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

Phase 2
18 Years
Not Enrolling
Stage IIIB Melanoma, Stage IIIC Melanoma, Stage IV Melanoma

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Trial Information

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


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.


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.

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

- Able to swallow tablets

- No known history of hepatitis or have a history of liver disease or other forms of

- No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or
hypokalemia despite adequate electrolyte supplementation

- No uncontrolled intercurrent illness including, but not limited to, any of the

- 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

- No concurrent granulocyte colony-stimulating factors

- No other concurrent investigational agents

Type of Study:


Study Design:

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

Outcome Measure:

Molecular effects of notch-signaling inhibition

Outcome Description:

All statistics will be descriptive.

Outcome Time Frame:

Up to 2 years

Safety Issue:


Principal Investigator

Anna Pavlick

Investigator Role:

Principal Investigator

Investigator Affiliation:

Albert Einstein College of Medicine of Yeshiva University


United States: Food and Drug Administration

Study ID:




Start Date:

September 2010

Completion Date:

Related Keywords:

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



Montefiore Medical CenterBronx, New York  10467-2490
New York University Langone Medical CenterNew York, New York  10016