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A Phase 2 Open-Label Study of RO4929097 in Metastatic Colorectal Cancer

Phase 2
18 Years
Not Enrolling
Recurrent Colon Cancer, Recurrent Rectal Cancer, Stage IV Colon Cancer, Stage IV Rectal Cancer

Thank you

Trial Information

A Phase 2 Open-Label Study of RO4929097 in Metastatic Colorectal Cancer


I. To determine the objective radiographic response rate associated with RO4929097 in
patients with metastatic colorectal cancer who have progressed following at least two prior
treatments in the metastatic setting.


I. To determine the progression-free survival (PFS) and overall survival (OS) associated
with this agent.

II. To determine the safety and tolerability of RO4929097 in this patient population.

III. To assess whether response correlates with up regulation of the Notch pathway, to be
determined through immunohistochemical analysis of Notch1, ICN and HES1 on available
paraffin-embedded tissue samples (exploratory aim).


Participants will take 20 mg of RO4929097 by mouth at home in the morning for 3 days and
then not take it for 4 days, continuously. The tablet is to be taken at approximately the
same time the days they take it on an empty stomach, 1 hour before a meal or 2 hours after a
meal. Participants will be asked to keep a "pill diary" recording each dose of study drug
(including missed, skipped, or vomited doses) and return the diary to the study staff each
visit. Participants will be informed that tablets should not be broken or opened; that they
should avoid eating grapefruits or drinking grapefruit juice while on the study; that if
they miss a dose of study drug, they should not try to make up that dose; that instead, they
should wait until their next scheduled dose. Participants will see their study doctor and
undergo standard blood work (approximately 12 mL) every 4 weeks. During these visits,
participants will be asked about side effects of the RO4929097 and undergo a physical
examination. Participants will continue taking the RO4929097 as long as they are tolerating
it and as long as the cancer is shrinking or remains stable.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed colorectal cancer (NOS
10010029) with evidence of stage 4 disease (distant metastases)

- 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 for
non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional
techniques or as >= 10 mm with spiral CT scan

- Patients must have received at least two prior lines of treatment in the metastatic
setting; patients must have received 5-Fluorouracil (5-FU) or capecitabine,
oxaliplatin and irinotecan, either in the adjuvant or metastatic setting; at least 4
weeks must have elapsed since prior chemotherapy or radiation therapy (6 weeks if the
last regimen included mitomycin C)

- Life expectancy of greater than 3 months

- ECOG performance status =<2 (Karnofsky >= 60%)

- Absolute neutrophil count >= 1,000/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 9 g/dL

- Total bilirubin =< 1.5 x institutional upper limit of normal

- AST(SGOT)/ALT(SGPT) =< 2.5 x institutional upper limit of normal (or =< 5 x
institutional upper limit of normal in patients with liver metastases)

- Creatinine =< 1.5 x institutional upper limit of normal

- The effects of RO4929097 on the developing human fetus at the recommended therapeutic
dose are unknown; Notch signal pathway inhibitors are known to cause interruption of
the embryonic signaling pathway and may lead to serious or life-threatening birth
defects, including brain deformities, facial malformation, heart problems, or
abnormal organs; therefore, 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 3 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 3 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) will
be administered every 4 weeks if their menstrual cycles are regular or every 2 weeks
if their cycles are irregular while on study; 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 potential of RO4929097 to cause serious or life-threatening birth defects; 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

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
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 may not be receiving any other investigational agents

- Patients with known brain or leptomeningeal 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

- Patients receiving any medications or substances that are inhibitors or inducers of
CYP3A4 are ineligible

- Patients with malabsorption syndrome or other condition that would interfere with
intestinal absorption; patients must be able to swallow tablets

- Known history of cirrhosis or clinically significant liver dysfunction

- Clinically significant hypocalcemia, hypomagnesemia or hypophosphatemia despite
electrolyte supplementation

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, 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 serious or life-threatening birth defects 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; appropriate studies will be undertaken in patients
receiving combination antiretroviral therapy when indicated

- Cardiovascular: baseline QTcF > 450 msec (male) or QTcF > 470 msec (female)

- Patients who have not recovered to < CTCAE grade 2 toxicities related to prior
therapy are not eligible to participate in this study

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Number of Participants With Objective Radiographic Response (ORR)

Outcome Description:

To determine the objective radiographic response rate associated with RO4929097 in patients with metastatic colorectal cancer who have progressed following at least 2 prior treatments in the metastatic setting. Radiologic assessment of tumor burden (CT scans of the chest, abdomen and pelvis, or MRI of the abdomen and pelvis and CT of the chest) was scheduled every 8 weeks. Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) were used for evaluation of the primary endpoint.

Outcome Time Frame:

2 months from enrollment for each participant

Safety Issue:


Principal Investigator

Jonathan Strosberg

Investigator Role:

Principal Investigator

Investigator Affiliation:

H. Lee Moffitt Cancer Center and Research Institute


United States: Food and Drug Administration

Study ID:




Start Date:

May 2010

Completion Date:

Related Keywords:

  • Recurrent Colon Cancer
  • Recurrent Rectal Cancer
  • Stage IV Colon Cancer
  • Stage IV Rectal Cancer
  • Colonic Neoplasms
  • Rectal Neoplasms
  • Colorectal Neoplasms



H. Lee Moffitt Cancer Center and Research Institute Tampa, Florida  33612