Clinical trial NCT01120275: Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Stage IV Melanoma
Official title: Phase II Study of RO4929097 (NSC-749225) in Advanced Melanoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: 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
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2010-05-10
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase II trial is studying how well gamma-secretase/Notch signalling pathway inhibitor RO4929097 works in treating patients with stage IV melanoma. Gamma-secretase/Notch signalling pathway inhibitor RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description: PRIMARY OBJECTIVES:

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).

SECONDARY OBJECTIVES:

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.

Eligibility criteria: 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 registration
* 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 pectoris
* 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 following:

  * 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 regimen
* 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 guidelines
* 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

Primary outcomes:
measure: Progression-free Survival According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
timeFrame: Disease assessments were performed every 6 weeks, up to 3 years.
measure: Overall Survival
timeFrame: Weekly, up to 3 years.
Secondary outcomes:
measure: Percentage of Participants With Confirmed and Unconfirmed Complete or Partial Response
timeFrame: Disease assessments for response were performed every 6 weeks, up to 3 years
measure: Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs
timeFrame: Toxicity assessment was evaluated at least every 3 weeks at the beginning of each cycle, up to 3 years
Other outcomes:
Locations:
city: Mobile
country: United States
facility: Providence Hospital
state: Alabama
city: Fairbanks
country: United States
facility: Fairbanks Memorial Hospital
state: Alaska
city: Tucson
country: United States
facility: University of Arizona Health Sciences Center
state: Arizona
city: Ft. Smith
country: United States
facility: Saint Edward Mercy Medical Center
state: Arkansas
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Loma Linda
country: United States
facility: Loma Linda University Medical Center
state: California
city: Marysville
country: United States
facility: Fremont - Rideout Cancer Center
state: California
city: Orange
country: United States
facility: University of California Medical Center At Irvine-Orange Campus
state: California
city: Sacramento
country: United States
facility: University of California at Davis Cancer Center
state: California
city: Truckee
country: United States
facility: Tahoe Forest Cancer Center
state: California
city: Aurora
country: United States
facility: University of Colorado Cancer Center - Anschutz Cancer Pavilion
state: Colorado
city: Denver
country: United States
facility: Denver Veterans Administration Medical Center
state: Colorado
city: Fort Collins
country: United States
facility: Poudre Valley Hospital
state: Colorado
city: Grand Junction
country: United States
facility: Saint Mary's Hospital and Regional Medical Center
state: Colorado
city: Hartford
country: United States
facility: Saint Francis Hospital and Medical Center
state: Connecticut
city: Gainesville
country: United States
facility: Northeast Georgia Medical Center
state: Georgia
city: Aiea
country: United States
facility: Pali Momi Medical Center
state: Hawaii
city: Honolulu
country: United States
facility: Oncare Hawaii Inc-POB II
state: Hawaii
city: Honolulu
country: United States
facility: Queen's Medical Center
state: Hawaii
city: Honolulu
country: United States
facility: Straub Clinic and Hospital
state: Hawaii
city: Honolulu
country: United States
facility: University of Hawaii
state: Hawaii
city: Honolulu
country: United States
facility: Oncare Hawaii Inc-Kuakini
state: Hawaii
city: Honolulu
country: United States
facility: The Cancer Center of Hawaii-Liliha
state: Hawaii
city: Honolulu
country: United States
facility: Kapiolani Medical Center for Women and Children
state: Hawaii
city: Kailua
country: United States
facility: Castle Medical Center
state: Hawaii
city: Lihue
country: United States
facility: Wilcox Memorial Hospital and Kauai Medical Clinic
state: Hawaii
city: Wailuku
country: United States
facility: Maui Memorial Medical Center
state: Hawaii
city: Alton
country: United States
facility: Saint Anthony's Health
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Decatur
country: United States
facility: Decatur Memorial Hospital
state: Illinois
