RMC-5552 for the Treatment of Recurrent Glioblastoma

Inclusion Criteria

• COHORTS A & C: Participants must have histologically or cytologically confirmed 1st, 2nd or 3rd recurrence GBM that has recurred or progressed (per standard [Response Assessment in Neuro-Oncology] RANO criteria) after standard treatment regimen (surgery and radiotherapy with or without chemotherapy or +/- tumor treating fields therapy (TTF), +/- concordant investigational agent)
• COHORTS A & C: Participants have confirmed measurable disease per RANO criteria. Patients are eligible after surgery for recurrent disease so long as there is residual enhancing disease and they are deemed medically able to start study treatment within 28 days of the surgical procedure
• COHORT B: Participants must have 1st, 2nd or 3rd recurrence of GBM that has recurred or progressed (per standard RANO criteria) after standard treatment regimen (surgery and radiotherapy with or without chemotherapy) or +/- tumor treating fields therapy (TTF), +/- concordant investigational agent) and be a candidate for repeat resection per standard of care); that is patients planning to have routine surgery for resection of recurrent disease
• COHORT B: Confirmed measurable disease per RANO prior to surgical resection
• COHORT B: Archival tissue available in the form of a formalin-fixed paraffin-embedded block (sample derived from the diagnostic tumor). If this is not possible, 20 slides of freshly prepared unstained 4-5 um sections from the archival tumor block
• ALL COHORTS: Participants must have completed radiation therapy at least 12 weeks before starting treatment with RMC-5552
• ALL COHORTS: Participants must have completed treatment with chemotherapy or tyrosine kinase/serine/threonine inhibitors at least 2 weeks or 5 half-lives (whichever is longer) prior to first dose of RMC-5552 * For nitrosourea and mitomycin C, Participants must have completed treatment at least 6 weeks prior to first dose of RMC-5552
• ALL COHORTS: Participants must have completed treatment with biologics/monoclonal antibodies, hormonal therapy, and immunotherapy at least 4 weeks prior to first dose of RMC5552
• ALL COHORTS: Participants must be age >= 18 years
• ALL COHORTS: Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status <2 or Karnofsky Performance >70
• ALL COHORTS: Participants must have a life expectancy > 12 weeks
• ALL COHORTS: Absolute neutrophil >= 1,500/mcL (14 days before starting treatment)
• ALL COHORTS: Platelets >= 100,000/mcL (14 days before starting treatment)
• ALL COHORTS: Total bilirubin within normal institutional limits, unless elevated due to Gilbert’s syndrome and direct bilirubin is within normal limits (14 days before starting treatment)
• ALL COHORTS: Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 3 X institutional upper limit of normal (14 days before starting treatment)
• ALL COHORTS: Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =<3 X institutional upper limit of normal (14 days before starting treatment)
• ALL COHORTS: Creatinine =< 1.5 x within institutional upper limit of normal (14 days before starting treatment) OR Creatinine clearance glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2, calculated using the Cockcroft-Gault equation, unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m^2 (14 days before starting treatment)
• ALL COHORTS: Participants must have recovered from all toxicities/adverse events (AEs) from prior anticancer therapy to grade 1 or within normal limits or baseline grade (per Common Terminology Criteria for Adverse Events [CTCAE] version [v].5), except for the following: * Alopecia * Grade 2 prior peripheral neuropathy * Grade 2 anemia * Grade 2 lymphopenia, for participants with prior temozolomide therapy
• ALL COHORTS: Participants with hypothyroidism must be on a stable dose of thyroid replacement therapy for at least 60 days prior to enrollment
• ALL COHORTS: Participants must have the ability to understand and the willingness to sign a written informed consent document
• ALL COHORTS: Human immunodeficiency virus (HIV)-infected individuals on effective antiretroviral therapy with undetectable viral load within 6 months are eligible for this trial
• ALL COHORTS: For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• ALL COHORTS: Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For individuals with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• ALL COHORTS: Participant has agreed to use a highly effective form of contraception. Those who can get pregnant must have a negative blood pregnancy test within 14 days of commencement of study intervention. Participants must refrain from donating sperm during the course of the study and for at least 3 months after completion of study intervention

