Gamma-Secretase Inhibitor RO4929097 in Treating Patients With Metastatic or Unresectable Solid Malignancies

Inclusion Criteria:

• Histologically or cytologically confirmed solid malignancy

  • Metastatic or unresectable disease
  • Standard curative or palliative measures do not exist or are no longer effective
• Measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT scan
• No known brain metastases
• ECOG performance status (PS) 0-1 (Karnofsky PS 70-100%)
• Life expectancy > 12 weeks
• Leukocytes ≥ 3,000/mm^3
• ANC ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥ 9 g/dL
• Total bilirubin normal
• AST/ALT ≤ 2.5 times upper limit of normal
• Serum creatinine normal OR creatinine clearance ≥ 60 mL/min
• No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or hypokalemia, defined as < lower limit of normal despite adequate electrolyte supplementation
• QTc ≤ 450 msec in males and a QTc ≤ 470 in females, as measured by ECG using Bazett's formula
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use 2 forms of contraception (i.e., barrier contraception and 1 other method of contraception) for ≥ 4 weeks before, during, and for ≥ 12 months after completion of study treatment
• Willing to undergo 2 tumor biopsies (unless medically contraindicated)
• Able to swallow medication
• No malabsorption syndrome or other condition that would interfere with intestinal absorption
• No diarrhea ≥ grade 2 not under control with standard antidiarrhea medications

• No uncontrolled concurrent illness including, but not limited to, any of the following:

  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia other than chronic, stable atrial fibrillation
  • Psychiatric illness or social situations that would limit compliance with study requirements

• No history of risk factors for QT interval prolongation including, but not limited to, a family or personal history of any of the following:

  • Long QT syndrome
  • A history of torsades de pointes
  • Recurrent syncope without known etiology
  • Sudden unexpected death
• Female patients may not donate ova during or after study treatment
• No blood donation during and for ≥ 12 months after completion of study treatment
• No serologic positivity for hepatitis A, B, or C; history of liver disease; or other forms of hepatitis or cirrhosis
• No HIV-positive patients on combination antiretroviral therapy
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to gamma-secretase inhibitor RO4929097 or other agents used in this study
• No other concurrent agents or therapies administered with the intent to treat the patient's malignancy
• No prior gamma-secretase inhibitors
• Any number of prior treatment regimens allowed

• At least 4 weeks since prior radiotherapy or systemic therapy (6 weeks for prior carmustine or mitomycin C)

  • Exceptions may be made for low-dose, nonmyelosuppressive radiotherapy for symptomatic palliation
• Recovered from the adverse events due to prior therapy to < CTCAE grade 2 (except alopecia)
• No other concurrent investigational agents
• No concurrent medications with narrow therapeutic indices that are metabolized by cytochrome P450, including warfarin sodium (Coumadin®)
• No concurrent medications that are strong inducers/inhibitors or substrates of CYP3A4
• No concurrent medications or food that may interfere with the metabolism of gamma-secretase inhibitor RO4929097 including ketoconazole, grapefruit, or grapefruit juice
• No antiarrhythmics or other concurrent medications with known potential to prolong QT interval