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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01143402
• Collaborator: (none)
• Enrollment: 120
• Locations: 33
• Arms: 2
• Duration (Months): 71
• Patients Per Site: 3.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Iris Melanoma; Medium/Large Size Posterior Uveal Melanoma; Ocular Melanoma With Extraocular Extension; Recurrent Uveal Melanoma; Small Size Posterior Uveal Melanoma; Stage IV Uveal Melanoma	Drug: Dacarbazine; Other: Laboratory Biomarker Analysis; Other: Quality-of-Life Assessment; Drug: Selumetinib; Drug: Temozolomide	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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:

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

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

TERTIARY OBJECTIVES:

1. 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.

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

3. 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.

4. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 120 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized Phase II Trial of Temozolomide Versus Hyd-Sulfate AZD6244 [NSC 748727] in Patients With Metastatic Uveal Melanoma
• Study Start Date: Jun 1, 2010
• Actual Primary Completion Date: May 1, 2016
• Actual Study Completion Date: May 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (temozolomide) Patients receive temozolomide PO 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 IV every 3 weeks (with approval from the Principal Investigator). Patients who experience disease progression may crossover to arm II.	Drug: Dacarbazine; Given IV; Other Names: 4-(Dimethyltriazeno)imidazole-5-carboxamide 5-(Dimethyltriazeno)imidazole-4-carboxamide Asercit Biocarbazine Dacarbazina Dacarbazina Almirall Dacarbazine - DTIC Dacatic Dakarbazin Deticene Detimedac DIC Dimethyl (triazeno) imidazolecarboxamide Dimethyl Triazeno Imidazol Carboxamide Dimethyl Triazeno Imidazole Carboxamide dimethyl-triazeno-imidazole carboxamide Dimethyl-triazeno-imidazole-carboximide DTIC DTIC-Dome Fauldetic Imidazole Carboxamide Imidazole Carboxamide Dimethyltriazeno WR-139007 ; Other: Laboratory Biomarker Analysis; Correlative studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment ; Drug: Temozolomide; Given PO; Other Names: CCRG-81045 Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo- M & B 39831 M and B 39831 Methazolastone RP-46161 SCH 52365 Temcad Temodal Temodar Temomedac
Experimental: Arm II (selumetinib) Patients receive selumetinib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment ; Drug: Selumetinib; Given PO; Other Names: ARRY-142886 AZD6244 MEK Inhibitor AZD6244

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival (PFS) (Evaluable Randomized Patients) [The time from randomization to the earlier date of objective disease progression per Response Evaluation Criteria In Solid Tumors (RECIST) criteria or death due to any cause in the absence of progression, assessed up to 5 years]

   The primary analysis will be performed among the Gnaq/Gna11 mutant patients. A stratified logrank test will be performed stratified by mutation status, M stage, and number of prior systemic therapies for metastatic disease. Due to the potential for a large number of strata and small strata sizes, the standard asymptotic stratified logrank test will be verified for robustness utilizing a permutation reference distribution.

Secondary Outcome Measures

1. Median Overall Survival (Evaluable Randomized Patients) [The time from randomization to death due to any cause, assessed up to 5 years]

   The primary analysis will be performed among the Gnaq/Gna11 mutant patients. A stratified logrank test will be performed stratified by mutation status, M stage, and number of prior systemic therapies for metastatic disease. Due to the potential for a large number of strata and small strata sizes, the standard asymptotic stratified logrank test will be verified for robustness utilizing a permutation reference distribution.

Other Outcome Measures

1. Objective Disease Progression [assessed up to 5 years]

   per Response Evaluation Criteria In Solid Tumors (RECIST) criteria or death due to any cause in the absence of progression

2. Overall Survival [The time from randomization to death due to any cause, assessed up to 5 years]

   The primary analysis will be performed among the Gnaq/Gna11 mutant patients. A stratified logrank test will be performed stratified by mutation status, M stage, and number of prior systemic therapies for metastatic disease. Due to the potential for a large number of strata and small strata sizes, the standard asymptotic stratified logrank test will be verified for robustness utilizing a permutation reference distribution.

