RO4929097 in Treating Patients With Stage IIIB, Stage IIIC, or Stage IV Melanoma That Can Be Removed by Surgery

Stage IV Melanoma Clinical Trial

Official title:

A Pilot Trial to Evaluate the Molecular Effects of RO4929097 as Neoadjuvant Therapy for Resectable Stage IIIB, IIIC or IV Melanoma

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT01216787
• Other study ID #: NCI-2011-02512
• Secondary ID: 10-01704N01CM622
• Status: Withdrawn
• Phase: Phase 2
• First received: October 6, 2010
• Last updated: January 30, 2013
• Start date: September 2010

Study information

• Verified date: January 2013
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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

Description:

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. primary completion date: November 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically or cytologically confirmed melanoma

• Stage IIIB, IIIC, or IV disease

• Disease that is deemed resectable by surgical consultation

• Patients must agree to pretreatment biopsies of their tumor

• 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

• Measurable lesions must be deemed resectable

• Skin metastases must be photographed and measured

• No non-target disease

• 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:

• Ongoing or active infection

• Symptomatic congestive heart failure

• Unstable angina pectoris

• Cardiac arrhythmia other than chronic

• Unstable atrial fibrillation

• Psychiatric illness and/or social situations that would limit compliance with study requirements

• 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

Study Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Melanoma
• Stage IIIB Melanoma
• Stage IIIC Melanoma
• Stage IV Melanoma

Intervention

Drug:
• gamma-secretase/Notch signalling pathway inhibitor RO4929097

Other:
• pharmacological study

Procedure:
• therapeutic conventional surgery

Other:
• laboratory biomarker analysis
Correlative studies

Locations

Country	Name	City	State
United States	Montefiore Medical Center	Bronx	New York
United States	New York University Langone Medical Center	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Molecular effects of notch-signaling inhibition	All statistics will be descriptive.	Up to 2 years	No
Secondary	Toxicity as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0		2 years	Yes
Secondary	Response rate (complete or partial response) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1		Up to 2 years	No
Secondary	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.	From baseline to 4 weeks at the time of surgery	No
Secondary	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.	From baseline to 4 weeks at the time of surgery	No
Secondary	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.	At baseline and at 4 weeks at the time of surgery	No
Secondary	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.	Up to 2 years	No
Secondary	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.	Up to 2 years	No
Secondary	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.	At days 1 and 10	No
Secondary	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.	At days 1 and 10	No
Secondary	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.	Up to 2 years	No
Secondary	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.	Up to 2 years	No