NEO212 for Brain Tumors

Recruiting at 1 trial location

Overseen By Chloe Richmond

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Neonc Technologies, Inc.

Must be taking: Anti-epileptics

Must not be taking: QT prolonging drugs

Disqualifiers: Spinal cord metastases, Meningeal metastases, Secondary cancer, others

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

Compensation: Varies

Number of Visits: 0

134 Participants Needed

Trial Summary

What is the purpose of this trial?

This multi-site, Phase 1/2 clinical trial is an open-label study to identify the safety, pharmacokinetics, and efficacy of a repeated dose regimen of NEO212 alone for the treatment of patients with radiographically-confirmed progression of Astrocytoma IDH- mutant, Glioblastoma IDH-wildtype, and the safety, pharmacokinetics and efficacy of a repeated dose regimen of NEO212 when given with select SOC for the treatment of solid tumor patients with radiographically confirmed uncontrolled metastases to the brain. The study will have three phases, Phase 1, Phase 2a and Phase 2b.

Will I have to stop taking my current medications?

Participants may need to stop certain medications before starting the trial. There is a required 'washout period' (time without taking certain medications) for some treatments, such as 28 days for experimental agents and 7 days for non-cytotoxic agents. However, if you are on a protocol-approved Standard of Care regimen, you may continue it during the trial.

What data supports the effectiveness of the drug NEO212 for brain tumors?

Research shows that NEO212, a combination of temozolomide and perillyl alcohol, is effective against brain tumors that are resistant to standard chemotherapy. It reduces tumor growth and increases survival in animal models without significant side effects. ^{1 2 3 4 5}

Is NEO212 safe for use in humans?

Temozolomide, a component of NEO212, has shown an acceptable safety profile in clinical studies for treating malignant glioma, a type of brain tumor. This suggests that NEO212 may also be generally safe, but specific safety data for NEO212 in humans is not provided in the available research. ^{1 2 3 4 6}

What makes the drug NEO212 unique for treating brain tumors?

NEO212 is unique because it combines temozolomide (a chemotherapy drug) with perillyl alcohol (a natural compound) to create a new molecule that targets brain tumors. This combination aims to enhance the effectiveness of the treatment by using both components together, potentially offering a novel approach compared to standard treatments. ^{1 2 3 4 7}

Research Team

Tom Chen, MD, PhD

Principal Investigator

NeOnc Technologies

Vincent Simmons, PhD

Principal Investigator

NeOnc Technologies

Patrick Walters

Principal Investigator

NeOnc Technologies

Eligibility Criteria

This trial is for adults with specific brain cancers (Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype) or uncontrolled brain metastasis from solid tumors. Participants must have completed prior treatments and be on stable steroids. They should understand the study and consent to join. Those recently treated with certain drugs or therapies may need to wait before joining.

Inclusion Criteria

The patient must possess the cognizance to comprehend, as well as the eagerness to sign a legally binding informed consent document.

I am in the first phase of the trial, focusing on finding the right dose.

I am 18 years old or older.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1

Dose escalation study to determine the maximum tolerated dose (MTD) of NEO212

6 months

Regular visits for dose escalation and monitoring

Phase 2a

Safety run-in study to confirm the safety of the MTD/RP2D of NEO212 with select SOC regimens

6 months

Regular visits for safety assessment and monitoring

Phase 2b

Dose expansion study to assess efficacy of NEO212 alone and in combination with SOC regimens

6 months

Regular visits for efficacy assessment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• Bevacizumab
• Carboplatin
• FOLFIRI Protocol
• Ipilimumab
• NEO212
• Nivolumab
• Paclitaxel
• Pembrolizumab
• Regorafenib

Trial Overview NEO212 Oral Capsule is being tested in patients with certain types of brain cancer and those with uncontrolled brain metastasis alongside standard-of-care treatments. The trial will assess safety, how the body processes the drug, and its effectiveness across three phases: dose escalation (Phase 1), initial efficacy testing (Phase 2a), and expanded efficacy evaluation (Phase 2b).

Participant Groups

Group I: Phase 2b efficacy - NEO212 for Astrocytoma IDH-mutant and Glioblastoma IDH-wildtype Experimental Treatment 1 Intervention

Patients receiving NEO212 alone for treatment of Astrocytoma IDH-mutant and Glioblastoma IDH-wildtype. NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules.

