search
Back to results

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

Primary Purpose

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

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Dabrafenib
Trametinib
Hydroxychloroquine
Sponsored by
Pediatric Brain Tumor Consortium
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Low Grade Glioma (LGG) of Brain With BRAF Aberration focused on measuring LGG, HGG, BRAF, NF-1, Autophagy

Eligibility Criteria

1 Year - 30 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • • 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
      • Patients enrolled on the 20 mg/kg/day (dose level 3) must have a weight < 68 kg

        • 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
        • 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

      • 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 the subject was enrolled at the RP2D and may be counted as part of the phase II study

      • 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
      • 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 or monoclonal antibodies with a prolonged half-life, at least three half-lives must have elapsed prior to enrollment
      • 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

      • Patients with neurological deficits should have deficits that are stable for a minimum of 7 days prior to enrollment.
      • Patients with seizure disorders may be enrolled if seizures are controlled. Patients may take non-enzyme inducing anti-epileptic medications
      • Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to enrollment
      • 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

      • Absolute neutrophil count >= 1.0 x 10^9 cells/ L
      • Platelets >= 100 x 10^9 cells/ L (unsupported, defined as no platelet transfusion within 7 days)
      • Hemoglobin >= 8 g/dl (may receive transfusions)
      • Total bilirubin =< 1.5 times institutional upper limit of normal (ULN)
      • Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 3 x institutional upper limit of normal (ULN)
      • Albumin >= 3 g/dl
      • 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)

      • Left ventricular ejection fraction greater than the institutional lower limit of normal by echo (while not receiving medications for cardiac function)
      • Corrected QT (QTc) =< 480 msec
      • Female patients of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
      • 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.
      • 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
      • 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

Exclusion Criteria:

  • • 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

Sites / Locations

  • Phoenix Children's HospitalRecruiting
  • Children's Hospital Los AngelesRecruiting
  • Lucile Packard Children's Hospital at Stanford University Medical CenterRecruiting
  • Children's Hospital ColoradoRecruiting
  • Children's National Medical CenterRecruiting
  • University of FloridaRecruiting
  • Children's Healthcare of AtlantaRecruiting
  • Lurie Children's Hospital-ChicagoRecruiting
  • National Cancer Institute Pediatric Oncology Branch
  • Memorial Sloan Kettering Cancer CenterRecruiting
  • Cincinnati Children Hospital Medical CenterRecruiting
  • Nationwide Children's HospitalRecruiting
  • Children's Hospital of PittsburghRecruiting
  • St. Jude Children Research HospitalRecruiting
  • Texas Children's Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

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

Arm Description

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.

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.

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.

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

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.

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.

Outcomes

Primary Outcome Measures

Maximum Tolerated Dose (MTD)/ Recommended Phase 2 Dose (RP2D)
Testing the safety/tolerability of adding HCQ to Dabrafenib + Trametinib or to Trametinib
Maximum Plasma Concentration
Maximum plasma concentration Dabrafenib+Trametinib+Hydroxychloroquine or Trametinib +Hydroxychloroquine
Area under the curve (AUC)
AUC for Dabrafenib+Trametinib+Hydroxychloroquine or Trametinib +Hydroxychloroquine
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

Secondary Outcome Measures

Phase I: Dose limiting toxicities of D + T HCQ or T + HCQ
Describe the dose limiting toxicities separately for each stratum
Phase I: Response Rate
Proportion of patients who achieve either a partial or a complete response among those with measureable disease at enrollment.
Phase II: Progression-free survival
Time from enrollment up to disease progression or death or loss to follow-up, whichever is first
Phase II: Visual outcome based on Teller Grating Acuity at 55 cm in the left eye in children with tumor involving the visual pathway
Teller Grating Acuity at 55 cm in the left eye in children with tumor involving the visual pathway
Phase I and II: Autophagy inhibition as assessed by the accumulation of LC3II in peripheral blood mononuclear cells
Accumulation of LC3II in peripheral blood mononuclear cells
Phase I and II: Autophagy inhibition as assessed by the accumulation of p62 in peripheral blood mononuclear cells
Accumulation of p62 in peripheral blood mononuclear cells
Phase I and II: Presence of MAPK pathway aberrations (other than BRAF) as assessed by whole exome sequencing
MAPK pathway aberrations (other than BRAF) assessed by whole exome sequencing
Phase I and II: biomarker of resistance to RAF or MEK inhibitor therapy by evaluating matched primary and recurrent/progressive in tumor in plasma (and CSF if clinically indicated)
Evaluating matched primary and recurrent/progressive in tumor in plasma (and CSF if clinically indicated)

