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A Phase I Dose-Escalation Study of the Hedgehog Smoothened Antagonist GDC-0449 (NSC # 747691) Plus Pan-Notch Inhibitor RO4929097 (NSC # 749225) Administered in Patients With Advanced Breast Cancer

Phase 1
18 Years
Open (Enrolling)
HER2-negative Breast Cancer, Recurrent Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Stage IV Breast Cancer

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Trial Information

A Phase I Dose-Escalation Study of the Hedgehog Smoothened Antagonist GDC-0449 (NSC # 747691) Plus Pan-Notch Inhibitor RO4929097 (NSC # 749225) Administered in Patients With Advanced Breast Cancer


I. To determine the safety and tolerability of continuous daily administration of 150 mg/day
of GDC0449 (vismodegib) in combination with escalating doses of RO4929097
(gamma-secretase/Notch signalling pathway inhibitor RO4929097) administered on a repeated
schedule of days 1-3, 8-10 every 21 days (for a total of 6 days of RO4929097 administration
per 21 day cycle) in patients with advanced breast cancer.

II. To determine the dose limiting toxicity (DLT) and identify the maximum tolerated dose
(MTD) and/or recommended phase 2 dose (RP2D) for this administration schedule.


I. To determine the pharmacokinetics (PK) and pharmacogenetics (PG) of GDC0449 and
RO4929097, each alone and in combination.

II. To attempt to evaluate select pharmacodynamic (PD) stem cell differentiation biomarkers
in the hedgehog and notch signaling pathways (e.g. GLI family zinc finger [Gli]1/2/3,
patched [Ptch] 1/2, hairy and enhancer of split 1, [Drosophila] [Hes1], huntingtin
interacting protein 1 [Hip1], hairy/enhancer-of-split related with YRPW motif 1 [Hey1],
Notch4, Jagged1, numb homolog [Drosophila] [numb], BMI1 polycomb ring finger oncogene
[Bmi-1], cluster of differentiation [CD]44/CD24, aldehyde dehydrogenase [ALDH]) and the
percentage of breast cancer stem cell (BCSC) in serial breast tumor biopsies before and
after GDC0449 or RO4929097 alone and after 1 cycle of treatment with the combination of
GDC0449 and RO4929097.

III. To determine tumor response in patients with measurable disease as assessed by the
Response Evaluation Criteria in Solid Tumors (RECIST).

IV. To perform molecular profiling of the tumor cell and BCSC populations before and after
GDC0449 or RO4929097 alone and after 1 cycle of treatment with the combination of GDC0449
and RO4929097 at the MTD.

OUTLINE: This is a dose-escalation study of gamma-secretase/Notch signalling pathway
inhibitor RO4929097.

Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 orally (PO) on
day 1 or days -2, -1, and 1 of course 1 and days 1-3 and 8-10 of course 2 and all subsequent
courses. Patients also receive vismodegib PO once daily (QD) beginning day 8 of course 1.
Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Inclusion Criteria:

- Patients must be women with histologically or cytologically confirmed advanced breast
cancer that is metastatic or unresectable and for which standard curative or
palliative measures do not exist or are no longer effective

- Patients must be human epidermal growth factor receptor 2 (Her-2) non-expressing (if
immunohistochemistry [IHC] 0 or 1+; fluorescent in situ [FISH] ratio less than 2; if
IHC 2+, FISH ratio must be less than 2.0); once the MTD has been determined, the
expansion phase will be limited to patients with ER, PR, and HER2 negative (i.e.
"triple negative") disease; Her-2 will be assessed as above; ER and PR are considered
negative if immunoperoxidase staining of tumor cell nuclei is <5%

- Patients must have measurable disease per Response Evaluation Criteria in Solid
Tumors (RECIST) guidelines or evaluable (non-measurable) disease

- Patients MUST have tumor accessible and suitable for serial biopsy with 4-6 passes of
a 16 or 18 gauge needle

- Patients must have Eastern Cooperative Oncology Group (ECOG) performance status =< 2
(Karnofsky >= 60%)

- Prior therapy:

- Patients must have failed at least 1 prior systemic therapy for metastatic or
locally advanced breast cancer

- IMPORTANT: Patients with chronic grade 1 or 2 toxicity may be eligible at the
discretion of the Principal Investigator (e.g. grade 2 chemo-induced
neuropathy); note that patients with ongoing alopecia of any grade will be

- Chemotherapy: Prior chemotherapy is allowed; patients must not have received
chemotherapy for 3 weeks prior to the initiation of study treatment and must
have full recovery from any acute effects of any prior chemotherapy; patients
must not have had nitrosoureas or mitomycin C for 6 weeks prior to the
initiation of study treatment

- Radiation: Prior radiation therapy is allowed; patients must not have received
minimal radiation therapy (≤ 5% of their total marrow volume) within 3 weeks
prior to the initiation of study treatment; otherwise, patients must not have
received radiation therapy (> 5% of their total marrow volume) within 4 weeks
prior to the initiation of study treatment; patients who have received prior
radiation to 50% or more of their total marrow volume will be excluded

- Other therapies: Prior experimental (non-FDA approved) therapies and
immunotherapies are allowed; patients must not have received these therapies for
30 days or five half lives of the drug prior to the initiation of study
treatment and must have full recovery from any acute effects of these therapies;
patients who have prior treatment with either a γ-secretase or hedgehog
inhibitor will be excluded from participating in this study

- Patients must not have received allogeneic stem cell transplant

- Patients must not have co-morbid condition(s) that, at the opinion of the
investigator, prevent safe treatment