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Mount Vernon
country: United States
facility: Good Samaritan Regional Health Center
state: Illinois
city: Springfield
country: United States
facility: Memorial Medical Center
state: Illinois
city: Beech Grove
country: United States
facility: Saint Francis Hospital and Health Centers
state: Indiana
city: Richmond
country: United States
facility: Reid Hospital and Health Care Services
state: Indiana
city: Davenport
country: United States
facility: Genesis Medical Center - East Campus
state: Iowa
city: Hays
country: United States
facility: Hays Medical Center
state: Kansas
city: Hutchinson
country: United States
facility: Promise Regional Medical Center-Hutchinson
state: Kansas
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Lawrence
country: United States
facility: Lawrence Memorial Hospital
state: Kansas
city: Overland Park
country: United States
facility: Menorah Medical Center
state: Kansas
city: Overland Park
country: United States
facility: Saint Luke's South Hospital
state: Kansas
city: Pittsburg
country: United States
facility: Via Christi Hospital-Pittsburg
state: Kansas
city: Prairie Village
country: United States
facility: Kansas City CCOP
state: Kansas
city: Salina
country: United States
facility: Salina Regional Health Center
state: Kansas
city: Shawnee Mission
country: United States
facility: Shawnee Mission Medical Center
state: Kansas
city: Topeka
country: United States
facility: Saint Francis Hospital and Medical Center - Topeka
state: Kansas
city: Wichita
country: United States
facility: Wesley Medical Center
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Monroe
country: United States
facility: Louisiana State University Sciences Center- Monroe
state: Louisiana
city: Shreveport
country: United States
facility: Highland Clinic
state: Louisiana
city: Shreveport
country: United States
facility: Louisiana State University Health Sciences Center Shreveport
state: Louisiana
city: Baltimore
country: United States
facility: Sinai Hospital of Baltimore
state: Maryland
city: Ann Arbor
country: United States
facility: Saint Joseph Mercy Hospital
state: Michigan
city: Ann Arbor
country: United States
facility: Michigan Cancer Research Consortium Community Clinical Oncology Program
state: Michigan
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Battle Creek
country: United States
facility: Bronson Battle Creek
state: Michigan
city: Big Rapids
country: United States
facility: Spectrum Health Big Rapids Hospital
state: Michigan
city: Dearborn
country: United States
facility: Oakwood Hospital
state: Michigan
city: Detroit
country: United States
facility: Wayne State University/Karmanos Cancer Institute
state: Michigan
city: Detroit
country: United States
facility: Saint John Hospital and Medical Center
state: Michigan
city: Flint
country: United States
facility: Hurley Medical Center
state: Michigan
city: Flint
country: United States
facility: Genesys Regional Medical Center-West Flint Campus
state: Michigan
city: Grand Rapids
country: United States
facility: Grand Rapids Clinical Oncology Program
state: Michigan
city: Grand Rapids
country: United States
facility: Mercy Health Saint Mary's
state: Michigan
city: Grand Rapids
country: United States
facility: Spectrum Health at Butterworth Campus
state: Michigan
city: Jackson
country: United States
facility: Allegiance Health
state: Michigan
city: Lansing
country: United States
facility: Sparrow Hospital
state: Michigan
city: Livonia
country: United States
facility: Saint Mary Mercy Hospital
state: Michigan
city: Muskegon
country: United States
facility: Mercy Health Mercy Campus
state: Michigan
city: Pontiac
country: United States
facility: Saint Joseph Mercy Oakland
state: Michigan
city: Port Huron
country: United States
facility: Saint Joseph Mercy Port Huron
state: Michigan
city: Royal Oak
country: United States
facility: William Beaumont Hospital-Royal Oak
state: Michigan
city: Saginaw
country: United States
facility: Saint Mary's of Michigan
state: Michigan
city: Traverse City
country: United States
facility: Munson Medical Center
state: Michigan
city: Warren
country: United States
facility: Saint John Macomb-Oakland Hospital
state: Michigan
city: Wyoming
country: United States
facility: Metro Health Hospital
state: Michigan
city: Bolivar
country: United States
facility: Central Care Cancer Center-Carrie J Babb Cancer Center
state: Missouri
city: Branson
country: United States
facility: CoxHealth Cancer Center
state: Missouri
city: Cape Girardeau
country: United States
facility: Saint Francis Medical Center
state: Missouri
city: Kansas City
country: United States
facility: Truman Medical Center
state: Missouri
city: Kansas City
country: United States
facility: Saint Luke's Cancer Institute
state: Missouri
city: Kansas City
country: United States
facility: Saint Luke's Hospital of Kansas City
state: Missouri
city: Kansas City
country: United States
facility: Saint Joseph Health Center
state: Missouri
city: Kansas City
country: United States
facility: North Kansas City Hospital
state: Missouri
city: Kansas City
country: United States
facility: Research Medical Center
state: Missouri
city: Lee's Summit
country: United States
facility: Saint Luke's East - Lee's Summit
state: Missouri
city: Liberty
country: United States
facility: Liberty Hospital
state: Missouri
city: Saint Joseph
country: United States
facility: Heartland Regional Medical Center
state: Missouri
city: Saint Louis
country: United States
facility: Saint Louis Cancer and Breast Institute-South City
state: Missouri
city: Saint Louis
country: United States
facility: Saint John's Mercy Medical Center
state: Missouri
city: Saint Louis
country: United States
facility: Saint Louis-Cape Girardeau CCOP
state: Missouri
city: Springfield
country: United States
facility: Ozark Health Ventures LLC dba Cancer Research for The Ozarks Springfield
state: Missouri
city: Springfield
country: United States
facility: Mercy Hospital Springfield
state: Missouri
city: Springfield
country: United States
facility: CoxHealth South Hospital
state: Missouri
city: Billings
country: United States
facility: Montana Cancer Consortium CCOP
state: Montana
city: Billings
country: United States
facility: Saint Vincent Healthcare
state: Montana
city: Billings
country: United States
facility: Hematology-Oncology Centers of the Northern Rockies PC
state: Montana
city: Billings
country: United States
facility: Billings Clinic
state: Montana
city: Bozeman
country: United States
facility: Bozeman Deaconess Cancer Center
state: Montana
city: Bozeman
country: United States
facility: Bozeman Deaconess Hospital
state: Montana
city: Great Falls
country: United States
facility: Benefis Healthcare- Sletten Cancer Institute
state: Montana
city: Great Falls
country: United States
facility: Great Falls Clinic
state: Montana
city: Helena
country: United States
facility: Saint Peter's Community Hospital
state: Montana
city: Kalispell
country: United States
facility: Glacier Oncology PLLC
state: Montana
city: Kalispell
country: United States
facility: Kalispell Regional Medical Center
state: Montana
city: Missoula
country: United States
facility: Montana Cancer Specialists
state: Montana
city: Missoula
country: United States
facility: Saint Patrick Hospital - Community Hospital
state: Montana
city: Las Vegas
country: United States
facility: University Medical Center of Southern Nevada
state: Nevada
city: Las Vegas
country: United States
facility: Nevada Cancer Research Foundation CCOP
state: Nevada
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Asheville
country: United States
facility: Mission Hospital-Memorial Campus
state: North Carolina
city: Charlotte
country: United States
facility: Novant Health Presbyterian Medical Center
state: North Carolina
city: Goldsboro
country: United States
facility: Wayne Memorial Hospital
state: North Carolina
city: Hendersonville
country: United States
facility: Margaret R Pardee Memorial Hospital
state: North Carolina
city: Statesville
country: United States
facility: Iredell Memorial Hospital
state: North Carolina
city: Bellefontaine
country: United States
facility: Mary Rutan Hospital
state: Ohio
city: Chillicothe
country: United States
facility: Adena Regional Medical Center
state: Ohio
city: Cincinnati
country: United States
facility: Good Samaritan Hospital - Cincinnati
state: Ohio
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Columbus
country: United States
facility: Riverside Methodist Hospital
state: Ohio
city: Columbus
country: United States
facility: Columbus CCOP
state: Ohio
city: Columbus
country: United States
facility: Grant Medical Center
state: Ohio
city: Columbus
country: United States
facility: Mount Carmel Health Center West
state: Ohio
city: Columbus
country: United States
facility: Doctors Hospital
state: Ohio
city: Dayton
country: United States
facility: Grandview Hospital
state: Ohio
city: Dayton
country: United States
facility: Good Samaritan Hospital - Dayton
state: Ohio
city: Dayton
country: United States
facility: Miami Valley Hospital
state: Ohio
city: Dayton
country: United States
facility: Samaritan North Health Center
state: Ohio
city: Dayton
country: United States
facility: Dayton CCOP
state: Ohio
city: Delaware
country: United States
facility: Grady Memorial Hospital
state: Ohio
city: Findlay
country: United States
facility: Blanchard Valley Hospital
state: Ohio