Full Information

First Posted
December 12, 2019
Last Updated
January 10, 2023
Sponsor
Pediatric Brain Tumor Consortium
search

1. Study Identification

Unique Protocol Identification Number
NCT04201457
Brief Title
A Trial of Dabrafenib, Trametinib and Hydroxychloroquine for Patients With Recurrent LGG or HGG With a BRAF Aberration
Official Title
Phase I/II Trial of Dabrafenib, Trametinib, and Hydroxychloroquine (HCQ) for BRAF V600E-mutant or Trametinib and HCQ for BRAF Fusion/Duplication Positive or NF1-associated Recurrent or Progressive Gliomas in Children and Young Adults
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 17, 2020 (Actual)
Primary Completion Date
August 30, 2025 (Anticipated)
Study Completion Date
June 30, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Pediatric Brain Tumor Consortium

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.
Detailed Description
In this phase I/II study, the investigators will investigate the safety and efficacy of dabrafenib + trametinib + HCQ (D+T+HCQ) and trametinib + HCQ (T+HCQ) in pediatric and young adult patients with BRAF-altered or NF1-associated gliomas who have previously received a RAF and/or MEK inhibitor. The goal of this study is to optimize the clinical effect of dabrafenib and trametinib by addressing intrinsic and acquired resistance that is well-described in V600E-mutant melanoma and for which there is preclinical and clinical evidence in pediatric gliomas. Aside from overlapping skin toxicity of dabrafenib and trametinib, which preliminarily does not appear worse in the D+T combination in adults and children, potential for ocular toxicity, which has been observed with each agent as monotherapy, will require close monitoring. An important outcome of this study will be improved understanding of resistance mechanisms and the role of autophagy in BRAF-altered or NF1-associated gliomas through sequencing of pre- and post-RAFi or MEKi tumor (when available) and measurement of autophagy inhibition in throughout protocol therapy. Phase I: The primary objective of the Phase I component is to estimate the maximum tolerated doses (MTD) and recommended Phase II doses (RP2D) of 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. Patients with BRAF V600E LGG or HGG will receive the combination of D+T+HCQ given orally in the form of capsules which must be taken whole, or an oral solution made from tablets. Hydroxychloroquine will only be administered by oral suspension. Within each combination, Dabrafenib and Hydroxychloroquine will be administered twice a day in a 28-day course. Trametinib will be administered once a day for 28 days during each course. One course is equivalent to 28 days. Therapy with either combination may continue for up to 2 years (26 courses) in the absence of disease progression or unacceptable toxicity. Phase II Potential patients for the Phase II portion of the trial must provide magnetic resonance imaging studies for central review for screening prior to enrollment: (1) prior targeted MEK/RAF therapy baseline, (2) prior MEK/RAF therapy best response, (3) scan at off treatment, and if different from off treatment (4) scan documenting PD associated with prior MEK/RAF targeted therapy. Additional scans may be requested from the site if the required eligibility assessments cannot be completed based on these minimal imaging requirements. In the Phase II portion of the trial, patients will continue to receive either the D +T+HCQ or T+HCQ combination at the RP2D defined in the Phase I portion. All drugs will be given continuously without a break unless required for excess toxicity. For Phase I subjects who are treated at the MTD a similar review will take place retrospectively to determine whether the patients meet the criteria to be included in the Phase II cohort.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
75 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Phase 1 Stratum 1 BRAF V600E LGG or HGG
Arm Type
Experimental
Arm Description
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.
Arm Title
Phase 1 Stratum 2 BRAF aberration or LGG with NF1
Arm Type