- Patients must not have active infection or fever > 38.5*C

- Patients must not be human immunodeficiency virus (HIV)+, hepatitis B+ or hepatitis
C+ (active or previous treatment)

- All patients must provide archival tissue block or paraffin sample from archival
tissue block (approximately 10 sections) for use in pharmacodynamic and
pharmacogenomic correlative studies

- Patients must agree to undergo a total of three serial biopsies for research purposes

- Patients with brain metastases will be eligible if condition is treated and stable
for >= 1 month

- Patients must have a life expectancy of greater than 12 weeks

- Hemoglobin >= 9 g/dL

- Absolute neutrophil count (ANC) >= 1,500/mcL

- Platelets (PLT) >= 100,000/mcL

- Aspartate aminotransferase (AST), alanine aminotransferase (ALT) =< 2.5 x upper limit
of normal (ULN); if liver metastases are present, =< 5 x ULN

- Alkaline phosphatase =< 2.0 x ULN; if bone or liver metastases are present, =< 5 x

- Bilirubin =< 1.5 x ULN

- Creatinine =< 1.5 x ULN OR calculated or measured creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine above institutional normal

- Women of childbearing potential 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

- 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 or GDC-0449
(serum or urine); a pregnancy test (serum or urine) will be administered every
cycle 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 study drug; a positive urine test must be confirmed by a serum pregnancy
test; prior to dispensing study drug, 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 and GDC-0449

- 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

- Patient must have the ability to understand and the willingness to sign a written
informed consent document

- Patients must have a corrected QT (QTc) interval of =< 470 ms as measured by
electrocardiogram (ECG) using Bazett's formula

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 3 weeks (4 weeks for those
who received radiation therapy of > 5% of their total marrow volume; 6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events >= grade 2 due to agents administered more than 3 weeks
earlier; patients who have been administered GDC-0449 or RO4929097 as part of a
single or limited dosing study, such as a phase 0 study, should not necessarily be
excluded from participating in this study solely because of receiving prior GDC-0449
or RO4929097

- Patients may not have received any other investigational agents within the preceding
30 days or five half lives of the drug and must have full recovery from any acute
effects of these investigational therapies

- Patients must not have received prior treatment with either a gamma-secretase or
hedgehog inhibitor

- Patients with a requirement for antiarrhythmics or other medications known to prolong
corrected QT interval (QTc)

- Patients must not receive any other anti-cancer therapy (cytotoxic, biologic,
radiation, or hormonal other than for replacement) while on this study except for
medications that are prescribed for supportive care but may potentially have an
anti-cancer effect (i.e. megestrol acetate, bisphosphonates); these medications must
have been started 1 month prior to enrollment on this study

- Patients with a prior history of seizures

- Patients with known active brain metastases will be excluded from this clinical
trial; patients with prior treated brain metastases (treated and stable for >= 1
month) are allowed, providing that they were not accompanied by seizures and that a
baseline brain magnetic resonance imaging (MRI) scan prior to study entry
demonstrates no current evidence of progressive brain metastases

- Any patient requiring chronic maintenance of white blood cell counts or granulocyte
counts through the use of growth factor support (e.g. Neulasta, Neupogen)

- HIV-positive patients on combination antiretroviral therapy are ineligible

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with GDC-0449 or RO4929097

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

- Patients with clinically active liver disease, including active viral or other
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

- GDC is a cytochrome P450 2C9 (CYP2C9) inhibitor; CYP2C9 is an enzyme that metabolizes
warfarin sodium (Coumadin) into an inactive metabolite; patients who are on warfarin
anticoagulation are allowed to participate as long as they fit the following 4

- They are therapeutic on a stable warfarin dose

- Their international normalized ratio (INR) target range is no greater than 3

- They are monitored with weekly INR testing

- They have no active bleeding or pathological condition that carries high risk of

- Other anticoagulants, including enoxaparin (Lovenox) and fondaparinux (Arixtra)
are also permitted

- Caution should be exercised when dosing RO4929097 and GDC-0449 concurrently with
CYP2C8, CYP2C9, CYP2C19, and CYP3A4 substrates; furthermore, patients who are taking
concurrent medications that are strong inducers/inhibitors or substrates of CYP2C8,
CYP2C9, CYP2C19, and CYP3A4 should be switched to alternative medications to minimize
any potential risk; investigators will make every effort to switch to another agent
and assess the eligibility of the patient to participate in this study

- Baseline QTc > 470 msec by ECG using Bazett's formula

- Patients without accessible tumor or who refuse serial biopsies

Type of Study:


Study Design:

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

Outcome Measure:

Occurrence of adverse events and the associated NCI CTCAE grade

Outcome Time Frame:

Up to 30 days after completion of study treatment

Safety Issue:


Principal Investigator

Patricia LoRusso

Investigator Role:

Principal Investigator

Investigator Affiliation:

Barbara Ann Karmanos Cancer Institute


United States: Food and Drug Administration

Study ID:




Start Date:

August 2011

Completion Date:

Related Keywords:

  • HER2-negative Breast Cancer
  • Recurrent Breast Cancer
  • Stage IIIB Breast Cancer
  • Stage IIIC Breast Cancer
  • Stage IV Breast Cancer
  • Breast Neoplasms



Johns Hopkins UniversityBaltimore, Maryland  21205
University of Michigan Comprehensive Cancer CenterAnn Arbor, Michigan  48109-0752
Barbara Ann Karmanos Cancer InstituteDetroit, Michigan  48201
Dana-Farber Harvard Cancer CenterBoston, Massachusetts  02115