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.

This clinical trial is designed as a pilot, signal-finding study to demonstrate the feasibility of detecting ctDNA at C1D1 (baseline) and pre-C2 (week 4) (primary endpoint), as well as correlating with disease status as per radiographic response (RR; secondary endpoint). In addition, the investigators will generate preliminary data for the activity of plixorafenib co-administered with retifanlimab in this heavily-pretreated population. Patients with measurable (by RANO 2.0), recurrent BRAF-V600E mutant glioma will be screened and consented for the study prior to surgery. Patients will undergo pre-operative MRI and clinically-indicated resection or biopsy (specific approach as per treating neurosurgeon) for confirmation of progression and characterization of potential acquired resistance alterations. All patients will have a ventricular reservoir placed at time of surgery with CSF and plasma sampling.

Arm A: Patients 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.

Arm B: This arm will evaluate the safety and biological effect of plixorafenib in combination with retifanlimab. Participants will receive one dose of retifanlimab prior to surgery. Following surgery, the participants will start plixorafenib 7-28 days post-operatively, when clinically stable. Retifanlimab (administered by IV every 28 days) will be restarted after one cycle of plixorafenib or after the 2nd cycle of plixorafenib per physician discretion. Patients will take the drugs in 28-day cycles until progressive disease or up to 24 cycles. MRI, blood, CSF and other study assessments will be performed as for Arm A.

Inclusion Arm A Only:

• Patient must have received prior BRAF and/or MEK inhibitor therapy.

  1. Prior RAF dimer disruptor or pan-RAF inhibitor not allowed
  2. Prior immunotherapy allowed

• The following intervals from previous treatments should have elapsed prior to enrollment:

  a. BRAFi/MEKi should be stopped 2 weeks prior to surgery

• 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.

Inclusion Arm B Only:

• Patient must have received prior BRAF and/or MEK inhibitor therapy.

  1. Prior RAF dimer disruptor or pan-RAF inhibitor allowed,
  2. Prior immunotherapy not allowed (anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-CTLA-4 antibody or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathway).

• The following intervals from previous treatments should have elapsed prior to first infusion:

  a. BRAFi/MEKi should be stopped 7 days prior to first retifanlimab infusion and at least 2 weeks prior to surgery.

• Patients must be maintained on a stable (<4mg daily dexamethasone) or decreasing dose of systemic corticosteroid regimen (no increase for 5 days) prior to screening MRI. Topical and inhaled steroid treatment is allowed.

Inclusion Both Arms:

