Inclusion Criteria:
For Cohort A and C (non-surgical):
1. 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).
2. 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.
For Cohort B (surgical):
1. 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 are planning to have routine surgery for
resection 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 of
freshly 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 starting
treatment with RMC-5552.
6. 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.
7. Participants must have completed treatment with biologics/monoclonal antibodies,
hormonal therapy, and immunotherapy at least 4 weeks before starting treatment with
RMC-5552.
8. Participants must be age >=18 years. 9. Participants must have an Eastern
Cooperative Oncology Group (ECOG) performance status < 2 or Karnofsky Performance
>70.
10. Participants must have a life expectancy > 12 weeks. 11. Participants must
demonstrate adequate organ function 14 days before starting treatment with RMC-5552
as defined below:
1. 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 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.
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 supporting
safe 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 or
baseline grade (per NCI Common Terminology Criteria for Adverse Events
(CTCAE) version 5), except for the following:
- - Grade 2 prior peripheral neuropathy.
- - Grade 2 lymphopenia, for participants with prior temozolomide therapy 13.
Participants with hypothyroidism must be on a stable dose of thyroid
replacement therapy for at least 60 days prior to enrollment.
14. Participants must have the ability to understand and the willingness to
sign a written informed consent document.
15. Human immunodeficiency virus (HIV)-infected individuals on effective
antiretroviral therapy with undetectable viral load within 6 months are
eligible 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 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.
18. 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.
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:
1. Medically uncontrolled hypertension (eg, >=160 mmHg systolic or >= 100 mmHg
diastolic).
2. Acute coronary syndrome (eg, unstable angina, coronary artery stenting or
angioplasty, bypass grafting) within the previous 6 months.
3. 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.
4. History of congenital long QT syndrome or prolonged QT interval corrected with
Fridericia's method (QTcF) > 480 ms (unless a pacemaker is in place)
5. Left ventricular ejection fraction (LVEF) below the institutional lower limit
of normal or < 50%, whichever is lower. 6. Symptomatic congestive heart failure, New York Heart Association Class II or
higher.
4. Participants with active, clinically significant interstitial lung disease or
pneumonitis.
5. Participants with abnormal fasting glucose (a fasting blood glucose level greater
than or equal to 100 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.
6. Participants with an active infection requiring systemic therapy within 72 hours of
the first dose of RMC-5552.
7. Participants with known active severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2).
8. 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: 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).
9. 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)).
10. Participants with a history of severe allergic reaction to any of the study
intervention components.
11. Participant has had major surgery (any surgery requiring systemic general
anesthesia) within 2 weeks prior to their first dose of RMC-5552. 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.
12. Participants with stomatitis or mucositis of any grade.
13. Participants with 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.
14. 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 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 28
days of C1D1.
- - Treatment with radiation therapy within 12 weeks of starting treatment with
RMC-5552.
- - Treatment with immunotherapy (eg, checkpoint inhibitors) within 28 days of
starting treatment with RMC-5552.
- - Treatment with any other anticancer treatment within 28 days of starting
treatment 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 cytochrome
P450 (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 viral
or other hepatitis, current alcohol abuse or cirrhosis.
20. Participants with unresolved toxicity from prior therapy with the exception of the
following:
1. Alopecia. 2. Grade 2 prior peripheral neuropathy. 3. Grade 2 anemia. 4. Grade 2 lymphopenia, for participants with prior temozolomide therapy. 21. Participants diagnosed with infratentorial GBM, a tumor outside of brain, or
gliomatosis cerebri.
22. 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 (eg, basal
cell or squamous cell carcinoma of the skin post-curative surgical resection;
carcinoma in situ of the cervix post-curative surgical resection). Approval from the
PI is required for exceptions.
23. Participants with a history of cerebrovascular stroke within the previous 6 months
or transient ischemic attack within the previous 3 months
