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Phase I/II Study of MEK162 for Children With Ras/Raf Pathway Activated Tumors

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ClinicalTrials.gov Identifier: NCT02285439
Recruitment Status : Recruiting
First Posted : November 7, 2014
Last Update Posted : February 2, 2018
Sponsor:
Collaborator:
Dana-Farber Cancer Institute
Information provided by (Responsible Party):
Nathan Robison, M.D., Children's Hospital Los Angeles

Brief Summary:

The main purpose of phase I studies in general is to determine the best dose ("maximum tolerated dose") of a drug, and to find out the most common side effects. The main purpose of the phase I component of this study specifically is to determine the best dose of the experimental drug MEK162 and to find out whether the drug is safe in children and adolescents with tumors that have grown or come back despite standard therapy.

Another purpose of this study is to measure the concentration of drug in the blood to help understand how much drug gets into the body and how quickly the drug is removed from the body. Another purpose of this study is to determine whether MEK162 turns off the Ras/Raf/MAP pathway as expected by measuring this pathway in blood cells. Finally, in this study, the investigators hope to start finding out whether or not MEK162 causes different types of tumors in children to shrink or stop growing.

The main purpose of the phase II component of the study is to determine whether MEK162 causes specific types of tumors in children and adolescents to shrink or stop growing. These specific types of tumors include low-grade gliomas, tumors in patients with a genetic condition called neurofibromatosis type 1, and other tumors thought to be caused by abnormal activation of the Ras/Raf/MEK molecular pathway.

Another purpose of this study is for researchers to learn whether specific abnormalities in the DNA of tumors can help predict whether tumors will respond to MEK162.


Condition or disease Intervention/treatment Phase
Low-Grade Gliomas Malignant Neoplasms, Brain Soft Tissue Neoplasms Drug: MEK162 Phase 1 Phase 2

Detailed Description:

PROTOCOL SUMMARY:

Phase 1: Patients with non-hematologic malignancies that are recurrent, progressive, or refractory after standard up-front therapy receiving MEK162 will define the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and toxicity profile.

Phase 2: Patients with recurrent or progressive tumors signaling through the ras/raf pathway after standard up-front therapy will be treated in three strata to define the activity of MEK162.

Stratum 1: Pediatric patients with recurrent or progressive low-grade glioma (LGG) characterized by a BRAF truncated fusion (KIAA1549 and similar translocations).

Stratum 2: Pediatric patients with neurofibromatosis type 1 (NF1) and recurrent or progressive LGG.

Stratum 3: Pediatric patients with recurrent or progressive tumors thought to involve the ras/raf/MAP pathway but not included in strata 1 or 2. This includes any LGG not included in strata 1 or 2 (i.e., any LGG without a BRAF truncated fusion in a patient without NF1), any tumor other than LGG in a patient with NF1, and any other tumor with a known activating BRAF, NRAS or KRAS mutation.

Target validation phase: Patient enrolled on the phase 2 component (any stratum) for whom tumor biopsy or resection is clinically indicated. Patients will receive MEK162 for 7 to 21 days prior to their surgery. Samples will be analyzed for concentration of drug and target inhibition.

Length of therapy:

Protocol treatment will last approximately 48 weeks from the start of MEK162 in the absence of significant toxicity. Treatment will be administered based on the dose escalation schema for phase 1. Patients in the phase 2 component of the trial will also receive a planned 48 weeks of therapy. Those undergoing planned tumor resection based on clinical criteria will be eligible to receive 7-21 days of treatment with MEK162 prior to the surgical procedure.

Imaging to assess response will be obtained at the end of cycle 1 (+/- 1 week), at the end of cycle 3 (+/- 2 weeks) and after every three cycles thereafter (+/- 2 weeks). A cycle will consist of 28 days (+/- 3 days) and MEK162 will be given continuously. Patients deriving benefit may continue therapy beyond study completion but all protocol specific evaluations (other than survival or progression) will conclude after one year. All patients will be followed with progression as the end point.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of MEK162 for Children With Progressive or Recurrent Cancer and a Phase II Study for Children With Low-Grade Gliomas and Other Ras/Raf/MAP Pathway Activated Tumors
Study Start Date : April 2016
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : June 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Phase 1
Patients with non-hematologic malignancies that are recurrent, progressive, or refractory after standard up-front therapy receiving MEK162 will define the MTD, DLT, and toxicity profile.
Drug: MEK162
• MEK162 is currently supplied as film-coated tablets in dose strength of 15 mg. The film-coated tablets consist of MEK162 drug substance, lactose monohydrate, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, and a commercial film coating. The original tablets are yellow to dark yellow capsule-shaped
Other Name: ARRY 438162

