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

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ClinicalTrials.gov Identifier: NCT04923126
Recruitment Status : Recruiting
First Posted : June 11, 2021
Last Update Posted : June 28, 2021
Sponsor:
Collaborator:
SpringWorks Therapeutics, Inc.
Information provided by (Responsible Party):
St. Jude Children's Research Hospital

Brief 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).

Condition or disease Intervention/treatment Phase
Low-Grade Glioma Recurrent Low-Grade Glioma Progressive Low-Grade Glioma Drug: Mirdametinib Phase 1 Phase 2

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Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 132 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : June 21, 2021
Estimated Primary Completion Date : June 2031
Estimated Study Completion Date : June 2031


Arm Intervention/treatment
Experimental: Phase I: Recurrent and/or progressive low-grade glioma without prior exposure to MEK inhibitors
Participants will receive mirdametinib at one of the dose levels twice daily days 1-28. For the first cycle of treatment, participants will take mirdametinib tablets dissolved in water. After the first cycle of treatment, participants may receive the medicine the same way (dissolved in water) or may receive capsules. Treatment repeats every 28 days for up to 26 cycles of treatment (24 months) in the absence of disease progression or unacceptable toxicity.
Drug: Mirdametinib
By mouth, nasogastric (NG) tube or gastrostomy tube (G-tube) BID, days 1-28
Other Name: PD-0325901

Experimental: Phase 2, Cohort 1: Newly diagnosed and/or previously untreated (except surgery)
Participants will receive the RP2D of mirdametinib. Therapy will be administered in cycles of 28 days and may be continued for up to 24 months (26 cycles) in absence of disease progression or unacceptable toxicity.
Drug: Mirdametinib
By mouth, nasogastric (NG) tube or gastrostomy tube (G-tube) BID, days 1-28
Other Name: PD-0325901

Experimental: Phase 2, Cohort 2: Recurrent and/or Progressive without prior exposure to MEK inhibitors
Participants will receive the RP2D of mirdametinib. Participants may take mirdametinib tablets dissolved in water, or receive capsules. Therapy will be administered in cycles of 28 days and may be continued for up to 24 months (26 cycles) in absence of disease progression or unacceptable toxicity.
Drug: Mirdametinib
By mouth, nasogastric (NG) tube or gastrostomy tube (G-tube) BID, days 1-28
Other Name: PD-0325901

Experimental: Phase 2, Cohort 3a:
Participants with recurrent and/or progressive low-grade glioma who previously received ≥ 6 courses MEK inhibitor (including mirdametinib) and did not progress while on active MEKi therapy. Participants will receive the RP2D of mirdametinib. Participants with previous exposure to mirdametinib may receive a starting dose lower than the RP2D, depending on the dose they tolerated during their previous exposure. Participants may take mirdametinib tablets dissolved in water, or receive capsules. Therapy will be administered in cycles of 28 days and may be continued for up to 24 months (26 cycles) in absence of disease progression or unacceptable toxicity.
Drug: Mirdametinib
By mouth, nasogastric (NG) tube or gastrostomy tube (G-tube) BID, days 1-28
Other Name: PD-0325901

Experimental: Phase 2, Cohort 3b:
Participants with recurrent and/or progressive low-grade glioma who previously received ≥ 6 courses MEK inhibitor (including mirdametinib) and did not progress while on active MEKi therapy. Participants will receive the RP2D of mirdametinib. Participants may take mirdametinib tablets dissolved in water, or receive capsules. Therapy will be administered in cycles of 28 days and may be continued for up to 24 months (26 cycles) in absence of disease progression or unacceptable toxicity.
Drug: Mirdametinib
By mouth, nasogastric (NG) tube or gastrostomy tube (G-tube) BID, days 1-28
Other Name: PD-0325901




Primary Outcome Measures :
  1. 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. [ Time Frame: 1 month after start of mirdametinib treatment ]
    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.

  2. 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. [ Time Frame: Up to 25 months after start of mirdametinib treatment ]
    Incidence of adverse event data at least possibly related to treatment will be summarized in cohort specific tables by grade and attribution throughout treatment.

