Phase I Study of Cetuximab With RO4929097 in Metastatic Colorectal Cancer
5 other identifiers
interventional
60
1 country
1
Brief 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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_1
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
Study Start
First participant enrolled
September 1, 2010
CompletedFirst Submitted
Initial submission to the registry
September 9, 2010
CompletedFirst Posted
Study publicly available on registry
September 10, 2010
CompletedPrimary Completion
Last participant's last visit for primary outcome
July 1, 2012
CompletedMay 18, 2015
December 1, 2012
1.8 years
September 9, 2010
May 15, 2015
Conditions
Outcome Measures
Primary Outcomes (1)
MTD of RO4929097
21 days
Study Arms (2)
Arm A (RO4929097, cetuximab)
EXPERIMENTALPatients in Arm A will receive cetuximab at the standard dose: 400 mg/m2 IV loading dose on Day 1 followed by cetuximab 250 mg/m2 IV weekly. The RO4929097 will be dose escalated starting at 20 mg given daily 3 days on, 4 days off, weekly. The dose levels of RO4929097 to be explored will be 20 mg, 30 mg, 45 mg, 90 mg, 140 mg given days 1-3 weekly. No intrapatient dose escalation will be allowed.
Arm B (RO4929097, cetuximab)
EXPERIMENTALPatients in Arm B will receive cetuximab 200 mg/m2 IV weekly without a loading dose. The RO4929097 will be dose escalated starting at 20 mg given daily 3 days on, 4 days off, weekly. The dose levels of RO4929097 to be explored will be 20 mg, 30 mg, 45 mg, 90 mg, 140 mg given days 1-3 weekly. No intrapatient dose escalation will be allowed.
Interventions
Given IV
Given PO
Correlative studies
Correlative studies
Eligibility Criteria
You may qualify if:
- 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
- Total bilirubin \< 1.5 X the institutional upper limit of normal if liver metastases are present
- AST(SGOT)/ALT(SGPT) =\< 2.5 X institutional upper limit of normal if no liver metastases
- AST(SGOT)/ALT(SGPT) \< 5 X institutional upper limit of normal if liver metastases are present
- Creatinine within normal institutional limits OR creatinine clearance \>= 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal
- For the phase I dose expansion, tumor must be KRAS wildtype
- +12 more criteria
You may not qualify if:
- 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
- HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with RO4929097; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy
- Cardiovascular: baseline QTcF \> 450 msec (male) or QTcF \> 470 msec (female)
- Patients whose tumor contains a mutation in KRAS are not eligible for the phase I dose expansion portion of the study
- Patients with prior exposure to γ-secretase inhibitors
- Patients with another active malignancy
- +1 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (1)
Vanderbilt University/Ingram Cancer Center
Nashville, Tennessee, 37232, United States
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Emily Chan
Vanderbilt University/Ingram Cancer Center
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
September 9, 2010
First Posted
September 10, 2010
Study Start
September 1, 2010
Primary Completion
July 1, 2012
Last Updated
May 18, 2015
Record last verified: 2012-12