Neoplasms

All Conditions

Nervous System Diseases

Rare Diseases

Glioblastoma

Glioma

Diffuse Intrinsic Pontine Glioma

Astrocytoma

Oligodendroglioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Brain Stem Neoplasms

Infratentorial Neoplasms

Brain Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Anaplastic Astrocytoma

Oligoastrocytoma

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Bevacizumab

Cetuximab

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Superselective Intraarterial Cerebral Infusion (SIACI) of Erbitux (200 mg/m\^2) and Bevacizumab (15 mg/kg)

Subjects will receive a single intra-arterial dose of Cetuximab (200 mg/m\^2) and Bevacizumab (15 mg/kg) via Superselective Intraarterial Cerebral Infusion (SIACI).

SIACI of Erbitux and Bevacizumab

Jeffery Greenfield, MD PhD

Central nervous system (CNS) malignancies are the second most common malignancy and the most common solid tumor of childhood, including adolescence. Annually in the United States, approximately 2,200 children are diagnosed with CNS malignancy and rates appear to be increasing. CNS tumors are the leading cause of death from solid tumors in children. Survival duration after diagnosis in children is highly variable depending in part on age at diagnosis, location of tumor, and extent of resection; however, most children with high grade glioma die within 3 years of diagnosis. All patients with high grade glioma experience a recurrence after first-line therapy, so improvements in both first-line and salvage therapy are critical to enhancing quality-of-life and prolonging survival. It is unknown if currently used intravenous (IV) therapies even cross the blood brain barrier (BBB). We have shown in previous phase I trials that a single Superselective Intra-arterial Cerebral Infusion (SIACI) of Cetuximab and/or Bevacizumab is safe for the treatment of recurrent glioblastoma multiforme (GBM) in adults, and we are currently evaluating the efficacy of this treatment. Therefore, this phase I/II clinical research trial is an extension of that trial in that we seek to test the hypothesis that intra-arterial Cetuximab and Bevacizumab is safe and effective in the treatment of relapsed/refractory glioma in patients \<22 years of age. We expect that this project will provide important information regarding the utility of SIACI Cetuximab and Bevacizumab therapy for malignant glioma in patients \<22 years of age and may alter the way these drugs are delivered to our patients in the near future.

The experimental aspects of this treatment plan will include:

1. Subjects will first be treated with Mannitol prior to chemotherapy infusion (Mannitol 25%; 10 mL over 2 minutes) in order to disrupt the blood brain barrier. This technique has been used in several thousand patients in previous studies for the IA delivery of chemotherapy for malignant glioma. We have used this without complication in our patients from our Phase I protocols as well.
2. To treat patients \<22 years of age with recurring or relapsing glioma with a single intraarterial delivery (SIACI) of Cetuximab and Bevacizumab. Our Phase I trials have demonstrated the safety of SIACI delivery of these drugs in adults. This trial will focus on the safety and efficacy in patients \<22 years of age.

Intraarterial Infusion Of Erbitux and Bevacizumab For Relapsed/Refractory Intracranial Glioma In Patients Under 22

Phase I/II Trial Of Super-Selective Intraarterial Infusion Of Erbitux (Cetuximab) And Avastin (Bevacizumab)For Treatment Of Relapsed/Refractory Intracranial Glioma In Patients Under 22 Years Of Age

Overall Survival (OS) will be measured from the date of the first dose of SIACI Cetuximab/Avastin to the date of death.

The overall response proportion along with a 95% confidence interval will be estimated via binomial proportions. The investigator will define "evaluable" patients as patients who met eligibility requirements and have initiated therapy.

All treatment emergent adverse events will be assessed and graded according to Common Terminology Criteria for Adverse Events (CTCAE)v. 4.0 terminology for severity, duration, and relationship to research protocol treatment.

PFS will be assessed by Kaplan-Meier survival analysis, assuming adequate follow-up time. PFS will be measured from the date of the first dose of SIACI Cetuximab/Avastin to the date of progression.

