Phase I/II Study of MEK162 for Children With Ras/Raf Pathway Activated Tumors
Study Details
Study Description
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 |
|---|---|---|
| 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 Design
Arms and Interventions
| 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 Names:
|
| 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 Names:
|
| 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 Names:
|
Outcome Measures
Primary Outcome Measures
- Response rate [Study duration (up to 3 years)]
Phase 2: Response rate (strata 1 and 2)
Secondary Outcome Measures
- Survival [Study duration (up to 3 years)]
12-month progression-free and overall survival (strata 1 and 2)
Other Outcome Measures
- Stratum 3 Response Rate [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).
- Tumor response as a function of BRAF tumoral genotype [Study duration (up to 3 years)]
Tumor response as a function of BRAF tumoral genotype.
- Target Validation (Intra-tumoral MEK162 concentration, and intra-tumoral inhibition of downstream mediators of the ras/raf/MEK/ERK pathway (e.g., pERK). [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).
Eligibility Criteria
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.
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Stratum 1: patients with LGG with a BRAF truncated fusion that is measurable in at least two dimensions on imaging.
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Stratum 2: patients with NF1 and LGG that is measurable in at least two dimensions on imaging.
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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.
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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.
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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.
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Patients must have received at least one prior chemotherapy or radiation regimen prior to progression.
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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.
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At least 3 months must have elapsed since the last dose of irradiation to the target tumor(s) at the time of enrollment.
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Patients must be >1 year and <18 years old.
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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.
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Participants must have normal organ and marrow function as defined below within two weeks prior to enrollment:
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Absolute neutrophil count > 1,000/mcL
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Platelets > 75,000/mcL and > 7 days since last platelet transfusion. Hemoglobin > 9 gm/dL and > 7 days since last red blood cell transfusion
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Not refractory to red cell or platelet transfusions
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Hepatic: Total bilirubin ≤ 1.5 times the upper limit of normal; SGPT (ALT) and SGOT (AST) < 3 times the institutional upper limit of normal
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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
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QTc interval < 450ms
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Left ventricular ejection fraction (LVEF) > 50% as determined by an echocardiogram
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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.
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Patient must be able to take oral/enteral medication.
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Patient, parent, or legal guardian must be able to understand and willing to provide informed consent.
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Patients must have recovered from the effects of prior therapy.
Exclusion Criteria
Patients with any of the following characteristics will not be eligible:
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Patients for whom other curative or established standard-of-care therapeutic options with acceptable morbidity exist.
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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.
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History of Gilbert's syndrome
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Patients receiving any other anticancer or experimental drug therapy.
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Use of hematopoietic growth factors within 2 weeks prior to initiation of therapy.
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Any other investigational agents within 2 weeks or ≤ 3 half-lives (whichever is longer) before start of study therapy.
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Patients who have undergone surgery ≤ 3 weeks or who have not recovered from side effects of this procedure prior to receiving study drug.
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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.
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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).
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History of retinal degenerative disease
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Prior therapy with a MEK inhibitor
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Impairment of gastrointestinal function (e.g., active ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)
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Patients who have a neuromuscular disorder that is associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
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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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Children's Hospital of Alabama | Birmingham | Alabama | United States | 35233 |
| 2 | Children's Hospital Los Angeles | Los Angeles | California | United States | 90027 |
| 3 | Children's Hospital of Colorado | Aurora | Colorado | United States | 80045 |
| 4 | Children's National Heath Systems | Washington | District of Columbia | United States | 20010 |
| 5 | Nicklaus Children's Hospital | Miami | Florida | United States | 33155 |
| 6 | Children's Healthcare of Atlanta | Atlanta | Georgia | United States | 30322 |
| 7 | Johns Hopkins University | Baltimore | Maryland | United States | 21287 |
| 8 | Dana Farber Cancer Institute | Boston | Massachusetts | United States | 02215 |
| 9 | Children's Hospitals and Clinics of Minnesota-Minneapolis | Minneapolis | Minnesota | United States | 55404 |
| 10 | Washington University School of Medicine | Saint Louis | Missouri | United States | 63110 |
| 11 | New York University | New York | New York | United States | 10016 |
| 12 | Oregon Health and Science University | Portland | Oregon | United States | 97239 |
| 13 | University of Texas Southwestern Medical | Dallas | Texas | United States | 75390 |
| 14 | Texas Children's Hospital | Houston | Texas | United States | 77030 |
| 15 | Seattle Children's Hospital | Seattle | Washington | United States | 98145 |
Sponsors and Collaborators
- Children's Hospital Los Angeles
- Dana-Farber Cancer Institute
Investigators
- Principal Investigator: Nathan Robison, MD, CHLA
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- ChildrenHLA