Experimental: Phase 2
Children with recurrent tumors signaling through the Ras/Raf pathway will be treated in 3 strata to define the activity of MEK162. S1: Children with LGG characterized by a BRAF truncated fusion (KIAA1549 and similar translocations). S2: Children with NF1 and LGG. S 3: Children with tumors involving the Ras/Raf pathway not included in strata 1 or 2.
Drug: MEK162
• MEK162 is currently supplied as film-coated tablets in dose strength of 15 mg. The film-coated tablets consist of MEK162 drug substance, lactose monohydrate, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, and a commercial film coating. The original tablets are yellow to dark yellow capsule-shaped
Other Name: ARRY 438162

Experimental: Target Validation
Patients eligible for phase 2 (any stratum) for whom tumor biopsy or resection is clinically indicated may be enrolled on the target validation arm. Patients will receive MEK162 for 7 to 21 days prior to their surgery. Tumor sample will be analyzed for drug concentration and target inhibition.
Drug: MEK162
• MEK162 is currently supplied as film-coated tablets in dose strength of 15 mg. The film-coated tablets consist of MEK162 drug substance, lactose monohydrate, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, and a commercial film coating. The original tablets are yellow to dark yellow capsule-shaped
Other Name: ARRY 438162




Primary Outcome Measures :
  1. Response rate [ Time Frame: Study duration (up to 3 years) ]
    Phase 2: Response rate (strata 1 and 2)


Secondary Outcome Measures :
  1. Survival [ Time Frame: Study duration (up to 3 years) ]
    12-month progression-free and overall survival (strata 1 and 2)


Other Outcome Measures:
  1. Stratum 3 Response Rate [ Time Frame: Study duration (up to 3 years) ]
    Response rate for patients in stratum 3 (other tumors with known or presumed activation of the ras/raf/MEK/ERK pathway, not included in strata 1 or 2).

  2. Tumor response as a function of BRAF tumoral genotype [ Time Frame: Study duration (up to 3 years) ]
    Tumor response as a function of BRAF tumoral genotype.

  3. Target Validation (Intra-tumoral MEK162 concentration, and intra-tumoral inhibition of downstream mediators of the ras/raf/MEK/ERK pathway (e.g., pERK). [ Time Frame: Study duration (up to 3 years) ]
    Target Validation: Intra-tumoral MEK162 concentration, and intra-tumoral inhibition of downstream mediators of the ras/raf/MEK/ERK pathway (e.g., pERK).



Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Patients with recurrent or progressive disease, as defined in the following three strata below, will be eligible. For eligibility determination, tumor imaging from at least two time-points must be available to document radiographic progression or recurrence. Patients with non-progressive refractory tumors will not be eligible.

  • Stratum 1: patients with LGG with a BRAF truncated fusion that is measurable in at least two dimensions on imaging.
  • Stratum 2: patients with NF1 and LGG that is measurable in at least two dimensions on imaging.
  • Stratum 3: Pediatric patients with a recurrent or progressive tumor thought to involve the Ras/Raf/ERK pathway but not included in strata 1 or 2 that is measurable in at least two dimensions on imaging. This includes any LGG not included in strata 1 or 2 (i.e., any LGG without a BRAF truncated fusion in a patient without NF1), any tumor other than LGG in a patient with NF1, and any other tumor with a documented activating BRAF, NRAS, or KRAS mutation.
  • Stratum 4 (surgical arm, target validation): Patients who meet criteria for stratum 1, 2, or 3 for whom tumor biopsy and/or resection is clinically indicated.
  • Tumor tissue for correlative studies must be available for all patients except those with NF1 and LGG (stratum 2) or any patient with optic pathway glioma (stratum 2 or 3), for whom tumor tissue is optional.
  • Patients must have received at least one prior chemotherapy or radiation regimen prior to progression.
  • At the time of enrollment, at least 6 weeks must have elapsed since the last dose of any nitrosourea, and the longer of 2 weeks or 3 half-lives must have elapsed since the last dose of any other tumor-directed medication. or biologic therapy.
  • At least 3 months must have elapsed since the last dose of irradiation to the target tumor(s) at the time of enrollment.
  • Patients must be >1 year and <18 years old.
  • Performance Score using the Karnofsky Performance Scale (patients > 12 years old) or Lansky Play - Performance Scale (patients ≤ 12 years old) must be ≥ 60 assessed within two weeks prior to enrollment.
  • Participants must have normal organ and marrow function as defined below within two weeks prior to enrollment:

    • Absolute neutrophil count > 1,000/mcL
    • Platelets > 75,000/mcL and > 7 days since last platelet transfusion. Hemoglobin > 9 gm/dL and > 7 days since last red blood cell transfusion
    • Not refractory to red cell or platelet transfusions
    • Hepatic: Total bilirubin ≤ 1.5 times the upper limit of normal; SGPT (ALT) and SGOT (AST) < 3 times the institutional upper limit of normal
    • Renal: Serum creatinine which is less than 1.5 time the upper limit of institutional normal for age or GFR > 70 ml/min/1.73m2
    • QTc interval < 450ms
    • Left ventricular ejection fraction (LVEF) > 50% as determined by an echocardiogram
  • Female patients of childbearing potential must have negative serum or urine pregnancy test within 72 hours of the first dose of MEK162. Patient must not be pregnant or breast-feeding. Patients of childbearing or child-fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study and for 30 days following cessation of treatment.
  • Patient must be able to take oral/enteral medication.
  • Patient, parent, or legal guardian must be able to understand and willing to provide informed consent.
  • Patients must have recovered from the effects of prior therapy.

Exclusion Criteria

Patients with any of the following characteristics will not be eligible:

  • Patients for whom other curative or established standard-of-care therapeutic options with acceptable morbidity exist.
  • Patients with any significant medical illnesses that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy.
  • History of Gilbert's syndrome
  • Patients receiving any other anticancer or experimental drug therapy.
  • Use of hematopoietic growth factors within 2 weeks prior to initiation of therapy.
  • Any other investigational agents within 2 weeks or ≤ 3 half-lives (whichever is longer) before start of study therapy.
  • Patients who have undergone surgery ≤ 3 weeks or who have not recovered from side effects of this procedure prior to receiving study drug.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, impaired gastrointestinal function, or psychiatric illness/social situations that would limit compliance with study requirements.
  • History or current evidence of retinal vein occlusion (RVO) or predisposing factors to RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes).
  • History of retinal degenerative disease
  • Prior therapy with a MEK inhibitor
  • Impairment of gastrointestinal function (e.g., active ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)
  • Patients who have a neuromuscular disorder that is associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
  • Patients with uncontrolled hypertension

Inclusion of Women, Minorities, and Other Underrepresented Populations This protocol is open to males and females of all races. See Inclusion Criteria above regarding specific eligibility requirements for female and male patients of child-bearing or child-fathering potential, respectively.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02285439


Contacts
Contact: Nathan Robison NRobison@chla.usc.edu
Contact: Jasmine Pauly mek162@chla.usc.edu

Locations
United States, Alabama
Children's Hospital of Alabama Recruiting
Birmingham, Alabama, United States, 35233
Contact: Alyssa Reddy, MD         
United States, California
Children's Hospital Los Angeles Recruiting
Los Angeles, California, United States, 90027
Contact: Jasmine Pauly, CCRP    323-361-7673    jpauly@chla.usc.edu   
United States, Colorado
Children's Hospital of Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Kathleen Doris, MD         
United States, District of Columbia
Children's National Heath Systems Recruiting
Washington, District of Columbia, United States, 20010
Contact: Miriam Bornhorst, MD         
United States, Georgia
Children's Healthcare of Atlanta Recruiting
Atlanta, Georgia, United States, 30322
Contact: Tobey MacDonald, MD         
United States, Massachusetts
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Mark Kieran, MD         
United States, Minnesota
Children's Hospitals and Clinics of Minnesota-Minneapolis Recruiting
Minneapolis, Minnesota, United States, 55404
Contact: Anne Bendel, MD         
United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Karen Gauvain, MD         
United States, New York
New York University Recruiting
New York, New York, United States, 10016
Contact: Sharon Gardner, MD         
United States, Oregon
Oregon Health and Science University Recruiting
Portland, Oregon, United States, 97239
Contact: Rebecca Loret DeMola, DO         
United States, Texas
University of Texas Southwestern Medical Recruiting
Dallas, Texas, United States, 75390
Contact: Daniel Bowers, MD         
United States, Washington
Seattle Children's Hospital Recruiting
Seattle, Washington, United States, 98145
Contact: Sarah Leary, MD         
Sponsors and Collaborators
Children's Hospital Los Angeles
Dana-Farber Cancer Institute
Investigators
Principal Investigator: Nathan Robison, MD CHLA

Responsible Party: Nathan Robison, M.D., Principal Investigator, Children's Hospital Los Angeles
ClinicalTrials.gov Identifier: NCT02285439     History of Changes
Other Study ID Numbers: ChildrenHLA
First Posted: November 7, 2014    Key Record Dates
Last Update Posted: February 2, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Nathan Robison, M.D., Children's Hospital Los Angeles:
Pediatric Oncology
Ras/Raf pathway
Low-Grade Glioma
MEK inhibitor

Additional relevant MeSH terms:
Neoplasms
Glioma
Soft Tissue Neoplasms
Brain Neoplasms
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms by Site
Central Nervous System Neoplasms
Nervous System Neoplasms
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases