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A Phase 1 Study of Neoadjuvant Chemotherapy With The Gamma Secretase Inhibitor RO4929097 in Combination With Paclitaxel And Carboplatin In Patients With Clinical Stage II-III Triple Negative Breast Cancer

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

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Trial Information

A Phase 1 Study of Neoadjuvant Chemotherapy With The Gamma Secretase Inhibitor RO4929097 in Combination With Paclitaxel And Carboplatin In Patients With Clinical Stage II-III Triple Negative Breast Cancer


I. To determine the maximum-tolerated dose (MTD) and dose limiting toxicity (DLT) of
RO4929097 (gamma-secretase/Notch signalling pathway inhibitor RO4929097) given 3 days on, 4
days off in combination with weekly paclitaxel and every 3 weeks carboplatin that will not
cause a 30% or more decrease in paclitaxel AUC0-24hr on day 15 compared to day-1 in patients
with clinical stage II-III triple negative breast cancer (TNBC).


I. To measure real-time pharmacokinetics of RO4929097 when administered in combination with
paclitaxel and carboplatin in patients with stage II or III TNBC.

II. To measure real-time pharmacokinetics of paclitaxel when administered in combination
with RO4929097 and carboplatin in patients with stage II or III TNBC.

III. To evaluate the rate of pathologic and clinical complete response to the combination of
RO492097, paclitaxel, and carboplatin in patients with clinical stage II or III TNBC.

OUTLINE: This is a dose-escalation study of gamma secretase inhibitor RO4929097 (RO4929097).

Patients receive oral gamma-secretase/Notch signalling pathway inhibitor RO4929097 once
daily on days 1-3, 8-10, and 15-17, paclitaxel IV over 60 minutes on days 1, 8, and 15 (day
-1 of course one), and carboplatin IV over 60 minutes on day 1. Treatment repeats every 21
days for 6 courses in the absence of disease progression or unacceptable toxicity. Within 4
weeks after completion of neoadjuvant therapy, patients undergo definitive breast surgery.

Patients undergo blood sample collection at baseline and periodically during study for
pharmacokinetic studies.

After completion of study therapy, patients are followed up for 1 year.

Inclusion Criteria:

- Histologically confirmed breast cancer meeting the following criteria:

- HER2-negative by any of the following:

- IHC 0-1+ without fluorescence in situ hybridization (FISH)

- IHC2+ with negative FISH

- HER2/CEP17 < 2.0 if only FISH is done

- Hormone receptor-negative

- Estrogen receptor-negative (ER-) and progesterone receptor-negative (PR-)
by IHC present in < 10% of invasive cancer cells

- Clinical stage II or III disease

- Measurable disease

- Clinically or radiologically measurable primary breast cancer tumor ≥ 2.0 cm

- No inflammatory breast cancer

- No history of invasive breast cancer treated with systemic chemotherapy

- History of ductal carcinoma in situ or lobular carcinoma in situ allowed

- Menopausal status unknown

- ECOG performance status (PS) 0-1 (Karnofsky 90-100%)

- WBC ≥ 3,000/mm³

- ANC ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Hemoglobin ≥ 9 g/dL

- Total bilirubin normal

- AST and ALT < 2.5 times upper limit of normal (ULN)

- Creatinine < 1.5 times ULN OR creatinine clearance ≥ 60 mL/min

- Fertile patients must use two forms of contraception (i.e., barrier contraception
and one other method of contraception) ≥ 4 weeks prior to, during, and for ≥ 12
months after study treatment

- Negative pregnancy test

- Not pregnant or nursing

- Ability to swallow pills

- At least 5 years since other malignancy except for curatively treated carcinoma in
situ of the cervix, carcinoma in situ of the colon, melanoma in situ, and basal or
squamous cell carcinoma of the skin

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

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

- Not serologically positive for hepatitis A, B, or C

- No history of liver disease, other forms of hepatitis, or cirrhosis

- No uncontrolled electrolyte abnormalities including hypocalcemia, hypomagnesemia, and

- No symptomatic congestive heart failure, unstable angina pectoris, and a history of
torsades de pointes or other significant cardiac arrhythmias

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

- Ongoing or active infection

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

- No baseline QTc > 450 msec in males or QTc > 470 in females

- No peripheral neuropathy ≥ grade 2

- No requirement for antiarrhythmics or other medications known to prolong QTc

- No prior radiotherapy, chemotherapy, or biotherapy for currently diagnosed breast

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

- 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
CYP3A4 or CYP2C8

- Switching to alternative medications allowed

- No concurrent combination antiretroviral therapy for HIV-positive patients

Type of Study:


Study Design:

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

Outcome Measure:

MTD of gamma-secretase/Notch signalling pathway inhibitor RO4929097 based on DLT as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.0

Outcome Description:

Analysis will consist of descriptive statistics only. Frequency will be computed for discrete variables with 95% confidence intervals for the proportion.

Outcome Time Frame:


Safety Issue:


Principal Investigator

Ewa Mrozek

Investigator Role:

Principal Investigator

Investigator Affiliation:

Ohio State University


United States: Food and Drug Administration

Study ID:




Start Date:

December 2010

Completion Date:

Related Keywords:

  • Estrogen Receptor-negative Breast Cancer
  • HER2-negative Breast Cancer
  • Male Breast Cancer
  • Progesterone Receptor-negative Breast Cancer
  • Stage II Breast Cancer
  • Stage IIIA Breast Cancer
  • Stage IIIB Breast Cancer
  • Stage IIIC Breast Cancer
  • Triple-negative Breast Cancer
  • Breast Neoplasms
  • Breast Neoplasms, Male



Ohio State University Medical CenterColumbus, Ohio  43210