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

Low-Grade Glioma Clinical Trial

Official title: SJ901: Phase 1/2 Evaluation of Single Agent Mirdametinib (PD-0325901), a Brain-Penetrant MEK1/2 Inhibitor, for the Treatment of Children, Adolescents, and Young Adults With Low-Grade Glioma

Status Recruiting

Clinical Trial Summary

This is an open-label, multi-center, Phase 1/2 study of the brain-penetrant MEK inhibitor, mirdametinib (PD-0325901), in patients with pediatric low-grade glioma (pLGG).

Clinical Trial Description

The objectives of this study are:

Phase 1

Primary Objectives:

• To determine the safety and tolerability and 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.

• To characterize the plasma pharmacokinetics (PK) of mirdametinib.

Phase 2

Cohort 1: Newly diagnosed and/or previously untreated (except surgery)

Primary Objectives:

• To assess the efficacy, defined as the sustained objective response rate [a Partial Response (PR), Major Response, and/or Complete Response (CR) sustained over 8 weeks] observed over any time on active treatment with mirdametinib in previously untreated patients (except surgery) with WHO grade I or grade II glioma.

• To characterize the plasma pharmacokinetics of mirdametinib in children, adolescents, and young adults with low-grade gliomas.

• To describe the toxicity profile of mirdametinib in pediatric patients.

Secondary Objectives:

• Estimate the efficacy of mirdametinib as measured by progressive free survival (PFS) and overall survival (OS) in patients with previously untreated WHO grade I or grade II glioma.

• To describe treatment responses (Progressive Disease, Stable Disease, Minor Response, Partial Response, Major Response, and Complete Response) observed in previously untreated patients (except surgery) with WHO grade I or grade II glioma over any time on active treatment with mirdametinib.

• To characterize and monitor patient neurocognitive function and quality of life in patients while on study.

Cohort 2: Recurrent and/or Progressive without prior exposure to MEK inhibitors

Primary Objectives:

• To assess the efficacy, defined as the sustained objective response rate (a PR, Major Response, and/or CR sustained over 8 weeks) observed anytime on active treatment with mirdametinib in patients with recurrent and/or progressive WHO grade I or grade II glioma not previously treated with MEK inhibitors.

• To characterize the plasma pharmacokinetics of mirdametinib in children, adolescents, and young adults with low-grade gliomas.

• To describe the toxicity profile of mirdametinib in pediatric patients with recurrent or progressive disease, not previously treated with MEK inhibitors.

Secondary Objectives:

• Estimate the efficacy of mirdametinib as measured by PFS and OS in patients with recurrent and/or progressive WHO grade I or grade II glioma not previously treated with MEKi

• To describe treatment responses (Progressive Disease, Stable Disease, Minor Response, Partial Response, Major Response, and Complete Response) observed in patients with recurrent and/or progressive WHO grade I or grade II glioma without prior exposure to MEK inhibitors.

• To characterize and monitor patient neurocognitive function and quality of life in patients while on study.

Cohort 3: Re-treatment (recurrent and/or progressive disease previously treated with a MEK inhibitor)

Primary Objectives:

• To estimate the 1-year disease stabilization rate (defined as lack of disease progression for ≥ 12 courses of mirdametinib) in patients with recurrent and/or progressive WHO grade I or grade II glioma who previously received ≥ 6 courses MEK inhibitor (including mirdametinib) and did not progress while on active MEKi therapy (cohort 3A).

• To estimate the 6-month disease stabilization rate (defined as lack of disease progression for ≥ 6 courses of mirdametinib) in patients with recurrent and/or progressive WHO grade I or grade II glioma who previously received a MEK inhibitor, other than mirdametinib, and progressed while on active MEKi therapy (cohort 3B).

• To characterize the plasma pharmacokinetics of mirdametinib in children, adolescents, and young adults with low-grade gliomas.

• To describe the toxicity profile of mirdametinib in pediatric patients with recurrent or progressive disease, previously treated with MEK inhibitors.

