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