A Trial of Dabrafenib, Trametinib and Hydroxychloroquine for Patients With Recurrent LGG or HGG With a BRAF Aberration

NCT04201457 | Active Not Recruiting Phase 1 DMC FDA Drug

• 3 other identifiers: PBTC-055UM1CA081457NCI-2019-06216
• Study Type: interventional
• Target: 57
• Locations: 1 country
• Sites: 15

Brief Summary

This phase I/II trial is designed to study the side effects, best dose and efficacy of adding hydroxychloroquine to dabrafenib and/or trametinib in 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. Hydroxychloroquine, works in different ways to stop the growth of tumor cells by killing the cells or stopping them from dividing. 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 growing or spreading compared to usual treatments.

Conditions

Low Grade Glioma (LGG) of Brain With BRAF Aberration; High Grade Glioma (HGG) of the Brain With BRAF Aberration; Low Grade Glioma of Brain With Neurofibromatosis Type 1

Keywords

LGG; HGG; BRAF; NF-1; Autophagy

Outcome Measures

Primary Outcomes (4)

• Maximum Tolerated Dose (MTD)/ Recommended Phase 2 Dose (RP2D)

  Testing the safety/tolerability of adding HCQ to Dabrafenib + Trametinib or to Trametinib

  Approximately 28 days from start of therapy

• Maximum Plasma Concentration

  Maximum plasma concentration Dabrafenib+Trametinib+Hydroxychloroquine or Trametinib +Hydroxychloroquine

  1-4 days

• Area under the curve (AUC)

  AUC for Dabrafenib+Trametinib+Hydroxychloroquine or Trametinib +Hydroxychloroquine

  1-4 days

• Phase II: Sustained objective response rate.

  Number of patients who meet the "better response" criteria, which is a comparison of response on this current protocol therapy versus their best response to previous RAF and/or MEK inhibitor therapy

  Up to approximately 2 years from the start of therapy

Secondary Outcomes (8)

• Phase I: Dose limiting toxicities of D + T HCQ or T + HCQ

  course 1 of therapy, approximately 28 days from start of therapy

• Phase I: Response Rate

  Up to approximately 2 years from start of therapy

• Phase II: Progression-free survival

  Start of protocol therapy until progression or last follow-up, up to approximately 2 years from start of treatment

• Phase II: Visual outcome based on Teller Grating Acuity at 55 cm in the left eye in children with tumor involving the visual pathway

  Throughout study therapy, up to approximately 2 years from start of therapy

• Phase I and II: Autophagy inhibition as assessed by the accumulation of LC3II in peripheral blood mononuclear cells

  Approximately 2 years from start of therapy]

Study Arms (6)

Phase 1 Stratum 1 BRAF V600E LGG or HGG

EXPERIMENTAL

LGG or HGG with BRAF V600E/D/K mutation will receive Dabrafenib, Trametinib and Hydroxychloroquine. All medications are administered orally with Dabrafenib and HCQ given twice a day and Trametinib given once per day at the assigned dose for a 28 day course. Courses may repeat until the patient meets an off treatment criteria.

Drug: Dabrafenib; Drug: Trametinib; Drug: Hydroxychloroquine

Phase 1 Stratum 2 BRAF aberration or LGG with NF1

EXPERIMENTAL

LGG with BRAF duplication or fusion with any partner or LGG with NF1 will received Trametinib and Hydroxychloroquine. All medications are administered orally with Trametinib given once per day and HCQ give twice per day at the assigned dose for a 28 day course. Courses may repeat until the patient meets an off treatment criteria.

Drug: Trametinib; Drug: Hydroxychloroquine

Phase 2 Stratum 3 LGG with BRAF V600 mutation

EXPERIMENTAL

LGG with BRAF V600E/D/K mutation will receive Dabrafenib, Trametinib and Hydroxychloroquine. All medications are administered orally with Dabrafenib and HCQ given twice a day and Trametinib given once per day at the recommended Phase 2 dose for a 28 day course. Courses may repeat until the patient meets an off treatment criteria.

Drug: Dabrafenib; Drug: Trametinib; Drug: Hydroxychloroquine

Phase 2 Stratum 4 HGG with BRAF V600 mutation

EXPERIMENTAL

HGG with BRAF V600E/D/K mutation will receive Dabrafenib, Trametinib and Hydroxychloroquine. All medications are administered orally with Dabrafenib and HCQ given twice a day and Trametinib given once per day at the recommended Phase 2 dose for a 28 day course. Courses may repeat until the patient meets an off treatment criteria

Drug: Dabrafenib; Drug: Trametinib; Drug: Hydroxychloroquine

Phase 2 Stratum 5 LGG with BRAF aberration

EXPERIMENTAL

LGG with BRAF duplication or fusion with any partner will receive Trametinib and Hydroxychloroquine. All medications are administered orally with Trametinib given once per day and HCQ give twice per day at the recommended Phase 2 dose for a 28 day course. Courses may repeat until the patient meets an off treatment criteria.