3. Response Rate (Complete and Partial Response) [Up to 5 years]

   Calculated along with a 95% confidence interval.

4. Toxicity According to the National Cancer Institute Common Toxicity Criteria [Up to 5 years]

   Toxicity will be reported by type, frequency, and severity. Please see adverse events.

5. PFS (Group 3) [4 months]

   Evaluated using a Simon mini-max design. Curves will be generated using Kaplan-Meier methodology.

6. Apoptosis in the Paired Samples, Performed by Caspase 3 Cleavage [Up to 5 years]

   Changes will be assessed by a Wilcoxon test

7. Change in Ki67 [Baseline up to 4 months]

   Correlated with disease status using Fishers exact test.

8. Change in p-AKT [Baseline up to 4 months]

   Correlated with disease status using Fishers exact test.

9. Change in p-ERK [Baseline up to 4 months]

   Decrease in p-ERK will be correlated with disease status using Fishers exact test.

10. Change in PTEN [Baseline up to 4 months]

    Correlated with disease status using Fishers exact test.

11. Changes in Maximum Standardized Uptake Value on FLT-PET Scans [Baseline up to 60 minutes post injection]

    A paired student's t-test will be performed. Analysis of variance will also be performed to obtain the significance of FLT-PET uptake on each lesion between patients.

12. FACT-M Total Score [Up to 5 years]

    Summarized using descriptive statistics for each assessment time and by treatment group. The scores will be compared between treatment groups using a mixed effect model for repeated measures analysis method. Treatment difference will be estimated from the model for each assessment time.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado Cancer Center - Anschutz Cancer Pavilion	Aurora	Colorado	United States	80045
2	Mount Sinai Medical Center	Miami Beach	Florida	United States	33140
3	Moffitt Cancer Center	Tampa	Florida	United States	33612
4	Emory University/Winship Cancer Institute	Atlanta	Georgia	United States	30322
5	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
6	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa	United States	52242
7	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109
8	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan	United States	48201
9	Fairview Ridges Hospital	Burnsville	Minnesota	United States	55337
10	Mercy Hospital	Coon Rapids	Minnesota	United States	55433
11	Fairview-Southdale Hospital	Edina	Minnesota	United States	55435
12	Unity Hospital	Fridley	Minnesota	United States	55432
13	Hutchinson Area Health Care	Hutchinson	Minnesota	United States	55350
14	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota	United States	55109
15	Saint John's Hospital - Healtheast	Maplewood	Minnesota	United States	55109
16	Abbott-Northwestern Hospital	Minneapolis	Minnesota	United States	55407
17	Hennepin County Medical Center	Minneapolis	Minnesota	United States	55415
18	North Memorial Medical Health Center	Robbinsdale	Minnesota	United States	55422
19	Mayo Clinic	Rochester	Minnesota	United States	55905
20	Metro Minnesota Community Oncology Research Consortium	Saint Louis Park	Minnesota	United States	55416
21	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota	United States	55416
22	Regions Hospital	Saint Paul	Minnesota	United States	55101
23	United Hospital	Saint Paul	Minnesota	United States	55102
24	Saint Francis Regional Medical Center	Shakopee	Minnesota	United States	55379
25	Ridgeview Medical Center	Waconia	Minnesota	United States	55387
26	Minnesota Oncology and Hematology PA-Woodbury	Woodbury	Minnesota	United States	55125
27	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
28	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065
29	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania	United States	19107
30	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee	United States	37232
31	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792
32	Wisconsin Clinical Cancer Center	Milwaukee	Wisconsin	United States	53226
33	University Health Network-Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Paul Chapman, Memorial Sloan Kettering Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01143402
• Other Study ID Numbers: NCI-2011-01411; NCI-2011-01411; CDR0000674866; 10-053; 8443; N01CM00070; N01CM00071; N01CM00099; N01CM00100; N01CM62206; N01CM62208; P30CA008748; U01CA132123
• First Posted: Jun 14, 2010
• Last Update Posted: Jul 26, 2017
• Last Verified: Jun 1, 2017

