The investigators will evaluate the sensitivity of ctDNA from plasma and CSF at baseline (defined as C1D1) and over time in response to treatment with plixorafenib alone or in combination with retifanlimab in patients with BRAF-V600E mutant glioma refractory to prior therapies.
Patient must have received prior BRAF and/or MEK inhibitor therapy.
Prior RAF dimer disruptor or pan-RAF inhibitor not allowed
Prior immunotherapy allowed
Patients must be maintained on a stable or decreasing dose of systemic corticosteroid regimen (no increase for 5 days) prior to screening MRI. No maximum dose. Topical and inhaled steroid treatment is allowed.
Prior RAF dimer disruptor or pan-RAF inhibitor.
Prior immunotherapy (of note prior RAF dimer-disruptor or pan-RAF inhibitor is allowed).
Known history of clinically significant autoimmune disease that, in the opinion of the investigator, may be exacerbated by immune checkpoint blockade (e.g., multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease), with the following exceptions: Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis or alopecia) not requiring systemic treatment (subjects with a history of flares requiring systemic treatment are excluded), or other autoimmune conditions not expected to recur in the absence of an external trigger are permitted to enroll.
Daily systemic steroids > 4mg daily dexamethasone or equivalent.
Parallel
Plixorafenib
DrugPatients will start the study drug (plixorafenib 900mg daily 30 minutes after a full meal or meal supplement) 7-28 days post-operatively, when clinically stable. Patients will take the drug daily by mouth continuously for 28-day cycles until progressive disease or up to 24 cycles. MRI will be performed post-operatively (between surgery and start of study drug) for evaluation of measurable disease, at the beginning of Cycle 2, then at the beginning of every odd cycle. Blood and CSF samples will be obtained on day of surgery, C1D1 (baseline), pre-C2 (week 4) and with every odd cycle up to and including C7 and EOT.
Retifanlimab
DrugInvestigators will evaluate the sensitivity of ctDNA from plasma and CSF at baseline and over time in response to treatment with plixorafenib alone or in combination with retifanlimab in patients with BRAF-V600E mutant glioma refractory to prior therapies.
Detection rate of BRAF-V600E ctDNA in CSF and/or plasma
Proportion of patients with detectable ctDNA in CSF and/or plasma detected at surgery, baseline (C1D1), and pre-Cycle 2 (week 4).
Compare BRAF-V600 ctDNA levels in CSF and plasma after treatment among patients with different radiographic responses
Quantify disease progression and treatment response rate over time BRAF-V600 ctDNA levels among patients with different radiographic responses (1="improved", 2="stable", 3="worsened" measured by RANO 2.0 criteria) at 4 and 16 weeks after the treatment initiation (pre-C2, pre-C5). Correlation of ctDNA levels in CSF and plasma samples at baseline, after 4 weeks (pre-C2) and 16weeks of treatment with radiographic disease status after 4 (pre-C2) and 16 weeks (pre-C5) of treatment
Radiographic response rate in each arm
Arm A: Radiographic response by RANO 2.0 criteria at 4 and 16 weeks (pre-C2 \& pre-C5). Arm B: Radiographic response by iRANO criteria at 4 and 16 weeks pre-C2 \& pre-C5).
Percentage of patients with serious Treatment-Emergent Adverse Events (TEAEs) treated with plixorafenib alone or in combination with retifanlimab.
CTCAE v5 will be utilized to determine serious TEAEs as outline in the study
Click on the lead sponsor to view all of their trials.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Lead sponsor
Fore Biotherapeutics
Collaborator
Ivy Brain Tumor Foundation
Collaborator
Incyte Corporation
Collaborator
