Temozolomide or Selumetinib in Treating Patients With Metastatic Melanoma of the Eye



Status:Active, not recruiting
Conditions:Skin Cancer
Therapuetic Areas:Oncology
Healthy:No
Age Range:18 - Any
Updated:4/21/2016
Start Date:June 2010

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Randomized Phase II Trial of Temozolomide Versus Hyd-Sulfate AZD6244 [NSC 748727] in Patients With Metastatic Uveal Melanoma

This randomized phase II trial studies temozolomide to see how well it works compared to
selumetinib in treating patients with melanoma of the eye that has spread to other places in
the body. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop
the growth of tumor cells, either by killing the cells, by stopping them from dividing, or
by stopping them from spreading. Selumetinib may stop the growth of tumor cells by blocking
some of the enzymes needed for cell growth. It is not yet known whether temozolomide is more
effective than selumetinib in treating melanoma of the eye.

PRIMARY OBJECTIVES:

I. To assess the progression-free survival (PFS) in three separate patient populations with
uveal melanoma: Patients on COHORT 1 (guanine nucleotide binding protein [G protein], q
polypeptide [Gnaq]/G protein, alpha 11 [Gna11] mutant uveal melanoma; temozolomide
[TMZ]/dacarbazine [DTIC] naive) treated with AZD6244 (selumetinib) or TMZ (or DTIC);
patients on both COHORT 1 and COHORT 2 (Gnaq/Gna11 mutant and Gnaq/Gna11 wild-type uveal
melanoma; TMZ/DTIC naive) treated with AZD6244 or TMZ (or DTIC); and patients on COHORT 3
(Gnaq/Gna11 mutant or wild-type uveal melanoma; previously treated with TMZ/DTIC) treated
with AZD6244.

SECONDARY OBJECTIVES:

I. Overall survival (OS). II. Overall response rate (RR). III. To determine the tolerability
of AZD6244 in patients with advanced uveal melanoma.

IV. To correlate PFS, OS, and overall RR with Gnaq and Gna11 mutational status.

TERTIARY OBJECTIVES:

I. To correlate clinical outcome with baseline phosphorylated (p)-extracellular
signal-regulated kinases (ERK), p-v-akt murine thymoma viral oncogene homolog 1 (AKT), and
phosphatase and tensin homolog (PTEN) expression by immunohistochemistry.

II. To correlate clinical outcome with changes in p-ERK, p-AKT, and PTEN expression by
immunohistochemistry.

III. To correlate clinical outcome with changes in Ki67 and cleaved caspase 3. IV. To
explore the overall quality of life (QoL) of the treatment groups as measured by the
Functional Assessment of Cancer Therapy-Melanoma (FACT-M) questionnaire.

V. To explore the radiographic effects of treatment with AZD6244 as assessed by 18F
fluorothymidine (FLT)-positron emission tomography (PET) imaging.

OUTLINE: Patients in groups 1 and 2 are randomized to 1 of 2 treatment arms. Patients in
group 3 are assigned to arm II.

ARM I: Patients receive temozolomide orally (PO) once daily (QD) on days 1-5. Courses repeat
every 28 days in the absence of disease progression or unacceptable toxicity. Patients who
are unable to be treated with temozolomide may be treated with dacarbazine intravenously
(IV) every 3 weeks (with approval from the Principal Investigator). Patients who experience
disease progression may crossover to arm II.

ARM II: Patients receive selumetinib PO twice daily (BID) on days 1-28. Courses repeat every
28 days in the absence of disease progression or unacceptable toxicity.

Inclusion Criteria:

- Patients must have metastatic histologically or cytologically confirmed uveal
melanoma; if histologic or cytologic confirmation of the primary is not available,
confirmation of the primary diagnosis of uveal melanoma by the treating investigator
can be clinically obtained, as per standard practice for uveal melanoma; pathologic
confirmation of diagnosis will be performed at Memorial Sloan-Kettering Cancer Center
(MSKCC) or at a participating site

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as >=
20 mm with conventional techniques or as >= 10 mm with spiral computed tomography
(CT) scan

- Life expectancy of greater than 3 months

- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

- Leukocytes >= 3,000/mcL

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

- Platelets >= 100,000/mcL

- Hemoglobin >= 9.0 g/dL (not requiring transfusions within the past 2 weeks)

