A Phase I Study of Various Administration Schedules of RO4929097 With Multi-parameter Assessment (Biomarkers, Pharmacokinetics, Pharmacodynamics) in Patients With Advanced Solid Cancers
A Phase I Study of Various Administration Schedules of RO4929097 With Multi-parameter Assessment (Biomarkers, Pharmacokinetics, Pharmacodynamics) in Patients With Advanced Solid Cancers
This phase I trial is studying the side effects, best way to give, and best dose of gamma-secretase inhibitor RO4929097 in treating patients with metastatic or unresectable solid malignancies. Enzyme inhibitors, such as gamma-secretase inhibitor RO4929097, may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
PRIMARY OBJECTIVES:
I. To determine the safety profile of 6 different administration schedules of gamma-secretase inhibitor RO4929097 in patients with advanced solid malignancies.
SECONDARY OBJECTIVES:
I. To determine pharmacokinetic (PK) parameters of gamma-secretase inhibitor RO4929097 administered using 6 different administration schedules.
II. To assess the preliminary antitumor activity of gamma-secretase inhibitor RO4929097 in these patients.
TERTIARY OBJECTIVES:
I. To assess the pharmacodynamic (PD) effects of gamma-secretase inhibitor RO4929097 on Notch signaling pathway in tumor and surrogate tissues, as well as soluble markers of angiogenesis in plasma, when administered using 6 different dosing schedules. (Exploratory) II. To evaluate the relationship between PK and PD effects in an attempt to define the optimal biological dosing schedule (OBDS) that can provide a sustained inhibition of Notch signaling pathway over time with a tolerable toxicity profile. (Exploratory) III. To correlate inhibition of Notch signaling pathway measured in tumor and surrogate tissues with preliminary antitumor activity and assess the potential clinical predictive value of OBDS as defined above. (Exploratory) IV. To assess the effect of the various pharmacogenomic polymorphisms of the cytochrome P450 pathway on PK and PD parameters. (Exploratory)
OUTLINE: This is a multicenter, dose-escalation study. Patients are assigned to 1 of 6 dose schedules.
GROUP A: Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-3 and 8-10.
GROUP B: Patients receive oral RO4929097 once daily on days 1-7.
GROUP C: Patients receive oral RO4929097 once daily on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21.
GROUP D: Patients receive oral RO4929097 once daily on days 1, 8, and 15.
GROUP E: Patients receive oral RO4929097 once daily on days 1, 4, 8, 11, 15, and 18.
GROUP F: Patients receive oral RO4929097 once daily days 1-5, 8-12, and 15-19.
Treatment in all groups repeats every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsies at baseline and between days 15 and 22 in the first course of treatment. Plasma samples are collected periodically for pharmacokinetic, pharmacodynamic, and pharmacogenomic analysis and to assess levels of adipsin and markers of angiogenesis.
After completion of study treatment, patients are followed up for 4 weeks.
Inclusion Criteria:
Histologically or cytologically confirmed solid malignancy
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 70-100%)
Life expectancy > 12 weeks
Leukocytes ≥ 3,000/mm^3
ANC ≥ 1,500/mm^3
Platelet count ≥ 100,000/mm^3
Hemoglobin ≥ 9 g/dL
Total bilirubin normal
AST/ALT ≤ 2.5 times upper limit of normal
Serum creatinine normal OR creatinine clearance ≥ 60 mL/min
No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or hypokalemia, defined as < lower limit of normal despite adequate electrolyte supplementation
QTc ≤ 450 msec in males and a QTc ≤ 470 in females, as measured by ECG using Bazett's formula
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use 2 forms of contraception (i.e., barrier contraception and 1 other method of contraception) for ≥ 4 weeks before, during, and for ≥ 12 months after completion of study treatment
Willing to undergo 2 tumor biopsies (unless medically contraindicated)
Able to swallow medication
No malabsorption syndrome or other condition that would interfere with intestinal absorption
No diarrhea ≥ grade 2 not under control with standard antidiarrhea medications
No uncontrolled concurrent illness including, but not limited to, any of the following:
No history of risk factors for QT interval prolongation including, but not limited to, a family or personal history of any of the following:
Female patients may not donate ova during or after study treatment
No blood donation during and for ≥ 12 months after completion of study treatment
No serologic positivity for hepatitis A, B, or C; 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 other agents used in this study
No other concurrent agents or therapies administered with the intent to treat the patient's malignancy
No prior gamma-secretase inhibitors
Any number of prior treatment regimens allowed
At least 4 weeks since prior radiotherapy or systemic therapy (6 weeks for prior carmustine or mitomycin C)
Recovered from the adverse events due to prior therapy to < CTCAE grade 2 (except alopecia)
No other concurrent investigational agents
No concurrent medications with narrow therapeutic indices that are metabolized by cytochrome P450, including warfarin sodium (Coumadin®)
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, grapefruit, or grapefruit juice
No antiarrhythmics or other concurrent medications with known potential to prolong QT interval