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

• Status: Completed
• Trial end date: 2013-10-01
• Target enrollment: 0
• Participant gender: All

Summary

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: National Cancer Institute (NCI)
• Treatments: Everolimus; R04929097; Sirolimus

Criteria

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