RMC-5552 Monotherapy in Adult Subjects With Recurrent Glioblastoma

NCT05557292 | Terminated Phase 1 DMC FDA Drug

• 3 other identifiers: 221014NCI-2022-07698P50CA097257
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Glioblastoma; Recurrent Glioblastoma

Outcome Measures

Primary Outcomes (10)

• Maximum Tolerated Dose (MTD) (Cohort A)

  MTD is defined as the maximal dose at which fewer than one-third of participants experience a dose-limiting toxicity (DLT).

  Up to 1 cycle (1 cycle is equal to 21 days)

• Recommended phase II dose (RP2D) (Cohort A)

  RP2D is defined as the selected dose that will be given to participants in Cohorts B and then C. The RP2D will be either the MTD or one dose level lower based on an analysis of the safety data collected in Cohort A, and discussions between the sponsor-investigator and representatives of RevMed.

  Up to 1 cycle (1 cycle is equal to 21 days)

• Number of Dose-Limiting Toxicities (DLTs) (Cohort A)

  The frequency of adverse events classified by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 determined to be DLTs will be reported by dose level.

  Up to 1 cycle (1 cycle is equal to 21 days)

• Frequency of Grade 3 or Higher Adverse Events (Cohort A)

  Adverse events and clinically significant laboratory abnormalities (meeting Grade 3, 4, or 5 criteria according to CTCAE) for participants in Cohort A will be summarized by maximum intensity and relationship to study drug.

  Up to 1 year after enrollment

• Median concentration of RMC-5552 in plasma (Cohort B)

  Median drug levels of RMC-5552 concentration in plasma of participants in Cohort B will be measured on the day of surgery.

  At end of infusion & at time of surgery, 1 day

• Median concentration of RMC-5552 in tumor (Cohort B)

  Median drug levels of RMC-5552 in tumor tissue of participants in Cohort B will be measured at time of tumor issue removal/surgical resection. The statistical analysis will be descriptive and will be limited to summary statistics for RMC-5552 concentration in tumor (non-enhancing, enhancing, and border).

  At time of surgery, 1 day

• Objective Response Rate (ORR) (Cohort C)

  ORR for participants in Cohort C is defined as the proportion of treated participants with a documented complete response (CR) or partial response (PR) per Response Assessment in Neuro-Oncology (RANO) criteria.

  Up to 3 years

• Median Duration of Response (DOR) (Cohort C)

  DOR is defined as the time of first documented response to trial therapy (PR or better) until the participants in Cohort C demonstrate disease progression per RANO criteria, initiates subsequent anti-cancer therapy, or completes study participation (whichever occurs first). If disease progression is not observed prior to initiating subsequent anti-cancer therapy or completing study participation, the DOR will be censored as the last available disease assessment.

  Up to 5 years

• Median Progression-free survival (PFS) (Cohort C)

  PFS for participants in Cohort C is defined as the time that elapses between cycle 1, day 1 (C1D1) and until the participant experiences disease progression (per RANO criteria), initiates subsequent anti-cancer therapy, completes study participation, or experiences death from any cause (whichever is sooner). If disease progression or death from any cause is not observed prior to initiating subsequent anti-cancer therapy or completing study participation, the PFS will be censored as the last available disease assessment.

  Up to 5 years

• Median Overall survival (OS) (Cohort C)

  OS is defined as the time from C1D1 until the participant completes study follow-up participation, experiences death from any cause or is documented as lost to follow up per institutional standard (whichever is sooner). If death from any cause is not observed prior to completing study participation, the OS will be censored as the time of the last available documentation of survival status.

