LY4101174 for Solid Tumors

(EXCEED Trial)

Recruiting at 32 trial locations

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

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

Trial Summary

What is the purpose of this trial?

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 metastatic solid tumors. The study is conducted in two parts - phase Ia (dose-escalation, dose-optimization) and phase Ib (dose-expansion). The study will last up to approximately 4 years.

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.

What data supports the effectiveness of the drug LY4101174 for solid tumors?

The research on LY2457546, a similar drug, shows it has strong anti-tumor effects in various solid tumor models and was well tolerated in animal studies, suggesting potential effectiveness for LY4101174. ^{1 2 3 4 5}

What makes the drug LY4101174 unique for treating solid tumors?

The drug LY4101174, also known as ETx-22, is unique because it is a bispecific antibody that targets both TIM-3 and PD-L1, which are proteins involved in suppressing the immune system's ability to fight cancer. This dual-targeting approach may enhance the immune response against advanced solid tumors, offering a novel mechanism compared to existing treatments. ^{6 7 8 9 10}

Research Team

Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)

Principal Investigator

Eli Lilly and Company

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

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]

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]

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 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]

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]

References

1. United States 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. [2023]

2. United States 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. [2021]

3. United States 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. [2022]

4. England 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. [2022]

5. United States 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. [2018]

6. Egypt pubmed.ncbi.nlm.nih.gov

Multidimension Analysis of the Prognostic Value, Immune Regulatory Function, and ceRNA Network of LY6E in Individuals with Colorectal Cancer. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

NSC243928 Treatment Induces Anti-Tumor Immune Response in Mouse Mammary Tumor Models. [2023]

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

Novel Anti-LY6G6D/CD3 T-Cell-Dependent Bispecific Antibody for the Treatment of Colorectal Cancer. [2023]

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

An Oral Formulation of YK-4-279: Preclinical Efficacy and Acquired Resistance Patterns in Ewing Sarcoma. [2020]

10. United States 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. [2022]