Trial Title:
RMC-5552 Monotherapy in Adult Subjects With Recurrent Glioblastoma
NCT ID:
NCT05557292
Condition:
Glioblastoma
Recurrent Glioblastoma
Conditions: Official terms:
Glioblastoma
Recurrence
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Sequential Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
RMC-5552
Description:
Given IV
Arm group label:
Cohort A 1(Dose Escalation, Recurrent Non-surgical GBM)
Arm group label:
Cohort A2 (Dose Escalation, Recurrent Non-surgical GBM)
Arm group label:
Cohort B (Dose Expansion, Recurrent Surgical GBM)
Arm group label:
Cohort C (Dose Expansion, Recurrent Non-surgical GBM)
Other name:
mTORC1/4EBP1
Summary:
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.
Detailed description:
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD) and/or the recommended phase II dose
(RP2D) of mTORC1 kinase inhibitor RMC-5552 (RMC- 5552). (Cohort A).
II. To characterize the safety and tolerability of RMC-5552 monotherapy. (Cohort A).
III. To characterize the pharmacokinetics (PK) of RMC-5552 after a single dose of
RMC-5552 prior to surgical resection. (Cohort B).
IV. To evaluate the preliminary antitumor effect of RMC-5552. (Cohort C).
SECONDARY OBJECTIVES:
I. To measure the pharmacokinetics (PK) of RMC-5552. (Cohort A). II. To evaluate the
preliminary antitumor effect of RMC-5552. (Cohort A). III. To assess pharmacodynamic (PD)
markers of drug activity, including biochemical markers of mTORC1 pathway inhibition in
tumor tissue. (Cohort B).
IV. To characterize the safety and tolerability of RMC-5552 monotherapy. (Cohort B).
V. To evaluate the preliminary antitumor effect of RMC-5552 in recurrent glioblastoma
multiforme (GBM). (Cohort B).
VI. To characterize the safety and tolerability of RMC-5552 monotherapy. (Cohort C).
VII. To measure the PK of RMC-5552. (Cohort C).
OUTLINE: This is a phase I, dose-escalation study (Cohort A) followed by a phase Ib study
(Cohorts B and C). Patients are assigned to 1 of 3 cohorts.
COHORT A: Non-surgical patients receive RMC-5552 intravenously (IV) on study. Patients
undergo a pulmonary function test and chest x-ray during screening. Patients also undergo
a brain magnetic resonance imaging (MRI) throughout the trial. Patents undergo blood
sample collection on study.
COHORT B: Surgical patients receive a single dose of RP2D RMC-5552 IV prior to standard
of care surgery and then on study. Patients undergo a pulmonary function test and chest
x-ray during screening. Patients also undergo a brain MRI throughout the trial. Patents
undergo blood sample collection on study.
COHORT C: Non-surgical patients receive RP2D of RMC-5552 IV on study. Patients undergo a
pulmonary function test and chest x-ray during screening. Patients also undergo a brain
MRI throughout the trial. Patents undergo blood sample collection on study.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
For Cohort A and C (non-surgical):
1. Participants must have histologically or cytologically confirmed 1st recurrence GBM
that has recurred or progressed (per standard Response assessment in neuro-oncology
criteria (RANO)) 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.
For Cohort B (surgical):
1. Participants must have 1st 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
2. Participants are planning to have routine surgery for resection of brain tumors.
3. Confirmed measurable disease per RANO prior to surgical resection.
4. 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:
- 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 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
lymphopenia (for participants with prior temozolomide) and 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
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
University of California, San Francisco
Address:
City:
San Francisco
Zip:
94143
Country:
United States
Status:
Recruiting
Contact:
Last name:
Neuro-Oncology New Patient Coordinator
Phone:
415-353-2193
Email:
neurooncnewpatientcoord@ucsf.edu
Contact backup:
Phone:
877-827-3222
Email:
cancertrials@ucsf.edu
Investigator:
Last name:
Nicholas Butowski, MD
Email:
Principal Investigator
Start date:
April 3, 2023
Completion date:
December 31, 2025
Lead sponsor:
Agency:
Nicholas Butowski
Agency class:
Other
Collaborator:
Agency:
Revolution Medicines, Inc.
Agency class:
Industry
Collaborator:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
University of California, San Francisco
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05557292
