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

Inclusion Criteria: Screening Phase

• Participants with histologically confirmed or suspected low-grade glioma, includingneuronal and mixed neuronal-glial tumors

• Participant must have adequate tumor tissue from primary and/or relapsed tumor forcentral pathology review

• For Phase 1: Projected to be ≥ 2 years and < 25 years at the time of studyenrollment

• Participant's body surface area (BSA) at time of study enrollment must fall withinthe range outlined in the protocol for the specific dose level under evaluation:

• Phase 1: Dose Finding/Dose-escalation

• For Phase 1 participant's BSA must fall within the range specified in theprotocol for the specific dose level under evaluation.

• Phase 2: All Cohorts:

• For Phase 2 of the study the upper BSA restrictions will be removed.

• Participant and/or guardian can understand and is willing to sign a written informedconsent document according to institutional guidelines

Exclusion Criteria: Screening Phase

• Participants with known current retinal pathology that is consistent with or aprecursor for central serous retinopathy, retinal vein occlusion (RVO), orneovascular macular degeneration

• Participants with a known malabsorption syndrome or preexisting gastrointestinalconditions that may impair absorption of mirdametinib (e.g., gastric bypass, lapband, or other gastric procedures)

• Participant with a known history of liver disease or known hepatic or biliaryabnormalities (except for Gilbert's syndrome or asymptomatic gallstones)

• Participants with a clinically significant history of chronic interstitial lungdisease (such as bronchopulmonary dysplasia, chronic bronchiolitis, obliterativebronchiolitis, chronic aspiration pneumonia, surfactant protein disorder, or otherserious chronic pulmonary condition). Participants with a history of asthma,reactive airways disease, or viral pneumonitis are not to be excluded if disease hasresolved or is well-controlled.

Inclusion Criteria: Phase 1 and Phase 2, All Cohorts

• Participant must be ≥ 2 years and < 25 years of age at the time of enrollment

• Participant's BSA at time of study enrollment must fall within the range outlinedbelow for the specific dose level under evaluation:

• Phase 1: Dose-finding/Dose-escalation

• For Phase 1 participant's BSA must fall within the range specified in theprotocol for the specific dose level under evaluation.

• Phase 2: All Cohorts

• For Phase 2 of the study the upper BSA restrictions will be removed.

• Participant must have confirmation of one of the following diagnosis per St. JudeChildren's Research Hospital central pathology review of primary and/or relapsedtumor:

• Eligible tumors include:

• Low-grade glioma/astrocytic tumor/glioneuronal tumor/neuroepithelialtumor, not otherwise specified (NOS) or not elsewhere classified (NEC)

• Pilocytic astrocytoma

• Pilomyxoid astrocytoma

• Pleomorphic xanthroastrocytoma

• Ganglioglioma

• Gangliocytoma

• Diffuse glioma, diffuse astrocytoma, oligodendroglioma, oroligoastrocytoma

• Papillary glioneuronal tumor

• Rosette-forming glioneuronal tumor

• Diffuse leptomeningeal glioneuronal tumor

• Central neurocytoma, extraventricular neurocytoma

• Angiocentric glioma

• Dysembryoplastic neuroepithelial tumor (DNET), septal DNET, myxoidglioneuronal tumor

• Tectal glioma

• Desmoplastic infantile astrocytoma / ganglioglioma

• Polymorphous low-grade neuroepithelial tumor of the young

• Multinodular and vacuolating neuronal tumor

• In addition, tumor on central review must show evidence supporting MAPK pathwayactivation as defined by IHC, FISH and/or DNA/RNA sequencing (i.e. BRAF fused orrearranged, FGFR1/2/3 aberration, NF1, NF2, PTPN11, SOS1, RAF1 mutations, MYB orMYBL1 fused or rearranged, etc.) or occur in a participant with known NF1, NF2,SOS1, RAF1, or PTPN11 germline mutation. (Note: tests that show evidence supportingMAPK pathway activation that have been already performed do not need to be repeatedas long as deemed acceptable by central review).