  Up to 5 years

Secondary Outcomes (16)

• Area under the plasma concentration time curve (AUC) (Cohort A & C)

  Pre-dose and end of infusion on Cycle 1 Day 1 and Cycle 1 Day 15 (1 cycle is equal to 21 days)

• Median Maximum concentration (Cmax) (Cohort A & C)

  Pre-dose and end of infusion on Cycle 1 Day 1 and Cycle 1 Day 15 (1 cycle is equal to 21 days)

• Median time to maximum concentration (Tmax) (Cohort A & C)

  Pre-dose and end of infusion on Cycle 1 Day 1 and Cycle 1 Day 15 (1 cycle is equal to 21 days)

• Objective Response Rate (ORR) (Cohort A)

  Up to 3 years

• Median Duration of Response (DOR) (Cohort A)

  Up to 5 years

Study Arms (4)

Cohort A 1(Dose Escalation, Recurrent Non-surgical GBM)

EXPERIMENTAL

Participants will start at dose level 1 (6 mg) of RMC-5552 administered intravenously. Participants will receive RMC-5552 weekly in 21-day cycles until disease progression or unacceptable toxicity.

Drug: RMC-5552

Cohort A2 (Dose Escalation, Recurrent Non-surgical GBM)

EXPERIMENTAL

Participants receive dose level 2 (12 mg) of RMC-5552 administered intravenously if the toxicity profile from participants in dose level 1 (A1) is acceptable. Participants will receive RMC-5552 weekly in 21-day cycles until disease progression or unacceptable toxicity.

Drug: RMC-5552

Cohort B (Dose Expansion, Recurrent Surgical GBM)

EXPERIMENTAL

Participants will receive a single dose of RMC-5552 at the RP2D approximately 4 hours prior to participants' scheduled surgical resection as part of standard of care. After recovering from surgery (about 3-6 weeks), participants will continue receiving RMC-5552 weekly in 21-day cycles until disease progression or unacceptable toxicity.

Drug: RMC-5552

Cohort C (Dose Expansion, Recurrent Non-surgical GBM)

EXPERIMENTAL

Participants will be given the RP2D of RMC-5552 weekly in 21-day cycles until disease progression or unacceptable toxicity

Drug: RMC-5552

Interventions

RMC-5552 DRUG

Given IV

Also known as: mTORC1/4EBP1

Cohort A 1(Dose Escalation, Recurrent Non-surgical GBM); Cohort A2 (Dose Escalation, Recurrent Non-surgical GBM); Cohort B (Dose Expansion, Recurrent Surgical GBM); Cohort C (Dose Expansion, Recurrent Non-surgical GBM)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• Participants has had any prior treatment with anMechanistic target of rapamycin (mTOR) or phosphatidylinositol 3-kinase (PI3K) inhibitor.
• Participants with any contraindication to MRI examinations.
• Participants with any of the following cardiovascular abnormalities:
• Medically uncontrolled hypertension (eg, \>=160 mmHg systolic or \>= 100 mmHg diastolic).
• Acute coronary syndrome (eg, 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.
• Participants with 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 (HbA1c) \< 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.
• Participants with an active infection requiring systemic therapy within 72 hours of the first dose of RMC-5552.
• Participants with known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
• 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).
• 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)).

Sponsors & Collaborators

• Nicholas Butowski: lead
• Revolution Medicines, Inc.: collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (1)

University of California, San Francisco

San Francisco, California, 94143, United States

Location

MeSH Terms

Conditions

Glioblastoma

Interventions

Mechanistic Target of Rapamycin Complex 1; EIF4EBP1 protein, human

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Multiprotein Complexes; Macromolecular Substances; TOR Serine-Threonine Kinases; Protein Serine-Threonine Kinases; Protein Kinases; Phosphotransferases (Alcohol Group Acceptor); Phosphotransferases; Transferases; Enzymes; Enzymes and Coenzymes; Intracellular Signaling Peptides and Proteins; Proteins; Amino Acids, Peptides, and Proteins

Study Officials

• Nicholas Butowski, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: September 21, 2022
• First Posted: September 28, 2022
• Study Start: April 3, 2023
• Primary Completion: December 31, 2025
• Study Completion: December 31, 2025
• Last Updated: May 6, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)