  3. Characterize the maximum plasma concentration and area under the concentration-time curve (AUC0-8h) of mirdametinib. [ Time Frame: Course 1: Days 1 and 15 ]
    Mirdametinib plasma concentration will be provided and area under the curve (AUC0-8h) estimated based on course 1, days 1 and 15 PK samples

  4. Phase 2, Cohort 1: Objective response rate observed anytime during active treatment and sustained for at least 8 weeks [ Time Frame: Up to 24 months after start of mirdametinib treatment ]
    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.

  5. Phase 2, Cohort 2: Objective response rate observed anytime during active treatment and sustained for at least 8 weeks [ Time Frame: Up to 24 months after start of mirdametinib treatment ]
    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.

  6. Phase 2, Cohort 3a: Estimate 1-year disease stabilization rate [ Time Frame: Up to 12 months (slight departures from this timing allowed based on MRI screening) after start of mirdamentinib treatment ]
    Rate of stable disease from start of treatment until the time of progression or time of last follow-up.

  7. Phase 2, Cohort 3b: Estimate 6-month disease stabilization rate [ Time Frame: Up to 6 months (slight departures from this timing allowed based on MRI screening) after start of mirdametinib treatment ]
    Rate of stable disease from start of treatment until the time of progression or time of last follow-up.

  8. Describe the toxicity profile of mirdametinib by cohort. [ Time Frame: Up to 25 months after start of mirdametinib treatment ]
    Incidence of adverse event data at least possibly related to treatment will be summarized in cohort specific tables by grade and attribution throughout treatment.


Secondary Outcome Measures :
  1. Progression-free survival (PFS) by cohort [ Time Frame: Up to 5 years after the last enrolled patient starts treatment ]
    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.

  2. Rates of Minor Response, by cohort [ Time Frame: Up to 5 years after the last enrolled patient starts treatment ]
    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.

  3. Rates of Partial Response (PR), by cohort [ Time Frame: Up to 5 years after the last enrolled patient starts treatment ]
    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.

  4. Rates of Major Response, by cohort [ Time Frame: Up to 5 years after the last enrolled patient starts treatment ]
    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.

  5. Rates of Complete Response (CR), by cohort [ Time Frame: Up to 5 years after the last enrolled patient starts treatment ]
    Complete Response is defined as disappearance of the target lesion and, if applicable, all areas of metastatic disease as compared to reference scan (baseline or best recorded MRI). 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.

  6. Rates of Stable Disease, by cohort [ Time Frame: Up to 5 years after the last enrolled patient starts treatment ]
    Stable disease is defined as an increase or decrease in target lesion area that is not sufficient to qualify as progressive or responsive disease (i.e. minor, partial, major, or complete). 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.

  7. Rates of Progressive Disease (PD), by cohort [ Time Frame: Up to 5 years after the last enrolled patient starts treatment ]
    Progressive Disease is defined as any of the following: A greater than 25% increase in target lesion area relative to reference scan, the development of a new tumor lesion, substantial growth (>25%) of a measurable metastatic lesion, or worsening of clinical and/or functional assessment directly related to tumor progression. Responses 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.

  8. Longitudinal change in intellectual function, by cohort [ Time Frame: Baseline (at enrollment), 9 months, 2 years, and 5 years after start of mirdametinib treatment ]
    To evaluate the effects of mirdametinib treatment on intellectual function among children treated for low-grade glioma. This will be assessed in children 2.6-5.11 years of age using Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV), in children 6-16.11 years of age using the Wechsler Intelligence Scale for Children (WISC-V), and for children 17 years and older using Wechsler Adult Intelligence Scale (WAIS-IV). Scores for each measure will be summarized by timepoint and cohort using descriptive statistics and appropriate plots.