• Additional relevant MeSH terms: Melanoma; Uveal Neoplasms; Temozolomide; Dacarbazine; Imidazole

Study Results

Participant Flow

Arm/Group Title	Arm I (Temozolomide)	Arm II (Selumetinib)	Non-Randomized (Selumetinib)
Arm/Group Description	Randomized to Temozolomide	Randomized to Selumetinib	Non-Randomized to Selumetinib
Period Title: Overall Study
STARTED	51	50	19
COMPLETED	50	49	18
NOT COMPLETED	1	1	1

Baseline Characteristics

Arm/Group Title	Arm I (Temozolomide)	Arm II (Selumetinib)	Non-Randomized (Selumetinib)	Total
Arm/Group Description	Randomized to Temozolomide	Randomized to Selumetinib	Non-Randomized to Selumetinib	Total of all reporting groups
Overall Participants	51	50	19	120
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	62	62	63	62
Sex: Female, Male (Count of Participants)
Female	20 39.2%	24 48%	10 52.6%	54 45%
Male	31 60.8%	26 52%	9 47.4%	66 55%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS) (Evaluable Randomized Patients)
Description	The primary analysis will be performed among the Gnaq/Gna11 mutant patients. A stratified logrank test will be performed stratified by mutation status, M stage, and number of prior systemic therapies for metastatic disease. Due to the potential for a large number of strata and small strata sizes, the standard asymptotic stratified logrank test will be verified for robustness utilizing a permutation reference distribution.
Time Frame	The time from randomization to the earlier date of objective disease progression per Response Evaluation Criteria In Solid Tumors (RECIST) criteria or death due to any cause in the absence of progression, assessed up to 5 years

Outcome Measure Data

Analysis Population Description

Analysis of progression-free survival in all evaluable randomized patients

Arm/Group Title	Arm I (Temozolomide)	Arm II (Selumetinib)
Arm/Group Description	Randomized to Temozolomide	Randomized to Selumetinib
Measure Participants	49	47
Median (95% Confidence Interval) [weeks]	7	15.9

2. Secondary Outcome

Title	Median Overall Survival (Evaluable Randomized Patients)
Description	The primary analysis will be performed among the Gnaq/Gna11 mutant patients. A stratified logrank test will be performed stratified by mutation status, M stage, and number of prior systemic therapies for metastatic disease. Due to the potential for a large number of strata and small strata sizes, the standard asymptotic stratified logrank test will be verified for robustness utilizing a permutation reference distribution.
Time Frame	The time from randomization to death due to any cause, assessed up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Temozolomide)	Arm II (Selumetinib)
Arm/Group Description	Randomized to Temozolomide	Randomized to Selumetinib
Measure Participants	50	49
Median (95% Confidence Interval) [Months]	9.1	11.8

3. Other Pre-specified Outcome

Title	Objective Disease Progression
Description	per Response Evaluation Criteria In Solid Tumors (RECIST) criteria or death due to any cause in the absence of progression
Time Frame	assessed up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Other Pre-specified Outcome

Title	Overall Survival
Description	The primary analysis will be performed among the Gnaq/Gna11 mutant patients. A stratified logrank test will be performed stratified by mutation status, M stage, and number of prior systemic therapies for metastatic disease. Due to the potential for a large number of strata and small strata sizes, the standard asymptotic stratified logrank test will be verified for robustness utilizing a permutation reference distribution.
Time Frame	The time from randomization to death due to any cause, assessed up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Other Pre-specified Outcome

Title	Response Rate (Complete and Partial Response)
Description	Calculated along with a 95% confidence interval.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Other Pre-specified Outcome

Title	Toxicity According to the National Cancer Institute Common Toxicity Criteria
Description	Toxicity will be reported by type, frequency, and severity. Please see adverse events.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Other Pre-specified Outcome

