarcinomaRecurrent Rectal CarcinomaStage IVA Colon CancerStage IVA Rectal CancerStage IVB Colon CancerStage IVB Rectal Cancer

Interventions

Cetuximab

BIOLOGICAL

Gamma-Secretase Inhibitor RO4929097

DRUG

Laboratory Biomarker Analysis

OTHER

Pharmacological Study

OTHER

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NCT00068692

Rectal Mucinous AdenocarcinomaRectal Signet Ring Cell Adenocarcinoma+9 more

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Data Source & Attribution

This clinical trial information is sourced from ClinicalTrials.gov, a service of the U.S. National Institutes of Health.

ClinicalTrials.gov last update: May 18, 2015Data synced to Clareo: March 29, 2026

Modifications: This data has been reformatted for display purposes. Eligibility criteria have been parsed into inclusion/exclusion sections. Location data has been geocoded to enable distance-based search. For the authoritative and most current information, please visit ClinicalTrials.gov.

Neither the United States Government nor Clareo Health make any warranties regarding the data. Check ClinicalTrials.gov frequently for updates.

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