RMC-5552 Monotherapy in Adult Subjects with Recurrent Glioblastoma

Inclusion Criteria:

For Cohort A and C (non-surgical):

1. Participants must have histologically or cytologically confirmed 1st, 2nd or 3rdrecurrence GBM that has recurred or progressed (per standard RANO criteria) afterstandard treatment regimen (surgery and radiotherapy with or without chemotherapy or +/- Tumor treating fields therapy (TTF), +/- concordant investigational agent).

2. Participants have confirmed measurable disease per RANO criteria. Patients areeligible after surgery for recurrent disease so long as there is residual enhancingdisease and they are deemed medically able to start study treatment within 28 daysof the surgical procedure.

For Cohort B (surgical):

1. Participants must have 1st, 2nd or 3rd recurrence of GBM that has recurred orprogressed (per standard RANO criteria) after standard treatment regimen (surgeryand radiotherapy with or without chemotherapy) or +/- Tumor treating fields therapy (TTF), +/- concordant investigational agent) and be a candidate for repeat resectionper standard of care); that is patients are planning to have routine surgery forresection of recurrent disease.

2. Confirmed measurable disease per RANO prior to surgical resection.

3. 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 offreshly prepared unstained 4-5 μm sections from the archival tumor block.

For all Cohorts (A, B, and C):

5. Participants must have completed radiation therapy at least 12 weeks before startingtreatment with RMC-5552.

6. Participants must have completed treatment with chemotherapy or tyrosinekinase/serine/threonine inhibitors at least 2 weeks or 5 half-lives (whichever islonger) 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.

7. Participants must have completed treatment with biologics/monoclonal antibodies,hormonal therapy, and immunotherapy at least 4 weeks before starting treatment withRMC-5552.

8. Participants must be age >=18 years. 9. Participants must have an EasternCooperative Oncology Group (ECOG) performance status < 2 or Karnofsky Performance >70.

9. Participants must have a life expectancy > 12 weeks. 11. Participants mustdemonstrate adequate organ function 14 days before starting treatment with RMC-5552as defined below:

10. Adequate bone marrow function:

• Absolute neutrophil count >=1,500/microliter (mcL).

• Platelets >=100,000/mcL.

2. Adequate hepatic function:

• Total bilirubin within normal institutional limits, unless elevated due toGilbert'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)) <=3X institutional upper limit of normal.

3. 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 supportingsafe use at lower kidney function values, no lower than 30 mL/min/1.73 m^2.

12. Participants must have recovered from all toxicities/adverse events (AE)from prior anticancer therapy to Grade 1 or within normal limits orbaseline 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 13.Participants with hypothyroidism must be on a stable dose of thyroidreplacement therapy for at least 60 days prior to enrollment.

14. Participants must have the ability to understand and the willingness tosign a written informed consent document.
15. Human immunodeficiency virus (HIV)-infected individuals on effectiveantiretroviral therapy with undetectable viral load within 6 months areeligible for this trial.
16. For participants with evidence of chronic hepatitis B virus (HBV)infection, the HBV viral load must be undetectable on suppressive therapy,if indicated.
17. Participants with a history of hepatitis C virus (HCV) infection must havebeen treated and cured. For individuals with HCV infection who arecurrently on treatment, they are eligible if they have an undetectable HCVviral load.
18. Female participants of childbearing potential and male participants withfemale partners of childbearing potential must agree to always use highlyeffective forms of contraception during the course of the study and for atleast 3 months after completion of study intervention. Contraceptive useby men and women should be consistent with local regulations regarding themethods of contraception for those participating in clinical studies.Female participants of childbearing potential must have a negative bloodpregnancy test within 14 days of commencement of study intervention. Maleparticipants must refrain from donating sperm during the course of thestudy and for at least 3 months after completion of study intervention.

Exclusion Criteria:

1. Participants with any prior treatment with an mTOR or phosphatidylinositol 3-kinase (PI3K) inhibitor.

2. Participants with any contraindication to MRI examinations.

3. Participants with any of the following cardiovascular abnormalities:

4. Medically uncontrolled hypertension (eg, >=160 mmHg systolic or >= 100 mmHgdiastolic).

5. Acute coronary syndrome (eg, unstable angina, coronary artery stenting orangioplasty, bypass grafting) within the previous 6 months.

6. History of or current uncontrolled clinically significant unstable arrhythmias.Note: Participants who have pacemakers to control atrial arrhythmias arecandidates for the study. Participants with medically controlled atrialfibrillation > 1 month prior to first dose of RMC-5552 are eligible.

