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A Phase II Study of RO4929097 (IND 109291) in Advanced Platinum Resistant Ovarian Cancer

Phase 2
18 Years
Open (Enrolling)
Recurrent Fallopian Tube Cancer, Recurrent Ovarian Epithelial Cancer, Recurrent Primary Peritoneal Cavity Cancer, Stage IV Fallopian Tube Cancer, Stage IV Ovarian Epithelial Cancer, Stage IV Primary Peritoneal Cavity Cancer

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Trial Information

A Phase II Study of RO4929097 (IND 109291) in Advanced Platinum Resistant Ovarian Cancer


I. To assess the antitumor activity of RO4929097 in recurrent and / or metastatic epithelial
ovarian cancer, fallopian tube cancer and primary peritoneal cancer by progression free
survival rate at the end of 4 cycles.


I. To assess the antitumor activity of RO4929097 through secondary endpoints including:
overall response rate and CA125 response rate (GCIC criteria).

II. To assess the safety of single agent RO4929097 in advanced platinum resistant ovarian,
fallopian tube and primary peritoneal cancers.

III. To explore expression of Notch biomarkers in advanced platinum resistant ovarian,
fallopian, and primary peritoneal cancers.

IV. To explore the impact of RO49097 on ascitic fluid circulating tumor cells.

OUTLINE: This is a multicenter study.

Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-3, 8-10, and
15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable

Blood and tumor tissue samples are collected for correlative studies. Ascitic fluid may also
be collected.

After completion of study therapy, patients are followed up every month for at least 1 year.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed ovarian epithelial
carcinoma, fallopian tube carcinoma, or primary peritoneal carcinoma that is
recurrent or metastatic; patients must have platinum resistant disease, as defined as
treatment free interval less than 6 months post completion of platinum-based

- 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

- OR patients must have evidence of progression based on an elevated CA-125
(defined as a value of > 2 x ULN documented on two separate determinations made
> 2 weeks apart, with the most recent being completed within 7 days prior to
start of study treatment) if the physical exam is normal and maximum lesion
diameter on the CT scan is < 20 mm with conventional techniques or as < 10 mm
with spiral CT scan

- Patients must have completed any prior chemotherapy, radiotherapy or surgery >= 4
weeks (6 weeks for nitrosoureas or mitomycin C) before study entry

- Prior radiotherapy is allowed provided that there is documented progression
(either locally or systemically)

- Patients may have had up to 2 prior lines of chemotherapy for recurrent or
metastatic disease

- Toxic effects from prior therapy must have resolved to grade 1 or less except
for peripheral neuropathy and alopecia

- Life expectancy of greater than 12 weeks

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

- Patients must have normal organ and marrow function as defined below (within 7 days
prior to start of study treatment):

- Hemoglobin >= 90 g/L

- Leukocytes >= 3.0 x 10^9/L

- Absolute neutrophil count >= 1.5 x 10^9/L

- Platelets >= 100 x 10^9/L

- Total bilirubin =< 2.5 ULN (institutional upper limit of normal)

- AST (SGOT)/ALT (SGPT) =< 1.5 x institutional upper limit of normal (=< 5 times the
ULN for patients with liver metastases)

- Creatinine within normal institutional limits OR creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal (using
Cockcroft-Gault Formula)

- All radiology studies must be performed =< 4 weeks prior to the start of therapy

- No serious medical conditions such as myocardial infarction within 6 months prior to
entry, congestive heart failure, unstable ventricular arrhythmia, uncontrolled
hypertension, uncontrolled diabetes mellitus, uncontrolled psychotic disorders,
serious infections, active peptic ulcer disease, psychiatric illness, or any other
medical conditions that might be aggravated by treatment or limit compliance

- Currently no active, second malignancy other than non-melanoma skin cancers

- NOTE: Patients are not considered to have a "current active" malignancy if they
have completed anti-cancer therapy and are considered by their physician to be
at less than 30% risk of relapse

- Absence of any psychological, familial, sociological or geographical condition
potentially hampering compliance with the study protocol and follow-up schedule;
those conditions should be discussed with the patient before registration in the

- The effects of RO4929097on the developing human fetus at the recommended therapeutic
dose are unknown; for this reason and because 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; if women of childbearing potential
do not abstain* from sexual activity they must use two forms of contraception (i.e.,
barrier contraception and one other method of contraception) at least 4 weeks prior
to study entry; women of childbearing potential can either be abstinent or use two
forms of contraception 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 is participating in this study and for 12 months after study participation,
the patient should inform the treating physician immediately

- Abstinent from sexual activity at least 4 weeks prior to study entry

- Pregnancy Testing: 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 or clinical staff must confirm
and document the patient's use of two contraceptive methods or abstinence, 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

- Pre-pubertal females; the parent or guardian of young female patients who
have not yet started menstruation should verify that menstruation has not
begun; if a young female patient reaches menarche during the study, then
she is to be considered as a woman of childbearing potential from that time

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

Exclusion Criteria:

- 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 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; 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, bowel obstruction, or other condition that
would interfere with intestinal absorption; patients must be able to swallow tablets

- Patients who are serologically positive for Hepatitis A, B or C, or have a history of
liver disease, other forms of hepatitis or cirrhosis are ineligible

- 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, 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

- Known 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 (within 7 days prior to start of study treatment): baseline QTc > 470
msec (female), QTc > 450 msec (male)

- History of risk factors for QT interval prolongation, including, but not limited
to family or personal history of long QT syndrome, recurrent syncope without
known etiology or sudden unexpected death

- History of torsade de pointes or other significant cardiac arrhythmias or the
need for concomitant meds with known potential to prolong QT interval or

Type of Study:


Study Design:

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

Outcome Measure:

Progression-free survival rate (symptomatic, RECIST progression, CA-125 progression)

Outcome Time Frame:

84 days (4 courses)

Safety Issue:


Principal Investigator

Amit Oza

Investigator Role:

Principal Investigator

Investigator Affiliation:

University Health Network-Princess Margaret Hospital


United States: Food and Drug Administration

Study ID:




Start Date:

July 2010

Completion Date:

Related Keywords:

  • Recurrent Fallopian Tube Cancer
  • Recurrent Ovarian Epithelial Cancer
  • Recurrent Primary Peritoneal Cavity Cancer
  • Stage IV Fallopian Tube Cancer
  • Stage IV Ovarian Epithelial Cancer
  • Stage IV Primary Peritoneal Cavity Cancer
  • Ovarian Neoplasms
  • Peritoneal Neoplasms
  • Fallopian Tube Neoplasms
  • Neoplasms, Glandular and Epithelial



University of Chicago Comprehensive Cancer Center Chicago, Illinois  60637-1470