Group II: Phase 2b efficacy - NEO212 & SOC for Uncontrolled Metastases to the Brain Experimental Treatment 9 Interventions

Patients receiving NEO212 in combination with select standard of care treatments for treatment of uncontrolled metastases to the brain. NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules. SOC treatments established to be safe in Phase 2a of the study will be used in this arm of Phase 2b.

Group III: Phase 2a Safety Run-In - NEO212 and Stivarga (Regorafenib) Experimental Treatment 2 Interventions

- Colorectal cancer (CRC) with uncontrolled metastases to the brain who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anU-EGFR therapy. NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules. Stivarga - 160 mg orally, once daily for the first 21 days of each 28-day cycle per package insert

Group IV: Phase 2a Safety Run-In - NEO212 and Pembrolizumab Experimental Treatment 2 Interventions

The following primary cancers with uncontrolled metrastases to the brain: * Unresectable or metastatic melanoma. * NSCLC expressing PD-L1, with no EGFR or ALK genomic tumor aberrations. * Metastatic NSCLC whose tumors express PD-L1. * EGFR or ALK genomic tumor aberrations must have disease progression. * SCLC. * Unresectable, recurrent HNSCC whose tumors express PD-L1. * HNSCC on or after platinum-containing chemotherapy. * Urothelial carcinoma whose tumors express PD-L1. * Urothelial carcinoma. * Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). * Microsatellite Instability-high or Mismatch Repair Deficient Colorectal Cancer (CRC). * Gastric or gastroesophageal junction adenocarcinoma. * Esophageal or gastroesophageal juncUon (GEJ). * Cervical cancer. * Merkel cell carcinoma. NEO212 - Same as Arm 1. Pembrolizumab - 200 mg administered every 3 weeks per package insert.

Group V: Phase 2a Safety Run-In - NEO212 and Nivolumab Experimental Treatment 2 Interventions

The following primary cancers with uncontrolled metrastases to the brain: * Unresectable or metastatic melanoma. * Metastatic non-small cell lung cancer. * Advanced renal cell carcinoma. * Squamous cell carcinoma of the head and neck. * Urothelial carcinoma. * Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer. * Unresectable esophageal squamous cell carcinoma (ESCC). NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules. Nivolumab - 240 mg administered every 2 weeks per package insert

Group VI: Phase 2a Safety Run-In - NEO212 and Ipilimumab Experimental Treatment 2 Interventions

- Unresectable or metastatic melanoma with uncontrolled metastases to the brain. NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules. Ipilimumab - 3 mg/kg administered IV over 90 minutes every 3 weeks for a maximum of 3 doses per package insert.

Group VII: Phase 2a Safety Run-In - NEO212 and FOLFIRI (Zaltrap) + Bevacizumab (Avastin) Experimental Treatment 3 Interventions

- Metastatic colorectal cancer (mCRC) with uncontrolled metastases to the brain, that is resistant to or has progressed following an oxaliplatin-containing regimen NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules. FOLFIRI - 4 mg/kg aIV over 1 hour every 2 weeks. Bevacizumab - 10 mg/kg IV every 2 weeks.

Group VIII: Phase 2a Safety Run-In - NEO212 and CarbolaUn (ParaplaUn) + Paclitaxel (Taxol) Experimental Treatment 3 Interventions

- Colorectal cancer (CRC) with uncontrolled metastases to the brain. NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules. Carboplatin - 300 mg/m2 IV on day 1 every 4 weeks for 6 cycles per package insert. Paclitaxel - 135mg/m2 IV administered over 24 hours, every 3 weeks per package insert.

Who Is Running the Clinical Trial?

Neonc Technologies, Inc.

Lead Sponsor

Trials

4

Recruited

230+

Findings from Research

NEO212, a new anticancer drug, shows a higher concentration in brain tumor tissue compared to normal brain tissue, which suggests it could be an effective treatment for brain cancers.

The drug has a longer half-life in mouse plasma (94 minutes) and a better brain-to-plasma ratio than temozolomide (TMZ), indicating its potential for targeted therapy in brain-localized malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic properties of the temozolomide perillyl alcohol conjugate (NEO212) in mice. Cho, HY., Swenson, S., Thein, TZ., et al.[2022]

NEO212, a novel temozolomide analog, shows promising anticancer effects in ovarian cancer cells by inhibiting cell proliferation, causing DNA damage, and inducing apoptosis, as demonstrated through various assays including xenograft models and flow cytometry.

The mechanism of action involves the inhibition of the transcription factor EB (TFEB) translocation, which disrupts lysosomal function and autophagic flux, potentially overcoming autophagy-mediated chemotherapy resistance, making NEO212 a strong candidate for ovarian cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NEO212 induces mitochondrial apoptosis and impairs autophagy flux in ovarian cancer. Song, X., Liu, L., Chang, M., et al.[2020]

In a pilot study involving 11 patients with recurrent or treatment-induced malignant brain tumors, the combination of TMZ and oral VP-16 showed promising activity, with 45% of patients achieving a partial response to treatment.

The treatment was well-tolerated, with no major acute toxicity reported during 52 treatment courses, and 45% of patients remained progression-free at 6 months, indicating the need for further investigation in larger studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pilot trial of the rate of response, safety, and tolerability of temozolomide and oral VP-16 in patients with recurrent or treatment-induced malignant central nervous system tumors. Terasaki, M., Bouffet, E., Katsuki, H., et al.[2018]

OncoGel™, which delivers paclitaxel locally, significantly improved median survival in rats with gliosarcoma, extending it to 33 days compared to 15 days for untreated controls, and 50% of treated animals lived beyond 120 days.

Combining OncoGel with either oral or locally delivered temozolomide (TMZ) and/or radiotherapy resulted in over 50% of the animals achieving long-term survival, with some groups reaching 100% long-term survival, indicating a strong potential for enhanced treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of paclitaxel thermal gel depot with temozolomide and radiotherapy significantly prolongs survival in an experimental rodent glioma model. Vellimana, AK., Recinos, VR., Hwang, L., et al.[2021]

NEO212, a novel drug combining temozolomide with perillyl alcohol, shows greater cytotoxicity against temozolomide-resistant glioma cells compared to temozolomide itself, while sparing normal cells from toxicity.

In animal studies, NEO212 effectively reduces tumor growth and improves survival rates in mice with temozolomide-resistant gliomas, indicating its potential as a safe and effective treatment option for patients with this aggressive brain tumor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NEO212, temozolomide conjugated to perillyl alcohol, is a novel drug for effective treatment of a broad range of temozolomide-resistant gliomas. Cho, HY., Wang, W., Jhaveri, N., et al.[2020]

Temozolomide (TMZ) is an effective oral treatment for malignant gliomas, showing meaningful efficacy in delaying disease progression and maintaining quality of life in a study of 525 patients.

TMZ has a favorable safety profile and does not require liver metabolism for activation, allowing it to rapidly penetrate the cerebrospinal fluid, making it a promising option for treating these aggressive brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide in malignant gliomas. Yung, WK.[2018]

In a phase II trial involving 32 patients with recurrent oligodendroglial tumors, temozolomide (TMZ) demonstrated a 25% objective response rate, indicating its potential as an effective second-line treatment after PCV chemotherapy.

TMZ was generally well tolerated, with hematological side effects being the most common, and a median time to progression of 8 months for those who responded, suggesting it could be a viable option for patients who do not respond to initial treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Second-line chemotherapy with temozolomide in recurrent oligodendroglioma after PCV (procarbazine, lomustine and vincristine) chemotherapy: EORTC Brain Tumor Group phase II study 26972. van den Bent, MJ., Chinot, O., Boogerd, W., et al.[2020]

References

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

Pharmacokinetic properties of the temozolomide perillyl alcohol conjugate (NEO212) in mice. [2022]

2. England pubmed.ncbi.nlm.nih.gov

NEO212 induces mitochondrial apoptosis and impairs autophagy flux in ovarian cancer. [2020]

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

Pilot trial of the rate of response, safety, and tolerability of temozolomide and oral VP-16 in patients with recurrent or treatment-induced malignant central nervous system tumors. [2018]

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

Combination of paclitaxel thermal gel depot with temozolomide and radiotherapy significantly prolongs survival in an experimental rodent glioma model. [2021]

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

NEO212, temozolomide conjugated to perillyl alcohol, is a novel drug for effective treatment of a broad range of temozolomide-resistant gliomas. [2020]

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

Temozolomide in malignant gliomas. [2018]

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

Second-line chemotherapy with temozolomide in recurrent oligodendroglioma after PCV (procarbazine, lomustine and vincristine) chemotherapy: EORTC Brain Tumor Group phase II study 26972. [2020]