PLX038 for Brain Tumors

Overseen By Jing Wu, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inhibitors, UGT1A1 inhibitors

Disqualifiers: HIV, Hepatitis B, Hepatitis C, others

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

Compensation: Varies

Number of Visits: 4

Duration: 7 months

120 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: About 90,000 new cases of brain and spinal cord tumors are diagnosed annually in the United States. Most of these tumors are benign; however, about 30% are malignant, and 35% of people with malignant tumors in the brain and spinal cord will die within 5 years. Many of these people have changes in certain genes (MYC or MYCN) that drive the development of their cancers. Objective: To test a study drug (PLX038) in people with tumors of the brain or spinal cord. Eligibility: People aged 18 years or older with a tumor of the brain or spinal cord. Some participants must also have tumors with changes in the MYC or MYCN genes. Design: Participants will be screened. They will have a physical exam and blood tests. They will have imaging scans and a test of their heart function. They may need to have a biopsy: A sample of tissue will be removed from their tumor. PLX038 is given through a tube attached to a needle inserted into a vein in the arm. All participants will receive PLX038 on the first day of each 21-day treatment cycle. They will take a second drug 3 days later to help reduce the risk of infection; for this drug, participants will be shown how to inject themselves under the skin at home. Blood tests, imaging scans, and other tests will be repeated during study visits. Hair samples will also be collected during these visits. Some participants may have an additional biopsy. Study treatment will continue up to 7 months. Follow-up visits will continue every few months for up to 5 years.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot take drugs that strongly affect certain liver enzymes (CYP3A or UGT1A1). It's best to discuss your current medications with the trial team to see if any adjustments are needed.

What data supports the effectiveness of the drug PLX038 for brain tumors?

Research shows that similar treatments using PEG (a component of PLX038) combined with other drugs like paclitaxel have been effective in treating glioblastoma, a type of brain tumor, by enhancing drug delivery and increasing survival rates in animal models. ^{1 2 3 4 5}

What makes the drug PLX038 unique for treating brain tumors?

PLX038 is unique because it is a PEGylated form of SN-38, which is the active metabolite of the chemotherapy drug irinotecan, and it is designed to improve delivery and reduce side effects compared to traditional forms. This formulation may offer better penetration into brain tumors and potentially enhance treatment effectiveness. ^{3 4 6 7 8}

Research Team

Jing Wu, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults with certain brain or spinal cord tumors, specifically those with changes in MYC or MYCN genes. They must have had previous specific treatments, be able to perform most daily activities (Karnofsky >= 70%), and have proper organ function. Women who can bear children and men must use contraception; breastfeeding women must stop breastfeeding.

Inclusion Criteria

I am mostly able to care for myself.

I am breastfeeding but willing to stop for the trial.

I can describe my own symptoms and how well I can move.

Exclusion Criteria

Pregnancy

History of allergic reactions to compounds of similar chemical composition to PLX038

I have not had major surgery in the last 2 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive PLX038 intravenously every 3 weeks for up to 10 cycles, with additional self-administered medication to reduce infection risk

7 months

Every 3 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Every few months (in-person)

Treatment Details

Interventions

• PLX038

Trial Overview The trial is testing PLX038, a drug for brain/spinal cord tumors with genetic changes. Participants receive PLX038 via IV on day one of each 21-day cycle and self-inject another drug at home after three days to prevent infection. The treatment lasts up to seven months, followed by check-ups for five years.

Participant Groups

Group I: Phase II Experimental Treatment 1 Intervention

RP2D of PLX038

Group II: Phase I Experimental Treatment 1 Intervention

Escalating and de-escalating doses of PLX038

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

The study demonstrated that a PLGA/PEG paste can effectively deliver temozolomide and etoposide directly into the cavity after surgical resection of high-grade gliomas, leading to a significant survival benefit in animal models.

In vivo results showed that over half of the treated animals were disease-free, indicating the potential of this delivery method to enhance the efficacy of chemotherapy when combined with adjuvant radiotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overall Survival in Malignant Glioma Is Significantly Prolonged by Neurosurgical Delivery of Etoposide and Temozolomide from a Thermo-Responsive Biodegradable Paste. Smith, SJ., Tyler, BM., Gould, T., et al.[2020]

The study identified an optimal dosing schedule for pegylated interferon alpha (PEG-IFN-alpha) at 10 KU twice a week, which significantly reduced cell proliferation and angiogenesis in glioblastoma cells in a mouse model.

Combining PEG-IFN-alpha with paclitaxel not only inhibited tumor growth effectively but also increased apoptosis in tumor-associated endothelial cells, suggesting a promising new treatment strategy for glioblastoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergistic effect and condition of pegylated interferon alpha with paclitaxel on glioblastoma. Son, MJ., Song, HS., Kim, MH., et al.[2018]

Co-loading paclitaxel and etoposide in methoxy poly(ethylene glycol)-poly(lactic-co-glycolic acid) nanoparticles significantly enhanced their cytotoxic effects against glioma cell lines, leading to lower IC50 values and increased cell apoptosis compared to the free drugs.

