Multi-Center Phase Ib Study of Intermittent Dosing of the MEK inhibitor, Selumetinib, in Patients with advanced Uveal Melanoma Not Previously Treated with a MEK Inhibitor
Sapna P. Patel
The goal of this clinical research study is to find the highest tolerable dose of selumetinib when given on an intermittent dosing schedule that can be given to patients with uveal melanoma. Intermittent dosing means that the study drug will be given on a "3 days on, 4 days off" schedule. The safety of selumetinib will also be studied.
Disease Group: Melanoma and other malignant neoplasms of skin
Treatment Agent: Selumetinib
Treatment Location: Both at MDACC & and Other Sites
Sponsor: AstraZeneca,Melanoma Research Alliance
Primary: Define the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of selumetinib (hyd-sulfate AZD6244) administered on an intermittent dosing schedule Assess the safety and tolerability of intermittent selumetinib (hyd-sulfate AZD6244) dosing Secondary: Assess the pharmacokinetics (PK) of intermittent selumetinib (hyd-sulfate AZD6244) Assess the response rate (RR) to intermittent selumetinib (hyd-sulfate AZD6244) Assess progression free survival (PFS) and overall survival (OS) with intermittent selumetinib (hyd-sulfate AZD6244) The biological activity of selumetinib will be assessed by performing tumor biopsies at baseline. day 3 of cyle 1, day 13 or 14 of cycle 1 and optionally at progression of disease for all patients.
IRB Review and Approval Date: 05/30/2017
Recruitment Status: Open
Projected Accrual: 28
1) 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
2) Able to provide informed consent prior to initiation of study
3) Age >/= 18 years old
4) 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 CT scan, MRI, or calipers by clinical exam. See Section 13.3 for more information regarding evaluation of measurable disease.
5) Karnofsky Performance Status >/=60% or ECOG </=2
6) Ability to take oral medications
7) All clinically significant toxicities from prior systemic therapy must be </=grade (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).
8) Organ and marrow function and laboratory values as follows: Adequate marrow function ANC >/=1500 cells/mm^3 platelet count >/=100,000/mm^3 hemoglobin >/=9.0g/dL Adequate hepatic function AST/ALT</=2.5x upper limit of normal if no documented liver disease or </=5x upper limit of normal if documented liver disease Total bilirubin </=1.5X upper limit of normal unless known diagnosis of Gilbert’s disease Alkaline phosphatase </=2.5x upper limit of normal if no documented liver disease or </=6x upper limit of normal if documented liver or bone disease Adequate renal function Creatinine </= 1.5x the upper limit of normal or creatinine clearance >/=60 mL/min/1.73 m^2 for patients with creatinine levels 1.5x the upper limit of normal.
9) Subjects must agree to undergo tumor biopsies until biopsies have been obtained from 20 subjects (i.e., biopsies are required in at least the first 20 enrolled subjects, or until a goal of 20 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
10) Negative pregnancy test (serum or urine) for women of child bearing potential The effects of selumetinib on the developing human fetus are unknown. For this reason, 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.
1) 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.
2) Patients who are receiving any other investigational agents concurently. Palliative radiation therapy will be allowed as long as the patient meets all other eligibility criteria.
3) 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.
4) History of allergic reactions attributed to compounds of similar chemical or biologic composition to selumetinib
5) Every effort must be made to avoid the use of a concomitant medication that can prolong the 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. A comprehensive list of agents with potential to cause QTc prolongation can be found at http://www.crediblemeds.org/everyone/composite-list-all-qtdrugs/?rf=US
6) 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.
7) 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 (LVEF</=45% on echocardiography or equivalent on MuGA) even if full recovery has occurred.
8) Atrial fibrillation with a ventricular rate >100 bpm on ECG at rest
9) Baseline Left ventricular ejection fraction (LVEF) below the LLN or </=55% measured by echocardiography or institution’s LLN for MUGA
10) Severe valvular heart disease
11) Uncontrolled Angina - Canadian Cardiovascular Society grade II-IV despite medical therapy
12) Acute coronary syndrome within 6 months prior to starting treatment
13) 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.
14) Pregnant women are excluded from this study because selumetinib may be teratogenic or have abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with selumetinib, breastfeeding should be discontinued if the mother is treated with selumetinib.
15) HIV positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with selumetinib.
16) Prior treatment with a MEK, Ras or Raf inhibitor.
17) History of current evidence/risk of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED) in the eye unaffected by uveal melanoma; IOP >/=21mmgHG or uncontrolled glaucoma
18) Patients with known Hepatitis B or C. Screening for hepatitis B and/or C is not required for eligibility for this study.
19) Refractory nausea and vomiting, active gastrointestinal disease (e.g. inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption
20) Patients taking vitamin E supplements while on study
21) 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
22) 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.
23) Patients being actively treated for a secondary malignancy
Information and next steps
Melanoma and other malignant neoplasms of skin
Sapna P. Patel
Melanoma Medical Oncology
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