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

Inclusion Criteria

• •Meets one of the following sets of criteria:
• •* Dose-escalation group:
• •* Histologically and/or cytologically confirmed solid malignancy
• •* Metastatic or unresectable disease
• •* Disease for which standard curative or palliative measures do not exist or are no longer effective
• •* Expansion group:
• •* Histologically and/or cytologically confirmed endometrial (endometrioid, uterine papillary serious carcinoma, or carcinosarcoma) or renal cell cancer
• •* Metastatic or unresectable disease
• •* Disease for which standard curative or palliative measures do not exist or are no longer effective
• •Measurable or non-measurable disease
• •* Measurable disease is 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 ≥ 90 g/L (or ≥ 9 g/dL)
• •Total bilirubin normal
• •AST/ALT ≤ 2.5 times upper limit of normal
• •Serum creatinine normal OR creatine clearance ≥ 60 mL/min
• •Fasting cholesterol ≤ 350 mg/dL (9.0 mmol/L)
• •Fasting triglycerides ≤ 400 mg/dL (4.56 mmol/L)
• •No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia or hypokalemia defined as less than the lower limit of normal for the institution, despite adequate electrolyte supplementation
• •* Note: it is acceptable to use corrected calcium when interpreting calcium levels
• •Not pregnant or nursing
• •Negative pregnancy test
• •Fertile patients must use two effective forms of contraception (i.e., barrier contraception and one other method of contraception) for ≥ 4 weeks before, during, and for ≥ 12 months after completion of study therapy
• •Able to swallow medication
• •No malabsorption syndrome or other condition that would interfere with intestinal absorption
• •No diarrhea ≥ grade 2 that is not under control with standard anti-diarrhea medications
• •No uncontrolled concurrent illness including, but not limited to, any of the following:
• •* Ongoing or active infection
• •* Symptomatic congestive heart failure
• •* Unstable anginal pectoris
• •* Cardiac arrhythmia other than chronic, stable atrial fibrillation
• •* Psychiatric illness or social situations that would limit compliance with study medications
• •QTc ≤ 450 msec in males and a QTc ≤ 470 msec in females, as measured by ECG using Bazett formula
• •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
• •* Torsades de pointes
• •* Recurrent syncope without known etiology
• •* Sudden unexpected death
• •No pre-existing significant pulmonary infiltrates of unknown origin
• •No serologic positivity for hepatitis A, B, or C or 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 temsirolimus
• •Female patients may not donate ova during or after study treatment
• •Male patients may not donate sperm during and for ≥ 12 months after completion of study treatment
• •Patients may not donate blood during and for ≥ 12 months after completion of study treatment
• •Any number of prior therapies allowed
• •Recovered from side effects of previous systemic anticancer therapy to \< CTCAE grade 2 toxicity (except alopecia)
• •Concurrent leuteinizing hormone-releasing hormone agonist allowed in patients with castration-resistant prostate cancer
• •No prior gamma-secretase inhibitor or any inhibitor of the PI3K/Akt/mTOR pathway
• •At least 4 weeks since prior radiotherapy or systemic therapy (6 weeks for carmustine, nitrosoureas, or mitomycin C)
• •* Exceptions may be made for low-dose, non-myelosuppressive radiotherapy for symptomatic palliation
• •No other concurrent investigational agents
• •No concurrent medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®)
• •No concurrent medications that are strong inducers, inhibitors, or substrates of CYP3A4
• •No antiarrhythmics or other concurrent medications with known potential to prolong QT interval
• •No concurrent food that may interfere with the metabolism of gamma-secretase inhibitor RO4929097, including grapefruit or grapefruit juice
• •No other concurrent anticancer agents or therapies