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A Phase Ib Neoadjuvant Study of the Gamma Secretase Inhibitor (RO4929097) in Combination With the Aromatase Inhibitor Letrozole in Post-Menopausal Women With Stage II/III Hormone Receptor-Positive Breast Cancer

Phase 1
18 Years
Open (Enrolling)
Estrogen Receptor-positive Breast Cancer, HER2-negative Breast Cancer, Progesterone Receptor-positive Breast Cancer, Stage II Breast Cancer, Stage IIIA Breast Cancer

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Trial Information

A Phase Ib Neoadjuvant Study of the Gamma Secretase Inhibitor (RO4929097) in Combination With the Aromatase Inhibitor Letrozole in Post-Menopausal Women With Stage II/III Hormone Receptor-Positive Breast Cancer


I. To establish the maximum-tolerated dose and the recommended phase II dose of
gamma-secretase inhibitor RO4929097 (RO4929097) in combination with letrozole in
post-menopausal women with hormone receptor-positive stage II or III breast cancer.

II. To assess the safety of this regimen in these patients.


I. To evaluate the pharmacokinetics of this regimen, taking into consideration the induction
of CYP3A4, in these patients.

II. To characterize the pharmacodynamic effects of letrozole prior to and during
administration of RO4929097 with attention to suppression of estradiol and estrone levels.

III. To describe the pharmacodynamic effects of letrozole with or without RO4929097 on the
NOTCH pathway, proliferation, angiogenesis, stromal cell infiltration/pathways, and
comprehensive genomic analysis in tumor tissue of these patients.

IV. To describe the response, including clinical complete or partial objective response,
pathological complete response, and attainment of pathologic stage 0 or I status in these

OUTLINE: This is a multicenter, dose-escalation study of gamma-secretase inhibitor

Patients receive oral letrozole once daily on days 1-21. Beginning in course 2, patients
also receive oral RO4929097 on days 1-3, 8-10, and 15-18. Treatment repeats every 21 days
for 6 courses in the absence of disease progression or unacceptable toxicity.

Beginning 1 week after completion of neoadjuvant therapy, patients undergo surgery or tumor
biopsy. Patients continue to receive oral letrozole once daily during surgery and for an
additional 4 weeks.

Blood and tumor tissue samples are collected at baseline and periodically during study for
pharmacokinetics, pharmacodynamics, and correlative studies.

After completion of study therapy, patients are followed up for 1 month and then every 6
months for 5 years.

Inclusion Criteria:

- Pathologically confirmed invasive breast cancer

- Stage II or III disease (T2-T3, N0-2)

- No N3, T4 disease

- Estrogen receptor-positive (ER+) and/or progesterone receptor-positive (PR+)

- H score ≥ 10 or positivity ≥ 10%

- HER2 negative as determined by IHC (1 or 2+) or FISH (< 2.0+)

- Bilateral disease allowed as long as all tumors are ER+ and ≥ 1 is T2-T3

- Patient must have disease that is palpable on physical exam and able to be imaged via
breast ultrasound

- Defined as ≥ 1 T2 tumor > 2 cm

- Multifocal disease allowed provided that ≥ 1 of the tumors is > 2 cm

- No metastatic disease by CT scans of the chest, abdomen, and pelvis, a PET/CT bone
scan, or nuclear medicine bone scan

- No inflammatory breast cancer or presence of breast tumor cells in the dermal
lymphatics of the breast

- Post-menopausal meeting 1 of the following criteria:

- Bilateral oophorectomy

- Age ≥ 50 years and amenorrheic for > 12 months in the absence of chemotherapy,
tamoxifen, toremifene, or ovarian suppression (spontaneous amenorrhea)

- ECOG performance status (PS) 0-2 (Karnofsky PS 60-100%)

- Life expectancy > 3 months

- ANC ≥ 1,000/mm³

- Platelet count ≥ 100,000/mm³

- Hemoglobin ≥ 9 g/dL

- Total bilirubin normal

- AST and ALT ≤ 2.5 times upper limit of normal

- Creatinine normal OR creatinine clearance ≥ 60 mL/min

- Baseline QTcF ≤ 470 msec

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to gamma secretase inhibitor RO4929097 or other agents used in
the study

- No malabsorption syndrome or other condition that would interfere with intestinal

- Able to swallow tablets

- Not serologically positive for hepatitis A, B, or C, or have a history of liver
disease, other forms of hepatitis, or cirrhosis

- No uncontrolled electrolyte abnormalities including hypocalcemia, hypomagnesemia,
hyponatremia, hypophosphatemia, or hypokalemia despite adequate electrolyte

- No uncontrolled intercurrent illness including, but not limited to, any of the

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- History of torsades de pointes or other significant cardiac arrhythmia other
than chronic, stable atrial fibrillation

- Psychiatric illness and/or social situations that would limit compliance with
study requirements

- Recovered to < grade 2 CTCAE toxicities related to prior therapy

- No prior chemotherapy, hormonal therapy, radiotherapy, or biological therapy for
breast cancer

- Prior treatment for non-melanoma skin cancer or carcinoma in situ of the cervix

- No prior hormone therapy for ductal carcinoma in situ (DCIS)

- No other concurrent investigational agents

- No concurrent medications with narrow therapeutic indices that are metabolized by
cytochrome P450 (CYP450), including warfarin sodium (Coumadin®)

- No concurrent medications that are strong inducers and/or inhibitors or substrates of

- Switching to alternative medications allowed

- No concurrent combination antiretroviral therapy for HIV-positive patients

- No concurrent antiarrhythmics or other medications known to prolong QTc

- No other concurrent anticancer agents or therapies

- No concurrent grapefruit juice

Type of Study:


Study Design:

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

Outcome Measure:

MTD defined as the dose level at which no more than 1 of 6 patients experience a DLT, and the dose below that at which at least 2/6 patients have DLT according to NCI CTCAE version 4.0

Outcome Time Frame:

21 days

Safety Issue:


Principal Investigator

Shannon Puhalla

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Pittsburgh


United States: Food and Drug Administration

Study ID:




Start Date:

November 2010

Completion Date:

Related Keywords:

  • Estrogen Receptor-positive Breast Cancer
  • HER2-negative Breast Cancer
  • Progesterone Receptor-positive Breast Cancer
  • Stage II Breast Cancer
  • Stage IIIA Breast Cancer
  • Breast Neoplasms



University of Pittsburgh Pittsburgh, Pennsylvania  15261
University of Alabama at Birmingham Birmingham, Alabama  35294-3300
Magee-Womens Hospital - University of Pittsburgh Medical Center Pittsburgh, Pennsylvania  15213