LY4101174 for Solid Tumors
(EXCEED Trial)
Recruiting in Palo Alto (17 mi)
+21 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Eli Lilly and Company
Disqualifiers: CNS metastases, Hypercalcemia, Diabetes, Cardiovascular disease, others
No Placebo Group
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.
12345What 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.
678910Eligibility 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.
+2 more
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.
+9 more
Trial 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
Participant Groups
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.
3Treatment groups
Experimental Treatment
Group I: LY4101174 (Dose-optimization, Cohort A2)Experimental Treatment1 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 Treatment1 Intervention
LY4101174 administered IV.
Group III: LY4101174 (Dose-escalation, Cohort A1)Experimental Treatment1 Intervention
Escalating doses of LY4101174 administered intravenously (IV).
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Laura & Isaac Perlmutter Cancer Center at NYU Langone HealthNew York, NY
Advent Health OrlandoOrlando, FL
South Texas Accelerated Research Therapeutics (START)San Antonio, TX
Emory UniversityAtlanta, GA
More Trial Locations
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Who Is Running the Clinical Trial?
Eli Lilly and CompanyLead Sponsor
Loxo Oncology, Inc.Industry Sponsor
References
First-In-Human Phase I Study of a Next-Generation, Oral, TGFβ Receptor 1 Inhibitor, LY3200882, in Patients with Advanced Cancer. [2023]A novel, selective, next-generation transforming growth factor beta (TGFβ) receptor type-1 small molecule inhibitor, LY3200882, demonstrated promising preclinical data. This first-in-human trial evaluated safety, tolerability, recommended phase II dose (RP2D), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of LY3200882 as monotherapy or with other anticancer agents in patients with advanced cancer.
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]LY2457546 is a potent and orally bioavailable inhibitor of multiple receptor tyrosine kinases involved in angiogenic and tumorigenic signalling. In biochemical and cellular assays, LY2457546 demonstrates potent activity against targets that include VEGFR2 (KDR), PDGFRβ, FLT-3, Tie-2 and members of the Eph family of receptors. With activities against both Tie2 and Eph receptors, LY2457546 possesses an activity profile that distinguishes it from multikinase inhibitors. When compared head to head with sunitinib, LY2457546 was more potent for inhibition of endothelial tube formation in an in vitro angiogenesis co-culture model with an intermittent treatment design. In vivo, LY2457546 inhibited VEGF-driven autophosphorylation of lung KDR in the mouse and rat in a dose and concentration dependent manner. LY2457546 was well tolerated and exhibited efficacy in a 13762 syngeneic rat mammary tumor model in both once and twice daily continuous dosing schedules and in mouse human tumor xenograft models of lung, colon, and prostate origin. Additionally, LY2457546 caused complete regression of well-established tumors in an acute myelogenous leukemia (AML) FLT3-ITD mutant xenograft tumor model. The observed efficacy that was displayed by LY2457546 in the AML FLT3-ITD mutant tumor model was superior to sunitinib when both were evaluated using equivalent doses normalized to in vivo inhibition of pKDR in mouse lung. LY2457546 was well tolerated in non-clinical toxicology studies conducted in rats and dogs. The majority of the toxicities observed were similar to those observed with other multi-targeted anti-angiogenic kinase inhibitors (MAKs) and included bone marrow hypocellularity, hair and skin depigmentation, cartilage dysplasia and lymphoid organ degeneration and necrosis. Thus, the unique spectrum of target activity, potent in vivo anti-tumor efficacy in a variety of rodent and human solid tumor models, exquisite potency against a clinically relevant model of AML, and non-clinical safety profile justify the advancement of LY2457546 into clinical testing.
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]Background MET is a tyrosine kinase receptor involved in the regulation of cell proliferation and migration. Reported here are the phase I dose-escalation results for LY2875358, a monoclonal antibody against MET, in Japanese patients with advanced malignancies. Methods The study comprised a 3 + 3 dose-escalation part for LY2875358 monotherapy in patients with advanced malignancies (Part A) followed by an assessment of LY2875358 in combination with erlotinib or gefitinib in patients with non-small cell lung cancer (Part B). LY2875358 was administered once every 2 weeks. The primary objective was to evaluate the safety and tolerability of LY2875358; secondary objectives included evaluation of pharmacokinetics, pharmacodynamics, and antitumor activity. Results Eleven patients received LY2875358 monotherapy at 3 dose levels (700 mg, N = 3; 1400 mg, N = 3; 2000 mg, N = 5) and 6 patients received LY2875358 2000 mg in combination with erlotinib (N = 3) or gefitinib (N = 3). No dose-limiting toxicities or serious adverse events related to LY2875358 were observed. The most frequently reported drug-related adverse events were hypoalbuminemia (2 patients) in Part A and dermatitis acneiform (4 patients) in Part B. LY2875358 area under the curve (AUC) and maximum concentration (Cmax) increased with dose over the dose range of 700 mg to 2000 mg. A best response of stable disease was achieved by 2/11 patients in Part A and 4/6 patients in Part B (disease control rate: 35 %). Conclusions LY2875358 at doses up to 2000 mg demonstrated a favorable safety and tolerability profile as monotherapy or in combination with erlotinib or gefitinib in Japanese patients with advanced malignancies.
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]LY2780301, a dual inhibitor of protein kinase B (AKT) and the downstream effector p70 ribosomal protein S6 kinase (p70S6K), may inhibit progression in tumours relying on phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signalling pathway activation. This phase IB trial investigated the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, pharmacokinetics (PK) and antitumour activity of LY2780301 plus gemcitabine in patients with advanced/metastatic solid tumours.
