LY3866288 for Healthy Subjects

Overseen By There may be multiple sites in this clinical trial. 1-877-CTLILLY (1-877-285-4559) or

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Eli Lilly and Company

Disqualifiers: Pregnancy, Liver disease, Cancer, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 3 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to assess the tolerance and side effects of the new drug, LY3866288, in healthy participants. Researchers will administer the drug in pill form and monitor its movement through the body using blood tests. Individuals who are generally healthy, have a BMI between 18.5 and 32, and do not smoke may be suitable for this trial. As a Phase 1 trial, participants will be among the first to receive this new treatment, aiding researchers in understanding its effects in people.

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, since the trial is for healthy subjects and requires good general health, it's possible that certain medications might not be allowed. Please consult with the trial coordinator for specific guidance.

Is there any evidence suggesting that LY3866288 is likely to be safe for humans?

A previous study found that LY3866288 was well-tolerated, with most participants experiencing only mild side effects, such as mild diarrhea. These side effects were not severe and were manageable. Since this study uses the same treatment, LY3866288 should be safe for healthy participants. However, each person can react differently. It is advisable to consult a healthcare professional before joining. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about LY3866288 because it might offer a new way to manage drug absorption related to meal consumption. Unlike many treatments that have a fixed absorption profile, LY3866288 is being studied in two different scenarios: with a high-fat meal and a low-fat meal. This approach could provide greater flexibility and effectiveness based on dietary intake, potentially improving treatment outcomes. The unique crossover design, where participants switch between fasted and fed states, helps determine how the drug's absorption and efficacy might change with different dietary conditions.

What evidence suggests that LY3866288 is effective for healthy subjects?

This trial will study LY3866288, also known as LOXO-435, in healthy subjects. Research has shown that LY3866288 holds promise for treating certain cancers. In earlier studies, patients who took 200 mg or more of LY3866288 experienced positive results, with the drug proving safe and showing early signs of tumor reduction. This drug targets a specific gene change called FGFR3, common in some cancers. While further testing is necessary, these early findings suggest LY3866288 could be effective against cancers with this gene change. ^{1 2 3 4 6}

Who Is on the Research Team?

Contact Lilly at 1-800-LillyRx (1-800-545-5979)

Principal Investigator

Eli Lilly and Company

Are You a Good Fit for This Trial?

This clinical trial is for healthy individuals who are interested in participating in a study to test the safety of a new drug called LY3866288. The participants will be required to take the drug orally and undergo blood tests.

Inclusion Criteria

My overall health is good, with no significant issues found in recent medical exams.

Females must be of nonchildbearing potential or of childbearing potential and agree to use contraception

Body mass index (BMI) between 18.5 and 32.0 kilogram per square meter (kg/m²)

Exclusion Criteria

History of alcohol and/or drug abuse within 2 years prior to screening

I haven't used tobacco, nicotine products, or e-cigarettes in the last 90 days.

I am currently pregnant or breastfeeding.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-3 weeks

Treatment

Participants receive LY3866288 orally under fasted/fed conditions in a crossover manner

3 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 weeks

What Are the Treatments Tested in This Trial?

Interventions

• LY3866288

Trial Overview The trial is testing LY3866288, an oral medication, to see how well it's tolerated by people without any underlying health conditions. It involves monitoring the drug levels in the bloodstream and observing how quickly the body gets rid of it over a period of up to 9 weeks.

How Is the Trial Designed?

Group I: LY3866288 Cohort 2 (Low-Fat Meal) Experimental Treatment 1 Intervention

LY3866288 single and multiple capsules administered orally under fasted/fed conditions in cross-over manner within cohort

Group II: LY3866288 Cohort 1 (High-Fat Meal) Experimental Treatment 1 Intervention

LY3866288 single and multiple capsules administered orally under fasted/fed conditions in cross-over manner within cohort

LY3866288 is already approved in United States for the following indications:

Approved in United States as LOXO-435 for:

• Urothelial cancer

Who Is Running the Clinical Trial?

Eli Lilly and Company

Lead Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Published Research Related to This Trial

The Lactobacillus casei HY2782 complex significantly reduced airway hyperresponsiveness and inflammation in an ovalbumin-induced asthma model in mice, suggesting its potential as a therapeutic intervention for allergic asthma.

Oral administration of the HY2782 complex led to decreased levels of total immunoglobulin E and Th2 cytokines, as well as lower inflammatory mediators and immune cell infiltration in the lungs, indicating its anti-inflammatory and immune-modulating effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lactic Acid Bacteria and Natural Product Complex Ameliorates Ovalbumin-Induced Airway Hyperresponsiveness in Mice. Nam, W., Kim, H., Kim, J., et al.[2022]

Mice lacking the Lypd8 gene developed spontaneous colitis when exposed to a high-fat diet, highlighting the importance of Lypd8 in maintaining the intestinal mucosal barrier and preventing inflammation.

