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A Phase 2 Study of RO4929097 (IND 109291) in Patients With Advanced Renal Cell Carcinoma (RCC, NOS 10038415) That Has Progressed After VEGF/VEGFR Directed Therapy

Phase 2
18 Years
Open (Enrolling)
Clear Cell Renal Cell Carcinoma, Recurrent Renal Cell Cancer, Stage IV Renal Cell Cancer

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Trial Information

A Phase 2 Study of RO4929097 (IND 109291) in Patients With Advanced Renal Cell Carcinoma (RCC, NOS 10038415) That Has Progressed After VEGF/VEGFR Directed Therapy


I. To assess the objective response rate of RO4929097 in patients with advanced kidney
cancer and failure of anti-VEGF directed therapy.


I. To assess the antitumor activity of RO4929097 through secondary endpoints including:
duration of radiologic response, rate of disease stabilizations, rate of tumor control rate
(CR+PR+SD), and progression-free & overall survival rates.

II. To assess the safety and tolerability of single agent RO4929097 in patients with
advanced RCC.

III. To explore expression of Notch biomarkers in RCC patients and their potential
interaction with RO4929097 response and toxicity.


Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 orally (PO) on
days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 12

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed predominant clear cell,
renal cell carcinoma, NOS, that is recurrent or metastatic

- 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; scans must be
completed within 4 weeks prior to starting study treatment

- Patients must have had one prior therapy for non-resectable renal cell carcinoma with
a VEGF/VEGFR targeted therapy (e.g. sunitinib, sorafenib, other VEGFR tyrosine kinase
inhibitor, or bevacizumab)

- Prior treatment with mTOR inhibitors (Everolimus, Temsirolimus, or rapamycin)
for non-resectable disease is permitted

- Prior immunotherapy is permitted

- Only one line of prior VEGF/VEGFR is permitted

- Life expectancy of greater than 3 months

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

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

- Hemoglobin >= 90 g/L

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

- Platelets >= 100 x 10^9/L

- Total bilirubin =< 1.25 x ULN

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

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

- Patients must have no serious medical conditions such as myocardial infarction within
6 months prior to entry, congestive heart failure, unstable angina, active
cardiomyopathy, unstable ventricular arrhythmia, uncontrolled hypertension,
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

- Patients must have no active malignancy at any other site

- Patients must be able to take oral medication and have no evidence of bowel

- The effects of RO4929097 on the developing human fetus at the recommended therapeutic
dose are unknown; for this reason and because Notch signal pathway inhibitors are
known to be teratogenic, if women of childbearing potential do not abstain from
sexual activity (documentation that they have been abstinent from sexual activity at
least 4 weeks prior to study entry) 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 be can either be abstinent or use two
forms of contraception for the duration of study participation, and be either
abstinent or use two forms of contraception for at least 12 months post-treatment;
men must use condoms when sexually active with women for the duration of study
participation and 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

- 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
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

- 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 must not have had major surgery, chemotherapy, or radiation therapy within 4
weeks of starting the study treatment (6 weeks for nitrosoureas or mitomycin C);
prior palliative radiotherapy to metastatic lesion(s) is permitted, provided there is
at least one measurable lesion that had not been irradiated; patients must have
recovered from the toxic effects from any prior therapy to =< grade 1, except

- Patients may not be receiving any other investigational agents concurrently

- Patients with controlled brain metastases (no radiographic progression following
radiation and/or surgical treatment and no neurological signs or symptoms) that are
clinically and radiologically stable for at least 6 months will be allowed but must
NOT be currently taking corticosteroids (e.g. dexamethasone) to control neurologic
symptoms of brain metastases

- Patients with unstable or symptomatic brain metastases, spinal core compression,
or carcinomatosis meningitis, or evidence of brain or leptomeningeal disease on
screening CT or MRI scan are excluded

- 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; 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 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 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

- 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: baseline (within 7days prior to starting study treatment) QTc > 450
msec (male) or QTc > 470 msec (female)

- 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 Torsades 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:

Objective response rate (PR + CR) using RECIST

Outcome Description:

Summary statistics, such as the mean, median, counts and proportion, will be used to summarize the patients. Potential association between variables will be measured using Pearson correlation coefficients, chi-square tests, one- or two-sample t-tests or logistic regression analyses as appropriate. Non-parametric tests such as Spearman correlation coefficients, Fisher's exact tests and Wilcoxon rank sum tests may be substituted if necessary. Ninety-five percent confidence intervals will be constructed and selected results will be illustrated using figures and plots.

Outcome Time Frame:

Up to 12 months

Safety Issue:


Principal Investigator

Christian Kollmannsberger

Investigator Role:

Principal Investigator

Investigator Affiliation:

University Health Network-Princess Margaret Hospital


United States: Food and Drug Administration

Study ID:




Start Date:

June 2010

Completion Date:

Related Keywords:

  • Clear Cell Renal Cell Carcinoma
  • Recurrent Renal Cell Cancer
  • Stage IV Renal Cell Cancer
  • Carcinoma
  • Carcinoma, Renal Cell