Gamma-secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Advanced, Metastatic, or Recurrent Triple Negative Invasive Breast Cancer
Condition: Estrogen Receptor-negative Breast Cancer; HER2-negative Breast Cancer; Male Breast Cancer; Progesterone Receptor-negative Breast Cancer; Recurrent Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Triple-negative Breast Cancer
MeSH terms: Breast Neoplasms; Triple Negative Breast Neoplasms; Breast Neoplasms, Male; Recurrence
Intervention: gamma-secretase/Notch signalling pathway inhibitor RO4929097; laboratory biomarker analysis
Intervention description: Given orally; Correlative studies
Intervention MeSH terms: 2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 6.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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