• Histologic diagnosis of a primary CNS tumor with documented BRAF-V600E mutation by a CLIA approved DNA or RNA-based sequencing test (NGS or RNAseq). Immunohistochemistry alone is insufficient.
• Karnofsky performance status ≥ 70.
• Patient is 18 years of age or older.
• Measurable disease by RANO 2.0 criteria on screening MRI. Leptomeningeal disease allowed.
• Willing to submit archival tumor sample if available.
• The following intervals from previous treatments should have elapsed prior to either day of surgery (for Arm A) or first infusion of Retifanlimab (for Arm B):
• 12 weeks from the completion of radiation.
• 8 weeks from an anti-VEGF therapy
• 4 weeks from a nitrosourea chemotherapy
• 2 weeks or 5 half-lives from any investigational (not FDA-approved) agents or FDA-approved non-nitrosourea chemotherapy (whichever is shorter)
• Patients must have the following organ and marrow function:
• Absolute neutrophil count >1,000/mcL
• Platelets >100,000/mcL
• Hemoglobin > 9 g/dL
• Total bilirubin < 1.5 x institutional upper limit of normal (ULN) OR total bilirubin >1.5 × ULN with direct bilirubin < 1.5 × ULN;
• AST (SGOT) and ALT (SGPT) < 2.5 x institutional ULN
• PT or PTT < 1.5 x institutional ULN
• Creatinine ≤ 1.5 x institutional ULN OR
• Estimated glomerular filtration rate (eGFR) ≥50 mL/min/1.73 m2 calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
• Patient must be able to provide written informed consent.
• All adverse events related to prior therapies (chemotherapy; radiotherapy; surgery) must have resolved to Grade 1 or baseline except for
• Alopecia (Grade ≤2)
• Sensory neuropathy (Grade ≤2)
• Lymphopenia (Grade <2)
• Other adverse events that have resolved to Grade ≤2 that, according to the clinical judgment of the investigator, do not constitute a safety risk to the participant.
• Ability to swallow and retain orally administered medications, including a liquid suspension.
• Female participants of childbearing potential (defined as all females who have experienced menarche and who are not postmenopausal or surgically sterile) must have a negative serum pregnancy test prior to study start. Surgical sterility (methods inclusive of hysterectomy, bilateral salpingectomy, and bilateral oophorectomy) or post-menopausal state (amenorrhea for ≥24 months without an alternative medical cause and FSH ≥30 mIU/mL) must be confirmed. Female participants of childbearing potential must agree to use highly effective contraception or practice true abstinence (defined as refraining from heterosexual intercourse during the entire specified period) and not to donate ova from screening through 30 days after the last dose of plixorafenib or 120 days after last dose of retifanlimab. Highly effective contraception is defined as 1) intrauterine device, 2) abstinence, or 3) combined estrogen and progesterone or progesterone only containing implants, injectables, transdermal, or intravaginal contraceptives.
• Male participants must also be documented to be surgically sterile or agree to use adequate contraception and not to donate sperm from screening until 30 days after the last dose of plixorafenib or 120 days after last dose of retifanlimab.
• Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or bladder. Patients with other malignancies must be disease-free for > 2 years.
• Life expectancy equal or greater than six months.

Exclusion Criteria

Exclusion Arm A Only:

• Prior RAF dimer disruptor or pan-RAF inhibitor.

Exclusion Arm B Only:

• 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.
• Have received a live vaccine within 28 days before the planned start of study treatment.

Exclusion Both Arms:

• Current use of any other standard or investigational agents (excepting tumor treating fields).
• Known co-occurring NF1 and/or RAS-related alteration known to cause resistance.
• Known hypersensitivity to plixorafenib, retifanlimab or to excipients.
• Current use of a prohibited medication (including herbal medications, supplements, or foods), as described in Section 5.6, or use of a prohibited medication ≤ 7 days prior to first infusion of retifanlimab.
• Impairment in gastrointestinal function or disease that may significantly alter the absorption of oral plixorafenib (such as ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
• Clinically significant cardiovascular disease including, but not limited to the following:
• History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary artery bypass grafting, coronary angioplasty or stenting ≤ 180 days prior to start date;
• Congestive heart failure requiring treatment (New York Heart Association Grade > 2);
• History or presence of clinically significant cardiac arrhythmias (including resting bradycardia, uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia);
• QTcF interval ≥ 480 ms.
• History of recent (≤ 90 days) thromboembolic or cerebrovascular event such as transient ischemic attack, cerebrovascular accident, or hemodynamically significant (massive or sub-massive) deep vein thrombosis or pulmonary emboli (DVT/PE). Note: Patients with DVT/PE that does not result in hemodynamic instability may enroll as long as the participants are anticoagulated for at least 4 weeks. Note: Patients with DVT/PE related to indwelling catheters or other procedures may enroll.
• Known history of any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection, and/or detectable virus. Subjects with previously treated viral hepatitis and undetectable virus may be eligible.
• Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements, are ineligible.
• Pregnant women are excluded from this study because the effects of plixorafenib or retifanlimab on a fetus are unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with plixorafenib, breastfeeding should be discontinued if the mother is treated on study.
• Contraindication to ventricular reservoir placement or biospecimen collection.
• Current use of strong inhibitors or inducers of CYP3A.