RO4929097 and Whole-Brain Radiation Therapy or Stereotactic Radiosurgery in Treating Patients With Brain Metastases From Breast Cancer
Condition: Estrogen Receptor-negative Breast Cancer; Extensive Stage Small Cell Lung Cancer; HER2-negative Breast Cancer; HER2-positive Breast Cancer; Male Breast Cancer; Recurrent Breast Cancer; Recurrent Melanoma; Recurrent Non-small Cell Lung Cancer; Recurrent Small Cell Lung Cancer; Stage IV Breast Cancer; Stage IV Melanoma; Stage IV Non-small Cell Lung Cancer; Tumors Metastatic to Brain; Unspecified Adult Solid Tumor, Protocol Specific
MeSH terms: Breast Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Melanoma; Small Cell Lung Carcinoma; Brain Neoplasms; Breast Neoplasms, Male; Recurrence
Intervention: Gamma-secretase/Notch signalling pathway inhibitor RO4929097; Whole-brain radiation therapy (WBRT); Stereotactic radiosurgery (SRS); Cognitive assessment; Laboratory biomarker analysis
Intervention description: Given PO; Undergo WBRT; Undergo SRS; Ancillary studies; 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 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 5.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This randomized phase I/II trial studies the side effects and the best dose of RO4929097
      (gamma-secretase/Notch signalling pathway inhibitor RO4929097) when given together with
      whole-brain radiation therapy or stereotactic radiosurgery and to see how well it works
      compared to whole-brain radiation therapy or stereotactic radiosurgery alone in treating
      patients with breast cancer or other cancers (such as lung cancer or melanoma) that have
      spread to the brain. RO4929097 may stop the growth of tumor cells by blocking some of the
      enzymes needed for cell growth. Whole-brain radiation therapy uses high energy x-rays deliver
      radiation to the entire brain to treat tumors that can and cannot be seen. Stereotactic
      radiosurgery may be able to deliver x-rays directly to the tumor and cause less damage to
      normal tissue. It is not yet known whether giving RO4929097 together with whole-brain
      radiation therapy or stereotactic radiosurgery may kill more tumor cells.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients who have histologically or cytologically confirmed breast cancer or other
             cancers (such as lung cancer, melanoma, etc) with newly diagnosed metastatic disease
             to the brain will be eligible for the Phase 1 study only, however, those patients who
             have available systemic therapeutic options with a demonstrated survival benefit will
             not be eligible; for Phase 2, patients must have histologically or cytologically
             confirmed estrogen receptor negative breast cancer with newly diagnosed metastatic
             disease to the brain

          -  Patients must have measurable disease in the brain, defined as at least one lesion
             that can be accurately measured in at least two dimensions (longest diameter and its
             longest perpendicular diameter to be recorded)

          -  There is no limit on type or number of prior therapies, except that prior therapy with
             notch inhibitors is not allowed, and patients should not have received prior cranial
             radiation; therapy naïve patients are eligible; at least 14 days (2 weeks) must have
             elapsed from any prior experimental therapy, chemotherapy or radiotherapy; toxicities
             from prior chemotherapy or radiotherapy should have resolved to < grade 2; patients
             with newly diagnosed brain metastases who have received therapeutic regimens with
             well-characterized, delayed toxicity (e.g. hematologic toxicity observed following
             carmustine [BCNU] or mitomycin C) will not receive experimental therapy until the
             patient has adequately recovered from all drug related toxicities

          -  Karnofsky performance status (KPS) >= 70%; Recursive Partitioning Analysis (RPA) class
             I or II; a small feasibility cohort of 10 RPA class III (KPS < 70%) patients may be
             enrolled, however these patients, if enrolled will not be included in the efficacy
             analysis

          -  Hemoglobin >= 9g/dL

          -  Absolute neutrophil count >= 1,000/mcL

          -  Platelets >= 100,000/mcL

          -  Total bilirubin within normal institutional limits

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =<
             2.5 x institutional upper limit of normal

          -  Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
             institutional upper limits of normal

          -  Creatinine within normal institutional limits OR creatinine clearance >= 60
             mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

          -  Tumor HER2/neu status may be positive or negative

          -  Women of childbearing potential and men must use two forms of contraception (i.e.,
             barrier contraception and one other method of contraception) 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; prior to dispensing RO4929097, the investigator must
             confirm and document the patient's agreement to the use of two contraceptive methods,
             dates of negative pregnancy test, and confirm the patient's understanding of the
             teratogenic potential of RO4929097

          -  Ability to understand and the willingness to sign a written informed consent document

          -  A tumor site (outside the central nervous system) for needle biopsy for research
             purposes is preferable

          -  Ability to swallow pills

        Exclusion Criteria:

          -  At least 14 days (2 weeks) must have elapsed from any prior experimental therapy,
             chemotherapy or radiotherapy; toxicities from prior chemotherapy or radiotherapy
             should have resolved to < grade 2

          -  Patients may not be receiving any other investigational agents

          -  Patients with leptomeningeal metastases should be excluded from this clinical trial

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to RO4929097

          -  Patients taking medications with narrow therapeutic indices that are metabolized by
             cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible

          -  Patients taking medications that are generally accepted by the QTdrugs.org Advisory
             Board to carry a risk of torsades de pointes, including antiemetics, are ineligible

          -  Preclinical studies indicate that RO4929097 is a substrate of CYP450 family 3,
             subfamily A, polypeptide 4 (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 who are known to be serologically positive for hepatitis A, B or C, or have a
             history of liver disease, other forms of 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

          -  Uncontrolled electrolyte abnormalities including hypocalcemia, hypomagnesemia, and
             hypokalemia; uncontrolled intercurrent illness including, but not limited to, ongoing
             or active infection, symptomatic congestive heart failure (New York Heart Association
             [NYHA] class III or IV), unstable angina pectoris, a history of torsades de pointes or
             other significant cardiac arrhythmias, stable atrial fibrillation, 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 RO4929097

          -  Cardiovascular: baseline QTcF > 450 msec (male) or QTcF > 470 msec (female)

          -  Patients who have not recovered to < Common Terminology Criteria for Adverse Events
             (CTCAE) grade 2 toxicities related to prior therapy are not eligible to participate in
             this study

          -  A requirement for antiarrhythmics or other medications known to prolong QTc