This is a 3-part open-label study (feasibility phase, treatment phase and follow-up phase) of orally administered mirdametinib in combination with intravenous vinblastine chemotherapy in patients with PLGG with activation of MAPK pathway.
Feasibility Phase:
The maximum tolerated/recommended phase 2 dose (MTD/RP2D) of the mirdametinib plus vinblastine combination will be assessed using a modified Rolling-6 design.
Treatment Phase:
Patients will receive mirdametinib twice daily (continuously) at a fixed dose (2mg/m2 po BID up to 4 mg BID) for a total of 13 cycles (28 days cycle). Weekly intravenous vinblastine at MTD will be given for a total of 17 cycles. If adverse events occur, two dose reductions are allowed.
Follow-up Phase:
Following the end of treatment, patients will be scheduled for a follow-up visit every 6 months for 36 months to evaluate PFS, TTP and OS.
Signed written informed consent prior to study participation.
Study activities compliance: must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study, including disease assessment by contrast enhanced MRI.
Aged ≥ 2 years to ≤ 25 years when starting mirdametinib.
BSA ≥ 0,40m2
Patients who are receiving other investigational agents.
Cardiac: QTcB ≥ 480 msec or an absolute resting left ventricular ejection fraction (LVEF) of ≤ 49%.
Patients who have any other malignancy, except if the other primary malignancy is neither currently clinically significant nor requiring active intervention.
Tumor with BRAF V600E mutation.
Single group
Mirdametinib
DrugParticipants will receive orally administered mirdametinib in combination with intravenous vinblastine chemotherapy
Determine maximum tolerated dose of Mirdametinib plus Vinblastine.
The maximum tolerated/recommended phase 2 dose (MTD/RP2D) of the mirdametinib plus vinblastine combination using a modified Rolling-6 design.
Determine the objective response rate of mirdametinib plus vinblastine for PLGG with Mitogen-activated Protein Kinase (MAPK) pathway activation in treatment naïve patients.
The proportion of patients with complete (CR), major (MaR), partial (PR) and minor response (MiR) as the best response on study based on RAPNO criteria. Response = MiR+PR+MaR+CR
Efficacy outcome measures: Overall Survival.
Overall Survival (OS) is defined as the time from starting mirdametinib (C1D1) to death due to any cause, or censored at date last known alive. OS will be evaluated from starting mirdametinib up to the end of the 3-year follow-up. Estimated using Kaplan-Meier methods.
Efficacy outcome measures: Progression-Free Survival.
Progression-Free Survival (PFS): the time from starting mirdametinib (C1D1) to the date of first observation of radiological progression or death due to any cause. Participants alive without disease progression or death are censored at date of last disease evaluation. Estimated using Kaplan-Meier methods.
Efficacy outcome measures: Time to Progression.
Time to Progression (TTP) is defined as the time from starting mirdametinib (C1D1) to radiological progression, or censored at date of last disease evaluation for those without progression reported. Estimated using Kaplan-Meier methods.
Efficacy outcome measures: Objective Response Rate.
Objective response rate (ORR) is defined as the percentage of patients experiencing their best response on study as CR or PR or MR or SD.
Evaluate the response rate based on the tumor volume.
Accurate quantification of tumor volumes using a semi-automated volumetric method.
To investigate and correlate biological features to tumor response.
Exploratory biology studies may include, but are not limited to: tumor molecular profiling, gene expression, methylation profiling and DNA sequencing to explore possible associations between candidate molecular predictors and clinical outcome. Descriptive statistics may be used to visualize biological feature results and compare to measures of efficacy.
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