Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Advanced Solid Tumors

Exclusion Criteria

• •Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered (=\< grade 1) from clinically significant adverse events due to agents administered more than 4 weeks earlier; prior palliative radiotherapy is allowed if greater than 2 weeks have elapsed and patient has also recovered to baseline or grade \< 1 from any treatment adverse effects
• •Patients may not be receiving any other investigational agents
• •History of allergic reactions attributed to compounds of similar chemical or biologic composition to RO4929097, or other agents used in study
• •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, and a history of torsades de pointes or other significant 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 gamma-secretase inhibitor 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
• •HIV-positive patients receiving 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 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; Note: it is acceptable to use corrected calcium when interpreting calcium levels
• •Patients must not be taking omeprazole or dextromethorphan, or be willing to take only the study dose and formulation on the PK days; patients who require or are likely to require therapeutic doses of these drugs are excluded
• •Patients must not be taking rifampin, ketoconazole, tolbutamide, or midazolam; patients who require or are likely to require therapeutic doses of these drugs are excluded
• •Patients must not be taking monoamine oxidase inhibitors, such as Clorgyline, Iproniazid, Isocarboxazid, Moclobemide, Nialamide, Pargyline, Phenelzine, Procarbazine, Rasagiline, Selegiline, Teloxantrone, or Tranylcypromine because of drug interactions with dextromethorphan
• •Patients must not have acute narrow-angle glaucoma or untreated open-angle glaucoma, as midazolam is contraindicated
• •Baseline QTcF \> 450 msec
• •Patients who are 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 malabsorption syndrome or other condition that would interfere with intestinal absorption; patients must be able to swallow tablets
• •Because opioid containing pain medications may be metabolized by the CYP3A4 pathway, patients should be monitored carefully to avoid toxicity and doses adjusted if necessary; subjects who would not tolerate adjustments in their opioid pain medications are excluded
• •Subjects with mild to severe skin exanthems are excluded
• •A requirement for antiarrhythmics or other medications known to prolong QTc