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

Study ID
STU 062016-047

Study Sites

  • Children’s Medical Center (Dallas, Plano, Southlake)

Contact
Darrell Stafford
214/456-8903
jay.stafford@childrens.com

Principal Investigator
Daniel Bowers, M.D.

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

Brief Overview

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.

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.

Eligibility

Inclusion Criteria:
- Patients with recurrent, refractory, or progressive non-hematologic malignancies (CNS or solid tumors) characterized by known or presumed Ras-Raf pathway activation will be eligible.
- Age >1 year and <18 years.
- Karnofsky Performance Scale (patients > 12 years old) or Lansky Play - Performance Scale (patients ≤ 12 years old) > 60.
- Normal organ and marrow function as defined below:
- Absolute neutrophil count > 1,000/mcL
- Platelets > 75,000/mcL and > 7 days since last platelet transfusion. Hemoglobin > 9gm/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 < 1.5 times the upper limit of institutional normal for age or GFR > 70 ml/min/1.73m2.
- QTc interval < 450ms.
- Left ventricular ejection fraction (LVEF) > 50%.
- 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.
- 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 must not have 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 ≤ 5 x t1/2 (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).