city: Franklin
country: United States
facility: Atrium Medical Center-Middletown Regional Hospital
state: Ohio
city: Greenville
country: United States
facility: Wayne Hospital
state: Ohio
city: Kettering
country: United States
facility: Kettering Medical Center
state: Ohio
city: Lancaster
country: United States
facility: Fairfield Medical Center
state: Ohio
city: Marietta
country: United States
facility: Marietta Memorial Hospital
state: Ohio
city: Mount Vernon
country: United States
facility: Knox Community Hospital
state: Ohio
city: Newark
country: United States
facility: Licking Memorial Hospital
state: Ohio
city: Springfield
country: United States
facility: Springfield Regional Medical Center
state: Ohio
city: Troy
country: United States
facility: Upper Valley Medical Center
state: Ohio
city: Westerville
country: United States
facility: Saint Ann's Hospital
state: Ohio
city: Wilmington
country: United States
facility: Clinton Memorial Hospital
state: Ohio
city: Xenia
country: United States
facility: Greene Memorial Hospital
state: Ohio
city: Zanesville
country: United States
facility: Genesis HealthCare System
state: Ohio
city: Portland
country: United States
facility: Adventist Medical Center
state: Oregon
city: Portland
country: United States
facility: SWOG
state: Oregon
city: Anderson
country: United States
facility: AnMed Health Hospital
state: South Carolina
city: Florence
country: United States
facility: McLeod Regional Medical Center
state: South Carolina
city: Spartanburg
country: United States
facility: Spartanburg Regional Medical Center
state: South Carolina
city: Spartanburg
country: United States
facility: Upstate Carolina CCOP
state: South Carolina
city: Kingsport
country: United States
facility: Wellmont Holston Valley Hospital and Medical Center
state: Tennessee
city: Knoxville
country: United States
facility: Thompson Cancer Survival Center
state: Tennessee
city: Danville
country: United States
facility: Danville Regional Medical Center
state: Virginia
city: Martinsville
country: United States
facility: Memorial Hospital Of Martinsville
state: Virginia
city: Anacortes
country: United States
facility: Cancer Care Center at Island Hospital
state: Washington
city: Bellingham
country: United States
facility: PeaceHealth Saint Joseph Medical Center
state: Washington
city: Bremerton
country: United States
facility: Harrison HealthPartners Hematology and Oncology-Bremerton
state: Washington
city: Burien
country: United States
facility: Highline Medical Center-Main Campus
state: Washington
city: Kennewick
country: United States
facility: Columbia Basin Hematology and Oncology PLLC
state: Washington
city: Kirkland
country: United States
facility: Evergreen Hospital Medical Center
state: Washington
city: Mount Vernon
country: United States
facility: Skagit Valley Hospital
state: Washington
city: Poulsbo
country: United States
facility: Harrison HealthPartners Hematology and Oncology-Poulsbo
state: Washington
city: Seattle
country: United States
facility: Virginia Mason CCOP
state: Washington
city: Seattle
country: United States
facility: Harborview Medical Center
state: Washington
city: Seattle
country: United States
facility: Minor and James Medical PLLC
state: Washington
city: Seattle
country: United States
facility: Pacific Medical Center-First Hill
state: Washington
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
state: Washington
city: Seattle
country: United States
facility: Group Health Cooperative-Seattle
state: Washington
city: Seattle
country: United States
facility: Swedish Medical Center-First Hill
state: Washington
city: Seattle
country: United States
facility: The Polyclinic
state: Washington
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Sedro-Woolley
country: United States
facility: United General Hospital
state: Washington
city: Spokane
country: United States
facility: Cancer Care Northwest - Spokane South
state: Washington
city: Spokane
country: United States
facility: Evergreen Hematology and Oncology PS
state: Washington
city: Wenatchee
country: United States
facility: Wenatchee Valley Medical Center
state: Washington
city: Casper
country: United States
facility: Rocky Mountain Oncology
state: Wyoming
city: Sheridan
country: United States
facility: Welch Cancer Center
state: Wyoming
Study officials:
affiliation: SWOG Cancer Research Network
name: Kim Margolin
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lee SM, Moon J, Redman BG, Chidiac T, Flaherty LE, Zha Y, Othus M, Ribas A, Sondak VK, Gajewski TF, Margolin KA. Phase 2 study of RO4929097, a gamma-secretase inhibitor, in metastatic melanoma: SWOG 0933. Cancer. 2015 Feb 1;121(3):432-440. doi: 10.1002/cncr.29055. Epub 2014 Sep 23.