Clinical Trials /

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

NCT04201457

Description:

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.

Related Conditions:
  • Low Grade Glioma
  • Malignant Glioma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: PBTC-055
  • NCT ID: NCT04201457

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

Interventions

DrugSynonymsArms
DabrafenibDabrafenib mesylate, TafinlarPhase 1 Arm 1 BRAF V600E LGG or HGG
TrametinibTrametinib dimethyl sulfoxide, MekinistPhase 1 Arm 1 BRAF V600E LGG or HGG
HydroxychloroquinePlaquenil, Plaquinol, Toremonil, ErcoquinnPhase 1 Arm 1 BRAF V600E LGG or HGG

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Phase 1 Arm 1 BRAF V600E LGG or HGGExperimentalLGG 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.
  • Dabrafenib
  • Trametinib
  • Hydroxychloroquine
Phase 1 Arm 2 BRAF aberration or LG with NF1ExperimentalLGG 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.
  • Trametinib
  • Hydroxychloroquine
Phase 2 Arm 3 LGG with BRAF V600 mutationExperimentalLGG 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.
  • Dabrafenib
  • Trametinib
  • Hydroxychloroquine
Phase 2 Arm 4 HGG with BRAF V600 mutationExperimentalHGG 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
  • Dabrafenib
  • Trametinib
  • Hydroxychloroquine
Phase 2 Arm 5 LGG with BRAF aberrationExperimentalLGG 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.
  • Trametinib
  • Hydroxychloroquine
Phase 2 Arm 6 LGG with NF Type 1ExperimentalLGG 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.
  • Trametinib
  • Hydroxychloroquine

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
      
Maximum Eligible Age:30 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD)/ Recommended Phase 2 Dose (RP2D)
Time Frame:28 days
Safety Issue:
Description:Testing the safety/tolerability of adding HCQ to Dabrafenib + Trametinib or to Trametinib

Secondary Outcome Measures

Measure:Phase 2 Study PFS
Time Frame:8 weeks from the initial documentation of an objective resonse
Safety Issue:
Description: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

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Pediatric Brain Tumor Consortium

Trial Keywords

  • LGG
  • HGG
  • BRAF
  • NF-1

Last Updated

January 2, 2020