• Participant must have measurable or evaluable disease (as defined in the protocol)

• Note: Participants with metastatic disease or multiple independent primary LGGsare allowed on study.

• Participants who are receiving corticosteroids must be on a stable or decreasingdose for at least 1 week prior to enrollment with no plans for escalation.

• Participant must have a Lansky (<16 years) or Karnofsky (≥16 years) performancescore of ≥ 50 and, in the opinion of the investigator, a minimum life expectancy ofat least 6 weeks.

• Note: Participants who are unable to walk because of paralysis, but who are upin a wheelchair, will be considered ambulatory for the purpose of assessing theperformance score.

• Participant must have adequate bone marrow and organ function as defined as:

• ANC ≥ 1.0 x 10^9/L without growth factor support within 7 days

• Platelet count ≥ 75x 10^9/L without support of a platelet transfusion within 7days

• Hemoglobin ≥8.0 g/dL without support of a blood transfusion within 7 days

• Potassium, total calcium (corrected for serum albumin), magnesium, sodium andphosphorus must be ≤ grade 1 or corrected to ≤ grade 1 with supplements beforefirst dose of study medication

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 xULN. For the purposes of this study the ULN of ALT and AST is 45 U/L.

• Total bilirubin ≤ ULN; or if > ULN then direct bilirubin ≤ 1.5 x ULN

• Adequate renal function defined as:

• Serum creatinine ≤ the maximum serum creatinine based on age/gender: Age: 2 to < 6 years: maximum serum creatinine (mg/dL) 0.8 (male, female), Age: 6 to <10years: maximum serum creatinine (mg/dL) 1 (male, female), Age: 10 to <13 years:maximum serum creatinine (mg/dL) 1.2 (male, female), Age: 13 to <16 years:maximum serum creatinine (mg/dL) 1.5 (male); 1.4 (female), Age: ≥ 16 years:maximum serum creatinine (mg/dL) 1.7 (male); 1.4 (female)

• Adequate cardiac function defined as:

• LVEF > 50% by ECHO

• QTc interval ≤ 450 msec for male participants, ≤ 470 msec for femaleparticipants after electrolytes have been corrected.

• Hypertension:

• Patients 2-12.99 years of age must have a blood pressure that is ≤ 95thpercentile +10 mmHg for age, height, and gender at the time of enrollment (withor without the use of anti-hypertensive medications).

• Patients ≥ 13 years of age must have a blood pressure ≤ 140/90 mmHg at the timeof enrollment (with or without the use of anti-hypertensive medications).

• Note for patients of all ages: Adequate blood pressure can be achievedusing medication for the treatment of hypertension.

• Participants of childbearing/child-fathering potential must agree to usecontraception.

• Participants and/or guardian have the ability to understand and the willingness tosign a written informed consent document according to institutional guidelines.

• Participants who are receiving P-gp and BCRP inhibitors must have received theirlast dose a week or 5 half-lives (whichever is greater) prior to the firstmirdametinib dose.

Inclusion Criteria: Phase 1: Progressive or Recurrent Low-Grade Glioma without Previous MEKi exposure

• Participant's tumor must have unambiguously progressed, relapsed, or recurred duringor after the most recent prior therapy (chemotherapy or radiotherapy) andpseudoprogression or treatment-related tumor changes have, in the opinion of theinvestigator, been thoroughly vetted.

• Progression may be radiographic or clinical (i.e. vision deterioration thoughtto be related to tumor in patients with optic pathway tumors, or neurologicdeterioration thought to be related to tumor) but it must be unequivocal andsufficient to warrant treatment in the opinion of the investigator.

