Back to resultsRO4929097 in Treating Patients With Stage IIIB, Stage IIIC, or Stage IV Melanoma That Can Be Removed by Surgery
Primary Purpose
Stage IIIB Melanoma, Stage IIIC Melanoma, Stage IV Melanoma
Status
Withdrawn
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
gamma-secretase/Notch signalling pathway inhibitor RO4929097
pharmacological study
therapeutic conventional surgery
laboratory biomarker analysis
Sponsored by
About this trial
This is an interventional treatment trial for Stage IIIB Melanoma
Eligibility Criteria
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
Sites / Locations
- Montefiore Medical Center
- New York University Langone Medical Center
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Treatment (gamma-secretase inhibitor RO4929097, surgery)
Arm Description
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.
Outcomes
Primary Outcome Measures
Molecular effects of notch-signaling inhibition
All statistics will be descriptive.
Secondary Outcome Measures
Toxicity as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Response rate (complete or partial response) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
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.
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.
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.
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.
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.
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.
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.
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.
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.
Full Information
NCT ID
NCT01216787
First Posted
October 6, 2010
Last Updated
January 30, 2013
Sponsor
National Cancer Institute (NCI)
1. Study Identification
Unique Protocol Identification Number
NCT01216787
Brief Title
RO4929097 in Treating Patients With Stage IIIB, Stage IIIC, or Stage IV Melanoma That Can Be Removed by Surgery
Official Title
A Pilot Trial to Evaluate the Molecular Effects of RO4929097 as Neoadjuvant Therapy for Resectable Stage IIIB, IIIC or IV Melanoma
Study Type
Interventional
2. Study Status
Record Verification Date
January 2013
Overall Recruitment Status
Withdrawn
Why Stopped
Study drug not available.
Study Start Date
September 2010 (undefined)
Primary Completion Date
November 2011 (Actual)
Study Completion Date
undefined (undefined)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief 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
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Stage IIIB Melanoma, Stage IIIC Melanoma, Stage IV Melanoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
0 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Treatment (gamma-secretase inhibitor RO4929097, surgery)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
gamma-secretase/Notch signalling pathway inhibitor RO4929097
Other Intervention Name(s)
R4733, RO4929097
Intervention Type
Other
Intervention Name(s)
pharmacological study
Other Intervention Name(s)
pharmacological studies
Intervention Type
Procedure
Intervention Name(s)
therapeutic conventional surgery
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Molecular effects of notch-signaling inhibition
Description
All statistics will be descriptive.
Time Frame
Up to 2 years
Secondary Outcome Measure Information:
Title
Toxicity as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Time Frame
2 years
Title
Response rate (complete or partial response) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
Time Frame
Up to 2 years
Title
Change in Akt-mediated downstream biomarkers by immunohistochemistry (IHC)
Description
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
Title
Change in stem cell subpopulation
Description
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
Title
Correlation between patient-specific micro-RNA signatures with response to therapy, recurrence and overall survival
Description
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
Title
Correlation of circulating melanoma endothelial cells (CECs) and circulating progenitor (CEPs) cell levels in the blood with recurrence and/or survival
Description
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
Title
Correlation between shedding of collagen cryptic epitopes with response and risk of recurrence
Description
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
Title
Pharmacokinetics of RO4929097
Description
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
Title
Pharmacodynamics of RO4929097
Description
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
Title
Impact of RO4929097 on serum markers of angiogenesis
Description
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
Title
Correlation between serum autoimmune biomarkers and clinical response
Description
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Anna Pavlick
Organizational Affiliation
Albert Einstein College of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Montefiore Medical Center
City
Bronx
State/Province
New York
ZIP/Postal Code
10467-2490
Country
United States
Facility Name
New York University Langone Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
12. IPD Sharing Statement
Learn more about this trial
RO4929097 in Treating Patients With Stage IIIB, Stage IIIC, or Stage IV Melanoma That Can Be Removed by Surgery
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