A Phase 2 interventional study of gamma-secretase/Notch signalling pathway inhibitor RO4929097 and pharmacological study in Stage IIIB Melanoma, Stage IIIC Melanoma and Stage IV Melanoma, sponsored by National Cancer Institute (NCI). Withdrawn at 2 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2013-01-31.
Sponsored by National Cancer Institute (NCI) · Phase 2, Interventional, and Treatment
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.
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Inclusion Criteria:
Histologically or cytologically confirmed melanoma
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 uncontrolled intercurrent illness including, but not limited to, any of the following:
Patients receive oral 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.
Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097 · Other: pharmacological study · Procedure: therapeutic conventional surgery · Other: laboratory biomarker analysis
Drug page: RG-4733
Also known as: R4733, RO4929097
Also known as: pharmacological studies
Correlative studies
Molecular effects of notch-signaling inhibition
All statistics will be descriptive.
Time frame: Up to 2 years
Toxicity as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Time frame: 2 years
Response rate (complete or partial response) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
Time frame: Up to 2 years
Change in Akt-mediated downstream biomarkers by immunohistochemistry (IHC)
Pre-and-post treatment comparisons for correlative endpoints will be performed by the paired t-test, Wilcoxon signed-rank test, McNemar's chi-square test, or the Spearman-rank correlation coefficient, as appropriate. Exact 95% confidence intervals will be calculated to assess the precision of the obtained estimates.
Time frame: From baseline to 4 weeks at the time of surgery
Change in stem cell subpopulation
Pre-and-post treatment comparisons for correlative endpoints will be performed by the paired t-test, Wilcoxon signed-rank test, McNemar's chi-square test, or the Spearman-rank correlation coefficient, as appropriate. Exact 95% confidence intervals will be calculated to assess the precision of the obtained estimates.
Time frame: From baseline to 4 weeks at the time of surgery
Correlation between patient-specific micro-RNA signatures with response to therapy, recurrence and overall survival
Pre-and-post treatment comparisons for correlative endpoints will be performed by the paired t-test, Wilcoxon signed-rank test, McNemar's chi-square test, or the Spearman-rank correlation coefficient, as appropriate. Exact 95% confidence intervals will be calculated to assess the precision of the obtained estimates.
Time frame: At baseline and at 4 weeks at the time of surgery
Correlation of circulating melanoma endothelial cells (CECs) and circulating progenitor (CEPs) cell levels in the blood with recurrence and/or survival
Pre-and-post treatment comparisons for correlative endpoints will be performed by the paired t-test, Wilcoxon signed-rank test, McNemar's chi-square test, or the Spearman-rank correlation coefficient, as appropriate. Exact 95% confidence intervals will be calculated to assess the precision of the obtained estimates.
Time frame: Up to 2 years
Correlation between shedding of collagen cryptic epitopes with response and risk of recurrence
Pre-and-post treatment comparisons for correlative endpoints will be performed by the paired t-test, Wilcoxon signed-rank test, McNemar's chi-square test, or the Spearman-rank correlation coefficient, as appropriate. Exact 95% confidence intervals will be calculated to assess the precision of the obtained estimates.
Time frame: Up to 2 years
Pharmacokinetics of RO4929097
Pre-and-post treatment comparisons for correlative endpoints will be performed by the paired t-test, Wilcoxon signed-rank test, McNemar's chi-square test, or the Spearman-rank correlation coefficient, as appropriate. Exact 95% confidence intervals will be calculated to assess the precision of the obtained estimates.
Time frame: At days 1 and 10
Pharmacodynamics of RO4929097
Pre-and-post treatment comparisons for correlative endpoints will be performed by the paired t-test, Wilcoxon signed-rank test, McNemar's chi-square test, or the Spearman-rank correlation coefficient, as appropriate. Exact 95% confidence intervals will be calculated to assess the precision of the obtained estimates.
Time frame: At days 1 and 10
Impact of RO4929097 on serum markers of angiogenesis
Pre-and-post treatment comparisons for correlative endpoints will be performed by the paired t-test, Wilcoxon signed-rank test, McNemar's chi-square test, or the Spearman-rank correlation coefficient, as appropriate. Exact 95% confidence intervals will be calculated to assess the precision of the obtained estimates.
Time frame: Up to 2 years
Correlation between serum autoimmune biomarkers and clinical response
Pre-and-post treatment comparisons for correlative endpoints will be performed by the paired t-test, Wilcoxon signed-rank test, McNemar's chi-square test, or the Spearman-rank correlation coefficient, as appropriate. Exact 95% confidence intervals will be calculated to assess the precision of the obtained estimates.
Time frame: Up to 2 years
The record gives a start of Sep 2010 and a primary completion of Nov 2011. It does not say whether these dates are actual or estimated.
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This study is withdrawn, as verified in Jan 2013. You cannot join it, but the record below documents what was studied.
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