- Total bilirubin =< 1.5 times upper limit of normal; note: patients with
hyperbilirubinemia clinically consistent with an inherited disorder of bilirubin
metabolism (e.g., Gilbert syndrome) will be eligible at the discretion of the
treating physician and/or the principal investigator

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 times upper limit of normal for patients with no concurrent liver metastases

- AST(SGOT)/ALT(SGPT) =< 5 X institutional ULN for patients with concurrent liver
metastases

- Creatinine =< 1.5 mg/dL

- Tumor Gnaq and Gna11 status must be determined on all patients using a Clinical
Laboratory Improvement Act (CLIA) approved assay; if initial CLIA testing is
performed locally, patients must consent to provide a tumor block or unstained slides
to MSKCC for central review of Gnaq and Gna11 status; this central review may be
performed retrospectively and will not delay patient treatment on study

- Patients must agree to provide all imaging studies for central radiology review; this
central radiology review may be performed retrospectively and will not be utilized
for decision making for patients on study

- Ability to understand and the willingness to sign a written informed consent document

- Eligibility for enrollment in each cohort is dependent upon tumor Gnaq/Gna11 status
and prior therapy as follows:

- Cohort 1: no prior TMZ or DTIC; mutant Gnaq/Gna11 status

- Cohort 2: no prior TMZ or DTIC; wild-type Gnaq/Gna11 status

- Cohort 3: received prior TMZ or DTIC; mutant or wild-type Gnaq/Gna11 status

- Every effort must be made to avoid administration of drugs that are inhibitors or
inducers of cytochrome P450 1A2 (CYP1A2) and CYP3A4

Exclusion Criteria:

- Patients may have had any number of prior therapies, but cannot have previously been
treated with a mitogen-activated protein kinase kinase (MEK) inhibitor; at least 3
weeks must have elapsed since the last dose of systemic therapy; at least 6 weeks
must have elapsed if the last regimen included carmustine (BCNU), mitomycin C or an
anti-CTLA4 antibody; patients must have experienced disease progression on their
prior therapy in the opinion of the treating investigator

- Patients may not be receiving any other investigational agents

- Patients with active or untreated brain metastases; treated brain metastases must
have been stable for at least 2 months

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to TMZ or DTIC or AZD6244

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection or bleeding, symptomatic congestive heart failure, unstable angina
pectoris, unstable cardiac arrhythmia, or psychiatric illness/social situations that
would limit compliance with study requirements

- Pregnant women are excluded from this study; breast-feeding should be discontinued if
the mother is treated with AZD6244

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and
for the duration of study participation; women of child-bearing potential must have a
negative pregnancy test prior to entry; should a woman become pregnant or suspect she
is pregnant while participating in this study, she should inform her treating
physician immediately; please note that the AZD6244 manufacturer recommends that
adequate contraception for male patients should be used for 16 weeks post-last dose
due to sperm life cycle

- Known human immunodeficiency virus (HIV)-positive patients on combination
antiretroviral therapy are ineligible; patients with compensated HIV, with adequate
cluster of differentiation (CD)4+ T-cell counts, and not requiring antiretroviral
medication will be allowed

- Patients taking vitamin E supplements while on study

- No concomitant anti-cancer chemotherapy or other systemic drugs; palliative radiation
therapy will be allowed as long as the patient meets all other eligibility criteria

- Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g. inflammatory
bowel disease), or significant bowel resection that would preclude adequate
absorption

- Patients with corrected QT (QTc) interval > 450 msecs or other factors that increase
the risk of QTc prolongation or arrhythmic events (e.g., heart failure, hypokalemia,
family history of long QT interval syndrome) including heart failure that meets New
York Heart Association (NYHA) class III and IV definitions are excluded

