Stage IIIB MelanomaPhase 2NCT01216787
RO4929097 in Treating Patients With Stage IIIB, Stage IIIC, or Stage IV Melanoma That Can Be Removed by Surgery
A Phase 2 study testing gamma-secretase/Notch signalling pathway inhibitor RO4929097, pharmacological study and therapeutic conventional surgery in people with Stage IIIB Melanoma and Stage IIIC Melanoma, run by National Cancer Institute (NCI) at 2 sites in United States.
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 Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Stage IIIB Melanoma, Stage IIIC Melanoma, Stage IV Melanoma
- What is being tested?
- gamma-secretase/Notch signalling pathway inhibitor RO4929097, pharmacological study and therapeutic conventional surgery
- Type of treatment
- Pill or oral medicine, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 2 sitesUnited States
- Study dates
- Sep 2010to Nov 2011
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 44Show fewer
- 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
Who cannot join
None listed.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
New York University Langone Medical Center
New York, New York, 10016
Montefiore Medical Center
The Bronx, New York, 10467-2490
About this study
Official title: 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
Read the detailed description
PRIMARY OBJECTIVES:
- 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:
- 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.
- 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.
- Conditions
- Stage IIIB Melanoma, Stage IIIC Melanoma, Stage IV Melanoma
- Being tested
- gamma-secretase/Notch signalling pathway inhibitor RO4929097, pharmacological study, therapeutic conventional surgery, laboratory biomarker analysis
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
gamma-secretase/Notch signalling pathway inhibitor RO4929097Drug
Also called R4733, RO4929097
Also called pharmacological studies
therapeutic conventional surgeryProcedure or surgery
laboratory biomarker analysisOther
Correlative studies
| Study group | Role | What they receive |
|---|---|---|
| Treatment (gamma-secretase inhibitor RO4929097, surgery) | Experimental | 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. Receives: Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097; Other: pharmacological study; Procedure: therapeutic conventional surgery; Other: laboratory biomarker analysis |
What is being measured
The primary outcome is the main question the study is designed to answer.
Molecular effects of notch-signaling inhibition
All statistics will be descriptive.
Measured: Up to 2 years
Secondary outcomes (11)
Toxicity as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Measured: 2 years
Response rate (complete or partial response) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Up to 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Oct 2010 (estimated)
- Study startSep 2010
- Primary completionNov 2011
Why it stopped: Study drug not available.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Stage IIIB MelanomaStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Anna Pavlick, Principal investigator, Albert Einstein College of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01216787
- Sponsor's protocol ID
- NCI-2011-02512
- Other IDs
- 10-01704, N01CM62204, CDR0000685418
- Status last verified
- Jan 2013
- First submitted
- 6 Oct 2010
- Last updated
- 31 Jan 2013
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 31 Jan 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pilot Trial to Evaluate the Molecular Effects of RO4929097 as Neoadjuvant Therapy for Resectable Stage IIIB, IIIC or IV Melanoma
- ClinicalTrials.gov ID
- NCT01216787
- Acronym / sponsor ID
- NCI-2011-02512
- Conditions
- Stage IIIB Melanoma, Stage IIIC Melanoma, Stage IV Melanoma
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Study drug not available.
- Enrolment
- 0 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- Sep 2010
- Primary completion
- Nov 2011 (actual)
- First posted
- 7 Oct 2010 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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:
- 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.
- 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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Treatment (gamma-secretase inhibitor RO4929097, surgery) | Experimental | Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097, Other: pharmacological study, Procedure: therapeutic conventional surgery, Other: laboratory biomarker analysisPatients 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (44 listed)
- Histologically or cytologically confirmed melanoma
- 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%)
Key exclusion criteria (0 listed)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| gamma-secretase/Notch signalling pathway inhibitor RO4929097Also: R4733, RO4929097 | Drug | Treatment (gamma-secretase inhibitor RO4929097, surgery) |
| pharmacological studyAlso: pharmacological studies | Other | Treatment (gamma-secretase inhibitor RO4929097, surgery) |
| therapeutic conventional surgery | Procedure or surgery | Treatment (gamma-secretase inhibitor RO4929097, surgery) |
| laboratory biomarker analysisCorrelative studies | Other | Treatment (gamma-secretase inhibitor RO4929097, surgery) |
Primary outcome
Molecular effects of notch-signaling inhibition
Time frame: Up to 2 years
All statistics will be descriptive.
11 secondary outcomes
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)
Time frame: From baseline to 4 weeks at the time of surgery
Change in stem cell subpopulation
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
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
Time frame: Up to 2 years
Correlation between shedding of collagen cryptic epitopes with response and risk of recurrence
Time frame: Up to 2 years
Pharmacokinetics of RO4929097
Time frame: At days 1 and 10
Pharmacodynamics of RO4929097
Time frame: At days 1 and 10
Impact of RO4929097 on serum markers of angiogenesis
Time frame: Up to 2 years
Correlation between serum autoimmune biomarkers and clinical response
Time frame: Up to 2 years
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Jan 2013.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Anna Pavlick principal investigator
Albert Einstein College of Medicine
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing gamma-secretase/Notch signalling pathway inhibitor RO4929097, pharmacological study and therapeutic conventional surgery in people with Stage IIIB Melanoma and Stage IIIC Melanoma, run by National Cancer Institute (NCI) at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 44 inclusion and 0 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 31 Jan 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Molecular effects of notch-signaling inhibition (time frame: Up to 2 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Jan 2013.