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


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Trial ID: NCT04201457


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.

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

Stanford Investigator(s)


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

      - 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

         - Patients enrolled on the 15 mg/kg/day (dose level 2) must have a weight < 80

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

            - 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

            - 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

      - 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

      - 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

         - 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

         - 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

      - 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


drug: Dabrafenib

drug: Trametinib

drug: Hydroxychloroquine


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Contact Information

Stanford University
School of Medicine
300 Pasteur Drive
Stanford, CA 94305
Erica Velasco

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