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Testing the Safety and Benefit of Adding Hydroxychloroquine to Dabrafenib and/or Trametinib in Children with Recurrent or Progressive Low Grade or High Grade Brain Tumor with Specific Genetic Mutations


Active: Yes
Cancer Type: Brain & Spinal Cord Tumor
Cancer-Related Syndrome
Unknown Primary
NCT ID: NCT04201457
Trial Phases: Phase I
Phase II
Protocol IDs: PBTC-055 (primary)
PBTC-055
NCI-2019-06216
Eligibility: 1 - 30 Years, Male and Female Study Type: Treatment
Study Sponsor: Pediatric Brain Tumor Consortium
NCI Full Details: http://clinicaltrials.gov/show/NCT04201457

Summary

This phase I/II trial studies the side effects and best dose of adding hydroxychloroquine to dabrafenib and/or trametinib, and to see how well they work in treating children with low grade or high grade brain tumors previously treated with similar drugs that did not respond completely (progressive) or tumors that came back while receiving a similar agent (recurrent). Patients must also have specific genetic mutations including BRAF V600 mutations or BRAF fusion/duplication, with or without neurofibromatosis type 1. Neurofibromatosis type 1 is an inherited genetic condition that causes tumors to grow on nerve tissue. Drugs used in chemotherapy, such as hydroxychloroquine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Trametinib and dabrafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving hydroxychloroquine with trametinib and/or dabrafenib may lower the chance of brain tumors from growing or spreading compared to usual treatments.

Objectives

PRIMARY OBJECTIVES:
I. To estimate the maximum tolerated doses (MTD) and recommended phase II doses (RP2D) of dabrafenib mesylate (dabrafenib) + trametinib dimethyl sulfoxide (trametinib) + hydroxychloroquine sulfate (hydroxychloroquine) (D+T+HCQ) and T+HCQ in children and young adults with recurrent or progressive glioma treated with prior RAF and/or MEK inhibitor therapy. (Phase I)
II. To characterize the pharmacokinetics of D+T+HCQ and T+HCQ in children with recurrent or progressive glioma. (Phase I)
III. To assess the sustained objective response rate (ORR) of recurrent/progressive BRAF V600E low-grade glioma (LGG)/high-grade glioma (HGG) to D+T+HCQ, and BRAF fusion/duplication positive or neurofibromatosis type 1 (NF1)-associated LGG to T+HCQ, respectively, at the combination RP2D in children and young adults who previously did not respond (achieved < partial response [PR]) or who progressed on RAF and/or MEK inhibitor therapy. (Phase II)

SECONDARY OBJECTIVES:
I. To define the toxicity profile and define the dose limiting toxicities (DLTs) of D+T+HCQ or T+HCQ in children with recurrent or progressive glioma. (Phase I)
II. To estimate progression free survival (PFS) distributions of patients receiving D+T+HCQ or T+HCQ at the RP2D who are stratified by World Health Organization (WHO) grade and NF status and who previously had suboptimal response to RAF and/or MEK inhibitor. (Phase II)

EXPLORATORY OBJECTIVES:
I. To describe the response rate of recurrent or progressive BRAF-altered gliomas to protocol therapy in the context of a phase I trial.
II. To explore the pharmacogenetic polymorphisms in D, T, and HCQ metabolizing enzymes and transporters and relate these polymorphisms to D, T, and HCQ pharmacokinetics.
III. To assess visual outcomes of children with tumors involving the visual pathway using Teller acuity cards, HOTV, or other age-appropriate method, and visual field assessment.
IV. To assess the association between clinical outcomes (e.g. PFS and response) and apparent diffusion coefficient (ADC) histogram metrics as measured using MR diffusion imaging in children and young adults with BRAF V600E-mutant recurrent or progressive gliomas undergoing treatment with dabrafenib, trametinib, and hydroxychloroquine (HCQ) and BRAF fusion/duplication-positive or NF1-associated recurrent or progressive gliomas undergoing treatment with trametinib and HCQ.
V. To assess autophagy inhibition by evaluating:
Va. Accumulation of LC3II and p62 in peripheral blood mononuclear cell (PBMC)s by Western blot analysis.
Vb. Accumulation of autophagic vesicles in PBMCs by electron microscopy.
Vc. Levels of IL-8, IL-1 beta, LIF, DKK3, and FAM3C in plasma by enzyme-linked immunosorbent assay (ELISA).
VI. To assess archival tumor tissue for MAPK pathway aberrations (other than BRAF) using whole exome sequencing (WES) and ribonucleic acid sequencing (RNASeq).
VII. To explore markers of resistance to RAF or MEK inhibition by performing whole exome sequencing (WES) and ribonucleic acid sequencing (RNASeq) on archival tumor tissue from diagnosis and/or relapse after single-agent RAFi, or single-agent MEKi, or combination RAFi/MEKi inhibitor therapy.
VIII. To evaluate mutant allele frequency of BRAF V600E (circulating tumor-derived deoxyribonucleic acid [ctDNA]) in plasma (and cerebrospinal fluid [CSF] if clinically appropriate) from patients receiving D+T+HCQ and to describe the correlation between BRAFV00E ctDNA and tumor response.

OUTLINE: This is a phase I, dose-escalation study of hydroxychloroquine sulfate followed by a phase II study. Patients are assigned to 1 of 2 strata.

STRATUM I: Patients with BRAF V600E mutant LGG or HGG, receive dabrafenib mesylate orally (PO) twice daily (BID), trametinib dimethyl sulfoxide PO once daily (QD), and hydroxychloroquine sulfate PO BID on days 1-28. Treatment repeats every 28 days for 26 cycles in the absence of disease progression or unacceptable toxicity.

STRATUM II: Patients with BRAF fusion/duplication or neurofibromatosis type 1 (NF-1)-associated LGG, receive trametinib dimethyl sulfoxide PO QD and hydroxychloroquine sulfate PO BID on days 1-28. Treatment repeats every 28 days for 26 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 5 years.
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