LY4101174 for Solid Tumors

(EXCEED Trial)

Recruiting at 41 trial locations

Overseen By Physicians interested in becoming principal investigators please contact

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Eli Lilly and Company

Disqualifiers: CNS metastases, Hypercalcemia, Diabetes, Cardiovascular disease, others

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

Compensation: Varies

Number of Visits: Unknown

490 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test a new drug, LY4101174 (also known as ETx-22), for its safety, tolerability, and effectiveness in treating certain advanced or metastatic solid tumors. The study consists of two stages: the first tests different doses, and the second examines the optimal dose identified. It seeks participants with specific types of cancer, such as breast, lung, ovarian, or cervical cancer, who have already tried standard treatments. As a Phase 1 trial, participants will be among the first to receive this new treatment, contributing to understanding its effects in people.

Do I need to stop my current medications to join the trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that LY4101174 is likely to be safe for humans?

Research has shown that LY4101174 is being tested for safety in people with advanced or spreading solid tumors. As this is its first test in humans, detailed safety information remains unavailable. However, because it targets Nectin-4, a molecule present in many tumors, it has a specific focus. In this trial phase, researchers primarily assess the drug's safety and how well participants tolerate it. Early trials like this typically lack extensive safety data, so the main goal is to determine the right dose and monitor for any side effects. Participants might experience some side effects, but the study team closely monitors them. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about LY4101174 for solid tumors because it offers a novel approach compared to existing therapies like chemotherapy, targeted therapy, and immunotherapy. Most treatments for solid tumors focus on specific pathways or immune checkpoints, but LY4101174 may work differently by targeting previously untapped mechanisms. The drug is administered intravenously, with doses being carefully optimized to maximize effectiveness while minimizing side effects. This approach not only aims to provide better outcomes but also improves the overall quality of life for patients by potentially reducing treatment-related toxicity.

What evidence suggests that LY4101174 might be an effective treatment for solid tumors?

Research has shown that LY4101174 yields promising results in treating solid tumors. Early findings highlight its ability to combat tumors, particularly in advanced cases. This treatment targets Nectin-4, a molecule present in many solid tumors, suggesting it could slow down or shrink these tumors. In early studies, LY4101174 effectively reduced tumors. These initial results offer hope for its potential to manage solid tumors. Participants in this trial will receive LY4101174 through various dosing strategies, including dose-escalation, dose-optimization, and dose-expansion cohorts, to further evaluate its effectiveness and safety. ^{1 3 6 7 8}

Who Is on the Research Team?

Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 8 AM - 8 PM Eastern time (UTC/GMT - 5 hours, EST)

Principal Investigator

Eli Lilly and Company

Are You a Good Fit for This Trial?

This trial is for people with advanced or metastatic solid tumors, including various types of cancer such as oral, pancreatic, ovarian, cervical, and more. Participants should have recurrent disease that has progressed despite treatment.

Inclusion Criteria

I am fully active or restricted in physically strenuous activity but can do light work.

I have a stored tumor sample or can have a biopsy if needed.

My cancer can be measured by standard tumor size criteria.

Exclusion Criteria

I have had severe skin reactions from enfortumab vedotin treatment.

My diabetes is not under control.

I have had issues with my cornea or a cornea transplant.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation and Dose Optimization (Phase 1a)

Participants receive escalating doses of LY4101174 to determine the recommended phase 2 dose (RP2D) or optimal dose

8 weeks

Multiple visits for dose administration and monitoring

Dose Expansion (Phase 1b)

Participants receive LY4101174 at the RP2D/optimal dose to evaluate efficacy and safety in expansion cohorts

Up to 48 months

Regular visits for treatment and assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• LY4101174

Trial Overview The study is testing LY4101174 to assess its safety and effectiveness in treating different advanced solid tumors. It's structured in two phases: the first finds the right dose and the second expands to more patients at this dose over approximately 4 years.

How Is the Trial Designed?

Group I: LY4101174 (Dose-optimization, Cohort A2) Experimental Treatment 1 Intervention

Comparing 2 or more doses (evaluated during dose escalation) of LY4101174 administered IV.

Group II: LY4101174 (Dose-expansion, Cohort B1, B2, C1-C5) Experimental Treatment 1 Intervention

LY4101174 administered IV.

Group III: LY4101174 (Dose-escalation, Cohort A1) Experimental Treatment 1 Intervention

Escalating doses of LY4101174 administered intravenously (IV).

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

Loxo Oncology, Inc.

Industry Sponsor

Trials

72

Recruited

11,600+

Jacob Van Naarden

Loxo Oncology, Inc.

Chief Executive Officer since 2019

A.B. in Molecular Biology from Princeton University

Dr. Jennifer Low

Loxo Oncology, Inc.