• Prior therapy:

• Patients who have received the following:

• ≤ 3 prior treatment regimens with either myelosuppressive chemotherapy orbiologic agents and/or

• focal radiotherapy

• Note that a treatment regimen is defined as a single agent (chemotherapeutic orbiologic), or a sequential combination of therapies that can include radiotherapy (with or without concurrent radiosensitizer, chemotherapy, or biologic therapy)followed by maintenance therapy (either single or combination) given over a periodof time at either diagnosis or relapse.

• Chemotherapy:

• Participant must have received their last dose of myelosuppressive anticancerchemotherapy at least 21 days prior to study enrollment or at least 42 days ifnitrosourea.

• Monoclonal antibody treatment and agents with known prolonged half-lives:

• Patient must have recovered from any acute toxicity potentially related to theagent and received their last dose of the agent ≥ 28 days prior to studyenrollment

• MEK inhibitors:

• Patients must not have received prior exposure to any MEK inhibitors

• XRT/External Beam Irradiation including Protons:

• Participant must have had their last fraction of radiation ≥ 3 months prior tostudy enrollment

Inclusion Criteria: Phase 2, Cohort 1: Newly Diagnosed and/or previously untreated (except surgery) Low-Grade Glioma

• No prior anti-cancer treatment except surgery.

• In the opinion of the investigator tumor must warrant treatment defined as any ofthe following: unsafe to observe, unequivocally progressing on serial imaging, tumoris causing or at high risk of causing neurologic or vision-related deficits.

Inclusion Criteria: Phase 2, Cohort 2: Progressive or Recurrent Low-Grade Glioma without Previous MEK Inhibitor Exposure

• Participant's tumor must have unambiguously progressed, relapsed, or recurred duringor after the most recent prior therapy (chemotherapy or radiotherapy) andpseudoprogression or treatment-related tumor changes have, in the opinion of theinvestigator, been thoroughly vetted.

• Progression may be radiographic or clinical (i.e. vision deterioration thoughtto be related to tumor in patients with optic pathway tumors, or neurologicdeterioration thought to be related to tumor) but it must be unequivocal andsufficient to warrant treatment in the opinion of the investigator.

• Prior therapy:

• Chemotherapy:

• Participant must have received their last dose of myelosuppressiveanticancer chemotherapy at least 21 days prior to study enrollment or atleast 42 days if nitrosourea.

• Monoclonal antibody treatment and agents with known prolonged half-lives:

• Patient must have recovered from any acute toxicity potentially related tothe agent and received their last dose of the agent ≥ 28 days prior tostudy enrollment

• MEK inhibitors:

• Patients must not have received prior exposure to any MEK inhibitors

• XRT/External Beam Irradiation including Protons:

• Participant must have had their last fraction of radiation ≥ 3 monthsprior to study enrollment.

• Note that for this cohort, there are no limitations on number of prior treatmentregimens and participants who have received craniospinal radiation are eligible

Inclusion Criteria: Phase 2, Cohort 3: Progressive or Recurrent Low-Grade Glioma with Previous MEK inhibitor Exposure

• Cohort 3A (MEKi responders): Patients who previously received 6 or more cycles ofany MEK inhibitor (including mirdametinib) and did NOT progress while on active MEKinhibitor therapy.

• The progression must have occurred off MEK inhibitor therapy

• Participant's tumor must have unambiguously relapsed or clinically progressed.Progression may be radiographic or clinical (i.e. vision deterioration thoughtto be related to tumor in patients with optic pathway tumors, or neurologicdeterioration thought to be related to tumor) but it must be unequivocal andsufficient to warrant treatment in the opinion of the investigator.

• Patient must not have discontinued MEKi (specifically mirdametinib) forunacceptable toxicity, and in the opinion of the PI be able to toleratesubsequent courses of MEKi therapy.

• Patients must have received treatment with a MEK inhibitor for ≥6 cycles andshowed no signs of progression while on active MEK inhibitor therapy.

• Patients who received additional anti-tumor therapy following discontinuationof MEK inhibitor can be enrolled in this cohort.