Weill Medical College of Cornell University

Patients were closely monitored for toxicity. The primary observation period after IA therapy was 28 days. After the 28 day period, the patient started treatment as recommended by patient's neurooncologist. Toxicities were monitored by history, physical examination, blood tests, and chest x-ray as outlined in the protocol. Within the 28 day period, AEs were assessed on day 0, day 1, and 1 month post-procedure. Participants were followed for grade 5 AEs (death) for 2 years.

Superselective Intraarterial Cerebral Infusion (SIACI) of Erbitux (200 m/m\^2) and Bevacizumab (15 mg/kg)

SIACI of Erbitux and Bevacizumab: Subjects will receive a single intra-arterial dose of Cetuximab (200 m/m\^2) and Bevacizumab (15 mg/kg) via Superselective Intraarterial Cerebral Infusion (SIACI).

Superselective Intraarterial Cerebral Infusion (SIACI) of Erbitux (200 mg/m\^2) and Bevacizumab (15 mg/kg)

SIACI of Erbitux and Bevacizumab: Subjects will receive a single intra-arterial dose of Cetuximab (200 mg/m\^2) and Bevacizumab (15 mg/kg) via Superselective Intraarterial Cerebral Infusion (SIACI).

Age, Categorical

Sex: Female, Male

Race and Ethnicity were not collected from any participant.

Race and Ethnicity Not Collected

United States

Region of Enrollment

This study was terminated early and participant enrollment was low, resulting in a small sample size (N=13). Having a small sample size may reduce statistical reliability and generalizability of results.

Median Overall Survival (OS)

The data for this outcome was not collected.

Composite Overall Response Rate (CORR)

Grade 1

Grade 2

Grade 3

Grade 4

Number of Treatment Emergent Adverse Events

Median Progression-free Survival (PFS)

Overall Study

Symptoms and General Pathology

Recurrence

Ganglioneuroma

Ganglioglioma

Neurocytoma

Gangliocytoma

Diffuse Astrocytoma

Pilocytic Astrocytoma

Desmoplastic Infantile Astrocytoma

Papillary Glioneuronal Tumors

Central Neurocytoma

Dysembryoplastic Neuroepithelial Tumor

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.

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.

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.

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.

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.

By mouth, nasogastric (NG) tube or gastrostomy tube (G-tube) BID, days 1-28

Mirdametinib

Tabatha E. Doyle, RN

Giles W. Robinson, MD

Anna Vinitsky, MD, MS

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).

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.

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

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

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

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.

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

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

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.

Rate of stable disease from start of treatment until the time of progression or time of last follow-up.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

SpringWorks Therapeutics, Inc.

St. Jude Children's Research Hospital

Eye Diseases

Gliosarcoma

Optic Nerve Glioma

Optic Nerve Neoplasms

Peripheral Nervous System Neoplasms

Cranial Nerve Diseases

Optic Nerve Diseases

Pleomorphic Xanthoastrocytoma

Anti-Infective Agents

Anticonvulsants

Anticoagulants

Other Dietary Supplements

Carboplatin

Irinotecan

Temozolomide

Vincristine

Piperazine

Mebendazole

Piperazine citrate

DMP 777

Citric Acid

Sodium Citrate

Topoisomerase I Inhibitors

Enzyme Inhibitors

Tubulin Modulators

Antimitotic Agents

Antineoplastic Agents, Alkylating

Alkylating Agents

Anthelmintics

Antiparasitic Agents

Citrate

Patients on the low-grade arm will receive treatment with seven 10-week cycles of carboplatin, vincristine, temozolomide, and mebendazole.

Patients on the high-grade glioma/pontine glioma arm will receive treatment with twelve 28-day cycles of bevacizumab, irinotecan, and mebendazole.

