- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01216787
RO4929097 in Treating Patients With Stage IIIB, Stage IIIC, or Stage IV Melanoma That Can Be Removed by Surgery
A Pilot Trial to Evaluate the Molecular Effects of RO4929097 as Neoadjuvant Therapy for Resectable Stage IIIB, IIIC or IV Melanoma
Study Overview
Status
Detailed 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.
Study Type
Phase
- Phase 2
Contacts and Locations
Study Locations
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New York
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Bronx, New York, United States, 10467-2490
- Montefiore Medical Center
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New York, New York, United States, 10016
- New York University Langone Medical Center
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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 Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Treatment (gamma-secretase inhibitor RO4929097, surgery)
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.
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Other Names:
Correlative studies
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Molecular effects of notch-signaling inhibition
Time Frame: Up to 2 years
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All statistics will be descriptive.
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Up to 2 years
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Toxicity as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Time Frame: 2 years
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2 years
|
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Response rate (complete or partial response) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
Time Frame: Up to 2 years
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Up to 2 years
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Change in Akt-mediated downstream biomarkers by immunohistochemistry (IHC)
Time Frame: From baseline to 4 weeks at the time of surgery
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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.
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From baseline to 4 weeks at the time of surgery
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Change in stem cell subpopulation
Time Frame: From baseline to 4 weeks at the time of surgery
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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.
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From baseline to 4 weeks at the time of surgery
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Correlation between patient-specific micro-RNA signatures with response to therapy, recurrence and overall survival
Time Frame: At baseline and at 4 weeks at the time of surgery
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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.
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At baseline and at 4 weeks at the time of surgery
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Correlation of circulating melanoma endothelial cells (CECs) and circulating progenitor (CEPs) cell levels in the blood with recurrence and/or survival
Time Frame: Up to 2 years
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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.
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Up to 2 years
|
Correlation between shedding of collagen cryptic epitopes with response and risk of recurrence
Time Frame: Up to 2 years
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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.
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Up to 2 years
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Pharmacokinetics of RO4929097
Time Frame: At days 1 and 10
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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.
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At days 1 and 10
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Pharmacodynamics of RO4929097
Time Frame: At days 1 and 10
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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.
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At days 1 and 10
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Impact of RO4929097 on serum markers of angiogenesis
Time Frame: Up to 2 years
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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.
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Up to 2 years
|
Correlation between serum autoimmune biomarkers and clinical response
Time Frame: Up to 2 years
|
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.
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Up to 2 years
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Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Anna Pavlick, Albert Einstein College of Medicine
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- NCI-2011-02512
- N01CM62204 (U.S. NIH Grant/Contract)
- 10-01704
- CDR0000685418 (Registry Identifier: PDQ (Physician Data Query))
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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