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Report for Clinical Trial NCT03363217

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

A Phase 2 Study of Trametinib for Patients With Pediatric Glioma or Plexiform Neurofibroma With Refractory Tumor and Activation of the MAPK/ERK Pathway.

This is a phase 1/2, open-label, interventional clinical trial that will study the response rate of pediatric glioma and plexiform neurofibroma (PN) to oral administration of trametinib. Patients meeting all inclusion criteria for a given study group will receive the study medication at a daily dose of 0.025 mg/kg up to a total of 18 cycles, in 28-day cycles. A total of 150 patients will be recruited as part of this clinical study. Patients aged between 1 month (corrected age) and 25 years old will be eligible, in order to include a maximum of patients affected by low-grade glioma (LGG) and PN. This study includes four groups: patients with neurofibromatosis type 1 (NF1) and LGG, NF1 patients with PN, patients with LGG with a B-Raf Serine/Threonine-protein Kinase/Proto-oncogene Encoding B-Raf (BRAF) fusion and patients with glioma of any grade with activation of the Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinases (MAPK/ERK) pathway. All patients except patients with PN must have failed at least one line of treatment. The study will also explore the molecular mechanisms behind tumor development, progression and resistance to treatment. Furthermore, this study will also explore important aspects for patients with brain tumors by including assessment of quality of life and neuropsychological evaluation.

NCT03363217 Low-grade Glioma Plexiform Neurofibroma Central Nervous System Glioma
MeSH: Glioma Neurofibroma Neurofibromatoses Neurofibroma, Plexiform
HPO: Glioma Neurofibromas Plexiform neurofibroma

1 Interventions

Name: Trametinib

Description: Daily administration of oral trametinib at a unique dose of 0.025 mg/kg.

Type: Drug

Neurofibromatosis Type 1 (NF1) with Plexiform Neurofibroma Neurofibromatosis Type 1 (NF1) with low-grade glioma Progressing/Refractory central nervous system (CNS) glioma. Progressing/refractory low grade-glioma, KIAA1549-BRAF fusion


Primary Outcomes

Description: Determination of the objective response rate of daily trametinib as a single agent for treatment of progressing/refractory low-grade tumors with MAPK/ERK pathway activation.

Measure: Objective Response Rate

Time: From date of study inclusion until the date of first documented progression, up to 504 treatment days.

Secondary Outcomes

Description: Time from registration to progression, or censored at the date of last disease evaluation for those without progression reported. Applicable to group 1-2-3-4.

Measure: Time to Progression (time from registration to progression)

Time: Every 6 months up to 3 years following completion of treatment (504 treatment days).

Description: Time from registration to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at the date of last disease evaluation. Applicable to group 1-2-3-4.

Measure: Progression Free Survival (time from registration to the earlier of progression or death).

Time: Every 6 months up to 3 years following completion of treatment (504 treatment days).

Description: Time from registration to death due to any cause, or censored at date last known alive. Applicable to group 1-2-3-4.

Measure: Overall Survival (time from registration to death)

Time: Every 6 months up to 3 years following completion of treatment (504 treatment days).

Description: Determination of the safety and tolerability of trametinib by assessment of toxicity associated with trametinib (Adverse Events (AEs), Serious Adverse Events (SAEs)). Applicable to group 1-2-3-4.

Measure: Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability).

Time: At treatment week 2, 3, 4, 5, 9, 13, 17, 21, 25, 48, 72; at the end of 504 treatment days and every 6 months for up to 3 years.

Description: Determination of the serum level of trametinib by assessment of the through level. Applicable to group 1-2-3-4.

Measure: Determination of the Serum Level of Trametinib.

Time: At day 22 and at tumor progression up to the end of treatment day 504.

Description: Evaluation of the quality of life during treatment with the PedsQL cancer/brain tumor modules. Applicable to group 1-2-3-4.

Measure: Evaluation of the Quality of Life During Treatment.

Time: At screening, week 13, week 25, week 37, week 49, week 61 and at the end of treatment day 504.

Other Outcomes

Description: Determine if there are cognitive changes in patients with NF1 during treatment with trametinib. The areas of development assessed to calculate the composite score are: cognition, communication, physical, social/emotional and adaptative. This scale ranges from a score of 40 to 160 with a mean score of 100, where higher scores are desirable.

Measure: Neurocognitive assessment of NF1 patients between 1 and 42 months using the Bayley Scales of Infant and Toddlers Development, Third Edition (Bailey-III).

Time: At study inclusion and at the end of treatment (up to treatment day 504).

Description: Determine if there are cognitive changes in patients with NF1 during treatment with trametinib.The areas of cognition assessed to calculate the composite score are: verbal comprehension, visual spatial, fluid reasoning, working memory and processing speed. This scale ranges from a score of 40 to 160 with a mean score of 100, where higher scores are desirable.

Measure: Neurocognitive assessment of NF1 patients between 2 years and 6 years using the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV).

Time: At study inclusion and at the end of treatment (up to treatment day 504).

Description: Determine if there are cognitive changes in patients with NF1 during treatment with trametinib.The areas of cognition assessed to calculate the composite score are: verbal comprehension, visual spatial, fluid reasoning, working memory and processing speed. This scale ranges from a score of 40 to 160 with a mean score of 100, where higher scores are desirable.

Measure: Neurocognitive assessment of NF1 patients between 6 years and 16 years and 11 months using the Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V).

Time: At study inclusion and at the end of treatment (up to treatment day 504).

Description: Determine if there are cognitive changes in patients with NF1 during treatment with trametinib.The areas of cognition assessed to calculate the composite score are: verbal comprehension, perceptual reasoning, working memory and processing speed. This scale ranges from a score of 40 to 160 with a mean score of 100, where higher scores are desirable.

Measure: Neurocognitive assessment of NF1 patients between 16 years 11 months and 25 years using the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV).

Time: At study inclusion and at the end of treatment (up to treatment day 504).

Description: Determination of trametinib usefulness in patients with refractory glioma with activation of the MAPK pathway other than BRAF fusion and NF1. Applicable to group 4

Measure: Response rate of patients with refractory glioma with activation of the MAPK pathway other than BRAF fusion and NF1

Time: At study inclusion and at the end of treatment (up to treatment day 504).

Description: Comparison of the best response rate using the RECIST 1.1 criteria and volumetric measurement. Applicable to group 2.

Measure: Comparison of responses with RECIST 1.1 and volumetric measurement for plexiform neurofibroma

Time: At the achievement of best response to treatment up to treatment day 504.

Description: Gene expression profiling on fresh frozen tissue and mutational analysis on paraffin-embedded tissue. Circulating tumor DNA (ctDNA) evolution through treatment.

Measure: Investigation and correlation of biological features to tumor response.

Time: Within 14 days prior to treatment start for investigations of tumor tissue. At screening, week 13, week 25, week 37, week 49, week 61, at the end of treatment day 504 and every 6 months up to 3 years for ctDNA evaluation.

Purpose: Treatment

Allocation: Non-Randomized

Parallel Assignment


There is one SNP

SNPs


1 V600E

5. Tumor with BRAF V600E mutation Patients with a tumor presenting a positive BRAF V600E mutation. --- V600E ---

5. Tumor with BRAF V600E mutation Patients with a tumor presenting a positive BRAF V600E mutation. --- V600E --- --- V600E ---



HPO Nodes


HPO:
Glioma
Genes 50
TSC2 GLI3 BRCA2 TSC1 LRP5 MLH1 PMS2 APC IDH1 MSH6 POT1 TSC2 CDKN2A NF2 MSH3 MSH6 APC NF1 EPCAM TSC1 TGFBR2 SEMA4A IDH1 IDH2 FAN1 APC MSH3 BMPR1A KRAS MLH1 MSH2 C11ORF95 PMS2 MLH3 PIK3CA NBN RELA SETBP1 IFNG RPS20 NF1 PMS1 CHEK2 APC TP53 MSH2 NBN ERBB2 APC NF2
Neurofibromas
Genes 14
NF2 NF1 PDGFB SDHC SPRED1 NF2 SDHB NF1 NF1 SMARCB1 NF1 SUFU KIT NF2
Plexiform neurofibroma
Genes 2
NF1 NF1