\*High grade arm enrollment complete, no additional spots

Mebendazole will be given orally twice daily for over the course of treatment (70 weeks for low-grade glioma patients, 48 weeks for high-grade glioma/pontine glioma patients). Mebendazole will be prescribed according to the particular dose cohort for each patient (50 mg/kg/day, 100 mg/kg/day, or 200 mg/kg/day).

Low-grade glioma patients only. Vincristine will be dosed as per the following: For patients \< 12kg: 0.05 mg/kg; for patient \> 12kg: 1.5mg/m2 (maximal dose 2.0 mg). Vincristine will be administered intravenously on Day 1 of weeks 0,1,2,3,4,5 during the 10-week induction cycle and on Day 1 of Weeks 0,1,2 of the six 10-week maintenance cycles.

Low-grade glioma patients only. Carboplatin will be dosed at 175 mg/m2. Carboplatin will be administered intravenously on Day 1 of Weeks 0,1,2,3 of the 10-week Induction cycle, and on Day 1 of Weeks 0,1,2,3 during the six 10-week maintenance cycles.

Low-grade glioma patients only. Temozolomide will be dosed at 200 mg/m2/day. Temozolomide will be given orally for 5 days during Week 6 of the 10-week induction cycle and for 5 days during Week 6 of the six 10-week maintenance cycles.

High-grade glioma/pontine glioma patients only. Bevacizumab will be dosed at 10mg/kg/dose. Bevacizumab will be administered intravenously on Days 1 and 15 of each maintenance cycle.

High-grade glioma/pontine glioma patients only. Irinotecan will be administered at doses 125 mg/m2, 150 mg/m2, 250 mg/m2, or 300 mg/m2, depending on patient tolerance and concomitant enzyme-inducing anti-epileptic medication use. Irinotecan will be administered intravenously on Days 1 and 15 of each maintenance cycle.

Julie Krystal, MD

Derek R Hanson, MD

Mark P Atlas, MD

This is a study to determine the safety and efficacy of the drug, mebendazole, when used in combination with standard chemotherapy drugs for the treatment of pediatric brain tumors. Mebendazole is a drug used to treat infections with intestinal parasites and has a long track record of safety in humans. Recently, it was discovered that mebendazole may be effective in treating cancer as well, in particular brain tumors. Studies using both cell cultures and mouse models demonstrated that mebendazole was effective in decreasing the growth of brain tumor cells.

This study focuses on the treatment of a category of brain tumors called gliomas. Low-grade gliomas are tumors arising from the glial cells of the central nervous system and are characterized by slower, less aggressive growth than that of high-grade gliomas. Some low-grade gliomas have a more aggressive biology and an increased likelihood of resistance or recurrence.

Low-grade gliomas are often able to be treated by observation alone if they receive a total surgical resection. However, tumors which are only partially resected and continue to grow or cause symptoms, or those which recur following total resection require additional treatment, such as chemotherapy. Due to their more aggressive nature, pilomyxoid astrocytomas, even when totally resected, will often be treated with chemotherapy. The current first-line treatment at our institution for these low-grade gliomas involves a three-drug chemotherapy regimen of vincristine, carboplatin, and temozolomide. However, based on our data from our own historical controls, over 50% of patients with pilomyxoid astrocytomas will continue to have disease progression while on this treatment. We believe that mebendazole in combination with vincristine, carboplatin, and temozolomide may provide an additional therapeutic benefit with increased progression-free and overall survival for low-grade glioma patients, particularly for those with pilomyxoid astrocytomas.

