Published: November 7, 2014, Updated: February 2, 2018
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.
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.
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