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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04201457
Recruitment Status : Recruiting
First Posted : December 17, 2019
Last Update Posted : February 10, 2020
Sponsor:
Information provided by (Responsible Party):
Pediatric Brain Tumor Consortium

Brief 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.

Condition or disease Intervention/treatment Phase
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 Drug: Dabrafenib Drug: Trametinib Drug: Hydroxychloroquine Phase 1 Phase 2

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 early preclinical and clinical evidence exists 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 the following for central review for screening prior to enrollment. The required prior treatment scans include (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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 75 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : November 20, 2019
Estimated Primary Completion Date : February 28, 2025
Estimated Study Completion Date : February 28, 2027


Arm Intervention/treatment
Experimental: Phase 1 Arm 1 BRAF V600E LGG or HGG
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
Dabrafenib capsule; Dabrafenib Dispersible Tablet
Other Names:
  • Dabrafenib mesylate
  • Tafinlar

Drug: Trametinib
Tablet; Powder for Oral Solution
Other Names:
  • Trametinib dimethyl sulfoxide
  • Mekinist

Drug: Hydroxychloroquine
Tablet
Other Names:
  • Plaquenil
  • Plaquinol
  • Toremonil
  • Ercoquinn

Experimental: Phase 1 Arm 2 BRAF aberration or LG with NF1
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
Tablet; Powder for Oral Solution
Other Names:
  • Trametinib dimethyl sulfoxide
  • Mekinist

Drug: Hydroxychloroquine
Tablet
Other Names:
  • Plaquenil
  • Plaquinol
  • Toremonil
  • Ercoquinn

Experimental: Phase 2 Arm 3 LGG with BRAF V600 mutation
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
Dabrafenib capsule; Dabrafenib Dispersible Tablet
Other Names:
  • Dabrafenib mesylate
  • Tafinlar

Drug: Trametinib
Tablet; Powder for Oral Solution
Other Names:
  • Trametinib dimethyl sulfoxide
  • Mekinist

Drug: Hydroxychloroquine
Tablet
Other Names:
  • Plaquenil
  • Plaquinol
  • Toremonil
  • Ercoquinn

Experimental: Phase 2 Arm 4 HGG with BRAF V600 mutation
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
Dabrafenib capsule; Dabrafenib Dispersible Tablet
Other Names:
  • Dabrafenib mesylate
  • Tafinlar

Drug: Trametinib
Tablet; Powder for Oral Solution
Other Names:
  • Trametinib dimethyl sulfoxide
  • Mekinist

Drug: Hydroxychloroquine
Tablet
Other Names:
  • Plaquenil
  • Plaquinol
  • Toremonil
  • Ercoquinn

Experimental: Phase 2 Arm 5 LGG with BRAF aberration
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
Tablet; Powder for Oral Solution
Other Names:
  • Trametinib dimethyl sulfoxide
  • Mekinist

Drug: Hydroxychloroquine
Tablet
Other Names:
  • Plaquenil
  • Plaquinol
  • Toremonil
  • Ercoquinn

Experimental: Phase 2 Arm 6 LGG with NF Type 1
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
Tablet; Powder for Oral Solution
Other Names:
  • Trametinib dimethyl sulfoxide
  • Mekinist

Drug: Hydroxychloroquine
Tablet
Other Names:
  • Plaquenil
  • Plaquinol
  • Toremonil
  • Ercoquinn




Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD)/ Recommended Phase 2 Dose (RP2D) [ Time Frame: 28 days ]
    Testing the safety/tolerability of adding HCQ to Dabrafenib + Trametinib or to Trametinib

  2. Maximum Plasma Concentration [ Time Frame: 1-4 days ]
    Maximum plasma concentration Dabrafenib+Trametinib+Hydroxychloroquine or Trametinib +Hydroxychloroquine

  3. Area under the curve [ Time Frame: 1-4 days ]
    AUC for Dabrafenib+Trametinib+Hydroxychloroquine or Trametinib +Hydroxychloroquine


Secondary Outcome Measures :
  1. Phase 2 Study PFS [ Time Frame: 8 weeks from the initial documentation of an objective resonse ]
    Comparison of response to the current protocol therapy vs best response to RAF and/or MEK inhibitor therapy received prior to enrolling on this study



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   1 Year to 30 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04201457


Contacts
Layout table for location contacts
Contact: Stacye Richardson, MSHS 901-595-3783 stacye.richardson@stjude.org
Contact: Shujie Han, PhD 901-595-4877 shujie.han@stjude.org

Locations
Layout table for location information
United States, California
Children's Hospital Los Angeles Not yet recruiting
Los Angeles, California, United States, 90026
Contact: Nathan Robison, MD    323-361-8147    nrobison@chla.usc.edu   
Principal Investigator: Nathan Robison, MD         
Lucile Packard Children's Hospital at Stanford University Medical Center Not yet recruiting
Palo Alto, California, United States, 94304
Contact: Michelle Monje, MD, PhD    650-721-5750    mmonje@stanford.edu   
United States, Colorado
Children's Hospital Colorado Not yet recruiting
Aurora, Colorado, United States, 80045
Contact: Kathleen Dorris    720-777-1234    kathleen.dorris@childrenscolorado.org   
United States, District of Columbia
Children's National Medical Center Not yet recruiting
Washington, District of Columbia, United States, 20010-2970
Contact: Gene Hwang, MD    202-476-5046    ghwang@childrensnational.org   
United States, Georgia
Children's Healthcare of Atlanta Not yet recruiting
Atlanta, Georgia, United States, 30322
Contact: Jason Fangusaro    404-785-5437    jfangus@emory.edu   
United States, Illinois
Lurie Children's Hospital-Chicago Not yet recruiting
Chicago, Illinois, United States, 60614
Contact: Stewart Goldman    312-227-4874    sgoldman@luriechildrens.org   
Principal Investigator: Stewart Goldman         
United States, Maryland
National Cancer Institute Pediatric Oncology Branch Not yet recruiting
Bethesda, Maryland, United States, 20892
Contact: John Glod, MD    301-451-0391    john.glod@nih.gov   
Principal Investigator: John Glod         
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Ira Dunkel    212-639-2153    dunkeli@mskcc.org   
Principal Investigator: Ira Dunkel         
United States, Ohio
Cincinnati Children Hospital Medical Center Not yet recruiting
Cincinnati, Ohio, United States, 45229
Contact: Mariko DeWire-Schottmiller, MD    513-803-1126    mariko.dewire@cchmc.org   
Principal Investigator: Maryam Fouladi         
United States, Pennsylvania
Children's Hospital of Pittsburgh Not yet recruiting
Pittsburgh, Pennsylvania, United States, 15224
Contact: Alberto Broniscer, MD    412-692-5056    alberto.broniscer@chp.edu   
Contact: Sharon DiBridge    412-692-7070    sharon.dibridge@chp.edu   
Principal Investigator: Alberto Broniscer, MD         
United States, Tennessee
St. Jude Children Research Hospital Not yet recruiting
Memphis, Tennessee, United States, 38105
Contact: Giles Robinson, MD    901-595-2907    giles.robinson@stjude.org   
Sub-Investigator: Amar Gajjar, MD         
United States, Texas
Texas Children's Cancer Center Not yet recruiting
Houston, Texas, United States, 77030
Contact: Patricia Baxter, MD    832-824-4681    pabaxter@txch.org   
Contact: Susan Burlingame, CCRP    832-824-1532    sxburlin@txch.org   
Principal Investigator: Patricia Baxter, MD         
Sponsors and Collaborators
Pediatric Brain Tumor Consortium
Investigators
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Study Chair: Lindsey Hoffman, MD Phoenix Children's Hospital
  Study Documents (Full-Text)

Documents provided by Pediatric Brain Tumor Consortium:

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Responsible Party: Pediatric Brain Tumor Consortium
ClinicalTrials.gov Identifier: NCT04201457    
Other Study ID Numbers: PBTC-055
First Posted: December 17, 2019    Key Record Dates
Last Update Posted: February 10, 2020
Last Verified: February 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Pediatric Brain Tumor Consortium:
LGG
HGG
BRAF
NF-1
Additional relevant MeSH terms:
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Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Nerve Sheath Neoplasms
Neoplastic Syndromes, Hereditary
Peripheral Nervous System Neoplasms
Nervous System Neoplasms
Glioma
Neurofibromatoses
Neurofibromatosis 1
Neurofibroma
Neurocutaneous Syndromes
Nervous System Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Peripheral Nervous System Diseases
Neuromuscular Diseases
Hydroxychloroquine
Trametinib
Dabrafenib
Dimethyl Sulfoxide
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action