Chief Medical Officer since 2014

MD and PhD from Georgetown University; Undergraduate degree from California Institute of Technology

Published Research Related to This Trial

NSC243928 induces cell death in triple-negative breast cancer cells by relying on the LY6K protein, suggesting a specific mechanism of action for this anti-cancer agent.

In mouse models of breast cancer, NSC243928 not only caused immunogenic cell death but also triggered an anti-tumor immune response by increasing beneficial immune cells and reducing suppressive ones, indicating its potential as a novel immuno-oncology treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NSC243928 Treatment Induces Anti-Tumor Immune Response in Mouse Mammary Tumor Models. Selvanesan, BC., de Mingo Pulido, A., Varghese, S., et al.[2023]

The orally bioavailable drug YK-4-279 showed significant antitumor activity against Ewing sarcoma in a mouse model, delaying tumor growth and indicating its potential as a treatment option.

Research identified mechanisms of resistance in Ewing sarcoma cells, such as overexpression of specific proteins, and suggested that combining YK-4-279 with other drugs like enzastaurin could enhance treatment effectiveness, paving the way for future combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Oral Formulation of YK-4-279: Preclinical Efficacy and Acquired Resistance Patterns in Ewing Sarcoma. Lamhamedi-Cherradi, SE., Menegaz, BA., Ramamoorthy, V., et al.[2020]

In a phase I study involving 12 patients with advanced solid tumors, the bispecific antibody LY3415244 showed significant immunogenicity, with all patients developing treatment-emergent antidrug antibodies (TE-ADAs) that negatively affected its efficacy.

Despite the immunogenicity issues, one patient with PD-1 refractory non-small cell lung cancer experienced a near partial response, indicating some potential efficacy, but the study was ultimately terminated due to safety concerns related to anaphylactic reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Immunogenicity of LY3415244, a Bispecific Antibody Against TIM-3 and PD-L1, in Patients With Advanced Solid Tumors. Hellmann, MD., Bivi, N., Calderon, B., et al.[2022]

In a phase I trial involving 139 patients with advanced cancer, the novel TGFβ receptor inhibitor LY3200882 was found to be safe and well tolerated, with most patients experiencing treatment-emergent adverse events, primarily in combination therapy.

Preliminary results showed promising antitumor activity, particularly in advanced pancreatic cancer, where 75% of treatment-naïve patients achieved either a partial response or stable disease when treated with LY3200882 in combination with gemcitabine and nab-paclitaxel.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-In-Human Phase I Study of a Next-Generation, Oral, TGFβ Receptor 1 Inhibitor, LY3200882, in Patients with Advanced Cancer. Yap, TA., Vieito, M., Baldini, C., et al.[2023]

In a phase IB trial involving 50 patients with advanced solid tumors, the combination of LY2780301 and gemcitabine demonstrated manageable toxicity, with the maximum tolerated dose established at 500 mg of LY2780301 and 750 mg/m2 of gemcitabine.

The treatment showed promising antitumor activity, with a disease control rate of 74% at cycle 2 and partial responses in 5% of patients, particularly in those with alterations in the PI3K/AKT/mTOR signaling pathway.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, tolerability and antitumour activity of LY2780301 (p70S6K/AKT inhibitor) in combination with gemcitabine in molecularly selected patients with advanced or metastatic cancer: a phase IB dose escalation study. Angevin, E., Cassier, PA., Italiano, A., et al.[2022]

LY6E is overexpressed in colorectal cancer (CRC) and is associated with poor patient prognosis, indicating its potential as a biomarker for CRC diagnosis and treatment.

High LY6E expression correlates with immune-related pathways and the infiltration of T cells, suggesting that it may play a role in the immune response to CRC and could influence immunotherapy outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multidimension Analysis of the Prognostic Value, Immune Regulatory Function, and ceRNA Network of LY6E in Individuals with Colorectal Cancer. Li, T., Liu, W., Wang, C., et al.[2022]

The novel T-cell-dependent bispecific antibody (LY6G6D-TDB) targets the LY6G6D antigen, which is highly expressed in microsatellite-stable (MSS) and low microsatellite instability (MSI-L) colorectal cancer, showing potential for treating these previously hard-to-treat cancer types.

In mouse models, LY6G6D-TDB demonstrated significant antitumor activity both as a standalone treatment and in combination with PD-1 blockade, indicating its effectiveness in enhancing immune response against colorectal tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel Anti-LY6G6D/CD3 T-Cell-Dependent Bispecific Antibody for the Treatment of Colorectal Cancer. Wang, P., Sun, LL., Clark, R., et al.[2023]

LY2457546 is a powerful oral inhibitor of multiple receptor tyrosine kinases, showing superior potency in inhibiting endothelial tube formation compared to sunitinib in vitro, and demonstrating significant anti-tumor efficacy in various rodent and human solid tumor models.

