A Pilot Trial to Evaluate the Molecular Effects of RO4929097 as Neoadjuvant Therapy for Resectable Stage IIIB, IIIC or IV Melanoma
A Pilot Trial to Evaluate the Molecular Effects of RO4929097 as Neoadjuvant Therapy for Resectable Stage IIIB, IIIC or IV Melanoma
This pilot phase II trial is studying how well RO4929097 works in treating patients with stage III, or stage IV melanoma that can be removed by surgery. RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth
PRIMARY OBJECTIVES:
I. Evaluate the molecular effects of Notch signaling inhibition using gamma-secretase inhibitor RO4929097 (RO4929097) in patients with resectable stage IIIB, IIIC, or IV intact melanoma tumors in the neoadjuvant setting.
SECONDARY OBJECTIVES:
I. Assess any indication of clinical activity of RO4929097 in these patients. II. Assess the effect of RO4929097 on Akt-mediated downstream biomarkers in melanoma tissue.
III. Assess the effect of RO4929097 on the melanoma stem cell subpopulation. IV. Identify patient-specific micro-RNA signatures that may correlate with response to therapy, recurrence, and overall survival.
V. Determine the clinical feasibility of measuring circulating melanoma tumor cells in the blood and correlating levels with recurrence and/or survival.
VI. Correlate the shedding of collagen cryptic epitopes in the serum and urine with tumor response and risk of recurrence.
VII. Measure the pharmacokinetics and pharmacodynamics of RO4929097 in these patients.
VIII. Evaluate the impact of RO4929097 on serum markers of angiogenesis. IX. Measure serum autoimmune biomarkers and correlate with clinical response and outcome in these patients.
OUTLINE: This is a multicenter study.
Patients receive oral gamma-secretase inhibitor RO4929097 (RO4929097) once daily on days 1-3, 8-10, and 15-17. Within 35-56 days after completion of therapy, patients with stable or responsive disease undergo surgery. Patients may continue RO4929097 for 28 days after surgery in the absence of disease progression or unacceptable toxicity.
Patients undergo tumor tissue biopsies at baseline and after completion of study therapy for 4E-BP1 and Akt-mediated downstream biomarkers, stem cell subpopulation, and patient-specific micro-RNA signatures studies by IHC and PCR assays. Blood and urine samples are also collected at baseline and periodically during study for pharmacokinetic and pharmacodynamic studies, circulating melanoma endothelial cells and progenitor cell levels, collagen cryptic epitopes, serum markers of angiogenesis, and autoimmune biomarker analysis by ELISA.
After completion of study therapy, patients are followed up every 3 months for 2 years.
Inclusion Criteria:
Histologically or cytologically confirmed melanoma
Stage IIIB, IIIC, or IV disease
Disease that is deemed resectable by surgical consultation
Measurable disease defined as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension (longest diameter to be recorded) as ≥ 20 mm by conventional techniques OR as ≥ 10 mm by spiral CT scan
No known brain metastases
Life expectancy > 3 months
ECOG performance status 0-2 (Karnofsky 60-100%)
WBC ≥ 3,000/mm³
ANC ≥ 1,500/mm³
Platelet count ≥ 75,000/mm³
Hemoglobin > 10 g/dL
Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
AST and ALT ≤ 2.5 times ULN
Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min
Fertile patients must agree to use 2 forms of contraception (i.e., barrier contraception and 1 other method of contraception) for ≥ 4 weeks prior to, during, and for ≥ 12 months post-treatment
Negative pregnancy test
Not pregnant or nursing
No history of allergic reactions attributed to compounds of similar chemical or biological composition of gamma-secretase inhibitor RO4929097 or other agents used in the study
No malabsorption syndrome or other condition that would interfere with intestinal absorption
Able to swallow tablets
No known history of hepatitis or have a history of liver disease or other forms of cirrhosis
No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or hypokalemia despite adequate electrolyte supplementation
No uncontrolled intercurrent illness including, but not limited to, any of the following:
No baseline QTcF > 450 msec (male) or QTcF > 470 msec (female)
No history of cancer within the past 5 years except curatively treated basal or squamous cell cancer of the skin, in situ cervical cancer, or lobular carcinoma in situ of the breast
No other concurrent anticancer agents or therapies
More than 4 weeks since prior immunotherapy or local radiotherapy and recovered
No prior chemotherapy for melanoma
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 concurrent combination antiretroviral therapy for HIV-positive patients
No concurrent ketoconazole or grapefruit juice while taking gamma-secretase inhibitor RO4929097
No concurrent granulocyte colony-stimulating factors
No other concurrent investigational agents