RO4929097 in Treating Patients With Advanced Non-Small Cell Lung Cancer Who Have Recently Completed Treatment With Front-Line Chemotherapy

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed non-small cell lungcancer that is incurable (stage IV or malignant effusion or recurrent)

• Patients must have measurable disease, defined as at least one lesion that can beaccurately measured in at least one dimension (longest diameter to be recorded) as >= 10 mm with CT scan with cuts at 2.5 or 5 mm

• Patients must have tumor amenable to core biopsy (or by incisional, excisional orpunch biopsy) for research purposes; the collaborating interventional radiologistswill make the determination whether or not the patient has a tumor amenable to biopsyand whether or not the patient is medically an appropriate candidate for tumor biopsy

• The patient must have received front line cytotoxic chemotherapy (combination orsingle agent, with or without the addition of targeted agents) for advanced NSCLC

• Patients will be eligible whether or not they have had a response or stable disease orprogression of tumor on the front line cytotoxic therapy, and whether or not they havetumor progression in the interval between their front line therapy and initiation oftherapy on this study

• Patients will also be eligible if they have received maintenance cytotoxicchemotherapy (eg pemetrexed) following completion of the front line chemotherapy,provided there had not been tumor progression between the end of the front linechemotherapy and the initiation of the maintenance chemotherapy

• Patients may also have received prior adjuvant chemotherapy or chemoradiotherapy withcurative intent (followed by tumor recurrence or progression) before being given thefront line therapy for advanced disease

• The last planned front-line therapy cycle or maintenance therapy cycle must have beenadministered >= 3 weeks (or >= 6 weeks after last therapy if it included a nitrosoureaor mitomycin-C) and =< 8 weeks prior to initiation of therapy on this study, althoughthey may be registered on study (prior to drug administration) any time from 0-8 weeksafter last planned front-line chemotherapy (to permit correlative studies to bearranged before therapy starts)

• ECOG performance status =< 2 (Karnofsky >= 60%)

• Leukocytes >= 3,000/mcL

• Absolute neutrophil count >= 1,000/mcL

• Platelets >= 100,000/mcL

• Total bilirubin within normal institutional limits

• AST(SGOT) and ALT(SGPT) =< 3 X institutional upper limit of normal

• Creatinine =< 1.5 X institutional upper limit of normal

• Hemoglobin ≥ 9 g/dL

• Since all patients on this study will undergo tumor biopsy, the patient must havecoagulation parameters in keeping with guidelines used by the Department ofInterventional Radiology at MD Anderson Cancer Center to decide whether or not apatient is suitable for biopsy; specifically, the patient must have an INR =< 1.7 xupper limit of normal (ULN), and the patient must not have received aspirin orcoumadin within the previous week or a therapeutic dose of a heparin product withinthe previous 24 hours

• The effects of RO4929097on the developing human fetus at the recommended therapeuticdose are unknown; for this reason and because Notch signal pathway inhibitors areknown to be teratogenic, women of childbearing potential must use two forms ofcontraception (i.e., barrier contraception and one other method of contraception) fromat least 4 weeks prior to initiation of therapy on this study, for the duration ofstudy participation, and for at least 2 months post-treatment; while it is unknown howlong after last drug administration drug that remains in the body would pose a risk toa subsequent pregnancy, the plasma half-life of the drug would suggest that it wouldprobably only be for a few days; should a woman become pregnant or suspect she ispregnant while she or her partner are participating in this study and for 2 monthsafter study participation, the patient should inform the treating physicianimmediately

• Women of childbearing potential are required to have a negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL) within 10-14 days and within 24 hours priorto the first dose of RO4929097 (serum or urine); following initiation of therapy withRO4929097, a pregnancy test (serum or urine) will be administered every 3 weeks whileon study; a positive urine test must be confirmed by a serum pregnancy test; prior todispensing RO4929097, the investigator or designate must confirm and document thepatient's use of two contraceptive methods, dates of negative pregnancy test, andconfirm the patient's understanding of the teratogenic potential of RO4929097

• Patients with lung cancer may have false-positive pregnancy tests due to production ofbeta-HCG by tumor; patients with a positive pregnancy test who are unlikely to bepregnant may be considered for entry on this trial if they are deemed to be unlikelyto be pregnant by an obstetrician or gynecologist and if the study sponsor is inagreement with their study entry

• Female patients of childbearing potential are defined as patients to whom any of thefollowing apply:

• Patients with regular menses

• Patients, after menarche with amenorrhea, irregular cycles, or using acontraceptive method that precludes withdrawal bleeding

• Women who have had tubal ligation

• Female patients may be considered to NOT be of childbearing potential for thefollowing reasons:

• The patient has undergone total abdominal hysterectomy with bilateralsalpingo-oophorectomy or bilateral oophorectomy

• The patient is medically confirmed to be menopausal (no menstrual period) for 24consecutive months