Drug: Trametinib; Drug: Hydroxychloroquine

Phase 2 Stratum 6 LGG with NF Type 1

EXPERIMENTAL

LGG with Neurofibromatosis Type 1 will receive Trametinib and Hydroxychloroquine. All medications are administered orally with Trametinib given once per day and HCQ give twice per day at the recommended Phase 2 dose for a 28 day course. Courses may repeat until the patient meets an off treatment criteria.

Drug: Trametinib; Drug: Hydroxychloroquine

Interventions

Dabrafenib DRUG

Dabrafenib capsule; Dabrafenib Dispersible Tablet

Also known as: Dabrafenib mesylate, Tafinlar

Phase 1 Stratum 1 BRAF V600E LGG or HGG; Phase 2 Stratum 3 LGG with BRAF V600 mutation; Phase 2 Stratum 4 HGG with BRAF V600 mutation

Trametinib DRUG

Tablet; Powder for Oral Solution

Also known as: Trametinib dimethyl sulfoxide, Mekinist

Phase 1 Stratum 1 BRAF V600E LGG or HGG; Phase 1 Stratum 2 BRAF aberration or LGG with NF1; Phase 2 Stratum 3 LGG with BRAF V600 mutation; Phase 2 Stratum 4 HGG with BRAF V600 mutation; Phase 2 Stratum 5 LGG with BRAF aberration; Phase 2 Stratum 6 LGG with NF Type 1

Hydroxychloroquine DRUG

Tablet

Also known as: Plaquenil, Plaquinol, Toremonil, Ercoquinn

Phase 1 Stratum 1 BRAF V600E LGG or HGG; Phase 1 Stratum 2 BRAF aberration or LGG with NF1; Phase 2 Stratum 3 LGG with BRAF V600 mutation; Phase 2 Stratum 4 HGG with BRAF V600 mutation; Phase 2 Stratum 5 LGG with BRAF aberration; Phase 2 Stratum 6 LGG with NF Type 1

Eligibility Criteria

• Age: 1 Year - 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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
• 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. Immunohistochemistry for BRAF V600E alone is not adequate and must be confirmed molecularly
• 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
• 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

You may not qualify if:

• Breast-feeding women are excluded from this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies
• Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator would compromise the patient's ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results:
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Patients with NF1 and history of plexiform neurofibroma will be permitted to enroll
• Patients with a previously documented retinal vein occlusion or severe retinopathy
• Presence of active gastrointestinal (GI) disease or other condition (e.g., small bowel or large bowel resection) that will interfere significantly with the absorption of drugs
• Patients who are unable to discontinue prohibited medications or herbal preparations within 7 days of enrollment and 14 days of starting study therapy
• Patients who are receiving any other anti-cancer or investigational drug therapy are ineligible
• Patients with a history of a known hypersensitivity to dabrafenib, trametinib, HCQ, or any of their excipients or compounds of similar chemical or biologic composition
• Prisoners will be excluded from this study.
• Patients who in the opinion of the investigator are unwilling or unable to return for required follow-up visits or obtain follow-up studies required to assess toxicity to therapy or to adhere to drug administration plan, other study procedures, and study restrictions

Sponsors & Collaborators

• Pediatric Brain Tumor Consortium: lead
• National Cancer Institute (NCI): collaborator
• American Lebanese Syrian Associated Charities: collaborator

Study Sites (15)

Phoenix Children's Hospital

Phoenix, Arizona, 85016, United States

Location

Children's Hospital Los Angeles

Los Angeles, California, 90026, United States

Location

Lucile Packard Children's Hospital at Stanford University Medical Center

Palo Alto, California, 94304, United States

Location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010-2970, United States

Location

University of Florida

Gainesville, Florida, 32608, United States

Location

Children's Healthcare of Atlanta

Atlanta, Georgia, 30322, United States

Location

Lurie Children's Hospital-Chicago

Chicago, Illinois, 60614, United States

Location

National Cancer Institute Pediatric Oncology Branch

Bethesda, Maryland, 20892, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Cincinnati Children Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, 15224, United States

Location

St. Jude Children Research Hospital

Memphis, Tennessee, 38105, United States

Location

Texas Children's Cancer Center

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Glioma

Interventions

dabrafenib; trametinib; Hydroxychloroquine

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Chloroquine; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Lindsey Hoffman, DO

  Phoenix Children's Hospital

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 12, 2019
• First Posted: December 17, 2019
• Study Start: January 17, 2020
• Primary Completion: March 31, 2026
• Study Completion: March 31, 2026
• Last Updated: February 3, 2026

Record last verified: 2026-02

Locations

US (15)