Experimental
Arm Description
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.
Arm Title
Phase 2 Stratum 3 LGG with BRAF V600 mutation
Arm Type
Experimental
Arm Description
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.
Arm Title
Phase 2 Stratum 4 HGG with BRAF V600 mutation
Arm Type
Experimental
Arm Description
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
Arm Title
Phase 2 Stratum 5 LGG with BRAF aberration
Arm Type
Experimental
Arm Description
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.
Arm Title
Phase 2 Stratum 6 LGG with NF Type 1
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Dabrafenib
Other Intervention Name(s)
Dabrafenib mesylate, Tafinlar
Intervention Description
Dabrafenib capsule; Dabrafenib Dispersible Tablet
Intervention Type
Drug
Intervention Name(s)
Trametinib
Other Intervention Name(s)
Trametinib dimethyl sulfoxide, Mekinist
Intervention Description
Tablet; Powder for Oral Solution
Intervention Type
Drug
Intervention Name(s)
Hydroxychloroquine
Other Intervention Name(s)
Plaquenil, Plaquinol, Toremonil, Ercoquinn
Intervention Description
Tablet
Primary Outcome Measure Information:
Title
Maximum Tolerated Dose (MTD)/ Recommended Phase 2 Dose (RP2D)
Description
Testing the safety/tolerability of adding HCQ to Dabrafenib + Trametinib or to Trametinib
Time Frame
Approximately 28 days from start of therapy
Title
Maximum Plasma Concentration
Description
Maximum plasma concentration Dabrafenib+Trametinib+Hydroxychloroquine or Trametinib +Hydroxychloroquine
Time Frame
1-4 days
Title
Area under the curve (AUC)
Description
AUC for Dabrafenib+Trametinib+Hydroxychloroquine or Trametinib +Hydroxychloroquine
Time Frame
1-4 days
Title
Phase II: Sustained objective response rate.
Description
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
Time Frame
Up to approximately 2 years from the start of therapy
Secondary Outcome Measure Information:
Title
Phase I: Dose limiting toxicities of D + T HCQ or T + HCQ
Description
Describe the dose limiting toxicities separately for each stratum
Time Frame
course 1 of therapy, approximately 28 days from start of therapy
Title
Phase I: Response Rate
Description
Proportion of patients who achieve either a partial or a complete response among those with measureable disease at enrollment.
Time Frame
Up to approximately 2 years from start of therapy
Title
Phase II: Progression-free survival
Description
Time from enrollment up to disease progression or death or loss to follow-up, whichever is first
Time Frame
Start of protocol therapy until progression or last follow-up, up to approximately 2 years from start of treatment
Title
Phase II: Visual outcome based on Teller Grating Acuity at 55 cm in the left eye in children with tumor involving the visual pathway
Description
Teller Grating Acuity at 55 cm in the left eye in children with tumor involving the visual pathway
Time Frame
Throughout study therapy, up to approximately 2 years from start of therapy
Title
Phase I and II: Autophagy inhibition as assessed by the accumulation of LC3II in peripheral blood mononuclear cells
Description
Accumulation of LC3II in peripheral blood mononuclear cells
Time Frame
Approximately 2 years from start of therapy]
Title
Phase I and II: Autophagy inhibition as assessed by the accumulation of p62 in peripheral blood mononuclear cells
Description
Accumulation of p62 in peripheral blood mononuclear cells
Time Frame
Approximately 2 years from start of therapy
Title
Phase I and II: Presence of MAPK pathway aberrations (other than BRAF) as assessed by whole exome sequencing
Description
MAPK pathway aberrations (other than BRAF) assessed by whole exome sequencing
Time Frame
At time of study enrollment
Title
Phase I and II: biomarker of resistance to RAF or MEK inhibitor therapy by evaluating matched primary and recurrent/progressive in tumor in plasma (and CSF if clinically indicated)
Description
Evaluating matched primary and recurrent/progressive in tumor in plasma (and CSF if clinically indicated)
Time Frame
At enrollment and at the time of every MRI study up to approximately 2 years from the start of therapy

