LAM561 for Pediatric Brain Tumor

Recruiting at 2 trial locations

Overseen By Adrian Gerald McNicholl

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Laminar Pharmaceuticals

Must not be taking: Warfarin, Phenytoin, Sulphonylureas

Disqualifiers: Age ≥ 18, Cardiovascular disease, others

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

Compensation: Varies

Number of Visits: 36

28 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment option called LAM561 (also known as 2-OHOA or Minerval) for children with serious brain tumors, such as high-grade gliomas. The goal is to determine the safest and most effective dose for future studies. Initially, the trial tests different dose levels to assess how much children can safely tolerate, then evaluates the safety of the optimal dose. It suits children under 18 with difficult-to-treat tumors that have not responded to other treatments. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you need warfarin, phenytoin, or certain diabetes medications. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Studies have shown that LAM561, a substance similar to a natural fatty acid that can reach the brain, is under testing for safety in people with various solid tumors. Previous research with adults determined the highest dose that doesn't cause serious side effects. In studies with children, researchers aim to find a safe dose based on what was safe for adults.

Earlier trials showed that LAM561 did not cause severe side effects at these safe doses. This suggests the treatment might be well-tolerated, but the current study will help confirm its safety in children with brain tumors. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the treatments 2-OHOA and LAM561 for pediatric brain tumors because they offer a fresh approach compared to existing therapies like surgery, radiation, and chemotherapy. LAM561 is particularly intriguing due to its novel mechanism of action, which involves adjusting the dose based on the maximum tolerated dose in adults, potentially enhancing safety and effectiveness for children. Additionally, 2-OHOA is a new active ingredient that targets the tumor's cellular membranes, offering a different way to attack the cancer cells. These features could lead to more effective and safer treatment options for young patients.

What evidence suggests that LAM561 might be an effective treatment for pediatric brain tumors?

Studies have shown that LAM561, also known as idroxioleic acid, yields promising results for treating certain brain tumors. In earlier research, patients with a recurring brain tumor called glioma had an 18.5% chance of their disease remaining stable for six months. Specifically, some patients experienced no worsening of their condition during this period. Additionally, combining LAM561 with the usual treatment for newly diagnosed glioblastoma slowed the disease's progression. This trial will explore the effectiveness of LAM561 in managing advanced brain tumors in children, focusing on dose escalation to determine the optimal dosing strategy. ^{1 3 6 7 8}

Are You a Good Fit for This Trial?

This trial is for children under 18 with advanced high-grade gliomas or other solid tumors that are getting worse, coming back, or not responding to standard treatments. They must be able to take oral medication and have good enough blood counts and organ function. Kids who can't walk due to paralysis but use a wheelchair can join too.

Inclusion Criteria

Recent mothers must agree not to breast feed while receiving medications on study.

My blood, kidney, and liver tests are within normal ranges.

My kidney function, measured by creatinine, is within the normal range for my age.

Exclusion Criteria

I have had a significant brain bleed detected by a scan in the last month.

I have high cholesterol that is hard to control or I am on medication to lower my cholesterol.

You have taken any experimental medication within a certain time frame before starting LAM561.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive LAM561 in a dose escalation phase to establish dose-limiting toxicity and a safe dose

3-18 weeks

Visits every 3 weeks for each cycle

Expanded Safety Cohort

Participants are treated at the Maximum Tolerated Dose to assess safety and determine the Recommended Phase 2 Dose

3-18 weeks

Visits every 3 weeks for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

End of study visit 30 days after last dose

Compassionate Use Extension

Participants demonstrating clinical benefit may continue treatment under compassionate use

What Are the Treatments Tested in This Trial?

Interventions

• 2-OHOA
• LAM561

Trial Overview The study tests LAM561 in two parts: first, finding the highest dose kids can handle without serious side effects (dose escalation), then giving more kids this dose to make sure it's safe (expanded safety cohort). It's an open-label trial, meaning everyone knows they're getting LAM561.

How Is the Trial Designed?

