A Phase I Study of R04929097 in Combination With Gemcitabine in Patients With Advanced Solid Tumors
A Phase I Study of R04929097 in Combination With Gemcitabine in Patients With Advanced Solid Tumors
This phase I trial is studying the side effects and best dose of gamma-secretase inhibitor RO4929097 when given together with gemcitabine hydrochloride in treating patients with advanced solid tumors. Gamma-secretase inhibitor RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving gamma-secretase inhibitor RO4929097 together with gemcitabine hydrochloride may kill more tumor cells.
PRIMARY OBJECTIVES:
I. To determine the safety profile and establish the maximum-tolerated dose and recommended phase II dose of gamma-secretase inhibitor RO4929097 in combination with gemcitabine hydrochloride in patients with advanced solid tumors.
SECONDARY OBJECTIVES:
I. To determine the pharmacokinetic profile of gamma-secretase inhibitor RO4929097 when given in combination with gemcitabine hydrochloride and to correlate the pharmacokinetic profile with toxicity and biological activity.
II. To assess the antitumor activity of gamma-secretase inhibitor RO4929097 and gemcitabine hydrochloride in patients with advanced solid tumors.
III. To correlate the expression of biomarkers of Notch signaling in archival tumor tissue with antitumor activity of gamma-secretase inhibitor RO4929097 in combination with gemcitabine hydrochloride.
OUTLINE: This is a multicenter, dose-escalation study of gamma-secretase inhibitor RO4929097.
Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-3, 8-10, 15-17, and 22-24 and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Plasma and blood samples may be collected periodically for pharmacokinetic studies and biomarker analysis.
After completion of study treatment, patients are followed up every 1 month for up to 1 year.
Inclusion Criteria:
Meets one of the following sets of criteria:
Histologically and/or cytologically confirmed solid malignancy
Histologically and/or cytologically confirmed adenocarcinoma of the pancreas (for patients in the expansion cohort)
Measurable disease, 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 60-100%)
Life expectancy > 12 weeks
Hemoglobin ≥ 90 g/L (or ≥ 9 g/dL)
Leukocytes ≥ 3,000/mm^3
ANC ≥ 1,500/mm^3
Platelet count ≥ 100,000/mm^3
Total bilirubin ≤ 1.25 times upper limit of normal (ULN)
AST/ALT ≤ 1.5 times ULN
Serum creatinine =< ULN OR creatinine clearance ≥ 60 mL/min
No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or hypokalemia, defined as less than the lower limit of normal despite adequate electrolyte supplementation
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use two forms of adequate contraception (i.e., barrier contraception and one other method of contraception) for ≥ 4 weeks before, during, and for ≥ 12 months after completion of study treatment
Able to swallow medication
No malabsorption syndrome or other condition that would interfere with intestinal absorption
No uncontrolled concurrent illness including, but not limited to, any of the following:
No baseline QTc > 450 msec (for male patients) or > 470 msec (for female patients)
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 history of torsade de pointes or other significant cardiac arrhythmias or the need for concomitant meds with known potential to prolong QT interval or antiarrhythmics
No diarrhea ≥ grade 2 not under control with standard anti-diarrhea medications
No serologic positivity for hepatitis A, B, or C
No history of liver disease or other forms of hepatitis or cirrhosis
No history of allergic reactions attributed to compounds of similar chemical or biologic composition to gamma-secretase inhibitor RO4929097 or to gemcitabine hydrochloride
Female patients may not donate ova during or after completion of 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
No other concurrent investigational or commercial agents or therapies administered with the intent to treat the patient's malignancy
Any number of prior therapies allowed
No prior therapy with a Notch inhibitor
At least 4 weeks since prior radiotherapy, chemotherapy, or systemic therapy (6 weeks if the last regimen included nitrosourea or mitomycin C) and recovered
Patients in the expansion cohort must meet the following criteria:
Recovered from side effects of previous systemic anticancer therapy to ≤ CTCAE grade 2
No concurrent combination antiretroviral therapy for HIV-positive patients
No concurrent medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®)
No concurrent medications with known potential to prolong QT interval
No concurrent medications that are strong inducers/inhibitors or substrates of CYP3A4
No concurrent medications or food that may interfere with the metabolism of gamma-secretase inhibitor RO4929097, including ketoconazole and grapefruit or grapefruit juice
No other concurrent investigational agents