Overview

RO4929097 and Vismodegib in Treating Patients With Breast Cancer That is Metastatic or Cannot Be Removed By Surgery

Status:
Terminated
Trial end date:
2014-06-01
Target enrollment:
0
Participant gender:
All
Summary
This phase I trial studies the side effects and best dose of RO4929097 (gamma-secretase/Notch signalling pathway inhibitor RO4929097) when given together with vismodegib in treating patients with breast cancer that is metastatic or cannot be removed by surgery. RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as vismodegib, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving RO4929097 and vismodegib together may slow the growth of tumor cells and may be a more active treatment for advanced breast cancer.
Phase:
Phase 1
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
National Cancer Institute (NCI)
Treatments:
R04929097
Criteria
Inclusion Criteria:

- Patients must be women with histologically or cytologically confirmed locally 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 estrogen receptor (ER), progesterone
receptor (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 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 eligible

- 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-Food and Drug Administration [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
gamma-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 degree Celsius (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
pharmacogenomics 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 ULN

- 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
forward

- 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 =< 450 msec in males and a QTc =<
470 msec in females 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 toxicities related to prior therapy are not eligible to participate in
this study; 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
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 study

- 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
criteria:

- 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
bleeding.

- 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 > 450 msec in males and QTc > 470 msec in females by ECG using Bazett's
formula

- Patients without accessible tumor or who refuse serial biopsies