Trial Summary
What is the purpose of this trial?This trial is testing LOXO-435, a new drug, to see if it can help treat advanced cancers with a specific genetic change. It aims to block a gene that helps cancer cells grow. The study will check the drug's safety and effectiveness in these patients. LOX may be a potential effective therapeutic target to treat colorectal cancer.
Do I have to stop taking my current medications for the trial?The trial protocol does not specify if you need to stop taking your current medications. However, it is common for clinical trials to have restrictions on certain medications, so it's best to discuss this with the trial coordinators.
Is the drug LOXO-435 a promising treatment for bladder cancer?The information provided does not mention LOXO-435 or its effects on bladder cancer, so we cannot determine if it is a promising treatment based on the given data.24111213
What data supports the idea that LOXO-435 for Bladder Cancer (also known as: LOXO-435, LY3866288) is an effective treatment?The available research does not provide specific data on the effectiveness of LOXO-435 for Bladder Cancer. Instead, it discusses various aspects of bladder cancer, including the complexity of the disease, the use of immunotherapy, and the need for new treatments. There is no direct comparison or outcome data for LOXO-435 in the context of bladder cancer in the provided information.178910
What safety data is available for LOXO-435 in bladder cancer treatment?The provided research does not contain specific safety data for LOXO-435 or LY3866288 in the treatment of bladder cancer. The studies focus on other treatments and mechanisms related to bladder cancer, such as intravesical pembrolizumab and the COX-LOX inhibitor licofelone, but do not mention LOXO-435 or LY3866288.356814
Eligibility Criteria
This trial is for adults with advanced or metastatic solid tumors, including bladder cancer, that have a specific gene change (FGFR3). They must have tried all standard treatments or refuse them and be in good physical condition. Pregnant women and those with uncontrolled brain metastases, serious heart conditions, unresolved side effects from prior therapies, or certain eye disorders cannot join.Inclusion Criteria
My cancer is advanced or has spread, and tests show a specific FGFR3 gene change.
My cancer has a specific genetic change in FGFR3 that can be targeted for treatment.
I have been treated with an FGFR inhibitor for my condition.
I am fully active or restricted in physically strenuous activity but can do light work.
Exclusion Criteria
I have a serious heart condition.
I don't have any serious side effects from past treatments that haven't gone away.
I do not have any uncontrolled infections or serious health issues.
I have a history or current signs of extensive tissue calcification.
I have or might have untreated brain metastases.
I have a primary brain tumor.
I have a current eye condition affecting my cornea or retina.
Treatment Details
The study tests LOXO-435's safety and effectiveness on cancers linked to the FGFR3 gene alteration. Participants will also receive Pembrolizumab. The trial involves different cohorts based on previous treatments and genetic profiles of the tumors. It can last up to 2.5 years.
6Treatment groups
Experimental Treatment
Group I: Phase 1b: Cohort C1 LOXO-435 Monotherapy Dose ExpansionExperimental Treatment1 Intervention
LOXO-435 administered orally to participants with advanced solid tumors who have not received a prior FGFR inhibitor.
Group II: Phase 1b: Cohort B3 LOXO-435 Plus PembrolizumabExperimental Treatment2 Interventions
LOXO-435 administered orally in combination with pembrolizumab administered intravenously (IV) to participants with FGFR3-altered advanced urothelial carcinoma who have not received a prior FGFR inhibitor.
Group III: Phase 1b: Cohort B2 LOXO-435 Monotherapy Dose ExpansionExperimental Treatment1 Intervention
LOXO-435 administered orally to participants with FGFR3-altered advanced urothelial carcinoma who have not received a prior FGFR inhibitor.
Group IV: Phase 1b: Cohort B1 LOXO-435 Monotherapy Dose ExpansionExperimental Treatment1 Intervention
LOXO-435 administered orally to participants with FGFR3-altered advanced urothelial carcinoma who were previously treated with an FGFR inhibitor.
Group V: Phase 1a: Cohort A2 LOXO-435 Monotherapy Dose OptimizationExperimental Treatment1 Intervention
LOXO-435 administered orally to participants with FGFR3-altered advanced urothelial carcinoma. (Cohort to be implemented as needed, based on Sponsor's discretion.)
Group VI: Phase 1a: Cohort A1 LOXO-435 Monotherapy Dose EscalationExperimental Treatment1 Intervention
LOXO-435 administered orally to participants with FGFR3-altered advanced solid tumors.