  9. Longitudinal change in attention and executive functions, by cohort [ Time Frame: Baseline (at enrollment), 6 months, 9 months, 2 years, 3 years, 4 years, and 5 years after start of mirdametinib treatment ]
    To evaluate the effects of mirdametinib treatment on attention and executive function in children treated for low-grade glioma. This will be assessed using different instruments as age appropriate: Cogstate will be used to measure attention, working memory and processing speed in children 4 years and older; WPPSI-IV (4-5.11 years of age), WISC-V (6-16.11 years of age) and WAIS-IV (17 years of age and older) will assess brief attention and working memory; Kaufman Test of Educational Achievement, Third Edition (KTEA-3) will assess verbal fluency in children 4-25 years of age; and Behavior Rating Inventory of Executive Function (BRIEF; BRIEF-2) will assess behavioral manifestations of executive function. Scores for each measure will be summarized by timepoint and cohort using descriptive statistics and appropriate plots.

  10. Longitudinal change in memory, by cohort [ Time Frame: 9 months, 2 years, and 5 years after start of mirdametinib treatment ]
    To evaluate the effects of mirdametinib treatment on memory in children treated for low-grade glioma. This will be assessed using different instruments as age appropriate: California Verbal Learning Test, Children's Version (CVLT-C) will be used to measure verbal list learning in children 6-16.11 years of age; the NEPSY-II Memory for Designs subtest (ages 6-16.11) and Wechsler Memory Scale (WMS-IV, ages 17 and older ) will assess nonverbal memory; the Children's Memory Scale (CMS, ages 5-16.11) and WMS-IV (ages 17 and older) Story Memory subtests will assess immediate recall, delayed recall, and recognition of details. Scores for each measure will be summarized by timepoint and cohort using descriptive statistics and appropriate plots.

  11. Longitudinal change in processing speed, by cohort [ Time Frame: 9 months, 2 years, and 5 years after start of mirdametinib treatment ]
    To evaluate the effects of mirdametinib treatment on processing speed in children treated for low-grade glioma. This will be assessed using the age appropriate Wechsler Processing Speed Index [WPPSI-IV (ages 4-5.11), WISC-V (ages 6-16), and WAIS-IV (ages 17 and older)]. Scores for each measure will be summarized by timepoint and cohort using descriptive statistics and appropriate plots.

  12. Longitudinal change in academic achievement, by cohort [ Time Frame: 2 years and 5 years after start of mirdametinib treatment ]
    To evaluate the effects of mirdametinib treatment on academic achievement in children treated for low-grade glioma. Reading and math abilities will be assessed using age-appropriate KTEA-3 subtests: Letter & Word Recognition (ages 4 and older), Word Recognition Fluency (ages 6 and older), Math Computation (ages 5 and older), and Math Fluency (ages 6 and older). Scores for each measure will be summarized by timepoint and cohort using descriptive statistics and appropriate plots.

  13. Longitudinal change in psychosocial functioning, by cohort [ Time Frame: Baseline (at enrollment), 6 months, 9 months, 2 years, 3 years, 4 years, and 5 years after start of mirdametinib treatment ]
    To evaluate the effects of mirdametinib treatment on psychosocial function in children treated for low-grade glioma. Social-emotional measures will include the Behavior Assessment System for Children, Third Edition (BASC-3, ages 2-20.11) to assess behavioral, emotional, and adaptive functioning, as well as the PedsQL (ages 2 and older) to assess health-related quality of life. Scores for each measure will be summarized by timepoint and cohort using descriptive statistics and appropriate plots.

  14. Longitudinal change in adaptive behavior, by cohort [ Time Frame: Baseline (at enrollment), 9 months, 2 years, and 5 years after start of mirdametinib treatment ]
    To evaluate the effects of mirdametinib treatment on adaptive behavior in children treated for low-grade glioma. This will be assessed using the Adaptive Behavior Assessment System, Third Edition (ABAS-3, ages 2-21.11), which rates the child's ability to independently perform age-appropriate daily living skills. Scores will be summarized by timepoint and cohort using descriptive statistics and appropriate plots.