High grade gliomas are more aggressive tumors with poor prognoses. The standard therapy is radiation therapy. A variety of adjuvant chemotherapeutic combinations have been used, but with disappointing results. For high-grade gliomas this study will add mebendazole to the established combination of bevacizumab and irinotecan to determine this combinations safety and efficacy

This is a phase I/II study of mebendazole in combination with standard of care agents for pediatric patients with gliomas. Patients with low-grade gliomas will receive a regimen of mebendazole in combination with vincristine, carboplatin, and temozolomide. Patients with high-grade gliomas and diffuse intrinsic pontine gliomas will receive a regimen of mebendazole in combination with bevacizumab and irinotecan. Surgical resection of the tumor will be attempted initially with the goal of achieving a gross total resection without substantial neurologic deficit. Subtotal resection may be preferable depending on the location of the tumor. Optic pathway gliomas and diffuse intrinsic pontine gliomas may remain unresected. Patients with high-grade gliomas or diffuse intrinsic pontine gliomas will undergo local irradiation of their tumor before beginning protocol treatment. Low-grade glioma patients will not receive radiation therapy. Patients who have been previously treated with chemotherapy will be eligible for the study provided they have not previously failed therapy with any of the chemotherapeutic agents.

Patients with eligible tumors will be consented for enrollment into the study. The study patients will be divided into two groups (low-grade glioma and high-grade/pontine glioma) for the purpose of determining the maximally tolerated dose of mebendazole. These two groups will be treated independently with regard to patient accrual, dose escalation, and evaluation of toxicity. In addition to their standard chemotherapy regimen, patients in both cohorts will receive mebendazole. Mebendazole doses will be escalated from the initial dose level of 50 mg/kg/day divided twice daily, to a second dose level of 100 mg/kg/day divided twice daily, to the final dose level of 200 mg/kg/day divided twice daily, in cohorts of three patients per dose level. A standard "3+3" design will be used for determining dose escalation.

Phase I safety monitoring for the low-grade group will take place during a trial period beginning with start of therapy and ending following the tenth week of induction therapy. Phase I safety monitoring for the high-grade/pontine glioma group will take place during a trial period beginning with the start of maintenance therapy through the twelfth week of maintenance therapy (3 cycles).

After determination of maximally tolerated dose for each group, the study will continue to evaluate efficacy of this regimen. The study will be amended for the maximally tolerated dose for each group to be used in the remainder of the study. Patients currently on study will continue with maintenance therapy. To document the degree of residual tumor, standard whole brain MRI with and without contrast (gadolinium) will be performed following a specified intervals. Following completion of therapy, patients will continue to be monitored by MRI to assess progression-free and overall-survival.

A Phase I Study of Mebendazole for the Treatment of Pediatric Gliomas

Low-grade glioma patients will receive an assigned dose of mebendazole twice daily in combination with vincristine, carboplatin and temozolomide. During a 10 week induction period, patients will be assessed for dose-limiting toxicity that is beyond the expected toxicity from the standard regimen of vincristine, carboplatin, and temozolomide alone. This outcome measure will use a standard 3+3 design to dose-escalate mebendazole in three dose cohorts of 50 mg/kg/day, 100 mg/kg/day, and 200 mg/kg/day.

High-grade glioma/pontine glioma patients will receive an assigned dose of mebendazole twice daily in combination with bevacizumab and irinotecan. During the first three maintenance therapy cycles (12 weeks), patients will be assessed for dose-limiting toxicity that is beyond the expected toxicity from the standard regimen of bevacizumab and irinotecan alone. This outcome measure will use a standard 3+3 design to dose-escalate mebendazole in three dose cohorts of 50 mg/kg/day, 100 mg/kg/day, and 200 mg/kg/day.

3-year event-free survival (EFS) and overall survival (OS) of patients with low-grade gliomas treated with carboplatin, vincristine, temozolomide, and mebendazole in combination following surgical resection, to the extent feasible.

3-year event-free survival (EFS) and overall survival (OS) of patients with high-grade gliomas treated with bevacizumab, irinotecan, and mebendazole in combination following surgical resection to the extent feasible and local irradiation.

The frequency of tumor dissemination in the CSF of patients with pilomyxoid astrocytomas treated with carboplatin, vincristine, temozolomide, and mebendazole.