Find a clinic near you
Research locations nearbySelect from list below to view details:
Memorial Sloan Kettering Cancer CenterNew York, NY
Massachusetts General HospitalBoston, MA
University of North Carolina at Chapel HillChapel Hill, NC
The University of Chicago Medical CenterChicago, IL
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Who is running the clinical trial?
Eli Lilly and CompanyLead Sponsor
Merck Sharp & Dohme LLCIndustry Sponsor
Loxo Oncology, Inc.Industry Sponsor
References
Dag-1 carcinoma cell in studying the mechanisms of progression and therapeutic resistance in bladder cancer. [2018]We describe a new human bladder carcinoma cell line (DAG-1) established from a resected bladder cancer fragment and maintained in culture for more than 5 years and over 300 passages.
In vitro and in vivo evaluation of intravesical docetaxel loaded hydrophobically derivatized hyperbranched polyglycerols in an orthotopic model of bladder cancer. [2018]The objective of this study was to evaluate the tolerability, to establish a dosing regimen, and to evaluate the efficacy of intravesical docetaxel (DTX) formulations in a mouse model of bladder cancer. DTX in commercial formulation (Taxotere, DTX in Tween 80) or loaded in hyperbranched polyglycerols (HPGs) was evaluated. The synthesis and characterization of HPGs with hydrophobic cores and derivatized with methoxy poly(ethylene glycol) in the shell and further functionalized with amine groups (HPG-C(8/10)-MePEG and HPG-C(8/10)-MePEG-NH(2)) is described. Intravesical DTX in either commercial or HPGs formulations (up to 1.0 mg/mL) was instilled in mice with orthotopic bladder cancer xenografts and was well tolerated with no apparent signs of local or systemic toxicities. Furthermore, a single dose of intravesical DTX (0.5 mg/mL) loaded in HPGs was significantly more effective in reducing the tumor growth in an orthotopic model of bladder cancer than the commercial formulation of Taxotere. In addition, DTX-loaded HPG-C(8/10)-MePEG-NH(2) was found to be more effective at lower instillation dose than DTX (0.2 mg/mL)-loaded HPG-C(8/10)-MePEG. Overall, our data show promising antitumor efficacy and safety in a recently validated orthotopic model of bladder cancer. Further research is warranted to evaluate its safety and efficacy in early phase clinical trials in patients refractory to standard intravesical therapy.
Bladder preservation for localized muscle-invasive bladder cancer: the survival impact of local utilization rates of definitive radiotherapy. [2021]This study examines the management and outcomes of muscle-invasive bladder cancer in the United States.
Receptor-targeted therapy of human experimental urinary bladder cancers with cytotoxic LH-RH analog AN-152 [AEZS- 108]. [2021]Many bladder cancers progress to invasion with poor prognosis; new therapeutic methods are needed. We developed a cytotoxic LH-RH analog, AN-152 (AEZS-108) containing doxorubicin (DOX), for targeted therapy of cancers expressing LHRH receptors. We investigated the expression of LH-RH receptors in clinical bladder cancers and in HT-1376, J82, RT-4 and HT-1197 human bladder cancer lines. The effect of analog, AN-152, on growth of these tumor lines xenografted into nude mice was analyzed. Using molecular and functional assays, we also evaluated the differences between the effects of AN-152, and DOX alone. We demonstrated the expression of LH-RH receptors on 18 clinical bladder cancers by immunohistochemistry and on four human urinary bladder cancer lines HT-1376, J82, RT-4 and HT-1197 by Western blotting and binding assays. AN-152 powerfully inhibited growth of these bladder cancers in nude mice. AN-152 exerted greater effects than DOX and was less toxic. DOX activated strong multidrug resistance mechanisms in RT-4 and HT-1197 cancers, while AN-152 had no or less such effect. PCR assays and in vitro studies revealed differences in the action of AN-152 and DOX on the expression of genes involved in apoptosis. These results suggest that targeted cytotoxic LH-RH analog, AN-152 (AEZS- 108), should be examined for treatment of patients with LH-RH receptor positive invasive bladder cancers.