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Layout table for eligibility information
Ages Eligible for Study:   2 Years to 24 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria: Screening Phase

  • Participants with histologically confirmed or suspected low-grade glioma, including neuronal and mixed neuronal-glial tumors
  • Participant must have adequate tumor tissue from primary and/or relapsed tumor for central pathology review
  • Projected to be ≥ 2 years and < 25 years at the time of study enrollment
  • Participant's body surface area (BSA) at time of study enrollment must fall within the 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 the protocol 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 informed consent document according to institutional guidelines

Exclusion Criteria: Screening Phase

  • Participants with retinal pathology on ophthalmologic examination that is consistent with or a precursor for central serous retinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration
  • Participants with a known malabsorption syndrome or preexisting gastrointestinal conditions that may impair absorption of mirdametinib (e.g., gastric bypass, lap band, or other gastric procedures)
  • Participant with a known history of liver disease or known hepatic or biliary abnormalities (except for Gilbert's syndrome or asymptomatic gallstones)
  • Participants with a clinically significant history of chronic interstitial lung disease (such as bronchopulmonary dysplasia, chronic bronchiolitis, obliterative bronchiolitis, chronic aspiration pneumonia, surfactant protein disorder, or other serious chronic pulmonary condition). Participants with a history of asthma, reactive airways disease, or viral pneumonitis are not to be excluded if disease has resolved 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 outlined below 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 the protocol 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. Jude Children's Research Hospital central pathology review of primary and/or relapsed tumor:

    • Eligible tumors include:

      • Low-grade glioma/astrocytic tumor/glioneuronal tumor/neuroepithelial tumor, not otherwise specified (NOS) or not elsewhere classified (NEC)
      • Pilocytic astrocytoma
      • Pilomyxoid astrocytoma
      • Pleomorphic xanthroastrocytoma
      • Ganglioglioma
      • Gangliocytoma
      • Diffuse glioma, diffuse astrocytoma, oligodendroglioma, or oligoastrocytoma
      • Papillary glioneuronal tumor
      • Rosette-forming glioneuronal tumor
      • Diffuse leptomeningeal glioneuronal tumor
      • Central neurocytoma, extraventricular neurocytoma
      • Angiocentric glioma
      • Dysembryoplastic neuroepithelial tumor (DNET), septal DNET, myxoid glioneuronal 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 pathway activation as defined by IHC, FISH and/or DNA/RNA sequencing (i.e. BRAF fused or rearranged, FGFR1/2/3 aberration, PTPN11, SOS1, RAF1 mutations, MYB or MYBL1 fused or rearranged, etc.) or occur in a participant with known NF1, NF2, SOS1, RAF1, or PTPN11 germline mutation. (Note: tests that show evidence supporting MAPK pathway activation that have been already performed do not need to be repeated as 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 LGGs are allowed on study.
  • Participants who are receiving corticosteroids must be on a stable or decreasing dose for at least 1 week prior to enrollment with no plans for escalation.
  • Participant must have a Lansky (<16 years) or Karnofsky (≥16 years) performance score of ≥ 50 and, in the opinion of the investigator, a minimum life expectancy of at least 6 weeks.

    • Note: Participants who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance 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 7 days
    • Hemoglobin ≥8.0 g/dL without support of a blood transfusion within 7 days
    • Potassium, total calcium (corrected for serum albumin), magnesium, sodium and phosphorus must be ≤ grade 1 or corrected to ≤ grade 1 with supplements before first dose of study medication
    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN. 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 <10 years: 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 female participants after electrolytes have been corrected.
  • Hypertension:

    • Patients 2-12.99 years of age must have a blood pressure that is ≤ 95th percentile +10 mmHg for age, height, and gender at the time of enrollment (with or without the use of anti-hypertensive medications).
    • Patients ≥ 13 years of age must have a blood pressure ≤ 140/90 mmHg at the time of enrollment (with or without the use of anti-hypertensive medications).

      • Note for patients of all ages: Adequate blood pressure can be achieved using medication for the treatment of hypertension.
  • Participants of childbearing/child-fathering potential must agree to use contraception.
  • Participants and/or guardian have the ability to understand and the willingness to sign a written informed consent document according to institutional guidelines.
  • Participants who are receiving P-gp and BCRP inhibitors must have received their last dose a week or 5 half-lives (whichever is greater) prior to the first mirdametinib 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 during or after the most recent prior therapy (chemotherapy or radiotherapy) and pseudoprogression or treatment-related tumor changes have, in the opinion of the investigator, been thoroughly vetted.

