Gamma-secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Advanced, Metastatic, or Recurrent Triple Negative Invasive Breast Cancer

A Phase II Study of RO4929097 (IND 109291) in Advanced, Metastatic, or Recurrent Triple Negative Invasive Breast Carcinoma

This phase II clinical trial studies how well gamma-secretase/Notch signalling pathway inhibitor RO4929097 works in treating patients with advanced, metastatic, or recurrent triple negative invasive breast cancer. Gamma-secretase/Notch signalling pathway inhibitor RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To assess the antitumour activity of RO4929097 in recurrent and/or metastatic triple negative breast cancer through co-primary endpoints of overall response rate (ORR) using RECIST and 6-month progression-free survival rate (PFS).

SECONDARY OBJECTIVES:

I. To assess the antitumour activity of RO4929097 through secondary endpoints including: duration of radiologic response, progression-free and overall survival rates within the protocol defined follow-up period.

II. To assess the safety and tolerability of single agent RO4929097 in breast cancer.

III. To explore expression of Notch biomarkers in triple negative breast cancer and potential interaction with RO4929097 response and toxicity.

IV. To evaluate the downstream effects of RO4929097 in advanced triple negative breast cancer.

OUTLINE:

Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 orally (PO) once daily 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 for 30 days.

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed invasive breast carcinoma that is recurrent or metastatic; patients must have "triple negative" breast cancer, defined as estrogen/progesterone receptor negative (< 10% positive on IHC for the respective receptor) and HER2/neu negative (0 or 1+ on IHC or FISH-negative)
• 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
• Prior adjuvant, neoadjuvant and unlimited lines of chemotherapy for metastatic disease will be permitted; there must be at least a 4-week interval since the last chemotherapy or investigational treatment and a 2-week interval since radiotherapy or surgery
• Life expectancy of greater than 12 weeks
• ECOG performance status =< 2 (Karnofsky >= 60%)
• Hemoglobin >= 90 g/L
• Leukocytes >= 3.0 x 10^9/L
• Absolute neutrophil count >= 1.5 x 10^9/L
• Platelets >= 100x 10^9/L
• Total bilirubin =< 1.25 x upper limit of normal
• AST(SGOT)/ALT(SGPT) =< 1.5 x upper limit of normal (=< 5 X if liver metastases)
• Serum creatinine within normal institutional limits OR creatinine clearance >= 50 mL/min for patients with creatinine levels above institutional (using Crockcroft-Gault Formula)
• All radiology studies must be performed within 28 days prior to start of therapy
• 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 diabetes mellitus, 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
• No active malignancy at any other site
• Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
• Patients must be able to swallow pills
• 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
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study; at least 2 weeks must have elapsed since any surgery or radiotherapy

• Patients may not be receiving any other investigational agents

• Patients with known symptomatic brain metastases are excluded; patients with controlled brain metastases (no radiographic progression following radiation and/or surgical treatment and no neurological signs or symptoms) will be allowed but must NOT be currently taking corticosteroids (e.g. dexamethasone) to control neurologic symptoms of brain metastases; patients with signs or symptoms suggestive of brain metastasis are not eligible unless brain metastases are ruled out by CT or MRI

• 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 with suspicion of active Hepatitis A, B or C infection and a resulting positive serological result, or have a history of liver disease, or other forms of hepatitis / 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

• 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

• Patients known to be HIV-positive who are 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

• Patients with 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 torsade de pointes or other significant cardiac arrhythmias or the need for concomitant meds with known potential to prolong QT interval or antiarrhythmics

• Patients who have not recovered to < CTCAE grade 2 toxicities related to prior therapy are not eligible to participate in this study