• Since there is a very small possibility that RO4929097 would reach high enoughconcentrations in semen of men participating in this study to pose a threat to a fetusbeing carried by their sexual partner, men participating in the study must also use 2methods of contraception including 1 barrier method from the time of initiation oftherapy on the study until 2 months after their last treatment on the study if theirsexual partner has childbearing potential; if their sexual partner is alreadypregnant, 1 barrier method must be used to minimize the probability of exposure of thefetus to potentially toxic concentrations of RO4929097; while teratogenicity fromexposure of a fetus to a drug in semen is a theoretical possibility, there has beenlittle documentation of this for any agent in humans, and it has been documented inanimals primarily only if the drug is present in semen at the time of fertilization;in addition, it is unknown how long the drug might remain detectable in semen;although the plasma half-life of the drug would suggest that its level in seminalfluids would probably be very low by a few days after last drug administration

• Because there is an unknown but potential risk for adverse events in nursing infantssecondary to treatment of the mother with RO4929097, breastfeeding should bediscontinued if the mother is treated with RO4929097

• With respect to patients with brain metastases, most drugs assessed reachconcentrations in brain metastases or in primary brain tumors that are comparable tothose in other tumor sites (although this has not yet been tested for RO4929097);furthermore, lung cancer brain metastases have response rates to systemic therapy thatare comparable to response rates in metastases in other sites, after correcting fornumber of organ systems involved by tumor, survival is not substantially different foradvanced NSCLC patients with vs without brain metastases, and risk of symptomatic CNShemorrhage is not substantially higher in NSCLC patients with vs without brainmetastases; brain metastases are very common in NSCLC; hence, patients withasymptomatic or minimally symptomatic brain metastases are eligible for this trialprovided it is not anticipated that they will require any of the following over thecourse of their participation in the trial:

• Corticosteroids for control of cerebral edema

• Enzyme-inducing anticonvulsants

• Radiotherapy, surgery or other local therapy for the brain metastases

• Patients must be able to swallow tablets

Exclusion Criteria:

• Patients may be registered on the protocol any time from 0-8 weeks afteradministration of last front-line therapy or maintenance therapy, but should notreceive their first treatment on this study until 3-8 weeks after administration oflast front-line therapy or maintenance therapy (or 6-8 weeks for prior nitrosoureas ormitomycin-C), and must have recovered adequately from adverse events to meet othereligibility criteria

• Patients may not be receiving any other investigational agents

• History of allergic reactions attributed to compounds of similar chemical or biologiccomposition to RO4929097 or other agents used in the study

• Patients taking medications with narrow therapeutic indices that are metabolized bycytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible

• Preclinical studies indicate that RO4929097 is a substrate of CYP3A4 and inducer ofCYP3A4 enzyme activity; caution should be exercised when dosing RO4929097 concurrentlywith CYP3A4 substrates, inducers, and/or inhibitors; furthermore, patients who aretaking concurrent medications that are strong inducers/inhibitors or substrates ofCYP3A4 should be switched to alternative medications to minimize any potential risk;if such patients cannot be switched to alternative medications, they will beineligible to participate in this study

• Patients with malabsorption syndrome or other condition that would interfere withintestinal absorption

• Diarrhea > grade 1 despite appropriate therapy

• Patients who are serologically positive for hepatitis A, B or C are ineligible

• Patients with > grade 1 (by CTCAE criteria) hyponatremia or hypocalcemia (based onmeasurement of ionized calcium), despite appropriate medical management are excludedfrom this study, as are patients with hypophosphatemia (serum phosphate below thelower limit of normal for the institution), hypomagnesemia, (serum magnesium below thelower limit of normal), hypokalemia, or hyperkalemia (serum potassium outside normallimits) despite appropriate medical management

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection requiring systemic therapy (with antibiotics, antiviral or antifungalagents), symptomatic congestive heart failure, unstable angina pectoris, angina atrest, a history of torsades des pointes, potentially life-threatening cardiacarrhythmias (patients are permitted to have chronic, stable atrial fibrillation,premature atrial or ventricular contractions, sinus tachycardia, provided the rate iscontrolled at < 115 per minute, and sinus bradycardia, provided the rate is > 50 perminute), myocardial infarction within the previous 3 months, or psychiatricillness/social situations that would limit compliance with study requirements

• Pregnant women are excluded from this study because RO4929097 is a Notch pathwayinhibiting agent with the potential for teratogenic or abortifacient effects

• HIV-positive patients on combination antiretroviral therapy are ineligible because ofthe potential for pharmacokinetic interactions with RO4929097

• Cardiovascular: baseline QTcF > 450 msec (male) or QTcF > 470 msec (female)

• Patients requiring drugs that are known to cause torsades des pointes and/or prolongedQTc intervals are excluded; patients requiring drugs with a possible but unprovenassociation with torsades des pointes and/or QTc prolongation may be eligible, butwill require additional electrocardiogram assessments

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