Title	PFS (Group 3)
Description	Evaluated using a Simon mini-max design. Curves will be generated using Kaplan-Meier methodology.
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Other Pre-specified Outcome

Title	Apoptosis in the Paired Samples, Performed by Caspase 3 Cleavage
Description	Changes will be assessed by a Wilcoxon test
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Other Pre-specified Outcome

Title	Change in Ki67
Description	Correlated with disease status using Fishers exact test.
Time Frame	Baseline up to 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Other Pre-specified Outcome

Title	Change in p-AKT
Description	Correlated with disease status using Fishers exact test.
Time Frame	Baseline up to 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Other Pre-specified Outcome

Title	Change in p-ERK
Description	Decrease in p-ERK will be correlated with disease status using Fishers exact test.
Time Frame	Baseline up to 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Other Pre-specified Outcome

Title	Change in PTEN
Description	Correlated with disease status using Fishers exact test.
Time Frame	Baseline up to 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Other Pre-specified Outcome

Title	Changes in Maximum Standardized Uptake Value on FLT-PET Scans
Description	A paired student's t-test will be performed. Analysis of variance will also be performed to obtain the significance of FLT-PET uptake on each lesion between patients.
Time Frame	Baseline up to 60 minutes post injection

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

14. Other Pre-specified Outcome

Title	FACT-M Total Score
Description	Summarized using descriptive statistics for each assessment time and by treatment group. The scores will be compared between treatment groups using a mixed effect model for repeated measures analysis method. Treatment difference will be estimated from the model for each assessment time.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	Arm I (Temozolomide)		Arm II (Selumetinib)		Non-Randomized (Selumetinib)
Arm/Group Description	Randomized to Temozolomide		Randomized to Selumetinib		Non-Randomized to Selumetinib
All Cause Mortality
	Arm I (Temozolomide)		Arm II (Selumetinib)		Non-Randomized (Selumetinib)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm I (Temozolomide)		Arm II (Selumetinib)		Non-Randomized (Selumetinib)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/50 (36%)		19/49 (38.8%)		7/18 (38.9%)
Blood and lymphatic system disorders
Alanine aminotransferase increased	1/50 (2%)		2/49 (4.1%)		1/18 (5.6%)
CPK increased	4/50 (8%)		9/49 (18.4%)		2/18 (11.1%)
Lymphocyte count decreased	1/50 (2%)		1/49 (2%)		0/18 (0%)
Neutrophil count decreased	1/50 (2%)		0/49 (0%)		1/18 (5.6%)
Aspartate aminotransferase increased	0/50 (0%)		2/49 (4.1%)		0/18 (0%)
Nausea	0/50 (0%)		1/49 (2%)		0/18 (0%)
Cardiac disorders
Supraventricular tachycardia	1/50 (2%)		0/49 (0%)		1/18 (5.6%)
Thromboembolic event	1/50 (2%)		1/49 (2%)		0/18 (0%)
Gastrointestinal disorders
Dehydration	0/50 (0%)		1/49 (2%)		0/18 (0%)
Vomiting	0/50 (0%)		1/49 (2%)		0/18 (0%)
General disorders
Abdominal pain	1/50 (2%)		2/49 (4.1%)		0/18 (0%)