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]LY2090314 (LY) is a glycogen synthase kinase 3 inhibitor with preclinical efficacy in xenograft models when combined with platinum regimens. A first-in-human phase 1 dose-escalation study evaluated the combination of LY with pemetrexed/carboplatin.
Multidimension Analysis of the Prognostic Value, Immune Regulatory Function, and ceRNA Network of LY6E in Individuals with Colorectal Cancer. [2022]Label="Background" NlmCategory="UNASSIGNED">Lymphocyte antigen 6 complex, locus E (LY6E) is abnormally expressed in several cancers and is associated with poor outcomes. However, the biological role of LY6E in colorectal cancer (CRC) remains largely unknown. Hence, we aimed to evaluate the expression levels, prognostic value, biological functions, and immune effects of LY6E via pan-cancer and CRC analyses using multiple databases.
NSC243928 Treatment Induces Anti-Tumor Immune Response in Mouse Mammary Tumor Models. [2023]NSC243928 induces cell death in triple-negative breast cancer cells in a LY6K-dependent manner. NSC243928 has been reported as an anti-cancer agent in the NCI small molecule library. The molecular mechanism of NSC243928 as an anti-cancer agent in the treatment of tumor growth in the syngeneic mouse model has not been established. With the success of immunotherapies, novel anti-cancer drugs that may elicit an anti-tumor immune response are of high interest in the development of novel drugs to treat solid cancer. Thus, we focused on studying whether NSC243928 may elicit an anti-tumor immune response in the in vivo mammary tumor models of 4T1 and E0771. We observed that NSC243928 induced immunogenic cell death in 4T1 and E0771 cells. Furthermore, NSC243928 mounted an anti-tumor immune response by increasing immune cells such as patrolling monocytes, NKT cells, B1 cells, and decreasing PMN MDSCs in vivo. Further studies are required to understand the exact mechanism of NSC243928 action in inducing an anti-tumor immune response in vivo, which can be used to determine a molecular signature associated with NSC243928 efficacy. NSC243928 may be a good target for future immuno-oncology drug development for breast cancer.
Novel Anti-LY6G6D/CD3 T-Cell-Dependent Bispecific Antibody for the Treatment of Colorectal Cancer. [2023]New therapeutics and combination regimens have led to marked clinical improvements for the treatment of a subset of colorectal cancer. Immune checkpoint inhibitors have shown clinical efficacy in patients with mismatch-repair-deficient or microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). However, patients with microsatellite-stable (MSS) or low levels of microsatellite instable (MSI-L) colorectal cancer have not benefited from these immune modulators, and the survival outcome remains poor for the majority of patients diagnosed with mCRC. In this article, we describe the discovery of a novel T-cell-dependent bispecific antibody (TDB) targeting tumor-associated antigen LY6G6D, LY6G6D-TDB, for the treatment of colorectal cancer. RNAseq analysis showed that LY6G6D was differentially expressed in colorectal cancer with high prevalence in MSS and MSI-L subsets, whereas LY6G6D expression in normal tissues was limited. IHC confirmed the elevated expression of LY6G6D in primary and metastatic colorectal tumors, whereas minimal or no expression was observed in most normal tissue samples. The optimized LY6G6D-TDB, which targets a membrane-proximal epitope of LY6G6D and binds to CD3 with high affinity, exhibits potent antitumor activity both in vitro and in vivo. In vitro functional assays show that LY6G6D-TDB-mediated T-cell activation and cytotoxicity are conditional and target dependent. In mouse xenograft tumor models, LY6G6D-TDB demonstrates antitumor efficacy as a single agent against established colorectal tumors, and enhanced efficacy can be achieved when LY6G6D-TDB is combined with PD-1 blockade. Our studies provide evidence for the therapeutic potential of LY6G6D-TDB as an effective treatment option for patients with colorectal cancer.
An Oral Formulation of YK-4-279: Preclinical Efficacy and Acquired Resistance Patterns in Ewing Sarcoma. [2020]Ewing sarcoma is a transcription factor-mediated pediatric bone tumor caused by a chromosomal translocation of the EWSR1 gene and one of several genes in the ETS family of transcription factors, typically FLI1 or ERG. Full activity of the resulting oncogenic fusion protein occurs only after binding RNA helicase A (RHA), and novel biologically targeted small molecules designed to interfere with that interaction have shown early promise in the preclinical setting. Herein, we demonstrate marked preclinical antineoplastic activity of an orally bioavailable formulation of YK-4-279 and identify mechanisms of acquired chemotherapy resistance that may be exploited to induce collateral sensitivity. Daily enteral administration of YK-4-279 led to significant delay in Ewing sarcoma tumor growth within a murine model. In advance of anticipated early-phase human clinical trials, we investigated both de novo and acquired mechanism(s) by which Ewing sarcoma cells evade YK-4-279-mediated cell death. Drug-resistant clones, formed by chronic in vitro exposure to steadily increased levels of YK-4-279, overexpressed c-Kit, cyclin D1, pStat3(Y705), and PKC isoforms. Interestingly, cross-resistance to imatinib and enzastaurin (selective inhibitors of c-Kit and PKC-β, respectively), was observed and the use of YK-4-279 with enzastaurin in vitro led to marked drug synergy, suggesting a potential role for combination therapies in the future. By advancing an oral formulation of YK-4-279 and identifying prominent mechanisms of resistance, this preclinical research takes us one step closer to a shared goal of curing adolescents and young adults afflicted by Ewing sarcoma.
Safety and Immunogenicity of LY3415244, a Bispecific Antibody Against TIM-3 and PD-L1, in Patients With Advanced Solid Tumors. [2022]Investigate the safety and efficacy of LY3415244, a TIM-3/PD-L1 bispecific antibody that blocks TIM-3 and PD-L1 in patients with advanced solid tumors.