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Phase I Study of Cetuximab With RO4929097 in Metastatic Colorectal Cancer

Phase 1
18 Years
Not Enrolling
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 IVA Colon Cancer, Stage IVA Rectal Cancer, Stage IVB Colon Cancer, Stage IVB Rectal Cancer

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Trial Information

Phase I Study of Cetuximab With RO4929097 in Metastatic Colorectal Cancer


I. Determination of the maximum tolerated dose (MTD) of the combination of cetuximab and


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.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed metastatic colorectal

- 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

- AST(SGOT)/ALT(SGPT) < 5 X institutional upper limit of normal if liver metastases are

- 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

- There must be available a tumor block or 20 unstained slides for correlative studies

- The effects of RO4929097on the developing human fetus at the recommended therapeutic
dose are unknown; for this reason and because Notch signal pathway inhibitors as well
as other therapeutic agents used in this trial are known to be teratogenic, women of
childbearing potential and men must use two forms of contraception (i.e., barrier
contraception and one other method of contraception) at least 4 weeks prior to study
entry, for the duration of study participation, and for at least 12 months
post-treatment; should a woman become pregnant or suspect she is pregnant while she
or her partner are participating in this study and for 12 months after study
participation, the patient should inform the treating physician immediately

- Women of childbearing potential are required to have a negative serum pregnancy
test (with a sensitivity of at least 25 mIU/mL) within 10-14 days and within 24
hours prior to the first dose of RO4929097 (serum or urine); a pregnancy test
(serum or urine) will be administered every 4 weeks if their menstrual cycles
are regular or every 2 weeks if their cycles are irregular while on study within
the 24-hour period prior to the administration of RO4929097; a positive urine
test must be confirmed by a serum pregnancy test; prior to dispensing RO4929097,
the investigator must confirm and document the patient's use of two
contraceptive methods, dates of negative pregnancy test, and confirm the
patient's understanding of the teratogenic potential of RO4929097

- Female patients of childbearing potential are defined as follows:

- Patients with regular menses

- Patients, after menarche with amenorrhea, irregular cycles, or using a
contraceptive method that precludes withdrawal bleeding

- Women who have had tubal ligation

- Female patients may be considered to NOT be of childbearing potential for the
following reasons:

- The patient has undergone total abdominal hysterectomy with bilateral
salpingo-oophorectomy or bilateral oophorectomy

- The patient is medically confirmed to be menopausal (no menstrual period)
for 24 consecutive months

- Ability to understand and the willingness to sign a written informed consent document

- Ability to swallow pills

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

- 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 ╬│-secretase inhibitors

- Patients with another active malignancy

- Patients on antiarrhythmics or other medications known to prolong QTc

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

MTD of RO4929097

Outcome Time Frame:

21 days

Safety Issue:


Principal Investigator

Emily Chan

Investigator Role:

Principal Investigator

Investigator Affiliation:

Vanderbilt-Ingram Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

September 2010

Completion Date:

Related Keywords:

  • 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 IVA Colon Cancer
  • Stage IVA Rectal Cancer
  • Stage IVB Colon Cancer
  • Stage IVB Rectal Cancer
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Colonic Neoplasms
  • Rectal Neoplasms
  • Cystadenocarcinoma
  • Colorectal Neoplasms



Vanderbilt-Ingram Cancer Center Nashville, Tennessee  37232-6838