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Phase II Study of RO4929097 (NSC-749225) in Advanced Melanoma

Phase 2
18 Years
Open (Enrolling)
Acral Lentiginous Malignant Melanoma, Lentigo Maligna Malignant Melanoma, Nodular Malignant Melanoma, Recurrent Melanoma, Solar Radiation-related Skin Melanoma, Stage IV Melanoma, Superficial Spreading Malignant Melanoma

Thank you

Trial Information

Phase II Study of RO4929097 (NSC-749225) in Advanced Melanoma


I. To assess the six-month progression-free survival and one-year overall survival
probability in Stage IV melanoma patients treated with RO4929097 (gamma-secretase/Notch
signalling pathway inhibitor RO4929097).


I. To investigate in a preliminary manner the relationship between Notch activation status
and gene expression profile of tumor and clinical outcomes from patients in this study.

II. To study the effects of the investigational therapy on T cell function, which will
provide a basis for subsequent trials combining Notch blockade with immunomodulatory therapy
for advanced melanoma.

III. To assess the response rate (confirmed and unconfirmed complete and partial responses).

IV. To assess toxicity.

OUTLINE: This is a multicenter study.

Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 orally (PO) on
days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease
progression or unacceptable toxicity.

Some patients undergo blood collection at baseline and during study for analysis of T-cell
function by flow cytometry and ELISA. Tumor tissue samples from biopsy or surgery are also
analyzed for Notch activation by IHC and qRT-PCR.

After completion of study therapy, patients are followed up every 3 months for 1 year and
then every 6 months for 2 years.

Inclusion Criteria:

- Patients must have histologically confirmed melanoma of cutaneous or unknown origin
(ocular primary and mucosal primary excluded); patients must have Stage IV disease

- All patients must undergo a computed tomography (CT) or magnetic resonance imaging
(MRI) of the brain within 42 days prior to registration that is negative for brain
metastases; patients with a history of brain metastases are ineligible

- Patients must have measurable disease; all measurable lesions must be assessed (by
physical examination, CT, or MRI scan) within 28 days prior to registration; tests to
assess non-measurable disease must be performed within 42 days prior to registration;
all disease must be assessed and documented on the Baseline Tumor Assessment Form
(Response Evaluation Criteria In Solid Tumors [RECIST] 1.1); the CT from a combined
positron emission tomography (PET)/CT must not be used to document measurable disease
unless it is of diagnostic quality

- Sites must offer all patients participation in translational medicine studies and
banking of paraffin embedded tissue and whole blood

- Patients must not have received any prior systemic therapy for Stage IV disease
except for noncytotoxic biologic agents (e.g., vaccines, cytokines, cell therapies
that do not require cytotoxic agents); patients may have received prior treatment
with up to two prior biological therapies - no cytotoxics or kinase inhibitors - for
advanced disease

- Patients may have had prior adjuvant immunotherapy with biological response modifiers
(examples include but are not limited to interferon, vaccines, GM-CSF, and CTLA-4
blocking antibodies); prior adjuvant immunotherapy must have been completed at least
28 days prior to registration

- Adjuvant therapy containing cytotoxic agents is allowed if completed >= 180 days
prior to registration

- Patients may have received prior radiation therapy; any side effects the patients had
due to prior radiation therapy must have resolved to =< Grade 1 prior to
registration; prior radiation therapy must have completed at least 28 days prior to

- Patients must have Zubrod performance status of 0-1

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count (ANC) >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 9 g/dL

- Total bilirubin =< institutional upper limit of normal (IULN)

- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 2.5 x IULN

- Serum creatinine =< IULN OR measured or calculated creatinine clearance >= 60 mL/min

- Patients must have the following serum electrolytes within the institutional ranges
of normal: potassium, sodium, magnesium, phosphorous, chloride and calcium (corrected
for serum albumin); these tests must be performed within 28 days prior to
registration; patient must not require parenteral replacement therapy

- Patients must not have a history of allergic reaction attributed to compounds of
similar chemical or biologic composition to RO4929097

- Patients must be able to swallow tablets

- Patients must not have malabsorption syndrome or other condition that would interfere
with intestinal absorption of the agent

- Patients taking medications with narrow therapeutic indices that are metabolized by
cytochrome P450 (CYP450), including warfarin sodium (Coumadin), are ineligible

- Patients must not be taking strong inducers or strong inhibitors of CYP3A4 at the
time of registration

- Patients must not be known to be serologically positive for Hepatitis A, B, or C, or
have a history of liver disease, other forms of hepatitis, or cirrhosis

- Patients must have an ECG within 28 days prior to registration. Patients must not
have a QTcF > 450 msec (males) or QTcF > 470 msec (females)

- Patients must not have symptomatic congestive heart failure or unstable angina

- Patients with a history of torsades de pointes or any significant cardiac arrhythmia
(except asymptomatic unifocal ventricular premature beats or supraventricular
tachycardia easily controlled with oral medications) are excluded; any patient
requiring or expected to require antiarrhythmics or other therapy known to prolong
QTc is also excluded

- No other prior malignancy is allowed except for the following: adequately treated
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
Stage I or II cancer from which the patient is currently in complete remission, or
any other cancer from which the patient has been disease free for five years

- Women of childbearing potential must have a negative pregnancy test within 14 days
prior to registration (the type of pregnancy test used is at the discretion of the
registering institution); female patients of childbearing potential include the

- Patients with regular menses

- Patients, after menarche with amenorrhea, irregular cycles, or using a
contraceptive method that precludes withdrawal bleeding

- Women who have had tubal ligation

- Women must not be nursing due to possible harm to a nursing infant from the treatment

- All patients must be informed of the investigational nature of this study and must
sign and give written informed consent in accordance with institutional and federal

- At the time of patient registration, the treating institution's name and ID number
must be provided to the Data Operations Center in Seattle in order to ensure that the
current (within 365 days) date of institutional review board approval for this study
has been entered into the data base

Type of Study:


Study Design:

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

Outcome Measure:

Progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

Outcome Time Frame:

From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause, assessed up to 6 months

Safety Issue:


Principal Investigator

Kim Margolin

Investigator Role:

Principal Investigator

Investigator Affiliation:

Southwest Oncology Group


United States: Food and Drug Administration

Study ID:




Start Date:

October 2010

Completion Date:

Related Keywords:

  • Acral Lentiginous Malignant Melanoma
  • Lentigo Maligna Malignant Melanoma
  • Nodular Malignant Melanoma
  • Recurrent Melanoma
  • Solar Radiation-related Skin Melanoma
  • Stage IV Melanoma
  • Superficial Spreading Malignant Melanoma
  • Lentigo
  • Melanoma
  • Hutchinson's Melanotic Freckle



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