MAPK Inhibition Combined With Anti-PD1 Therapy for BRAF-altered Pediatric Gliomas
Trial statusRecruiting
Trial phasePhase 1, Phase 2
Trial typeInterventional
Biological sexAll
Age1-26
SponsorAnn & Robert H Lurie Children's Hospital of Chicago
About this trial
Pediatric gliomas harboring BRAF-alterations, commonly BRAFV600 mutation or KIAA1549-BRAF fusion, are currently treated with either chemotherapy or mitogen activated protein kinase (MAPK) inhibitors, such as, dabrafenib and/or trametinib. Unfortunately, some BRAF-altered gliomas can progress or have rebound growth after discontinuation of therapy. Data from BRAFV600E-mutant melanoma has shown potential synergy between MAPK inhibition and anti-programmed cell death 1 (anti-PD1) checkpoint blockade. Anti-PD1 therapy, such as, nivolumab can block the PD1 receptor on T cells, a marker of T cell exhaustion, allowing a continued or more robust anti-tumor immune response. Here, investigators will combine MAPK inhibition with anti-PD1 therapy in recurrent, refractory low grade BRAF-altered glioma and newly diagnosed or recurrent BRAF-altered or NF-altered high grade glioma.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Patients with histologically confirmed diagnosis of pediatric high- or low-grade glioma harboring a KIAA1549-BRAF fusion: Low-grade glioma that is recurrent or progressive OR High-grade glioma that is newly diagnosed or recurrent OR
Patients with NF1-associated gliomas or NF1-altered glioma: Low-grade glioma that is recurrent or progressive OR High-grade glioma that is newly diagnosed or recurrent OR Transforming glioma that is newly diagnosed or recurrent
Patients with histologically confirmed diagnosis of pediatric low-grade glioma harboring a BRAFV600 mutation that is recurrent or progressive OR
Patients with histologically confirmed diagnosis of non-brainstem pediatric high-grade glioma harboring BRAFV600 mutation that is newly diagnosed, recurrent, or progressive
Disqualifiers
Patients with disseminated disease.
Patients who have had prior radiation therapy <12 weeks prior to registration.
Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > Grade 1) (with the exception of alopecia).
Patients who receiving any other investigational agents. Note: There will be a 21-day washout period for all chemotherapeutic agents, a washout period of two half-lives for any targeted agents (e.g., MAPK inhibitors), and/or a washout period of 4 weeks for any antibody therapies (e.g., bevacizumab).
Trial design
Design model
Parallel
Treatments tested in this trial
Trametinib and Nivolumab
DrugTrametinib combined with nivolumab (Cohort A)
Dabrafenib, trametinib, nivolumab
DrugDabrafenib + trametinib combined with nivolumab (Cohort B)
Treatment groups
27 Participants
are divided into 2 treatment groupsGroup A: Trametinib combined with nivolumab (Cohort A)Experimental treatment 1 intervention
Group B: Dabrafenib + trametinib combined with nivolumab (Cohort B)Experimental treatment 1 intervention
Trial outcomes
Primary outcomes
1
Safety based on number of participants with treatment-related adverse events based on scoring from CTCAE v4.0
This study will utilize a rolling 6 design and enroll 12 evaluable patients in each cohort (Cohort A and B). Two dose levels will be utilized to assess safety and tolerability. Dose level 1 includes 100% dosing of dabrafenib and/or trametinib and nivolumab. A dose level -1 will be utilized if dose level 1 is not tolerable and will include 100% dosing of nivolumab with 70% dosing of dabrafenib and/or trametinib.
Time frame
The dose limiting toxicity (DLT) period is 28 days.Secondary outcomes
1
Response assessment
Objective response rate will be utilized to assess response to combination therapy. Magnetic resonance imaging (MRI) will be evaluated for response utilizing RANO/iRANO criteria. Best response and duration of response be assessed. An objective response is a partial or complete response (PR or CR) sustained for at least 12 weeks.
Time frame
From enrollment through end of treatment at 1 year2
Assessment of "Better Response"
At enrollment, information will be entered by the study team regarding prior treatment with MAPK inhibition alone. The best response and duration of this response will be recorded. This will be compared to response on study treatment. A "better response" would be considered an improvement of best response from stable disease to partial response, partial response to complete response, or progressive disease to stable disease OR a similar best response that is maintained for 12 weeks longer or more.
Time frame
From enrollment to the end of treatment at 1 year3
Progression free survival
Progression will be determined by magnetic resonance imaging (MRI) assessment using RANO/iRANO criteria.
Time frame
From enrollment through long term follow up (5 years post treatment)4
Overall Survival (OS)
Overall survival will be assessed by time to event (death).
Time frame
Time of enrollment through long term follow up (5 years post treatment)Sponsors and contacts
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Source ClinicalTrials.gov