Intermittent Selumetinib for Uveal Melanoma

NCT02768766 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: AAAQ6999
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 3

Brief Summary

The purpose of this study is to find out what effects, good and/or bad, intermittent dosing of the drug Selumetinib will have on subjects with uveal melanoma. Selumetinib is a drug that blocks (or turns off) methyl ethyl ketone (MEK), a protein activated in some uveal melanoma cells. Selumetinib is a MEK inhibitor. Blocking MEK may stop the cancer from growing.

Conditions

Uveal Melanoma

Keywords

MEK inhibitor; Selumetinib; hyd-sulfate AZD6244; Uveal melanoma; Melanoma

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerated Dose (MTD) of intermittent selumetinib

  MTD is defined as the dose associated with a target probability of dose limiting toxicity (DLT) of 25%. DLT will be assessed over the course of first two cycles of treatment (i.e., 8 weeks) for dose selection for subsequent patient treatment initiation.

  Up to 8 weeks

Secondary Outcomes (6)

• Number of adverse events (AEs)

  Up to 2 years

• Number of serious adverse events (SAEs)

  Up to 2 years

• Number of subjects with Dose Limiting Toxicity (DLT)

  8 weeks

• Overall Response Rate (ORR)

  Up to 2 years

• Progression Free Survival (PFS)

  Up to 2 years

Study Arms (6)

Dose Level 1: Selumetinib

EXPERIMENTAL

Subjects will receive selumetinib (hyd-sulfate AZD6244) orally twice a day for three days followed by four days off in four week cycles at a dose of 100mg.

Drug: Selumetinib, 100mg

Dose Level 2: Selumetinib

EXPERIMENTAL

Subjects will receive selumetinib (hyd-sulfate AZD6244) orally twice a day for three days followed by four days off in four week cycles at a dose of 125mg.

Drug: Selumetinib, 125mg

Dose Level 3: Selumetinib

EXPERIMENTAL

Subjects will receive selumetinib (hyd-sulfate AZD6244) orally twice a day for three days followed by four days off in four week cycles at a dose of 150mg.

Drug: Selumetinib, 150mg

Dose Level 4: Selumetinib

EXPERIMENTAL

Subjects will receive selumetinib (hyd-sulfate AZD6244) orally twice a day for three days followed by four days off in four week cycles at a dose of 175mg.

Drug: Selumetinib, 175mg

Dose Level 5: Selumetinib

EXPERIMENTAL

Subjects will receive selumetinib (hyd-sulfate AZD6244) orally twice a day for three days followed by four days off in four week cycles at a dose of 200mg.

Drug: Selumetinib, 200mg

Dose Level 6: Selumetinib

EXPERIMENTAL

Subjects will receive selumetinib (hyd-sulfate AZD6244) orally twice a day for three days followed by four days off in four week cycles at a dose of 225mg.

Drug: Selumetinib, 225mg

Interventions

Selumetinib, 100mg DRUG

100mg, oral capsules, twice daily An orally active, small molecule with potential antineoplastic activity. Selumetinib is an ATP-independent inhibitor of mitogen-activated protein kinase kinase (MEK) or MAPK/extracellular-signal-regulated kinase (ERK) kinase) 1 and 2. Inhibition of both MEK1 and 2 by selumetinib prevents the activation of MEK1/2 dependent effector proteins and transcription factors, thereby leading to an inhibition of cellular proliferation in various cancers.

Also known as: hyd-sulfate AZD6244

Dose Level 1: Selumetinib

Selumetinib, 125mg DRUG

125mg, oral capsules, twice daily An orally active, small molecule with potential antineoplastic activity. Selumetinib is an ATP-independent inhibitor of mitogen-activated protein kinase kinase (MEK) or MAPK/extracellular-signal-regulated kinase (ERK) kinase) 1 and 2. Inhibition of both MEK1 and 2 by selumetinib prevents the activation of MEK1/2 dependent effector proteins and transcription factors, thereby leading to an inhibition of cellular proliferation in various cancers.

Also known as: hyd-sulfate AZD6244

Dose Level 2: Selumetinib

Selumetinib, 150mg DRUG

150mg, oral capsules, twice daily An orally active, small molecule with potential antineoplastic activity. Selumetinib is an ATP-independent inhibitor of mitogen-activated protein kinase kinase (MEK) or MAPK/extracellular-signal-regulated kinase (ERK) kinase) 1 and 2. Inhibition of both MEK1 and 2 by selumetinib prevents the activation of MEK1/2 dependent effector proteins and transcription factors, thereby leading to an inhibition of cellular proliferation in various cancers.