Group I: Dose Escalation Experimental Treatment 1 Intervention

The dose level corresponds to 80% of the maximum tolerated dose of LAM561 in adult patients when adjusted for body surface area. The escalation will be to the 100%, and 120% of the maximum tolerated dose of LAM561 in adult patients when adjusted for body surface area. Dose escalation decisions will be made by all active Investigators in collaboration with the Medical Monitor when at least three patients have completed the DLT observation period (Cycle 1) at each dose level. When the third patient at any given dose level has received 14 days of therapy, an "escalation teleconference" will be scheduled after that patient has completed the DLT observation period (Cycle 1). The decision to progress to the next dose level will be made on the basis of review of all significant LAM561-related toxicities.

2-OHOA is already approved in European Union, United States for the following indications:

Approved in European Union as LAM561 for:

• None approved yet; Orphan designation for glioma

Approved in United States as LAM561 for:

• None approved yet; Orphan designation for glioma and Fast-Track designation for glioblastoma

Who Is Running the Clinical Trial?

Laminar Pharmaceuticals

Lead Sponsor

Trials

4

Recruited

240+

Dana-Farber Cancer Institute

Collaborator

Trials

1,128

Recruited

382,000+

Laminar Pharma Inc

Collaborator

Trials

1

Recruited

30+

Hackensack Meridian Health

Collaborator

Trials

141

Recruited

42,900+

Published Research Related to This Trial

Gamma-linolenic acid (GLA) was found to be cytotoxic to malignant rat astrocytoma cells while showing no harmful effects on normal rat astrocytes, indicating its potential as a targeted treatment for cancer.

GLA not only increased the oxidative stress in astrocytoma cells but also enhanced their sensitivity to radiation therapy, suggesting that combining GLA with radiation could improve treatment outcomes for malignant astrocytoma without affecting normal cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gamma-linolenic acid (GLA) is cytotoxic to 36B10 malignant rat astrocytoma cells but not to 'normal' rat astrocytes. Vartak, S., McCaw, R., Davis, CS., et al.[2022]

2-Hydroxyoleic acid (2OHOA) selectively induces endoplasmic reticulum (ER) stress and autophagy in human glioma cells (1321N1, SF-767, U118) without affecting normal MRC-5 cells, highlighting its potential as a targeted anti-cancer treatment.

The compound causes cell cycle arrest in glioma cells and upregulates key markers associated with ER stress and autophagy, suggesting a specific mechanism of action that contributes to its anti-cancer efficacy while minimizing toxicity to normal cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

2-Hydroxyoleic acid induces ER stress and autophagy in various human glioma cell lines. Marcilla-Etxenike, A., Martín, ML., Noguera-Salvà, MA., et al.[2021]

In a Phase 1/2A trial involving 54 patients with glioma and other advanced solid tumors, the synthetic lipid 2-OHOA was found to be well-tolerated, with the most common side effects being mild nausea, vomiting, and diarrhea, establishing a recommended Phase-2 dose of 12,000 mg daily.

The treatment showed promising preliminary efficacy, particularly in patients with recurrent high-grade gliomas, where 24% experienced clinical benefits, including one patient with a remarkable response lasting over 2.5 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase 1/2A trial of idroxioleic acid: first-in-class sphingolipid regulator and glioma cell autophagy inducer with antitumor activity in refractory glioma. Lopez, J., Lai-Kwon, J., Molife, R., et al.[2023]

Intra-cerebral injection of gamma-Linolenic acid (GLA) was found to be safe and non-toxic to normal brain cells in dogs, indicating its potential for use in human treatments.

In a study involving 15 patients with malignant gliomas, GLA administration led to tumor regression and increased patient survival by 1.5 to 2 years, suggesting its efficacy as an anti-tumor agent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Local application of gamma-linolenic acid in the treatment of human gliomas. Das, UN., Prasad, VV., Reddy, DR.[2022]

In a study of 329 glioma patients, those with high levels of SMS1 and low levels of SMS2 had a significantly better 5-year survival rate, suggesting that the expression levels of these enzymes could serve as important prognostic biomarkers.

The study found that SMS1 and SMS2 have opposing effects on glioblastoma cell growth and response to 2-Hydroxyoleic acid (2OHOA), with low basal SMS1 levels predicting a more favorable response to 2OHOA treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Opposing Contribution of SMS1 and SMS2 to Glioma Progression and Their Value in the Therapeutic Response to 2OHOA. Fernández-García, P., Rosselló, CA., Rodríguez-Lorca, R., et al.[2020]

Octadecadienoic acid (ODA) significantly inhibits the proliferation of glioma cells and promotes their apoptosis, showing similar effects to the chemotherapy drug 5-FU in a study involving cultured human glioma cells.

The mechanisms behind ODA's effects include up-regulating apoptosis-related proteins (P21 and caspase-9) and down-regulating cell cycle proteins (P53, PI3K, and PKB/Akt), which together reduce cell division and enhance cell death.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effects of octadecadienoic acid on proliferation and apoptosis of glioma cells and its mechanisms]. Xie, MR., He, TX., Yuan, X., et al.[2023]

5-Lipoxygenase (5-LO) is significantly overexpressed in high-grade astrocytomas, with 90% of glioblastoma multiforme samples showing its presence, suggesting a potential role in tumor development.

Patients with tumors expressing 5-LO tend to be older and have poorer preoperative performance and shorter survival, indicating that 5-LO expression may be associated with worse clinical outcomes, although it was not directly linked to survival after adjusting for other factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased expression of 5-lipoxygenase in high-grade astrocytomas. Nathoo, N., Prayson, RA., Bondar, J., et al.[2007]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04299191

Study of LAM561 Acid in Pediatric Patients With Malignant ... An open label, non-randomized study in pediatric patients with advanced high-grade gliomas and other solid tumors. The study will be performed in two ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10449773/

A Phase 1/2A trial of idroxioleic acid: first-in-class sphingolipid ... An encouraging 6-month PFS rate of 18.5% was observed in the relapsed glioma population. Activity in the other advanced solid tumours cohort was ...

3. rarecancernews.com rarecancernews.com/news/lam561-combination-delay-glioblastoma-disease-progression/

LAM561 as add-on may delay glioblastoma disease ... Adding the investigational therapy LAM561 to standard of care treatment may delay disease progression or death in people with newly diagnosed glioblastoma.

4. laminarpharma.com laminarpharma.com/laminar-pharma-announces-first-open-label-progression-free-survival-data-for-lam561-in-combination-with-standard-of-care-in-first-line-therapy-for-newly-diagnosed-glioblastoma-mgmt-methylated-patients/

Laminar Pharma Announces first open-label Progression ... MGMT-methylated patients treated with LAM561 and SoC currently show a trend towards longer progression-free survival (86,4 weeks) compared to ...

5. withpower.com withpower.com/trial/phase-2-glioma-8-2020-63671?lat=34.60184&lng=-117.81218

LAM561 for Pediatric Brain Tumor It has been tested in a clinical trial for safety and preliminary effectiveness in patients with glioma, showing potential as a treatment.

6. prnewswire.com prnewswire.com/news-releases/laminar-pharma-announces-first-open-label-progression-free-survival-data-for-lam561-in-combination-with-standard-of-care-in-first-line-therapy-for-newly-diagnosed-glioblastoma-mgmt-methylated-patients-302393021.html

Laminar Pharma Announces first open-label Progression ... "Glioblastoma remains one of the most challenging cancers to treat, and these findings highlight the potential of LAM561 to improve outcomes for ...

7. io.nihr.ac.uk io.nihr.ac.uk/wp-content/uploads/2022/01/29360-LAM-561-for-Glioblastoma-v1.0-MAY21-NON-CONF.pdf

29360-LAM-561-for-Glioblastoma- ... LAM-561 is in development as a new oral treatment for newly diagnosed glioblastoma. It mimics the structure of oleic acid, a fatty acid, and can cross the blood ...

8. laminarpharma.com laminarpharma.com/news-and-press/

News and Press Laminar Pharma Announces first open-label Progression-Free Survival data for LAM561 in combination with standard of Care in First-Line Therapy for Newly ...