Supplementing with human LYPD8 protein significantly improved colitis symptoms in these mice, suggesting that hLYPD8 could be a promising therapeutic option for treating inflammatory bowel diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alleviation of colonic inflammation by Lypd8 in a mouse model of inflammatory bowel disease. Hsu, CC., Okumura, R., Motooka, D., et al.[2022]

The Lymphocyte antigen 6G6D gene is significantly downregulated in mucinous colorectal cancer (CRC) and its expression is influenced by DNA methylation changes, which could serve as a potential biomarker for cancer prognosis.

Inhibition of p38α MAPK signaling reduces LY6G6D expression and affects the anti-inflammatory effects of trametinib, suggesting that targeting this pathway may improve therapeutic strategies for CRC patients, particularly those with mucinous differentiation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lymphocyte antigen 6G6D-mediated modulation through p38α MAPK and DNA methylation in colorectal cancer. Caruso, FP., D'Andrea, MR., Coppola, L., et al.[2022]

Ivuxolimab, an OX40 agonist, was well tolerated in a phase I trial with 52 patients, showing that most adverse events were mild (grade ≤2) and no dose-limiting toxicities occurred, indicating a favorable safety profile.

The treatment demonstrated preliminary antitumor activity, with 5.8% of patients achieving a partial response and 56% showing disease control, alongside evidence of immune activation in the form of increased T-cell proliferation and infiltration in tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I, Open-Label, Dose-Escalation Study of the OX40 Agonist Ivuxolimab in Patients with Locally Advanced or Metastatic Cancers. Diab, A., Hamid, O., Thompson, JA., et al.[2023]

In a mouse model of inflammatory bowel disease (IBD), the novel 5-lipoxygenase inhibitor B-98 significantly reduced disease severity, as indicated by lower disease activity index (DAI), less colon shortening, and improved histopathological grading compared to the control group.

B-98 treatment also led to a significant decrease in the inflammatory cytokine IL-6 and reduced the proportion of pro-inflammatory Th1, Th9, and Th17 cells, suggesting its potential effectiveness in modulating immune responses in IBD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Benzoxazole derivative B-98 ameliorates dextran sulfate sodium-induced acute murine colitis and the change of T cell profiles in acute murine colitis model]. Song, EM., Jung, SA., Lee, JS., et al.[2019]

The systemic administration of mOX40L fusion protein effectively inhibited the growth of lung metastasis and established colon and breast tumors in experimental models, highlighting its potential as a cancer immunotherapy.

Combining OX40L treatment with a specific herpes simplex virus vector that encodes mGM-CSF significantly enhanced the effectiveness of the vaccination, indicating that this combination could improve immune responses against tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-tumour therapeutic efficacy of OX40L in murine tumour model. Ali, SA., Ahmad, M., Lynam, J., et al.[2020]

Oxymatrine (OM) demonstrated significant dose-dependent killing effects on human colon cancer cells (SW1116), leading to cell cycle arrest in the G1/G0 phase.

The antineoplastic mechanism of OM involves the suppression of telomerase activity, which is linked to decreased expression of hTERT and increased levels of tumor suppressor genes p53 and mad1.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experimental study of the killing effects of oxymatrine on human colon cancer cell line SW1116. Zou, J., Ran, ZH., Xu, Q., et al.[2016]

Glycine chloramine, produced from the reaction of glycine with HOCl, acts as an anti-inflammatory oxidant, which is important in the context of colitis treatment.

The synthesized celecoxib derivatives, particularly C-glycylaspart-1-ylcelecoxib (C-GA1C), show promise as colon-specific mutual prodrugs that effectively release celecoxib and glycine in the large intestine, potentially enhancing anti-inflammatory effects by targeting NFκB.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of glycine-bearing celecoxib derivatives as a colon-specific mutual prodrug acting on nuclear factor-κB, an anti-inflammatory target. Lee, S., Lee, Y., Kim, W., et al.[2018]

RBx 7796 effectively inhibits the 5-lipoxygenase enzyme and reduces the release of LTB4 from neutrophils, showing promise in treating airway reactivity in animal models.

The compound demonstrated good oral bioavailability (83% in rats and 47% in dogs) and did not accumulate in the body or induce its own metabolism, indicating a favorable pharmacokinetic profile for further development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacodynamic and pharmacokinetic characterisation of RBx 7796: a novel 5-lipoxygenase inhibitor. Shirumalla, RK., Sharma, P., Dastidar, SG., et al.[2013]

The newly developed 1,3-dioxolanes, particularly (S)-N-Methyl-4'-[[4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)thien-2-yl]thio]acetanilide ((S)-10d), demonstrated significantly higher potency as inhibitors of 5-lipoxygenase (5LO), with an in vitro IC50 of 0.039 microM, making it 25 times more effective than its (R) counterpart.

In vivo studies showed that (S)-10d effectively reduced leukotriene B4 synthesis by 70% in a rat model after an oral dose, indicating its potential as a powerful anti-inflammatory agent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chiral dioxolane inhibitors of leukotriene biosynthesis: structure-activity relationships and syntheses using asymmetric dihydroxylation. Crawley, GC., Briggs, MT.[2019]

Targeting inflammatory pathways, particularly through the enzymes COX-2 and 5-LOX, may offer a promising strategy for preventing colorectal cancer (CRC), which remains a significant public health issue despite advances in treatment.

Current nonsteroidal anti-inflammatory drugs targeting COX-1 and COX-2 have limitations due to side effects, highlighting the potential for developing safer drugs that simultaneously inhibit both 5-LOX and COX-2 to reduce CRC risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lipoxygenase and Cyclooxygenase Pathways and Colorectal Cancer Prevention. Rao, CV., Janakiram, NB., Mohammed, A.[2021]

Low doses of anti-Ly6G antibodies can inhibit neutrophil migration and reduce inflammation in experimental arthritis without causing sustained neutropenia, suggesting a novel therapeutic approach.

The study reveals that Ly6G plays a critical role in neutrophil migration by modulating β2-integrin expression, which is essential for neutrophils to adhere and move towards sites of inflammation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ly6G ligation blocks recruitment of neutrophils via a β2-integrin-dependent mechanism. Wang, JX., Bair, AM., King, SL., et al.[2021]

The engineered OX40L IgG4P Fc fusion protein, MEDI6383, enhances T cell survival, proliferation, and cytokine production, indicating its potential as a powerful immunotherapy for cancer.

In preclinical models, MEDI6383 improved the cytolytic activity of tumor-reactive T cells and reduced tumor growth, suggesting it could effectively boost antitumor immunity in human cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potent Immune Modulation by MEDI6383, an Engineered Human OX40 Ligand IgG4P Fc Fusion Protein. Oberst, MD., Augé, C., Morris, C., et al.[2020]

Bifidobacterium animalis ssp. lactis HY8002 has shown strong resistance to digestive conditions and can enhance intestinal immunity by increasing immunoglobulin A (IgA) secretion and restoring tight junction gene expression, which is crucial for maintaining the intestinal barrier.

HY8002 also effectively restores the balance of gut microbiota disrupted by antibiotics, and its beneficial effects on intestinal barrier function are mediated through Toll-like receptor 2 (TLR2), indicating its potential as a safe and effective probiotic supplement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Probiotic Strain Bifidobacterium animalis ssp. lactis HY8002 Potentially Improves the Mucosal Integrity of an Altered Intestinal Microbial Environment. Kim, JY., Bang, SJ., Kim, JY., et al.[2022]

N-Hydroxyureas derived from 1,4-benzodioxan showed increased potency in inhibiting 5-lipoxygenase (5-LO) when modified with 7-phenoxy or 7-p-fluorophenoxy groups, with compound 18 demonstrating an IC50 of 100 nM in vitro.

The 2S-(-)-enantiomer of compound 18 was found to be significantly more effective than its 2R-(+)-counterpart, with a longer duration of action (8.4 hours) in an ex vivo dog model, indicating its potential as a more effective therapeutic agent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Derivatives of 2-[[N-(Aminocarbonyl)-N-hydroxyamino]methyl]-1,4- benzodioxan as orally active 5-lipoxygenase inhibitors. Satoh, Y., Powers, C., Toledo, LM., et al.[2019]

Citations

1. trials.lilly.com trials.lilly.com/en-US/trial/367675

FORAGER-1: A Study of LOXO-435 (LY3866288 ... - Lilly Trials The main purpose of this study is to learn more about the safety, side effects, and effectiveness of LOXO-435.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05614739

NCT05614739 | FORAGER-1: A Study of LOXO-435 ... The main purpose of this study is to learn more about the safety, side effects, and effectiveness of LOXO-435 by itself or when it is combined with other ...

3. urotoday.com urotoday.com/conference-highlights/asco-gu-2025/asco-gu-2025-bladder-cancer/158302-asco-gu-2025-a-first-in-human-phase-1-study-of-ly3866288-loxo-435-a-potent-highly-isoform-selective-fgfr3-inhibitor-fgfr3i-in-advanced-solid-tumors-with-fgfr3-alterations-initial-results-from-forager-1.html

A First-in-Human Phase 1 Study of LY3866288 (LOXO-435 ... In patients treated at 200 mg twice daily and higher, LY3866288 demonstrates a favorable safety profile and promising preliminary antitumor ...

4. bcan.org bcan.org/clinicaltrials/loxo-435-in-patients-with-cancer-with-a-change-in-a-gene-called-fgfr3/

LOXO-435 in Patients With Cancer With a Change ... LOXO-435 may be used to treat cancer of the cells that line the urinary system and other solid tumor cancers that have a change in a particular gene (known as ...

5. georgiacancerinfo.org georgiacancerinfo.org/clinical-trials/detail/5376

A Study of LOXO-435 (LY3866288) in Participants With ... Tests the safety of a drug in healthy volunteers or subjects with indications. The aim is to find the best dose of a new drug with the fewest side effects ...

6. ucihealth.org ucihealth.org/clinical-trials/UCI-24-159

A Phase I, Open-Label, Multicenter Study of LOXO-435 ... The main purpose of this study is to learn more about the safety, side effects, and effectiveness of LOXO-435 by itself or when it is combined ...