Also known as: hyd-sulfate AZD6244

Dose Level 3: Selumetinib

Selumetinib, 175mg DRUG

175mg, oral capsules, twice daily An orally active, small molecule with potential antineoplastic activity. Selumetinib is an ATP-independent inhibitor of mitogen-activated protein kinase kinase (MEK) or MAPK/extracellular-signal-regulated kinase (ERK) kinase) 1 and 2. Inhibition of both MEK1 and 2 by selumetinib prevents the activation of MEK1/2 dependent effector proteins and transcription factors, thereby leading to an inhibition of cellular proliferation in various cancers.

Also known as: hyd-sulfate AZD6244

Dose Level 4: Selumetinib

Selumetinib, 200mg DRUG

200mg, oral capsules, twice daily An orally active, small molecule with potential antineoplastic activity. Selumetinib is an ATP-independent inhibitor of mitogen-activated protein kinase kinase (MEK) or MAPK/extracellular-signal-regulated kinase (ERK) kinase) 1 and 2. Inhibition of both MEK1 and 2 by selumetinib prevents the activation of MEK1/2 dependent effector proteins and transcription factors, thereby leading to an inhibition of cellular proliferation in various cancers.

Also known as: hyd-sulfate AZD6244

Dose Level 5: Selumetinib

Selumetinib, 225mg DRUG

225mg, oral capsules, twice daily An orally active, small molecule with potential antineoplastic activity. Selumetinib is an ATP-independent inhibitor of mitogen-activated protein kinase kinase (MEK) or MAPK/extracellular-signal-regulated kinase (ERK) kinase) 1 and 2. Inhibition of both MEK1 and 2 by selumetinib prevents the activation of MEK1/2 dependent effector proteins and transcription factors, thereby leading to an inhibition of cellular proliferation in various cancers.

Also known as: hyd-sulfate AZD6244

Dose Level 6: Selumetinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histopathologically confirmed diagnosis of metastatic or unresectable uveal melanoma. Note - 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
• Age ≥ 18 years old
• 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.
• Karnofsky Performance Status ≥ 60% or Eastern Cooperative Oncology Group (ECOG) ≤2
• Ability to take oral medications
• All clinically significant toxicities from prior therapy must be ≤ grade 1 (with the exception of alopecia)
• Organ and marrow function and laboratory values as follows:
• Adequate marrow function
• absolute neutrophil count (ANC) \>1500 cells/mm3
• platelet count \>100,000/mm3
• hemoglobin \>9.0g/dL
• Adequate hepatic function
• Angiotensin Sensitivity Test/alternative (AST/ALT)\<2.5x upper limit of normal if no documented liver disease or \<5x upper limit of normal if documented liver disease

You may not qualify if:

• Patients who have had chemotherapy or immunotherapy within 4 weeks or radiation therapy within 2 weeks prior to entering the study 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, with the exception of surgical placement for vascular access.
• 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, hypokalemia, family history of long QT syndrome) including heart failure that meets New York Heart Association (NYHA) class III and IV definitions (see Appendix A) 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 (LVEF \<45% on echocardiography or equivalent on MuGA) even if full recovery has occurred.
• Atrial fibrillation with a ventricular rate \>100 bpm on ECG at rest
• Baseline Left ventricular ejection fraction (LVEF) below the 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 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.
• HIV positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with selumetinib.

Sponsors & Collaborators

• Shaheer A. Khan: lead
• AstraZeneca: collaborator
• Melanoma Research Alliance: collaborator

Study Sites (3)

Columbia University Medical Center

New York, New York, 10032, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Carvajal RD, Piperno-Neumann S, Kapiteijn E, Chapman PB, Frank S, Joshua AM, Piulats JM, Wolter P, Cocquyt V, Chmielowski B, Evans TRJ, Gastaud L, Linette G, Berking C, Schachter J, Rodrigues MJ, Shoushtari AN, Clemett D, Ghiorghiu D, Mariani G, Spratt S, Lovick S, Barker P, Kilgour E, Lai Z, Schwartz GK, Nathan P. Selumetinib in Combination With Dacarbazine in Patients With Metastatic Uveal Melanoma: A Phase III, Multicenter, Randomized Trial (SUMIT). J Clin Oncol. 2018 Apr 20;36(12):1232-1239. doi: 10.1200/JCO.2017.74.1090. Epub 2018 Mar 12.

  PMID: 29528792 DERIVED

MeSH Terms

Conditions

Uveal Melanoma; Melanoma

Interventions

AZD 6244

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Uveal Neoplasms; Eye Neoplasms; Neoplasms by Site; Eye Diseases; Uveal Diseases; Skin Neoplasms; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Shaheer Khan, DO

  Columbia University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor of Medicine at the Columbia University Medical Center

Study Record Dates

• First Submitted: May 10, 2016
• First Posted: May 11, 2016
• Study Start: February 28, 2017
• Primary Completion: September 18, 2020
• Study Completion: September 18, 2020
• Last Updated: August 31, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)