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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug, PLX038, for individuals with brain or spinal cord tumors. Researchers aim to determine if PLX038 is safe and effective, particularly for tumors with specific gene changes (MYC or MYCN). Participants should have a brain or spinal cord tumor, with some having recurring tumors or specific gene changes. Treatment involves receiving PLX038 (an experimental treatment) through an IV and taking a second drug at home to prevent infections. The study seeks to provide new treatment options for these types of tumors. As a Phase 1 trial, participants will be among the first to receive this new treatment, aiding researchers in understanding its effects in people.

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.

Is there any evidence suggesting that PLX038 is likely to be safe for humans?

Research has shown that PLX038, a new chemotherapy drug, could effectively treat brain tumors. Studies have found that PLX038 can pass through the blood-brain barrier, a major challenge for many drugs, allowing it to reach and attack tumor cells more effectively.

Regarding safety, previous patients have tolerated PLX038 well. While all treatments can have side effects, data so far suggests that PLX038's side effects are manageable. These findings support the potential for PLX038 to be safe for use in humans.

Joining a clinical trial involves close monitoring, which helps ensure participant safety while contributing to important research. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about PLX038 for brain tumors because it introduces a new approach to treatment by targeting tumor cells with precision. Unlike standard treatments like surgery, radiation, and chemotherapy, which often affect both cancerous and healthy cells, PLX038 aims to selectively attack tumor cells, potentially reducing side effects. The trial explores both escalating and optimal dosing, which could lead to more personalized treatment plans. This targeted mechanism offers hope for improved effectiveness and a better quality of life for patients.

What evidence suggests that PLX038 might be an effective treatment for brain tumors?

Research has shown that PLX038 holds promise for treating brain tumors. In mouse studies, PLX038 successfully crossed the blood-brain barrier, reaching and destroying tumor cells in glioblastoma, a type of brain cancer. This treatment blocks Topoisomerase I, an enzyme essential for cancer cell growth. Its special formulation helps it remain in the body longer, potentially increasing its effectiveness against tumors. In these early studies, PLX038 not only slowed tumor growth but also increased survival rates. These findings suggest that PLX038 could be a strong option for people with brain tumors, especially those with certain genetic changes. Participants in this trial will receive PLX038, with some receiving escalating and de-escalating doses in the Phase I arm, and others receiving the recommended Phase II dose in the Phase II arm. ^{1 2 4 6 7}

Who Is on the Research Team?

Jing Wu, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

Citations

1. nature.com nature.com/articles/s41598-024-64186-2

PLX038A, a long-acting SN-38, penetrates the blood-tumor ... The prodrug was remarkably effective at suppressing growth of intracranial breast cancer and glioblastoma (GBM), significantly increasing the ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38898077/

PLX038A, a long-acting SN-38, penetrates the blood-tumor ... The prodrug was remarkably effective at suppressing growth of intracranial breast cancer and glioblastoma (GBM), significantly increasing the ...

3. ccr.cancer.gov ccr.cancer.gov/neuro-oncology-branch/a-new-study-shows-that-the-drug-plx038-increases-survival-in-preclinical-brain-cancer-models

A New Study Shows that the Drug PLX038 Increases Survival ... Researchers discovered that a novel chemotherapy, PLX038, can penetrate the blood-brain-barrier to reach and kill tumor cells in glioblastoma mouse models.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT06161519?cond=(FEINGOLD%20SYNDROME)%20OR%20(MYCN)&rank=1

PLX038 in Primary Central Nervous System Tumors ... SN38 binds to and inhibits Topoisomerase I and the unique formulation of PLX038 lead to a longer half-life, which is thought to increase tumor accumulation and ...

5. trials.braintumor.org trials.braintumor.org/trials/NCT06161519

PLX038 in Primary Central Nervous System Tumors ... 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.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04209595

PLX038 (PEGylated SN38) and Rucaparib in Solid Tumors ... In this study, we use a new form of chemotherapy called PLX038 (PEGylated SN38) to see if it can be safely combined with PARP inhibitors to shrink tumors.

7. ascopubs.org ascopubs.org/doi/10.1200/JCO-25-00236

Dendrimer-Nanoparticle (DEP) Delivery of Topoisomerase ... Collectively, these safety and tolerability data indicate that DEP-SN38 is well tolerated, supporting its potential clinical benefit ...