Secondary Objectives:

• Estimate the efficacy of mirdametinib as measured by PFS and OS in patients with recurrent and/or progressive WHO grade I or grade II glioma previously treated with MEK inhibitors

• To describe treatment responses (Progressive Disease, Stable Disease, Minor Response, Partial Response, Major Response, and Complete Response) observed in patients with recurrent and/or progressive WHO grade I or grade II glioma previously treated with a MEK inhibitor.

• To characterize and monitor patient neurocognitive function and quality of life in patients while on study.

SJ901 will proceed in two phases. Phase 1 will evaluate the safety, tolerability and pharmacokinetics of mirdametinib when dosed continuously up to 3 mg/m^2/dose twice daily (BID) in patients with progressive or recurrent pLGG without prior MEK inhibitor (MEKi) exposure. This phase will identify the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) and will contain a small expansion cohort before launching phase 2. Phase 2 will utilize the MTD/RP2D to evaluate mirdametinib efficacy, pharmacokinetics, safety and tolerability in broader cohorts of patients with newly diagnosed or progressive/recurrent pLGG (+/- prior MEK inhibitor exposure).

In Phase 1 of the study, participants with progressive or recurrent pLGG without prior MEKi exposure are eligible and will be enrolled onto a single dose level. The Rolling 6 design will be used to estimate the MTD/RP2D and to determine the dose limiting toxicities (DLTs) of the escalating doses. Once a candidate MTD or RP2D based on 6 subjects has been determined additional evaluable subjects will be enrolled as part of a Phase 1 expansion cohort in order to better describe the safety and tolerability of the MTD/RP2D. The data from all subjects treated at the MTD/RP2D (patients from the dose-finding/dose-escalation study plus expansion cohort) will also be used to assess the stage I efficacy criteria for cohort 2 as part of the Phase 2 design. If these criteria are met, cohort 2 sample size will be expanded beyond the interim analysis and the Phase 2 study will be initiated in cohort 1.

Mirdametinib will be administered twice daily in cycles of 28 days and may be continued for up to 24 months (26 cycles) in the absence of disease progression or unacceptable toxicity. Doses will be based on the BSA calculated before each cycle of therapy. During the DLT period (i.e., cycle 1), all phase 1 participants (including those in the phase 1 expansion cohort) will receive mirdametinib in dispersible tablets only. Thereafter, patients who can swallow capsules may transition to capsules if permitted by their specific dose level.

Once the phase 2 is open to enrollment, participants from the phase 1 on a dose level that differs from the RP2D, may choose to change to the RP2D as long as they have not undergone a dose-reduction for toxicity, and if the treating physician and the patient/family agree it is in the best interest of the patient.

In Phase 2 of the study, participants will be stratified into 3 disease cohorts:

• Cohort 1: Patients with Newly Diagnosed Low-Grade Glioma

• Cohort 2: Patients with Progressive or Recurrent Low-Grade Glioma without Previous MEKi Exposure

• Cohort 3: Patients with Progressive or Recurrent Low-Grade Glioma with Previous MEKi Exposure and:

• Cohort 3A: Previously received 6 or more cycles of MEKi therapy and did not progress on MEKi therapy

• Cohort 3B: Previously treated with MEKi, other than mirdametinib, and progressed while on MEKi therapy

Therapy will be administered at RP2D in cycles of 28 days and may be continued for up to 24 months (26 cycles) in absence of disease progression or unacceptable toxicity. Patients in Cohort 3 with previous exposure to mirdametinib may receive a starting dose lower than the RP2D, depending on the dose they tolerated during their previous exposure. Phase 2 will utilize both the dispersible tablet and capsule formulations. ;

Related Conditions & MeSH terms

• Glioma
• Low-Grade Glioma

• NCT number: NCT04923126
• Study type: Interventional
• Source: St. Jude Children's Research Hospital
• Contact: Tabatha E. Doyle, RN
• Phone: 901-595-2544
• Email: tabatha.doyle@stjude.org
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: June 21, 2021
• Completion date: June 2031