Ascites	1/50 (2%)		0/49 (0%)		0/18 (0%)
Multi-organ failure	1/50 (2%)		0/49 (0%)		0/18 (0%)
Confusion	0/50 (0%)		1/49 (2%)		0/18 (0%)
Death NOS	0/50 (0%)		1/49 (2%)		0/18 (0%)
Edema limbs	0/50 (0%)		1/49 (2%)		0/18 (0%)
Syncope	0/50 (0%)		1/49 (2%)		0/18 (0%)
General Disorders	0/50 (0%)		0/49 (0%)		1/18 (5.6%)
Hepatobiliary disorders
Hepatic failure	1/50 (2%)		1/49 (2%)		0/18 (0%)
Hepatobiliary disorders	1/50 (2%)		0/49 (0%)		0/18 (0%)
Metabolism and nutrition disorders
Creatinine increased	1/50 (2%)		0/49 (0%)		0/18 (0%)
Hypoglycemia	1/50 (2%)		0/49 (0%)		1/18 (5.6%)
Alkaline phosphatase increased	0/50 (0%)		1/49 (2%)		0/18 (0%)
Blood bilirubin increased	0/50 (0%)		3/49 (6.1%)		1/18 (5.6%)
GGT increased	0/50 (0%)		1/49 (2%)		0/18 (0%)
Hyponatremia	0/50 (0%)		1/49 (2%)		0/18 (0%)
Hypophosphatemia	0/50 (0%)		2/49 (4.1%)		0/18 (0%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	1/50 (2%)		0/49 (0%)		0/18 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/50 (0%)		2/49 (4.1%)		0/18 (0%)
Lung infection	0/50 (0%)		2/49 (4.1%)		0/18 (0%)
Skin and subcutaneous tissue disorders
Neoplasms	9/50 (18%)		3/49 (6.1%)		4/18 (22.2%)
Skin infection	1/50 (2%)		1/49 (2%)		1/18 (5.6%)
Other (Not Including Serious) Adverse Events
	Arm I (Temozolomide)		Arm II (Selumetinib)		Non-Randomized (Selumetinib)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	50/50 (100%)		49/49 (100%)		18/18 (100%)
Blood and lymphatic system disorders
Anemia	8/50 (16%)		15/49 (30.6%)		6/18 (33.3%)
Leukopenia	9/50 (18%)		6/49 (12.2%)		6/18 (33.3%)
Lymphopenia	5/50 (10%)		4/49 (8.2%)		4/18 (22.2%)
Neutropenia	5/50 (10%)		3/49 (6.1%)		3/18 (16.7%)
Thrombocytopenia	8/50 (16%)		5/49 (10.2%)		5/18 (27.8%)
Alanine Amino Transferase Elevation	4/50 (8%)		21/49 (42.9%)		7/18 (38.9%)
Aspartate Amino Transferase Elevation	6/50 (12%)		25/49 (51%)		7/18 (38.9%)
Eye disorders
Blurred Vision	0/50 (0%)		3/49 (6.1%)		1/18 (5.6%)
Eye Disorder	0/50 (0%)		4/49 (8.2%)		1/18 (5.6%)
Gastrointestinal disorders
Constipation	15/50 (30%)		3/49 (6.1%)		1/18 (5.6%)
Diarrhea	4/50 (8%)		20/49 (40.8%)		8/18 (44.4%)
Nausea	20/50 (40%)		18/49 (36.7%)		7/18 (38.9%)
Vomiting	12/50 (24%)		11/49 (22.4%)		3/18 (16.7%)
General disorders
Alopecia	0/50 (0%)		6/49 (12.2%)		1/18 (5.6%)
Anorexia	7/50 (14%)		4/49 (8.2%)		1/18 (5.6%)
CPK Elevation	0/50 (0%)		26/49 (53.1%)		14/18 (77.8%)
Edema Face	0/50 (0%)		6/49 (12.2%)		3/18 (16.7%)
Fatigue	22/50 (44%)		30/49 (61.2%)		8/18 (44.4%)
Mucositis	1/50 (2%)		6/49 (12.2%)		0/18 (0%)
Edema Limbs	1/50 (2%)		15/49 (30.6%)		10/18 (55.6%)
Musculoskeletal and connective tissue disorders
Arthralgias	0/50 (0%)		5/49 (10.2%)		0/18 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/50 (0%)		8/49 (16.3%)		2/18 (11.1%)
Skin and subcutaneous tissue disorders
Pruritis	0/50 (0%)		8/49 (16.3%)		1/18 (5.6%)
Rash Acneiform	3/50 (6%)		38/49 (77.6%)		12/18 (66.7%)

Limitations/Caveats

Limitations of this study include the unblinded trial design and the lack of central review of imaging studies. Additionally, this trial was designed before activating mutations in exon 4 of GNAQ and GNA11 were reported.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.