A Phase I/Ib, Open-Label, Dose-Escalation Study of RMC-5552 Monotherapy in Adult Subjects With Recurrent Glioblastoma
This phase I/Ib trial tests the side effects, best dose, tolerability, and effectiveness of RMC-5552 in treating patients with glioblastoma that has come back (recurrent). RMC-5552 is a type of medicine called an mechanistic target of rapamycin (mTOR) inhibitor. These types of drugs prevent the formation of a specific group of proteins called mTOR. This protein controls cancer cell growth, and the study doctors believe stopping mTOR from forming may help to kill tumor cells.
∙ For Cohort A and C (non-surgical):
• Participants must have histologically or cytologically confirmed 1st, 2nd or 3rd recurrence 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).
• Participants have confirmed measurable disease per RANO criteria. Participants 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.
• For Cohort B (surgical):
• 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 participants are planning to have routine surgery for resection of recurrent disease.
• Confirmed measurable disease per RANO prior to surgical resection.
• 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 μm sections from the archival tumor block.
• For all Cohorts (A, B, and C):
• Participants must have completed radiation therapy at least 12 weeks before starting treatment with RMC-5552.
• Participants must have completed treatment with chemotherapy or tyrosine kinase/serine/threonine inhibitors at least 2 weeks or 5 half-lives (whichever is longer) before starting treatment with RMC-5552.
• a. For nitrosourea and mitomycin C, Participants must have completed treatment at least 6 weeks before first dose of RMC-5552.
• Participants must have completed treatment with biologics/monoclonal antibodies, hormonal therapy, and immunotherapy at least 4 weeks before starting treatment with RMC-5552.
• Participants must be age \>=18 years.
⁃ Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 or Karnofsky Performance \>=70.
⁃ Participants must have a life expectancy \> 12 weeks.
⁃ Participants must demonstrate adequate organ function 14 days before starting treatment with RMC-5552 as defined below:
• Adequate bone marrow function:
‣ Absolute neutrophil count \>=1,500/microliter (mcL).
⁃ Platelets \>=100,000/mcL.
∙ Adequate hepatic function:
‣ Total bilirubin within normal institutional limits, unless elevated due to Gilbert's syndrome and direct bilirubin is within normal limits.
⁃ Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase (SGOT)) \<=3 X institutional upper limit of normal.
⁃ Alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase (SGPT)) \<=3 X institutional upper limit of normal.
∙ Adequate renal function:
‣ Creatinine \<= 1.5 x within institutional upper limit of normal. 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.
⁃ Participants must have recovered from all toxicities/adverse events (AE) from prior anticancer therapy to Grade 1 or within normal limits or baseline grade (per NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5), except for the following:
∙ Alopecia
‣ Grade 2 prior peripheral neuropathy
‣ Grade 2 anemia
‣ Grade 2 lymphopenia, for participants with prior temozolomide therapy.
⁃ Participants with hypothyroidism must be on a stable dose of thyroid replacement therapy for at least 60 days prior to enrollment.
⁃ Participants must have the ability to understand and the willingness to sign a written informed consent document.
⁃ Human immunodeficiency virus (HIV)-infected individuals on effective antiretroviral therapy with undetectable viral load within 6 months are eligible for this trial.
⁃ For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
⁃ 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.
⁃ Female participants of childbearing potential and male participants with female partners of childbearing potential must agree to always use highly effective forms of contraception during the course of the study and for at least 3 months after completion of study intervention. Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Female participants of childbearing potential must have a negative blood pregnancy test within 14 days of commencement of study intervention. Male participants must refrain from donating sperm during the course of the study and for at least 3 months after completion of study intervention.