SJ901: Evaluation of Mirdametinib in Children, Adolescents, and Young Adults With Low-Grade Glioma

Phase 1: Estimate the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of mirdametinib dosed twice daily on a continuous schedule in pediatric patients with progressive or recurrent low-grade glioma.

The maximum tolerated dose (MTD) is empirically defined as the highest dose level at which six patients have been treated with at most one patient experiencing a dose-limiting toxicity (DLT) and the next higher dose level determined to be too toxic. The MTD estimate will not be available if the lowest dose level studied is too toxic or the highest dose level studied is considered safe. In the latter case, the highest studied safe dose may be considered as the recommended phase 2 dose (RP2D). The MTD estimation will be limited to evaluable patients and toxicity assessments from course 1 (28 days). We will require that at least 12 DLT evaluable subjects are assessed before the MTD/RP2D is declared.

Phase 1: Determine the safety and tolerability of mirdametinib dosed twice daily on a continuous schedule in pediatric patients with progressive or recurrent low-grade glioma.

Incidence of adverse event data at least possibly related to treatment will be summarized in cohort specific tables by grade and attribution throughout treatment.

Characterize the maximum plasma concentration and area under the concentration-time curve (AUC0-8h) of mirdametinib.

Mirdametinib plasma concentration will be provided and area under the curve (AUC0-8h) estimated based on course 1, days 1 and 15 PK samples

Phase 2, Cohort 1: Objective response rate observed anytime during active treatment and sustained for at least 8 weeks

The response rate, defined as the rate of minor response, partial response (PR), major response, or complete response (CR) will be calculated as the percentage of confirmed responders among all response assessable patients. These rates as well as their exact confidence intervals will be provided and will be summarized by each response category (i.e., PR, major response, and CR). Subjects without an assessment will be considered non-responders.

Progression-free survival (PFS) by cohort

PFS will be measured using Kaplan Meier approaches from the date of initial treatment to the earliest date of progressive disease, death due to any cause, or date last follow-up.

Rates of Minor Response, by cohort

Minor Response is defined as a 25-49% reduction in target lesion area relative to baseline measurements. Overall, the patient should be clinically stable or have improved on physical examination and functional or neurological assessment. Responses and duration will be measured for each cohort from the date of initial treatment to the earliest date of progressive disease, or data of last follow-up.

Rates of Partial Response (PR), by cohort

Partial Response (PR) is defined as a 50-75% reduction in the target lesion area relative to baseline measurements. Overall, the patient should be clinically stable or have improved on physical examination and functional or neurological assessment. Responses and duration will be measured for each cohort from the date of initial treatment to the earliest date of progressive disease, or data of last follow-up.

Rates of Major Response, by cohort

Major Response is defined as more than 75% reduction in target lesion area relative to baseline measurements. Overall, the patient should be clinically stable or have improved on physical examination and functional or neurological assessment. Responses and duration will be measured for each cohort from the date of initial treatment to the earliest date of progressive disease, or data of last follow-up.