The percentage of patients demonstrating a partial (greater than 50% decrease in tumor volume in 3 dimensions) or complete response on MRI in patients with high-grade gliomas treated with mebendazole in combination with bevacizumab and irinotecan, after surgical resection, to the extent feasible and local irradiation.

The percentage of patients demonstrating a partial (greater than 50% decrease in tumor volume in 3 dimensions) or complete response on MRI in patients with low-grade gliomas treated with mebendazole in combination with vincristine, carboplatin and temozolomide after surgical resection, to the extent feasible.

Janssen Pharmaceuticals

Julie Krystal

Head, Developmental Therapeutics

Optic Pathway Glioma

Hippocampal-avoidance proton therapy

Thomas Merchant, MD

Thomas Merchant

Low-grade gliomas (LGGs) are the most common brain tumors in children, and a subset of these tumors are treated definitively with focal radiation therapy (RT). These patients often survive for many years after receiving RT and experience late deficits in memory. Verbal recall is an important measure of memory and is associated with other important functional outcomes, such as problem-solving, independence of every-day functioning, and quality of life. Decline in memory, as measured by verbal recall, is associated with RT dose to the hippocampi. Therefore, this phase II study investigates the feasibility of reducing RT doses to the hippocampi (i.e., hippocampal avoidance \[HA\]) by using proton therapy for midline or suprasellar LGGs.

Primary Objective:

* To determine the feasibility of HA with proton therapy in suprasellar or midline LGGs. Feasibility will be established if 70% of plans meet the first or second dose constraints shown below.

  1. First priority RT dose constraints for bilateral hippocampi: volume receiving 40 CGE (V40CGE) ≤ 25%, dose to 100% of Hippocampus (D100%) ≤ 5CGE.
  2. Second priority RT dose constraints for bilateral hippocampi: V40CGE ≤ 35%, D100% ≤ 10 CGE.

     Secondary Objectives:
* To estimate the 3-year event-free-survival (EFS) for LGGs treated with HA.
* To estimate the change in California Verbal Learning Test short-term delay (CVLT-SD) from baseline to 3 years and from baseline to 5 years
* To compare CVLT-SD and Cogstate neurocognitive scores in patients with proton therapy plans that: (1) meet first priority RT dose constraints, (2) meet second priority RT dose constraints but not first priority RT dose constraints, and (3) that did not meet either first or second RT priority dose constraints

Exploratory Objectives:

* To describe the change in overall cognitive performance from baseline to 3 years and from baseline to 5 years with an age appropriate battery, including gold standard measures shown in the published studies to be sensitive to attention, memory processing speed and executive function that will afford comparison to historical controls.
* To characterize longitudinal changes in connection strength within brain networks in the first 3 years after proton therapy and to investigate associations between these changes and neurocognitive performance with focus on the hippocampi.
* To correlate the distribution and change in L-methyl-11C-methionine positron emission tomography (MET-PET) uptake to tumor progression and from baseline to 3 years and to investigate whether cases of pseudoprogression exhibit a differential pattern of uptake and distribution compared to cases of true progression after controlling for histology.
* To investigate the effect of BRAF alteration, tumor histology and tumor location on PFS and OS in a prospective cohort of patients treated in a homogenous manner.
* To investigate whether the methylation profiles of LGGs differ by tumor location (thalamic/midbrain vs. hypothalamic/optic pathway vs. others) and histologies (pilocytic astrocytoma vs. diffuse astrocytoma vs. others), which, in conjunction with specific genetic alterations, may stratify patients into different subgroups and highlight different therapeutic targets.
* To record longitudinal measures of circulating tumor DNA (ctDNA) in plasma and correlate these measures with radiographic evidence of disease progression.
* To bank formalin-fixed, paraffin-embedded (FFPE)/frozen tumors and whole blood from subjects for subsequent biology studies not currently defined in this protocol.
* To quantify and characterize tumor infiltrating lymphocytes (TILs) and to characterize the epigenetics of T cells and the T cell receptor repertoire within the tumor microenvironment.
* To estimate the cumulative incidence of endocrine deficiencies, vision loss, hearing loss and vasculopathy after proton therapy and compare these data to those after photon therapy.