In vivo studies in rats with intracranial glioma showed that the co-loaded nanoparticles resulted in a median survival of 76 days, which is significantly longer than the 36 days for free paclitaxel and 37 days for free etoposide, along with improved tumor regression as confirmed by MRI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Paclitaxel/etoposide co-loaded polymeric nanoparticles on tumor size and survival rate in a rat model of glioblastoma. Maleki, H., Hosseini Najafabadi, MR., Webster, TJ., et al.[2021]

Paclitaxel-loaded methoxy poly(ethylene glycol)-poly(ɛ-caprolactone) nanoparticles (MPEG-NP/PTX) demonstrated enhanced anti-tumor effects against glioblastoma multiforme (GBM) in both in vitro and in vivo studies, showing higher cytotoxicity compared to standard Taxol and conventional nanoparticles.

In vivo studies revealed that MPEG-NP/PTX significantly increased survival time in glioblastoma-bearing mice (28 days) compared to Taxol (20 days) and conventional nanoparticles (23 days), indicating its potential as an effective drug delivery system for advanced glioblastoma treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhanced anti-glioblastoma efficacy by PTX-loaded PEGylated poly(ɛ-caprolactone) nanoparticles: In vitro and in vivo evaluation. Xin, H., Chen, L., Gu, J., et al.[2018]

Angiopep-conjugated PEG-PCL nanoparticles (ANG-PEG-NP) effectively penetrate the Blood-Brain Barrier (BBB) and target glioma cells, showing significantly better distribution and accumulation in glioma tissues compared to standard PEG-PCL nanoparticles.

The anti-glioblastoma efficacy of paclitaxel delivered via ANG-PEG-NP was enhanced compared to both Taxol and plain PEG-NP, with preliminary safety results indicating no acute toxicity to vital organs after a week of treatment at a dose of 100 mg/kg.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-glioblastoma efficacy and safety of paclitaxel-loading Angiopep-conjugated dual targeting PEG-PCL nanoparticles. Xin, H., Sha, X., Jiang, X., et al.[2018]

Beta-elemene, a natural compound from Curcuma wenyujin, effectively inhibits the growth of glioblastoma cells by activating the p38 MAPK pathway, leading to cell-cycle arrest and reduced cell proliferation.

In vivo studies showed that beta-elemene also significantly inhibited the growth of glioblastoma tumors in nude mice, suggesting its potential as a therapeutic agent for treating this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-tumor effect of beta-elemene in glioblastoma cells depends on p38 MAPK activation. Yao, YQ., Ding, X., Jia, YC., et al.[2021]

Anti-EPHA3-modified nanoparticles (NPs) effectively target glioblastoma cells, showing significantly enhanced cellular uptake and accumulation in glioma tissues compared to non-targeting NPs, as demonstrated in both in vitro and in vivo studies.

Treatment with these targeted NPs resulted in a significant increase in tumor cell apoptosis and prolonged the median survival time of glioma-bearing rats to 26 days, indicating their potential as an effective nose-to-brain drug delivery system for glioblastoma therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nose-to-brain delivery of temozolomide-loaded PLGA nanoparticles functionalized with anti-EPHA3 for glioblastoma targeting. Chu, L., Wang, A., Ni, L., et al.[2020]

A new treatment strategy using a p38MAPK inhibitor combined with a PD-L1 antibody has been shown to significantly prolong survival in mouse models of glioblastoma that are resistant to temozolomide (TMZ).

This combination therapy works by reducing harmful macrophages and microglia in the tumor environment, suggesting it could be a promising option for patients with recurrent or chronic TMZ-resistant glioblastoma, pending further clinical safety and efficacy studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of p38 MAPK inhibitor with PD-L1 antibody effectively prolongs survivals of temozolomide-resistant glioma-bearing mice via reduction of infiltrating glioma-associated macrophages and PD-L1 expression on resident glioma-associated microglia. Dang, W., Xiao, J., Ma, Q., et al.[2021]

References

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

Overall Survival in Malignant Glioma Is Significantly Prolonged by Neurosurgical Delivery of Etoposide and Temozolomide from a Thermo-Responsive Biodegradable Paste. [2020]

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

Synergistic effect and condition of pegylated interferon alpha with paclitaxel on glioblastoma. [2018]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Effect of Paclitaxel/etoposide co-loaded polymeric nanoparticles on tumor size and survival rate in a rat model of glioblastoma. [2021]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Enhanced anti-glioblastoma efficacy by PTX-loaded PEGylated poly(ɛ-caprolactone) nanoparticles: In vitro and in vivo evaluation. [2018]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Anti-glioblastoma efficacy and safety of paclitaxel-loading Angiopep-conjugated dual targeting PEG-PCL nanoparticles. [2018]

6. Ireland pubmed.ncbi.nlm.nih.gov

Anti-tumor effect of beta-elemene in glioblastoma cells depends on p38 MAPK activation. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Nose-to-brain delivery of temozolomide-loaded PLGA nanoparticles functionalized with anti-EPHA3 for glioblastoma targeting. [2020]

8. Japan pubmed.ncbi.nlm.nih.gov

Combination of p38 MAPK inhibitor with PD-L1 antibody effectively prolongs survivals of temozolomide-resistant glioma-bearing mice via reduction of infiltrating glioma-associated macrophages and PD-L1 expression on resident glioma-associated microglia. [2021]