MEK162, Phase I-II Study of MEK 162 for Children with Low-Grade Gliomas and Other Ras/Raf/ERK Pathway Activated Tumors
Study ID: STU 062016-047
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 toxicity (DLT), and toxicity profile. Phase 2: Patients with recurrent or progressive tumors signaling through the Ras/Raf (murine leukemia viral oncogene homolog) 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 3' BRaF (B-Raf proto-oncogene serine/threonine-protein kinase) rearrangement (Kiaa1549 fusion 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/eRK (guanosine triphosphatase protein/murine leukemia viral oncogene homolog/extracellular regulated signal kinase) 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 rearrangement 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 (neuroblastoma RaS viral (v-ras) oncogene homolog) or KRaS (kirsten rat sarcoma viral oncogene homolog) mutation. * Stratum 4 (Surgical arm, Target validation): Patient with eligible histology 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.
Phase I * Patients with recurrent, refractory, or progressive non-hematologic malignancies (central nervous system (CNS) or solid tumors) associated with activation of the RAS/RAF/ERK (guanosine triphosphatase protein/murine leukemia viral oncogene homolog/extracellular regulated signal kinase) pathway, including any low-grade glioma (LGG), any tumor in a patient with neurofibromatosis type 1 (NF1), or any tumor with a documented activating BRAF (B-Raf proto-oncogene serine/threonine-protein kinase), NRAS (neuroblastoma RAS viral (v-ras) oncogene homolog), or KRAS (kirsten rat sarcoma viral oncogene homolog) mutation, will be eligible. LGG is defined as any World Health Organization (WHO) grade I or II (or equivalent) astrocytic, oligodendroglial, and/or glioneuronal tumor. Phase II * Patients with recurrent or progressive disease as defined in the following three strata below, will be eligible: * Stratum 1: patients with low-grade gliomas 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 recurrent or progressive tumors 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. The remaining criteria apply for all phases: * 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 >= 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; serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase - ALT) and serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase - 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 glomerular filtration rate (GFR) > 70 ml/min/1.73m2. * QTc interval <= 450ms. * Left ventricular ejection fraction (LVEF) >= 50% as determined by a 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 breastfeeding. 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.
- Cancer Related
- Healthy Volunteers
- UT Southwestern Principal Investigator
- Daniel C Bowers
CHILDRENS HOSPITAL LOS ANGELES
Brain and Nervous System