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

NCT ID: NCT01216787

Last Updated: 2013-01-31

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE2
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-09-30

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.

Conditions

Stage IIIB Melanoma; Stage IIIC Melanoma; Stage IV Melanoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

gamma-secretase/Notch signalling pathway inhibitor RO4929097

Intervention Type: DRUG

pharmacological study

Intervention Type: OTHER

therapeutic conventional surgery

Intervention Type: PROCEDURE

laboratory biomarker analysis

Intervention Type: OTHER

Correlative studies

Interventions

gamma-secretase/Notch signalling pathway inhibitor RO4929097

Intervention Type: DRUG

pharmacological study

Intervention Type: OTHER

therapeutic conventional surgery

Intervention Type: PROCEDURE

laboratory biomarker analysis

Correlative studies

Intervention Type: OTHER

Other Intervention Names

R4733; RO4929097; pharmacological studies

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Anna Pavlick

Role: PRINCIPAL_INVESTIGATOR

Albert Einstein College of Medicine

Locations

New York University Langone Medical Center

New York, New York, United States

Montefiore Medical Center

The Bronx, New York, United States

Countries

United States

Other Identifiers

10-01704

Identifier Type: -

Identifier Source: secondary_id

N01CM62204

Identifier Type: NIH

Identifier Source: secondary_id

View Link

CDR0000685418

Identifier Type: REGISTRY

Identifier Source: secondary_id

NCI-2011-02512

Identifier Type: -

Identifier Source: org_study_id