7. History of congenital long QT syndrome or prolonged QT interval corrected withFridericia's method (QTcF) > 480 ms (unless a pacemaker is in place)

8. Left ventricular ejection fraction (LVEF) below the institutional lower limitof normal or < 50%, whichever is lower

9. Symptomatic congestive heart failure, New York Heart Association Class II orhigher.

10. Participants with active, clinically significant interstitial lung disease orpneumonitis.

11. Participants with abnormal fasting glucose (a fasting blood glucose level greaterthan or equal to 100 mg/dL), type 1 diabetes, or uncontrolled type 2 diabetes areexcluded. Note: Participants with type 2 diabetes with hemoglobin A1C < 8%, fasting bloodglucose <=130 mg/dL, and fasting triglycerides <=300 mg/dL with no modifications inhormonal or pharmacologic management may be eligible after discussion with theSponsor-Investigator.

12. Participants with an active infection requiring systemic therapy within 72 hours ofthe first dose of RMC-5552.

13. Participants with known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

14. Participants with active, untreated human immunodeficiency virus (HIV) infection (CD4+ T-cell counts ≤350 cells/μL and presence of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections in the past 12 months. Note: Antiretroviraltherapy is permitted but must not conflict with other study restrictions and subjectmust be on an established treatment for at least 28 days, and have an HIV viral loadless than 400 copies/mL prior to enrollment).

15. Participants with active or chronic hepatitis B (positive for hepatitis B surfaceantigen with detected hepatitis B virus) or C (positive for hepatitis C ribonucleicacid (RNA)).

16. Participants with a history of severe allergic reaction to any of the studyintervention components.

17. Participant has had major surgery (any surgery requiring systemic generalanesthesia) within 2 weeks prior to their first dose of RMC-5552. Participants onCohort B who are having Standard of Care (SOC) tumor resection as a part of theirtreatment on this trial are allowed. In all cases, the participant must besufficiently recovered and stable before study intervention administration.

18. Participants with stomatitis or mucositis of any grade.

19. Participants with any known unstable or clinically significant concurrent medicalcondition (e.g., substance abuse, uncontrolled intercurrent illness including activeinfection, symptomatic arterial thrombosis, and pulmonary embolism, etc.) thatwould, in the opinion of the investigator, jeopardize the safety of a subject, havean impact on their expected survival through the end of the study participation,and/or affect their ability to comply with the protocol.

20. 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 14 days or 5half-lives (for nitrosourea and mitomycin C within 6 weeks) of RMC-5552,whichever is longer.

• Treatment with biologics/monoclonal antibodies or hormonal therapy within 28days of C1D1.

• Treatment with radiation therapy within 12 weeks of starting treatment withRMC-5552.

• Treatment with immunotherapy (eg, checkpoint inhibitors) within 28 days ofstarting treatment with RMC-5552.

• Treatment with any other anticancer treatment within 28 days of startingtreatment with RMC-5552.

15. Treatment with any other investigational drugs (excluding COVID-19 vaccines) within 28 days of starting treatment with RMC-5552.

16. Participants that require medication that is known to prolong QTc interval.

17. Participants that require treatment with a medication that is a strong cytochromeP450 (CYP) 3A4 inducer and/or time-dependent strong CYP3A4 inhibitor.

18. Female participants who are pregnant or breastfeeding.

19. Participants with clinically significant history of liver disease, including viralor other hepatitis, current alcohol abuse or cirrhosis.

20. Participants with unresolved toxicity from prior therapy with the exception of thefollowing:

21. Alopecia

22. Grade 2 prior peripheral neuropathy

23. Grade 2 anemia

24. Grade 2 lymphopenia, for participants with prior temozolomide therapy

25. Participants diagnosed with infratentorial GBM, a tumor outside of brain, orgliomatosis cerebri.

26. Participants with a prior history of (< 5 years ago) or concurrent malignancy areexcluded. Note: Exceptions include prior malignancies considered to be clinicallyinsignificant and for which no systemic anti-cancer treatment is required (eg, basalcell or squamous cell carcinoma of the skin post-curative surgical resection;carcinoma in situ of the cervix post-curative surgical resection). Approval from thePI is required for exceptions.

27. Participants with a history of cerebrovascular stroke within the previous 6 monthsor transient ischemic attack within the previous 3 months