    • Progression may be radiographic or clinical (i.e. vision deterioration thought to be related to tumor in patients with optic pathway tumors, or neurologic deterioration thought to be related to tumor) but it must be unequivocal and sufficient 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 or biologic agents and/or
      • focal radiotherapy
  • Note that a treatment regimen is defined as a single agent (chemotherapeutic or biologic), 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 period of time at either diagnosis or relapse.
  • Chemotherapy:

    • Participant must have received their last dose of myelosuppressive anticancer chemotherapy at least 21 days prior to study enrollment or at least 42 days if nitrosourea.
  • Monoclonal antibody treatment and agents with known prolonged half-lives:

    • Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the agent ≥ 28 days prior to study 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 months prior to study 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 of the following: unsafe to observe, unequivocally progressing on serial imaging, tumor is 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 during or after the most recent prior therapy (chemotherapy or radiotherapy) and pseudoprogression or treatment-related tumor changes have, in the opinion of the investigator, been thoroughly vetted.

    • Progression may be radiographic or clinical (i.e. vision deterioration thought to be related to tumor in patients with optic pathway tumors, or neurologic deterioration thought to be related to tumor) but it must be unequivocal and sufficient to warrant treatment in the opinion of the investigator.
  • Prior therapy:

    • Chemotherapy:

      • Participant must have received their last dose of myelosuppressive anticancer chemotherapy at least 21 days prior to study enrollment or at least 42 days if nitrosourea.
    • Monoclonal antibody treatment and agents with known prolonged half-lives:

      • Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the agent ≥ 28 days prior to study 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 months prior to study enrollment.
  • Note that for this cohort, there are no limitations on number of prior treatment regimens 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 of any MEK inhibitor (including mirdametinib) and did NOT progress while on active MEK inhibitor 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 thought to be related to tumor in patients with optic pathway tumors, or neurologic deterioration thought to be related to tumor) but it must be unequivocal and sufficient to warrant treatment in the opinion of the investigator.
    • Patient must not have discontinued MEKi (specifically mirdametinib) for unacceptable toxicity, and in the opinion of the PI be able to tolerate subsequent courses of MEKi therapy.
    • Patients must have received treatment with a MEK inhibitor for ≥6 cycles and showed no signs of progression while on active MEK inhibitor therapy.
    • Patients who received additional anti-tumor therapy following discontinuation of MEK inhibitor can be enrolled in this cohort.
  • Prior Therapy:

    • Chemotherapy:

      • Participant must have received their last dose of myelosuppressive anticancer chemotherapy at least 21 days prior to study enrollment or at least 42 days if nitrosourea.
    • Monoclonal antibody treatment and agents with known prolonged half-lives:

      • Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the agent ≥ 28 days prior to study enrollment.
    • MEK inhibitors:

      • Participant must have received their last dose of MEKi at least 3 weeks prior to study enrollment.
    • XRT/External Beam Irradiation including Protons:

      • Participant must have had their last fraction of radiation ≥ 3 months prior to study enrollment.
  • Note that for this cohort, there are no limitations on number of prior treatment regimens and participants who have received craniospinal radiation are eligible
  • Cohort 3B (MEKi non-responders): Patients with previous exposure to alternative MEK inhibitors (excluding mirdametinib) who progressed while on active MEK inhibitor therapy

    • Participant's tumor must have unambiguously relapsed or clinically progressed.
    • Progression may be radiographic or clinical (i.e. vision deterioration thought to be related to tumor in patients with optic pathway tumors, or neurologic deterioration thought to be related to tumor) but it must be unequivocal and sufficient to warrant treatment in the opinion of the investigator. Progression or recurrence must have occurred while on active MEK inhibitor therapy (excluding mirdametinib)
    • Participants are eligible regardless of how many prior cycles were received or prior history of response (i.e. PR, Major Response, or CR)
  • Patients who received additional anti-tumor therapy following discontinuation of MEK inhibitor 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 myelosuppressive anticancer chemotherapy at least 21 days prior to study enrollment or at least 42 days if nitrosourea.
    • Monoclonal antibody treatment and agents with known prolonged half-lives:

      • Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the agent ≥ 28 days prior to study enrollment.
    • Alternative MEK inhibitor:

      • Participant must have received their last dose of MEKi (excluding mirdametinib) at least 3 weeks prior to study enrollment.
    • XRT/External Beam Irradiation including Protons:

      • Participant must have had their last fraction of radiation ≥ 3 months prior to study enrollment.
  • Note that for this cohort, there are no limitations on number of prior treatment regimens 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 investigational agents (^11C-methionine allowed) or still recovering from acute toxicity potentially related 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's age and ability to complete exam, patients with IOP > 22 mmHg or ULN adjusted by age are not eligible
  • Participants with other clinically significant medical disorders (i.e. serious infections or significant cardiac, pulmonary, hepatic, psychiatric, or other organ dysfunction) that in the investigator's judgement could compromise their ability to tolerate or absorb protocol therapy or would interfere with the study procedures or results.
  • Sexually active patients of reproductive potential who have not agreed to use an effective 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04923126


Contacts
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Contact: Tabatha E. Doyle, RN 901-595-2544 tabatha.doyle@stjude.org

Locations
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United States, Tennessee
St. Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38105
Contact: Tabatha E. Doyle, RN    901-595-2544    tabatha.doyle@stjude.org   
Principal Investigator: Giles W. Robinson, MD         
Principal Investigator: Anna Vinitsky, MD, MS         
Sponsors and Collaborators
St. Jude Children's Research Hospital
SpringWorks Therapeutics, Inc.
Investigators
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Principal Investigator: Giles W. Robinson, MD St. Jude Children's Research Hospital
Principal Investigator: Anna Vinitsky, MD, MS St. Jude Children's Research Hospital
Additional Information:
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Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT04923126    
Other Study ID Numbers: SJ901
NCI-2021-05912 ( Registry Identifier: NCI Clinical Trial Registration Program )
First Posted: June 11, 2021    Key Record Dates
Last Update Posted: June 28, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant de-identified datasets containing the variables analyzed in the published article will be made available (related to the study primary or secondary objectives contained in the publication). Supporting documents such as the protocol, statistical analyses plan, and informed consent are available through the CTG website for the specific study. Data used to generate the published article will be made available at the time of article publication. Investigators who seek access to individual level de-identified data will contact the computing team in the Department of Biostatistics (ClinTrialDataRequest@stjude.org) who will respond to the data request
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Data will be made available at the time of article publication.
Access Criteria: Data will be provided to researchers following a formal request with the following information: full name of requestor, affiliation, data set requested, and timing of when data is needed. As an informational point, the lead statistician and study principal investigator will be informed that primary results datasets have been requested.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by St. Jude Children's Research Hospital:
Brain tumors in Adolescent
Brain tumors in Children
Brain tumors in Young Adults
Astrocytic tumor
Glioneuronal tumor
Neuroepithelial tumor, not otherwise specified (NOS)
Neuroepithelial tumor, not elsewhere classified (NEC)
Pilocytic astrocytoma
Pilomyxoid astrocytoma
Pleomorphic xanthroastrocytoma
Ganglioglioma
Gangliocytoma
Diffuse glioma
Diffuse astrocytoma
Oligodendroglioma
Oligoastrocytoma
Papillary glioneuronal tumor
Rosette-forming glioneuronal tumor
Diffuse leptomeningeal glioneuronal tumor
Central neurocytoma
Extraventricular neurocytoma
Angiocentric glioma
Dysembryoplastic neuroepithelial tumor (DNET)
Septal Dysembryoplastic neuroepithelial tumor (DNET)
Myxoid glioneuronal tumor
Tectal glioma
Desmoplastic infantile astrocytoma
Desmoplastic infantile ganglioglioma
Polymorphous low-grade neuroepithelial tumor of the young
Multinodular and vacuolating neuronal tumor
Additional relevant MeSH terms:
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Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue