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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

Status
Active
Cancer Type
Brain & Spinal Cord Tumor
Cancer-Related Syndrome
Unknown Primary
Trial Phase
Phase I
Phase II
Eligibility
1 - 30 Years, Male and Female
Study Type
Treatment
NCT ID
NCT04201457
Protocol IDs
PBTC-055 (primary)
PBTC-055
NCI-2019-06216
Study Sponsor
Pediatric Brain Tumor Consortium

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.

Eligibility

  1. Patients must have one of the following histologies with molecularly-confirmed diagnosis that is recurrent or progressive. Patients enrolled will be stratified as follows: * Phase I: ** Stratum 1 LGG or HGG with BRAF V600E/D/K mutation ** Stratum 2 LGG with BRAF duplication or fusion with any partner or LGG with neurofibromatosis type 1. Patients with HGG histology with BRAF duplication/fusion or in association with neurofibromatosis type 1 may enroll on stratum 2 in the phase I study * Phase II: ** Stratum 3 LGG with BRAF V600E/D/K mutation ** Stratum 4 HGG with BRAF V600E/D/K mutation ** Stratum 5 LGG with BRAF duplication or fusion with any partner ** Stratum 6 LGG with neurofibromatosis type 1 * BRAF alterations will be locally determined using molecular methods in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory (does not need to be performed at the patient’s specific institution). BRAF alterations may be obtained at any point along the patient’s disease course and do not need to be repeated at the time of study entry. Immunohistochemistry for BRAF V600E alone is not adequate and must be confirmed molecularly
  2. Phase II patients must have bi-dimensionally measurable disease defined as at least one lesion that can be accurately measured in at least two planes. A target lesion should be chosen
  3. Patients are required to have weight >= 9 kg to enroll on any stratum in the Phase I or Phase II * Phase I only ** Patients enrolled on the 8 mg/kg/day (dose level 1) must have a weight < 90 kg ** Patients enrolled on the 15 mg/kg/day (dose level 2) must have a weight < 80 kg ** Patients enrolled on the 20 mg/kg/day (dose level 3) must have a weight < 68 kg
  4. Patients must have received prior therapy other than surgery and must have fully recovered from the acute treatment related toxicities (defined as =< grade 1) of all prior chemotherapy, immunotherapy, radiotherapy or any other treatment modality prior to entering this study
  5. Only applicable to LGG patients on Phase I and all patients on Phase II * Patients must have received prior RAF and/or MEK inhibitor therapy and meet one of the following criteria: ** Did not experience an objective response (defined as < PR) OR ** Achieved an objective response (CR or PR) but progressed while on active therapy * HGG patients on Phase I: may be enrolled regardless of prior MEK /RAF treatment
  6. Imaging must be available for central review to confirm eligibility for LGG patients on the Phase I study and all patients on the Phase II study * Patients with HGG on the phase I study do not require central imaging review for eligibility * Patients with LGG on the Phase I study will not require real-time central imaging review, but imaging must be available for retrospective review in case eligible to be considered enrolled at the RP2D and may be counted as part of the phase II study
  7. Patients must have received their last dose of known myelosuppressive anticancer therapy at least 21 days prior to enrollment or at least 42 days if nitrosourea
  8. Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the investigational or biologic agent >= 7 days prior to study enrollment. For biologic agents with a prolonged half-life, at least three half-lives must have elapsed prior to enrollment
  9. 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
  10. Patients must have had their last fraction of: * Craniospinal irradiation, whole brain radiation, total body irradiation or radiation to >= 50% of pelvis or spine >= 6 weeks (42 days) prior to enrollment ** Focal irradiation >= 14 days prior to enrollment
  11. Patients with neurological deficits should have deficits that are stable for a minimum of 7 days prior to enrollment. A baseline detailed neurological exam should clearly document the neurological status of the patient at the time of enrollment
  12. Patients with seizure disorders may be enrolled if seizures are controlled. Patients may take non-enzyme inducing anti-epileptic medications, such as felbamate, valproic acid, gabapentin, lamotrigine, tiagabine, topiramate, zonisamide, or levetiracetam
  13. Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to enrollment
  14. Karnofsky performance scale (KPS for > 16 years of age) or Lansky performance score (LPS for =< 16 years of age) assessed within 7 days of enrollment must be >= 50 * Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for assessing the performance score
  15. Absolute neutrophil count >= 1.0 x 10^9 cells/ L
  16. Platelets >= 100 x 10^9 cells/ L (unsupported, defined as no platelet transfusion within 7 days)
  17. Hemoglobin >= 8 g/dl (may receive transfusions)
  18. Total bilirubin =< 1.5 times institutional upper limit of normal (ULN)
  19. Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 3 x institutional upper limit of normal (ULN)
  20. Albumin >= 3 g/dl
  21. Serum creatinine based on age/gender. Patients that do not meet these criteria but have a 24-hour creatinine clearance or glomerular filtration rate (GFR) (radioisotope or iothalamate) >= 70 mL/min/1.73 m^2 are eligible * Age: 1 to < 2 years; maximum serum creatinine (mg/dL): 0.6 (male); 0.6 (female) * Age: 2 to < 6 years; maximum serum creatinine (mg/dL): 0.8 (male); 0.8 (female) * Age: 6 to < 10 years; maximum serum creatinine (mg/dL): 1 (male); 1 (female) * Age: 10 to < 13 years; maximum serum creatinine (mg/dL): 1.2 (male); 1.2 (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)
  22. Left ventricular ejection fraction greater than the institutional lower limit of normal by echocardiogram (echo) (while not receiving medications for cardiac function)
  23. Corrected QT (QTc) =< 480 msec
  24. Female patients of childbearing potential must not be pregnant or breast-feeding. Female patients of childbearing potential must have a negative serum or urine pregnancy test
  25. Females of child-bearing potential must use a highly effective method of contraception during dosing of study treatment and for 16 weeks after stopping study medication. Effective contraception methods include: * Total abstinence. Periodic abstinence and withdrawal are not acceptable methods of contraception * Placement of a non-hormonal intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of less than 1% per year * Double-barrier contraception: condom and occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/cream/suppository) * Note: Hormonal-based methods (e.g., oral contraceptives) are not permitted as contraception due to potential drug-drug interactions with dabrafenib and there is a possibility of decreased efficacy of hormonal contraceptives
  26. Sexually active males must use a condom during intercourse while on study and for 16 weeks after stopping study treatment and agree not to father a child during this period
  27. The patient or parent/guardian is able to understand the consent and is willing to sign a written informed consent document according to institutional guidelines
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