All patients will receive HA proton therapy to 52.2 CGE or 54 CGE in 29 or 30 fractions, depending on tumor location. Patients will receive weekly magnetic resonance imaging (MRI) scans during the course of proton therapy to monitor changes in solid tumor or cystic volume. Such changes may prompt adaptive therapy to improve coverage or minimize the RT dose to healthy structures. Neurocognitive outcomes, sensitive to measures of memory and learning, will be collected at baseline and continue to 5 years post therapy. Disease evaluation will be monitored with brain MRI.

Evaluation of Hippocampal-Avoidance Using Proton Therapy in Low-Grade Glioma

A Phase II Study of Hippocampal-Avoidance Using Proton Therapy in Low-Grade Glioma

To determine the feasibility of HA with proton therapy in suprasellar or midline LGGs. Feasibility will be established if 70% of plans meet the first or second dose constraints. First RT dose constraints for bilateral hippocampi: volume receiving 40 CGE (V40CGE) ≤ 25%, dose to 100% of hippocampus (D100%) ≤ 5CGE. Second RT dose constraints for bilateral hippocampi: V40CGE ≤ 35%, D100% ≤ 10 CGE.

EFS will be calculated from the date of RT starts until disease progression, second malignancy, death of any cause or last follow up date.

CVLT-SD scores change of patients with HA feasible from baseline evaluation date to 3 years after treatment

CVLT-SD scores change from baseline evaluation date to 5 years after treatment

Cogstate neurocognitive scores in patients with proton therapy plans

CVLT-SD neurocognitive scores in patients with proton therapy plans

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Intraarterial Infusion Of Erbitux and Bevacizumab For Relapsed/Refractory Intracranial Glioma In Patients Under 22	NCT01884740	Glioblastoma Mu... Fibrillary Astr... Glioma of Brain... Anaplastic Astr... Pilomyxoid Astr... Mixed Oligodend... Brain Stem Glio... Diffuse Intrins...	SIACI of Erbitu...	1 Year - 21 Years	Weill Medical College of Cornell University
SJ901: Evaluation of Mirdametinib in Children, Adolescents, and Young Adults With Low-Grade Glioma	NCT04923126	Low-Grade Gliom... Recurrent Low-G... Progressive Low...	Mirdametinib	2 Years - 24 Years	St. Jude Children's Research Hospital
Intraarterial Infusion Of Erbitux and Bevacizumab For Relapsed/Refractory Intracranial Glioma In Patients Under 22	NCT01884740	Glioblastoma Mu... Fibrillary Astr... Glioma of Brain... Anaplastic Astr... Pilomyxoid Astr... Mixed Oligodend... Brain Stem Glio... Diffuse Intrins...	SIACI of Erbitu...	1 Year - 21 Years	Weill Medical College of Cornell University
A Phase I Study of Mebendazole for the Treatment of Pediatric Gliomas	NCT01837862	Pilomyxoid Astr... Pilocytic Astro... Glioma, Astrocy... Optic Nerve Gli... Pleomorphic Xan... Glioblastoma Mu... Anaplastic Astr... Gliosarcoma Diffuse Intrins... DIPG Low-grade Gliom... Brainstem Gliom...	Mebendazole Vincristine Carboplatin Temozolomide Bevacizumab Irinotecan	1 Year - 21 Years	Northwell Health
Evaluation of Hippocampal-Avoidance Using Proton Therapy in Low-Grade Glioma	NCT04065776	Glioma Pilocytic Astro... Pilomyxoid Astr... Pleomorphic Xan... Ganglioglioma Optic Pathway G... Diffuse Astrocy...	Hippocampal-avo...	6 Years - 21 Years	St. Jude Children's Research Hospital

Spots Global Cancer Trial Database for pilomyxoid astrocytoma