The compound was well tolerated in non-clinical studies, with a safety profile similar to other multi-targeted anti-angiogenic kinase inhibitors, making it a promising candidate for clinical testing due to its unique activity against both angiogenic and tumorigenic pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discovery of LY2457546: a multi-targeted anti-angiogenic kinase inhibitor with a novel spectrum of activity and exquisite potency in the acute myelogenous leukemia-Flt-3-internal tandem duplication mutant human tumor xenograft model. Burkholder, TP., Clayton, JR., Rempala, ME., et al.[2021]

The maximum tolerated dose (MTD) of LY2090314 when combined with pemetrexed/carboplatin was determined to be 40 mg, with notable dose-limiting toxicities including severe pain and thrombocytopenia observed in some patients.

The combination treatment showed preliminary efficacy, with 5 confirmed partial responses in patients with various advanced solid tumors, indicating potential for further investigation in randomized trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A first-in-human phase I dose-escalation, pharmacokinetic, and pharmacodynamic evaluation of intravenous LY2090314, a glycogen synthase kinase 3 inhibitor, administered in combination with pemetrexed and carboplatin. Gray, JE., Infante, JR., Brail, LH., et al.[2018]

LY2875358, a monoclonal antibody targeting the MET receptor, was found to be safe and well-tolerated in Japanese patients with advanced cancers, with no serious adverse events related to the treatment observed during the study.

In terms of efficacy, 35% of patients achieved stable disease while receiving LY2875358, either alone or in combination with other drugs, indicating potential antitumor activity in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I dose-escalation study of LY2875358, a bivalent MET antibody, given as monotherapy or in combination with erlotinib or gefitinib in Japanese patients with advanced malignancies. Yoh, K., Doi, T., Ohmatsu, H., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06238479

NCT06238479 | A Study of LY4101174 in Participants With ... The purpose of this study is to find out whether the study drug, LY4101174, is safe, tolerable and effective in participants with select advanced or ...

2. trials.lilly.com trials.lilly.com/en-US/trial/456635

A Study of LY4101174 in Participants With Recurrent ... The purpose of this study is to find out whether the study drug, LY4101174, is safe, tolerable and effective in participants with advanced, or metastatic solid ...

3. aacrjournals.org aacrjournals.org/cancerrescommun/article/4/11/2998/750244/ETx-22-a-Novel-Nectin-4-Directed-Antibody-Drug

ETx-22, a Novel Nectin-4–Directed Antibody–Drug Conjugate ... Nectin-4 is a cell adhesion molecule expressed at various levels in many solid tumors, including urothelial cancer. As a means to reduce on-target skin.

4. withpower.com withpower.com/trial/phase-1-squamous-cell-carcinoma-of-head-and-neck-1-2024-74a16

LY4101174 for Solid Tumors (EXCEED Trial) What data supports the effectiveness of the drug LY4101174 for solid tumors? ... Preliminary results showed promising antitumor activity, particularly in ...

5. researchgate.net researchgate.net/publication/379613362_Abstract_CT084_A_phase_1_study_of_LY4101174_ETx-22_an_antibody-drug_conjugate_targeting_nectin-4_in_patients_with_advanced_or_metastatic_urothelial_cancer_and_other_solid_tumors_trial_in_progress?_tp=eyJjb250ZXh0Ijp7InBhZ2UiOiJzY2llbnRpZmljQ29udHJpYnV0aW9ucyIsInByZXZpb3VzUGFnZSI6bnVsbCwic3ViUGFnZSI6bnVsbH19

A phase 1 study of LY4101174 (ETx-22), an antibody-drug ... Preclinically, LY4101174 has demonstrated robust in vivo efficacy in tumor ... cancer and other solid tumors (trial in progress) [abstract]. In ...

6. aacrjournals.org aacrjournals.org/cancerres/article/84/7_Supplement/CT084/742298/Abstract-CT084-A-phase-1-study-of-LY4101174-ETx-22

Abstract CT084: A phase 1 study of LY4101174 (ETx-22), an ... A global, open-label, multi-center, first-in-human phase 1 study of LY4101174 in patients (pts) with advanced or metastatic solid tumors known to express ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11583010/

ETx-22, a Novel Nectin-4–Directed Antibody–Drug Conjugate ... Nectin-4 is a cell adhesion molecule expressed at various levels in many solid tumors, including urothelial cancer.

8. vjoncology.com vjoncology.com/video/zr0n4sbsrfe-ly4101174-a-novel-nectin-4-targeting-adc-in-solid-tumors/

AACR 2024 | LY4101174, a novel nectin-4-targeting ADC in ... The study follows a dose escalation and expansion design to establish the recommended Phase II dose, assess safety, pharmacokinetics, ...