RMC-5552 for Glioblastoma

Overseen By Neuro-Oncology New Patient Coordinator

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Nicholas Butowski

Must not be taking: mTOR inhibitors, PI3K inhibitors

Disqualifiers: Uncontrolled hypertension, Diabetes, Active infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

48 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Do I need to stop my current medications to join the trial?

Yes, you will need to stop certain medications before joining the trial. You must complete chemotherapy or specific inhibitors at least 2 weeks or 5 half-lives before starting, and biologics, hormonal therapy, and immunotherapy at least 4 weeks before starting the trial. There are also specific requirements for nitrosourea and mitomycin C, which must be stopped 6 weeks before the trial.

What makes the drug RMC-5552 unique for treating glioblastoma?

RMC-5552 is unique because it targets specific molecular pathways in glioblastoma that are not effectively addressed by standard treatments, which typically involve surgery, chemotherapy, and radiation. This drug may offer a novel approach by focusing on molecular targets that contribute to the resistance seen in traditional therapies. ^{1 2 3 4 5}

Research Team

Nicholas Butowski, MD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

Adults with a first recurrence of glioblastoma, who've completed standard treatments including radiation and chemotherapy. They must have measurable disease per RANO criteria, adequate organ function, and no major health issues that could interfere with the trial. Participants should not be pregnant or breastfeeding and must agree to use effective contraception.

Inclusion Criteria

I finished my chemotherapy or tyrosine kinase inhibitor treatment at least 2 weeks ago.

I finished radiation therapy at least 12 weeks ago.

Participants must have confirmed measurable disease per RANO criteria

Exclusion Criteria

I still have side effects from previous cancer treatments.

I have not had a stroke or mini-stroke in the past 6 months.

I have previously been treated with an mTOR or PI3K inhibitor.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Dose Escalation

Non-surgical patients receive RMC-5552 intravenously in 21-day cycles to determine the maximum tolerated dose

Up to 1 cycle (21 days)

Weekly visits for drug administration

Dose Expansion

Surgical patients receive a single dose of RMC-5552 prior to surgery, followed by weekly doses post-surgery in 21-day cycles

3-6 weeks post-surgery recovery, then ongoing

Pre-surgery and weekly post-surgery visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Regular follow-up visits

Treatment Details

Interventions

• RMC-5552

Trial Overview The trial is testing RMC-5552, an mTOR inhibitor believed to stop cancer cell growth by preventing the formation of mTOR proteins. It's for patients whose glioblastoma has returned after initial treatment. The study will determine the safest dose, side effects, and potential effectiveness.

Participant Groups

Group I: Cohort C (Dose Expansion, Recurrent Non-surgical GBM) Experimental Treatment 1 Intervention

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

Group II: Cohort B (Dose Expansion, Recurrent Surgical GBM) Experimental Treatment 1 Intervention

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.

Group III: Cohort A2 (Dose Escalation, Recurrent Non-surgical GBM) Experimental Treatment 1 Intervention

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.

Group IV: Cohort A 1(Dose Escalation, Recurrent Non-surgical GBM) Experimental Treatment 1 Intervention

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.

Who Is Running the Clinical Trial?

Nicholas Butowski

Lead Sponsor

Trials

3

Recruited

130+

Revolution Medicines, Inc.

Industry Sponsor

Trials

14

Recruited

4,500+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Current standard treatment for glioblastoma, which includes surgery and temozolomide, results in a median survival of only 12-14 months, highlighting the urgent need for new therapies.

Recent studies on targeted agents like bevacizumab show potential clinical benefits, and ongoing research is exploring various molecular targets and inhibitors to improve treatment outcomes for glioblastoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pathway inhibition: emerging molecular targets for treating glioblastoma. Wick, W., Weller, M., Weiler, M., et al.[2022]

An atypical protein kinase C inhibitor was found to induce rapid apoptosis in glioblastoma cells expressing the mutant EGFRvIII, with an effective concentration (IC50) of 16 microM.

The apoptosis caused by this inhibitor occurs through a caspase-independent mechanism, suggesting a novel pathway for targeting glioblastoma cells that are resistant to standard chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction of apoptosis in glioblastoma cells by an atypical protein kinase C pseudosubstrate peptide. Lorimer, IA., Parolin, DA., Lavictoire, SJ.[2018]

In a phase II trial involving 56 patients with recurrent glioblastoma (GBM) enriched for EGFR gene amplification, dacomitinib showed effective penetration into tumors, but only 14.3% of patients experienced a clinical benefit lasting at least 6 months.

The presence of specific EGFR mutations (EGFRvIII or EGFR ECD missense mutations) did not predict clinical benefit from dacomitinib, suggesting that alternative biomarkers, such as RNA signatures in circulating extracellular vesicles, may be more promising for identifying patients who could respond to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exploring Predictors of Response to Dacomitinib in EGFR-Amplified Recurrent Glioblastoma. Chi, AS., Cahill, DP., Reardon, DA., et al.[2021]

In a phase II trial involving 49 patients with recurrent glioblastoma and EGFR amplification, dacomitinib showed limited efficacy, with a 6-month progression-free survival rate of only 10.6%.

The treatment was associated with significant adverse effects, as 40.8% of patients experienced grade 3-4 drug-related side effects, primarily diarrhea and rash, highlighting the need for careful patient selection based on molecular characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of dacomitinib, a pan-human EGFR tyrosine kinase inhibitor, in recurrent glioblastoma patients with EGFR amplification. Sepúlveda-Sánchez, JM., Vaz, MÁ., Balañá, C., et al.[2022]

In a phase II trial involving 21 recurrent glioblastoma patients with EGFR amplification, GC1118 showed a low 6-month progression-free survival rate of only 5.6%, indicating limited efficacy in this patient population.

Despite not meeting the primary endpoint, the study found that GC1118 treatment was well tolerated, with skin rash as the most common side effect, and it upregulated immune-related signatures in tumors, suggesting potential immune-mediated antitumor effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicenter, phase II trial of GC1118, a novel anti-EGFR antibody, for recurrent glioblastoma patients with EGFR amplification. Choi, SW., Jung, HA., Cho, HJ., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Pathway inhibition: emerging molecular targets for treating glioblastoma. [2022]

2. Greece pubmed.ncbi.nlm.nih.gov

Induction of apoptosis in glioblastoma cells by an atypical protein kinase C pseudosubstrate peptide. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

Exploring Predictors of Response to Dacomitinib in EGFR-Amplified Recurrent Glioblastoma. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Phase II trial of dacomitinib, a pan-human EGFR tyrosine kinase inhibitor, in recurrent glioblastoma patients with EGFR amplification. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

A multicenter, phase II trial of GC1118, a novel anti-EGFR antibody, for recurrent glioblastoma patients with EGFR amplification. [2023]