- Every effort must be made to avoid the use of a concomitant medication that can
prolong the QTc interval while receiving AZD6244; if the patient cannot discontinue
medications that prolong the QTc interval while receiving AZD6244, close cardiac
monitoring should be performed
We found this trial at
33
sites
1455 St Francis Ave
Shakopee, Minnesota 55379
(952) 428-3000
Saint Francis Regional Medical Center St. Francis Regional Medical Center has a rich tradition of...
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1500 East Medical Center Drive
Ann Arbor, Michigan 48109
800-865-1125
University of Michigan Comprehensive Cancer Center The U-M Comprehensive Cancer Center's mission is the conquest...
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13001 E. 17th Pl.
Aurora, Colorado 80045
303-724-5000
University of Colorado Cancer Center - Anschutz Cancer Pavilion The University of Colorado Denver |...
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Aurora, CO
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201 E Nicollet Blvd
Burnsville, Minnesota 55337
(952) 892-2000
Fairview Ridges Hospital Fairview Ridges Hospital is a 150-bed, Level III Trauma Care facility, offering...
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5841 S Maryland Ave
Chicago, Illinois 60637
1-773-702-6180
University of Chicago Comprehensive Cancer Center The University of Chicago Comprehensive Cancer Center (UCCCC) is...
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4050 Coon Rapids Blvd NW
Coon Rapids, Minnesota 55433
(763) 236-6000
Mercy Hospital Mercy Hospital, located in Coon Rapids, Minnesota, is a 271-bed non-profit hospital that...
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4160 John R St #2122
Detroit, Michigan 48201
(313) 833-1785
Wayne State University/Karmanos Cancer Institute Karmanos is based in southeast Michigan, in midtown Detroit, and...
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6401 France Ave S
Edina, Minnesota 55435
(952) 924-5000
Fairview Southdale Hospital Fairview Health Services is an award-winning nonprofit health care system based in...
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550 Osborne Rd NE
Fridley, Minnesota 55432
(763) 236-5000
Unity Hospital Unity Hospital is one of the Twin Cities
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1095 Minnesota 15
Hutchinson, Minnesota 55350
(320) 234-5000
Hutchinson Area Health Care Hutchinson Health is a team of medical professionals and support staff...
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600 Highland Ave
Madison, Wisconsin 53792
(608) 263-6400
University of Wisconsin Hospital and Clinics UW Health strives to meet the health needs of...
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1575 Beam Ave
Maplewood, Minnesota 55109
(651) 232-7000
Saint John's Hospital - Healtheast St. John's Hospital is committed to providing superior health care...
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Maplewood, Minnesota 55109
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Miami Beach, Florida 33140
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Milwaukee, Wisconsin 53226
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800 E 28th St
Minneapolis, Minnesota 55407
(612) 863-4000
Abbott Northwestern Hospital Our hospital has a long and proud history as a health care...
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Minneapolis, Minnesota 55414
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Nashville, Tennessee 37232
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1275 York Ave
New York, New York 10021
(212) 639-2000
Memorial Sloan Kettering Cancer Center Memorial Sloan Kettering Cancer Center — the world's oldest and...
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111 S 11th St
Philadelphia, Pennsylvania 19107
(215) 955-6000
Thomas Jefferson University Hospital Our hospitals in Center City Philadelphia share a 13-acre campus with...
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3300 Oakdale Ave. N.
Robbinsdale, Minnesota 55422
763-520-5200
North Memorial Medical Health Center North Memorial Health Care is a comprehensive health care system...
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Rochester, Minnesota 55905
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660 S Euclid Ave
Saint Louis, Missouri 63110
(314) 362-5000
Washington University School of Medicine Washington University Physicians is the clinical practice of the School...
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Saint Louis Park, Minnesota 55416
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3850 Park Nicollet Blvd
Saint Louis Park, Minnesota 55416
(952) 993-3123
Park Nicollet Clinic - Saint Louis Park Park Nicollet Health Services is a nonprofit, integrated...
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640 Jackson Street
Saint Paul, Minnesota 55101
651-254-3456
Regions Hospital Established in 1872, Regions Hospital is a private, not-for-profit organization. The hospital provides...
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333 Smith Ave
Saint Paul, Minnesota 55102
(651) 241-8000
United Hospital United Hospital is the largest hospital in the Twin Cities east metro area,...
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Tampa, Florida 33612
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500 S Maple Street
Waconia, Minnesota 55387
952-442-2191
Ridgeview Medical Center Ridgeview Medical Center is an independent, nonprofit, regional health care system located...
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