Iris MelanomaPhase 2NCT01143402
Temozolomide or Selumetinib in Treating Patients With Metastatic Melanoma of the Eye
A Phase 2 study testing Dacarbazine, Laboratory Biomarker Analysis and Quality-of-Life Assessment in people with Iris Melanoma and Medium/Large Size Posterior Uveal Melanoma, run by National Cancer Institute (NCI) at 33 sites in 2 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Iris Melanoma, Medium/Large Size Posterior Uveal Melanoma, Ocular Melanoma With Extraocular Extension
- What is being tested?
- Dacarbazine, Laboratory Biomarker Analysis and Quality-of-Life Assessment
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 120 participants
- Where
- 33 sitesin 2 countries
- Study dates
- Jun 2010to May 2016
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
33 sites in 2 countries.
33 sites in 2 countries
United States32 sites
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, 48109
Emory University/Winship Cancer Institute
Atlanta, Georgia, 30322
University of Colorado Cancer Center - Anschutz Cancer Pavilion
Aurora, Colorado, 80045
Fairview Ridges Hospital
Burnsville, Minnesota, 55337
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, 60637
Mercy Hospital
Coon Rapids, Minnesota, 55433
Wayne State University/Karmanos Cancer Institute
Detroit, Michigan, 48201
Fairview-Southdale Hospital
Edina, Minnesota, 55435
Unity Hospital
Fridley, Minnesota, 55432
Hutchinson Area Health Care
Hutchinson, Minnesota, 55350
University of Iowa/Holden Comprehensive Cancer Center
Iowa City, Iowa, 52242
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, 53792
Minnesota Oncology Hematology PA-Maplewood
Maplewood, Minnesota, 55109
Saint John's Hospital - Healtheast
Maplewood, Minnesota, 55109
Mount Sinai Medical Center
Miami Beach, Florida, 33140
Wisconsin Clinical Cancer Center
Milwaukee, Wisconsin, 53226
Abbott-Northwestern Hospital
Minneapolis, Minnesota, 55407
Hennepin County Medical Center
Minneapolis, Minnesota, 55415
Vanderbilt University/Ingram Cancer Center
Nashville, Tennessee, 37232
Memorial Sloan-Kettering Cancer Center
New York, New York, 10065
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania, 19107
North Memorial Medical Health Center
Robbinsdale, Minnesota, 55422
Mayo Clinic
Rochester, Minnesota, 55905
Metro Minnesota Community Oncology Research Consortium
Saint Louis Park, Minnesota, 55416
Park Nicollet Clinic - Saint Louis Park
Saint Louis Park, Minnesota, 55416
Regions Hospital
Saint Paul, Minnesota, 55101
United Hospital
Saint Paul, Minnesota, 55102
Saint Francis Regional Medical Center
Shakopee, Minnesota, 55379
Washington University School of Medicine
St Louis, Missouri, 63110
Moffitt Cancer Center
Tampa, Florida, 33612
Ridgeview Medical Center
Waconia, Minnesota, 55387
Minnesota Oncology and Hematology PA-Woodbury
Woodbury, Minnesota, 55125
Canada1 site
University Health Network-Princess Margaret Hospital
Toronto, Ontario, M5G 2M9
About this study
Official title: 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.
Read the detailed description
PRIMARY OBJECTIVES:
- 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:
- 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:
- 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.
- 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.
- Conditions
- 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
- Being tested
- Dacarbazine, Laboratory Biomarker Analysis, Quality-of-Life Assessment, Selumetinib, Temozolomide
- Medical subject headings
- Uveal Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DacarbazineDrug
Also called 4-(Dimethyltriazeno)imidazole-5-carboxamide, 5-(Dimethyltriazeno)imidazole-4-carboxamide, Asercit, Biocarbazine
Given IV
Laboratory Biomarker AnalysisOther
Correlative studies
Quality-of-Life AssessmentOther
Also called Quality of Life Assessment
Ancillary studies
SelumetinibDrug
Also called ARRY-142886, AZD6244, MEK Inhibitor AZD6244
Given PO
TemozolomideDrug
Also called 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
Given PO
| Study group | Role | What they receive |
|---|---|---|
| Arm I (temozolomide) | Experimental | 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. Receives: Drug: Dacarbazine; Other: Laboratory Biomarker Analysis; Other: Quality-of-Life Assessment; Drug: Temozolomide |
| Arm II (selumetinib) | Experimental | Patients receive selumetinib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Receives: Other: Laboratory Biomarker Analysis; Other: Quality-of-Life Assessment; Drug: Selumetinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Progression-free Survival (PFS) (Evaluable Randomized Patients)
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.
Measured: 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
Secondary outcomes (1)
Median Overall Survival (Evaluable Randomized Patients)
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.
Measured: The time from randomization to death due to any cause, assessed up to 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Jun 2010 (estimated)
- Study startJun 2010
- Primary completionMay 2016
- Study completionMay 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Iris MelanomaStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 120 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Paul Chapman, Principal investigator, Memorial Sloan Kettering Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01143402
- Sponsor's protocol ID
- NCI-2011-01411
- Other IDs
- NCI-2011-01411, CDR0000674866, 10-053, 8443, N01CM00070, N01CM00071, N01CM00099, N01CM00100
- Status last verified
- Jun 2017
- First submitted
- 11 Jun 2010
- Last updated
- 26 Jul 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Atkinson TM, Hay JL, Shoushtari A, Li Y, Paucar DJ, Smith SC, Kudchadkar RR, Doyle A, Sosman JA, Quevedo JF, Milhem MM, Joshua AM, Linette GP, Gajewski TF, Lutzky J, Lawson DH, Lao CD, Flynn PJ, Albertini MR, Sato T, Lewis K, Marr B, Abramson DH, Dickson MA, Schwartz GK, Carvajal RD. Relationship between physician-adjudicated adverse events and patient-reported health-related quality of life in a phase II clinical trial (NCT01143402) of patients with metastatic uveal melanoma. J Cancer Res Clin Oncol. 2017 Mar;143(3):439-445. doi: 10.1007/s00432-016-2318-x. Epub 2016 Dec 5.
PubMed 27921276Carvajal RD, Sosman JA, Quevedo JF, Milhem MM, Joshua AM, Kudchadkar RR, Linette GP, Gajewski TF, Lutzky J, Lawson DH, Lao CD, Flynn PJ, Albertini MR, Sato T, Lewis K, Doyle A, Ancell K, Panageas KS, Bluth M, Hedvat C, Erinjeri J, Ambrosini G, Marr B, Abramson DH, Dickson MA, Wolchok JD, Chapman PB, Schwartz GK. Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial. JAMA. 2014 Jun 18;311(23):2397-405. doi: 10.1001/jama.2014.6096.
PubMed 24938562Chen X, Schwartz GK, DeAngelis LM, Kaley T, Carvajal RD. Dropped head syndrome: report of three cases during treatment with a MEK inhibitor. Neurology. 2012 Oct 30;79(18):1929-31. doi: 10.1212/WNL.0b013e318271f87e. Epub 2012 Oct 17. No abstract available.
PubMed 23077008