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
30 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: • 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 Patients enrolled on the 20 mg/kg/day (dose level 3) must have a weight < 68 kg 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 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 • 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 the subject was enrolled at the RP2D and may be counted as part of the phase II study 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 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 or monoclonal antibodies with a prolonged half-life, at least three half-lives must have elapsed prior to enrollment 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 Patients with neurological deficits should have deficits that are stable for a minimum of 7 days prior to enrollment. Patients with seizure disorders may be enrolled if seizures are controlled. Patients may take non-enzyme inducing anti-epileptic medications Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to enrollment 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 Absolute neutrophil count >= 1.0 x 10^9 cells/ L Platelets >= 100 x 10^9 cells/ L (unsupported, defined as no platelet transfusion within 7 days) Hemoglobin >= 8 g/dl (may receive transfusions) Total bilirubin =< 1.5 times institutional upper limit of normal (ULN) Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 3 x institutional upper limit of normal (ULN) Albumin >= 3 g/dl 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) Left ventricular ejection fraction greater than the institutional lower limit of normal by echo (while not receiving medications for cardiac function) Corrected QT (QTc) =< 480 msec Female patients of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required 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. 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 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 Exclusion Criteria: • 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Vanetria Stokes, MS
Phone
901-595-5762
Email
vanetria.stokes@stjude.org
First Name & Middle Initial & Last Name or Official Title & Degree
Nina Butingan, MBS
Phone
901-671-6767
Email
nina.butingan@stjude.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lindsey Hoffman, DO
Organizational Affiliation
Phoenix Children's Hospital
Official's Role
Study Chair
Facility Information:
Facility Name
Phoenix Children's Hospital
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85016
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lindsey Hoffman, DO
Phone
602-933-0920
Email
lhoffman1@phoenixchildren's.com
Facility Name
Children's Hospital Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90026
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nathan Robison, MD
Phone
323-361-8147
Email
nrobison@chla.usc.edu
First Name & Middle Initial & Last Name & Degree
Nathan Robison, MD
Facility Name
Lucile Packard Children's Hospital at Stanford University Medical Center
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michelle Monje, MD, PhD
Phone
650-721-5750
Email
mmonje@stanford.edu
Facility Name
Children's Hospital Colorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kathleen Dorris
Phone
720-777-1234
Email
kathleen.dorris@childrenscolorado.org
Facility Name
Children's National Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010-2970
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gene Hwang, MD
Phone
202-476-5046
Email
ghwang@childrensnational.org
Facility Name
University of Florida
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32608
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Elias Sayour, MD, PhD
Phone
352-294-5272
Email
elias.sayour@neurosurgery.ufl.edu
Facility Name
Children's Healthcare of Atlanta
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jason Fangusaro
Phone
404-785-5437
Email
jfangus@emory.edu
Facility Name
Lurie Children's Hospital-Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60614
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Stewart Goldman
Phone
312-227-4874
Email
sgoldman@luriechildrens.org
First Name & Middle Initial & Last Name & Degree
Stewart Goldman
Facility Name
National Cancer Institute Pediatric Oncology Branch
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
John Glod, MD
Phone
301-451-0391
Email
john.glod@nih.gov
First Name & Middle Initial & Last Name & Degree
John Glod
Facility Name
Memorial Sloan Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ira Dunkel
Phone
212-639-2153
Email
dunkeli@mskcc.org
First Name & Middle Initial & Last Name & Degree
Ira Dunkel
Facility Name
Cincinnati Children Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Natasha Pillay Smiley, DO
Phone
513-636-0673
Email
natasha.pillay-smiley@cchmc.org
Facility Name
Nationwide Children's Hospital
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43205
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ralph Salloum, MD
Phone
612-722-2490
Email
ralph.salloum@nationwidechildrens.org
Facility Name
Children's Hospital of Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alberto Broniscer, MD
Phone
412-692-5056
Email
alberto.broniscer@chp.edu
First Name & Middle Initial & Last Name & Degree
Sharon DiBridge
Phone
412-692-7070
Email
sharon.dibridge@chp.edu
First Name & Middle Initial & Last Name & Degree
Alberto Broniscer, MD
Facility Name
St. Jude Children Research Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Giles Robinson, MD
Phone
901-595-2907
Email
giles.robinson@stjude.org
First Name & Middle Initial & Last Name & Degree
Amar Gajjar, MD
Facility Name
Texas Children's Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Patricia Baxter, MD
Phone
832-824-4681
Email
pabaxter@txch.org
First Name & Middle Initial & Last Name & Degree
Susan Burlingame, CCRP
Phone
832-824-1532
Email
sxburlin@txch.org
First Name & Middle Initial & Last Name & Degree
Patricia Baxter, MD

12. IPD Sharing Statement

Learn more about this trial

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

We'll reach out to this number within 24 hrs