Selumetinib Sulfate in Treating Patients with Uveal Melanoma or GNAQ / GNA11 Mutated Melanoma That Is Metastatic or Cannot Be Removed by Surgery
This phase Ib trial studies the side effects and best dose of selumetinib sulfate in treating patients with uveal melanoma or GNAQ / GNA11 mutated melanoma that has spread from the primary site to other places in the body or cannot be removed by surgery. Selumetinib sulfate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
- Histopathologically confirmed diagnosis of metastatic or unresectable uveal melanoma or non-uveal melanoma harboring a GNAQ or GNA11 mutation; * Note: For subjects with a diagnosis of uveal melanoma documentation of mutation status for uveal melanoma will not be required prospectively given the high rate of GNAQ/11 mutations (> 90%) in this population
- Able to provide informed consent prior to initiation of study
- Measurable indicator lesion by RECIST v1.1 * 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 for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
- Karnofsky performance status >= 60% or Eastern Cooperative Oncology Group (ECOG) =< 2
- Ability to take oral medications
- All clinically significant toxicities from prior systemic therapy must be =< grade 1 (with the exception of alopecia, endocrinopathies associated with prior immunological therapies as long as they are stable with replacement therapy, and peripheral neuropathy, which may be =< grade 2)
- Absolute neutrophil count (ANC) > 1500 cells/mm^3
- Platelet count > 100,000/mm^3
- Hemoglobin > 9.0 g/dL
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 2.5 x upper limit of normal if no documented liver disease or < 5 x upper limit of normal if documented liver disease
- Total bilirubin < 1.5 X upper limit of normal unless known diagnosis of Gilbert’s disease
- Alkaline phosphatase < 2.5 x upper limit of normal if no documented liver disease or < 6 x upper limit of normal if documented liver or bone disease
- Creatinine =< 1.5 x the upper limit of normal or creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels > 1.5 x the upper limit of normal
- Subjects must agree to undergo tumor biopsies until triplicate biopsies have been obtained from 20 subjects (i.e., biopsies are required in at least the first 20 accrued subjects, or until a goal of 20 triplicate study biopsies are obtained); subjects in whom a biopsy is technically not feasible or in whom would result in unacceptable risk in the opinion of the investigator, may be exempted from the biopsy requirement with discussion with the principal investigator
- Negative pregnancy test (serum or urine) for women of child bearing potential * 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 and 4 weeks after study discontinuation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after completion of selumetinib administration
- Patients who have had chemotherapy or immunotherapy within 4 weeks or radiation therapy within 2 weeks prior to start of study treatment or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
- Patients who are receiving any other investigational agents concurrently; palliative radiation therapy will be allowed as long as the patient meets all other eligibility criteria
- Have had recent major surgery within a minimum 4 weeks prior to starting study treatment; minor surgeries such as surgical placement for vascular access are not exclusionary
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to selumetinib
- Every effort must be made to avoid the use of a concomitant medication that can prolong the corrected QT (QTc) interval while receiving selumetinib (hyd-sulfate AZD6244); if the patient cannot discontinue medications that prolong QTc interval while receiving selumetinib, close cardiac monitoring should be performed
- Patients with QTc interval > 450 msecs or other factors that increase the risk of QTc prolongation or arrhythmic events (ex. heart failure, clinically significant hypokalemia, clinically significant hypomagnesemia, family history of long QT syndrome) including heart failure that meets New York Heart Association (NYHA) class III and IV definitions are excluded
- Prior or current cardiomyopathy including but not limited to the following: known hypertrophic cardiomyopathy, known arrhythmogenic right ventricular cardiomyopathy, previous moderate or severe impairment of left ventricular systolic function (left ventricular ejection fraction [LVEF] < 45% on echocardiography or equivalent on multigated acquisition scan [MuGA]) even if full recovery has occurred
- Atrial fibrillation with a ventricular rate > 100 beats per minute (bpm) on echocardiograph (ECG) at rest
- Baseline left ventricular ejection fraction (LVEF) below the lower limit of normal (LLN) or < 55% measured by echocardiography or institution’s lower limit of normal (LLN) for MUGA
- Severe valvular heart disease
- Uncontrolled angina - Canadian Cardiovascular Society grade II-IV despite medical therapy
- Acute coronary syndrome within 6 months prior to starting treatment
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with selumetinib
- Human immunodeficiency virus (HIV) positive patients on combination antiretroviral therapy are ineligible
- Prior treatment with a MEK, Ras or Raf inhibitor
- History of current evidence/risk of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED) in the eye unaffected by uveal melanoma; intra-ocular pressure (IOP) > 21 mmHg or uncontrolled glaucoma
- Patients with known hepatitis B or C; screening for hepatitis B and/or C is not required for eligibility for this study
- Refractory nausea and vomiting, active gastrointestinal disease (e.g. inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption
- Patients taking vitamin E supplements while on study
- Have known or suspected brain metastases or spinal cord compression, unless the condition has been asymptomatic, has been treated with surgery and / or radiation, and has been stable for at least 4 weeks prior to the first dose of study medication
- Have evidence of any other significant clinical disorder or laboratory finding that, as judged by the investigator, makes it undesirable for the patient to participate in the study
- Patients being actively treated for a secondary malignancy
Locations & Contacts
Contact: Alexander Noor Shoushtari
Contact: Richard D. Carvajal
Contact: Sapna Pradyuman Patel
Trial Objectives and Outline
I. Define the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of selumetinib sulfate (selumetinib) (hyd-sulfate AZD6244) administered on an intermittent dosing schedule.
II. Assess the safety and tolerability of intermittent selumetinib (hyd-sulfate AZD6244) dosing.
I. Assess the pharmacokinetics (PK) of intermittent selumetinib (hyd-sulfate AZD6244).
II. Assess the response rate (RR) to intermittent selumetinib (hyd-sulfate AZD6244).
III. Assess progression free survival (PFS) and overall survival (OS) with intermittent selumetinib (hyd-sulfate AZD6244).
I. Explore the association between best tumor shrinkage (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) and inhibition of intratumoral ERK signaling, as determined by measuring ERK phosphorylation and expression of ERK-dependent genes.
II. Evaluate levels of tumor-derived cell free deoxyribonucleic acid (DNA) (cell free DNA [cfDNA]) as a measure of tumor burden and response to therapy.
III. Explore the effect of MEK inhibition on cardiac tissue.
IV. Compare clinical and correlative studies with data from NCT01974752 A Randomized, Double-Blind Study to Assess the Efficacy of Selumetinib (AZD6244, Hyd-Sulfate) in Combination with Dacarbazine Compared with Placebo in Combination with Dacarbazine as First Systemic Therapy in Patients with Metastatic Uveal Melanoma (SUMIT) when available.
OUTLINE: This is a dose-escalation study.
Patients receive selumetinib sulfate orally (PO) twice daily (BID) on days 1-3, 8-10, 15-17, and 22-24. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Dosing schedules may change to coincide with pharmacokinetic schedules, although selumetinib sulfate is always taken for 3 days continuously followed by 2 days off before restarting the following week.
After completion of study treatment, patients are followed up within 30 days and then every 8 and 12 weeks.
Trial Phase & Type
NYP / Columbia University Medical Center / Herbert Irving Comprehensive Cancer Center
Richard D. Carvajal
Secondary IDs NCI-2016-01205
Clinicaltrials.gov ID NCT02768766