Exclusion Criteria

• Participants has any prior treatment with an mTOR or PI3K inhibitor
• Participants has any contraindication to MRI examinations
• Participants has any of the following cardiovascular abnormalities: * Medically sustained uncontrolled hypertension (e.g., >= 160 mm Hg systolic or >= 100 mm Hg diastolic) * Acute coronary syndrome (e.g., unstable angina, coronary artery stenting or angioplasty, bypass grafting) within the previous 6 months * History of or current uncontrolled clinically significant unstable arrhythmias ** Note: Participants who have pacemakers to control atrial arrhythmias are candidates for the study. Participants with medically controlled atrial fibrillation > 1 month prior to first dose of RMC-5552 are eligible * History of congenital long QT syndrome or prolonged QT interval corrected with Fridericia’s method (QTcF) > 480 ms (unless a pacemaker is in place) * Left ventricular ejection fraction (LVEF) below the institutional lower limit of normal or < 50%, whichever is lower * Symptomatic congestive heart failure, New York Heart Association class II or higher
• Participant has an active, clinically significant interstitial lung disease or pneumonitis
• Participants with abnormal fasting glucose (a fasting blood glucose level greater than or equal to 125 mg/dL), type 1 diabetes, or uncontrolled type 2 diabetes are excluded. * Note: Participants with type 2 diabetes with hemoglobin A1C < 8%, fasting blood glucose =<130 mg/dL, and fasting triglycerides =< 300 mg/dL with no modifications in hormonal or pharmacologic management may be eligible after discussion with the sponsor-investigator
• Participant has an active infection requiring systemic therapy within 72 hours of the first dose of RMC-5552
• Participant has a known, active severe acute respiratory syndrome coronavirus 2 (SARSCoV-2)
• Participants with active, untreated human immunodeficiency virus (HIV) infection (CD4+ T cell counts =< 350 cells/uL and presence of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections in the past 12 months * Note: Antiretroviral therapy is permitted but must not conflict with other study restrictions and subject must be on an established treatment for at least 28 days, and have an HIV viral load less than 400 copies/mL prior to enrollment)
• Participants with active or chronic hepatitis B (positive for hepatitis B surface antigen with detected hepatitis B virus) or C (positive for hepatitis C ribonucleic acid [RNA])
• Participants with a history of severe allergic reaction to any of the study intervention components
• Participant has had major surgery (any surgery requiring systemic general anesthesia) within 2 weeks prior to their first dose of RMC-5552 for cohort A and C. Participants on Cohort B who are having standard of care (SOC) tumor resection as a part of their treatment on this trial are allowed. In all cases, the participant must be sufficiently recovered and stable before study intervention administration
• Participant has stomatitis or mucositis of any grade
• Participant has any known unstable or clinically significant concurrent medical condition (e.g., substance abuse, uncontrolled intercurrent illness including active infection, symptomatic arterial thrombosis, and pulmonary embolism, etc.) that would, in the opinion of the investigator, jeopardize the safety of a subject, have an impact on their expected survival through the end of the study participation, and/or affect their ability to comply with the protocol
• Participants receiving specific oncologic therapies are excluded: * History of treatment with approved or experimental mTOR and/or PI3K inhibitors * Treatment with chemotherapy or tyrosine kinase inhibitor within 2 weeks days or 5 half-lives (for nitrosourea and mitomycin C within 6 weeks) of RMC-5552, whichever is longer * Treatment with biologics/monoclonal antibodies or hormonal therapy within 4 weeks of cycle 1 day 1 (C1D1) * Participants must have completed treatment with biologics/monoclonal antibodies, hormonal therapy, and immunotherapy at least 4 weeks prior to first dose of RMC-5552 * Treatment with any other anticancer treatment within 28 days of starting treatment with RMC-5552
• Treatment with radiation therapy within 12 weeks of starting treatment with RMC5552
• Participant who has had treatment with any other investigational drugs (excluding coronavirus disease 2019 [COVID-19] vaccines) within 28 days of starting treatment with RMC-5552
• Participants that require medication that is known to prolong QTc interval
• Participants that require treatment with a medication that is a strong cytochrome P450 (CYP) 3A4 inducer and/or time-dependent strong CYP3A4 inhibitor
• Female participants who are pregnant or breastfeeding
• Participants with clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse or cirrhosis
• Participants with unresolved toxicity from prior therapy with the exception of the following: * Alopecia * Grade 2 prior peripheral neuropathy * Grade 2 anemia * Grade 2 lymphopenia, for participants with prior temozolomide therapy
• Participants diagnosed with infratentorial GBM, a tumor outside of brain, or gliomatosis cerebri
• Participants with a prior history of (< 5 years ago) or concurrent malignancy are excluded * Note: Exceptions include prior malignancies considered to be clinically insignificant and for which no systemic anti-cancer treatment is required (e.g., basal cell or squamous cell carcinoma of the skin post-curative surgical resection; carcinoma in situ of the cervix postcurative surgical resection). Approval from the principal investigator (PI) is required for exceptions
• Participants with a history of cerebrovascular stroke within the previous 6 months or transient ischemic attack within the previous 3 months