Safety and Efficacy of RO4929097 in Combination With Temsirolimus: A Pharmacokinetic and Pharmacodynamic Phase I Study in Patients With Advanced Solid Tumours With an Expansion of Cohort With Patients With Recurrent/Metastatic Endometrial and Renal Cell Cancers
Safety and Efficacy of RO4929097 in Combination With Temsirolimus: A Pharmacokinetic and Pharmacodynamic Phase I Study in Patients With Advanced Solid Tumours With an Expansion of Cohort With Patients With Recurrent/Metastatic Endometrial and Renal Cell Cancers
This phase I trial is studying the side effects and best dose of giving gamma-secretase/Notch signalling pathway inhibitor RO4929097 and temsirolimus together in treating patients with advanced solid tumors. Gamma-secretase/Notch signalling pathway inhibitor RO4929097 and temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
PRIMARY OBJECTIVES:
I. To determine the recommended phase II dose (RP2D) and safety profile of temsirolimus in combination with RO4929097 (gamma-secretase/Notch signalling pathway inhibitor RO4929097) in patients with advanced solid tumors.
SECONDARY OBJECTIVES:
I. To obtain pharmacokinetic (PK) profiles for both drugs when administered in combination in order to quantify the expected interactive effects in PK between these two agents.
II. To evaluate pharmacodynamic (PD) effects of both drugs when administered in combination, with the goal of identifying potential predictive and PD markers that need further exploration and validation in future trials.
OUTLINE: This is a multicenter, dose-escalation study.
Patients receive temsirolimus IV over 30 minutes on day -6 (course 1 only). Patients then receive temsirolimus IV or orally (PO) on days 1, 8, and 15 and gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Blood and tumor tissue samples may be collected periodically for pharmacokinetic and correlative analyses.
After completion of study treatment, patients are followed up for 4 weeks.
Inclusion Criteria:
Meets one of the following sets of criteria:
Dose-escalation group:
Expansion group:
Measurable or non-measurable disease
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
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:
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:
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)
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