• Prior Therapy:

• Chemotherapy:

• Participant must have received their last dose of myelosuppressiveanticancer chemotherapy at least 21 days prior to study enrollment or atleast 42 days if nitrosourea.

• Monoclonal antibody treatment and agents with known prolonged half-lives:

• Patient must have recovered from any acute toxicity potentially related tothe agent and received their last dose of the agent ≥ 28 days prior tostudy enrollment.

• MEK inhibitors:

• Participant must have received their last dose of MEKi at least 3 weeksprior to study enrollment.

• XRT/External Beam Irradiation including Protons:

• Participant must have had their last fraction of radiation ≥ 3 monthsprior to study enrollment.

• Note that for this cohort, there are no limitations on number of prior treatmentregimens and participants who have received craniospinal radiation are eligible

• Cohort 3B (MEKi non-responders): Patients with previous exposure to alternative MEKinhibitors (excluding mirdametinib) who progressed while on active MEK inhibitortherapy

• Participant's tumor must have unambiguously relapsed or clinically progressed.

• Progression may be radiographic or clinical (i.e. vision deterioration thoughtto be related to tumor in patients with optic pathway tumors, or neurologicdeterioration thought to be related to tumor) but it must be unequivocal andsufficient to warrant treatment in the opinion of the investigator. Progressionor recurrence must have occurred while on active MEK inhibitor therapy (excluding mirdametinib)

• Participants are eligible regardless of how many prior cycles were received orprior history of response (i.e. PR, Major Response, or CR)

• Patients who received additional anti-tumor therapy following discontinuation of MEKinhibitor can be enrolled in this cohort as long as they meet the above criteria.

• Prior Therapy:

• Chemotherapy:

• Participant must have received their last dose of myelosuppressiveanticancer chemotherapy at least 21 days prior to study enrollment or atleast 42 days if nitrosourea.

• Monoclonal antibody treatment and agents with known prolonged half-lives:

• Patient must have recovered from any acute toxicity potentially related tothe agent and received their last dose of the agent ≥ 28 days prior tostudy enrollment.

• Alternative MEK inhibitor:

• Participant must have received their last dose of MEKi (excludingmirdametinib) at least 3 weeks prior to study enrollment.

• XRT/External Beam Irradiation including Protons:

• Participant must have had their last fraction of radiation ≥ 3 monthsprior to study enrollment.

• Note that for this cohort, there are no limitations on number of prior treatmentregimens and participants who have received craniospinal radiation are eligible.

Exclusion Criteria: Phase 1 and Phase 2, All Cohorts

• Participants whose tumor on central review is any of the following:

• High-grade (WHO III or IV)

• Subependymal giant cell astrocytoma

• Ependymoma

• Histone H3 K27M/K28M or G34/G35-mutant

• BRAF V600 mutant

• NTRK1/2/3, ALK, or ROS1 fusion-positive

• IDH 1/2 mutant

• Participant who is currently receiving any other anticancer or investigationalagents (^11C-methionine allowed) or still recovering from acute toxicity potentiallyrelated to the agent.

• Ophthalmologic Conditions

• Patients with central serous retinopathy

• Patients with retinal vein occlusion or retinal detachment

• Patients with uncontrolled glaucoma

• If checking pressure is clinically indicated and feasible per patient'sage and ability to complete exam, patients with IOP > 22 mmHg or ULNadjusted by age are not eligible

• Participants with other clinically significant medical disorders (i.e. seriousinfections or significant cardiac, pulmonary, hepatic, psychiatric, or other organdysfunction) that in the investigator's judgement could compromise their ability totolerate or absorb protocol therapy or would interfere with the study procedures orresults.

• Sexually active patients of reproductive potential who have not agreed to use aneffective contraceptive method for the duration of their study participation and for 16 weeks after stopping study therapy are not eligible.

• Participants are excluded if unable to comply with protocol guidelines.