Chemoprevention of urothelial cell carcinoma growth and invasion by the dual COX-LOX inhibitor licofelone in UPII-SV40T transgenic mice. [2021]Epidemiologic and clinical data suggest that use of anti-inflammatory agents is associated with reduced risk for bladder cancer. We determined the chemopreventive efficacy of licofelone, a dual COX-lipoxygenase (LOX) inhibitor, in a transgenic UPII-SV40T mouse model of urothelial transitional cell carcinoma (TCC). After genotyping, six-week-old UPII-SV40T mice (n = 30/group) were fed control (AIN-76A) or experimental diets containing 150 or 300 ppm licofelone for 34 weeks. At 40 weeks of age, all mice were euthanized, and urinary bladders were collected to determine urothelial tumor weights and to evaluate histopathology. Results showed that bladders of the transgenic mice fed control diet weighed 3 to 5-fold more than did those of the wild-type mice due to urothelial tumor growth. However, treatment of transgenic mice with licofelone led to a significant, dose-dependent inhibition of the urothelial tumor growth (by 68.6%-80.2%, P
Intravesical Therapy for the Treatment of Nonmuscle Invasive Bladder Cancer: A Systematic Review and Meta-Analysis. [2022]We systematically review the benefits and harms of intravesical therapies for nonmuscle invasive bladder cancer.
Management of Muscle-Invasive Urothelial Cancer and the Emerging Role of Immunotherapy in Advanced Urothelial Cancer. [2018]The incidence of bladder cancer has increased in the past decade, and mortality from bladder cancer remains a substantial public health burden. After 3 decades of minimal progress in the treatment of advanced-stage disease, recent advances in the genomic characterization of urothelial cancer and breakthroughs in bladder cancer therapeutics have rejuvenated the field. This review highlights the landmark clinical trials of chemotherapy in both the neoadjuvant and advanced or metastatic urothelial carcinoma settings. We describe treatment paradigms for multimodal treatment of locally advanced bladder cancer, including discussion on bladder preservation strategies. Lastly, we discuss novel immunomodulatory, targeted, and combination therapies in development for the treatment of advanced urothelial carcinoma.
DDX11-AS1exacerbates bladder cancer progression by enhancing CDK6 expression via suppressing miR-499b-5p. [2021]We investigated DDX11-AS1 effects on bladder cancer (BLCA) progression to identify a new potential therapeutic target for BLCA.
Single-cell RNAseq and longitudinal proteomic analysis of a novel semi-spontaneous urothelial cancer model reveals tumor cell heterogeneity and pretumoral urine protein alterations. [2021]Bladder cancer, one of the most prevalent malignancies worldwide, remains hard to classify due to a staggering molecular complexity. Despite a plethora of diagnostic tools and therapies, it is hard to outline the key steps leading up to the transition from high-risk non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC). Carcinogen-induced murine models can recapitulate urothelial carcinogenesis and natural anti-tumor immunity. Herein, we have developed and profiled a novel model of progressive NMIBC based on 10 weeks of OH-BBN exposure in hepatocyte growth factor/cyclin dependent kinase 4 (R24C) (Hgf-Cdk4R24C) mice. The profiling of the model was performed by histology grading, single cell transcriptomic and proteomic analysis, while the derivation of a tumorigenic cell line was validated and used to assess in vivo anti-tumor effects in response to immunotherapy. Established NMIBC was present in females at 10 weeks post OH-BBN exposure while neoplasia was not as advanced in male mice, however all mice progressed to MIBC. Single cell RNA sequencing analysis revealed an intratumoral heterogeneity also described in the human disease trajectory. Moreover, although immune activation biomarkers were elevated in urine during carcinogen exposure, anti-programmed cell death protein 1 (anti-PD1) monotherapy did not prevent tumor progression. Furthermore, anti-PD1 immunotherapy did not control the growth of subcutaneous tumors formed by the newly derived urothelial cancer cell line. However, treatment with CpG-oligodeoxynucleotides (ODN) significantly decreased tumor volume, but only in females. In conclusion, the molecular map of this novel preclinical model of bladder cancer provides an opportunity to further investigate pharmacological therapies ahead with regards to both targeted drugs and immunotherapies to improve the strategies of how we should tackle the heterogeneous tumor microenvironment in urothelial bladder cancer to improve responses rates in the clinic.
Stage-stratified molecular profiling of non-muscle-invasive bladder cancer enhances biological, clinical, and therapeutic insight. [2022]Understanding the molecular determinants that underpin the clinical heterogeneity of non-muscle-invasive bladder cancer (NMIBC) is essential for prognostication and therapy development. Stage T1 disease in particular presents a high risk of progression and requires improved understanding. We present a detailed multi-omics study containing gene expression, copy number, and mutational profiles that show relationships to immune infiltration, disease recurrence, and progression to muscle invasion. We compare expression and genomic subtypes derived from all NMIBCs with those derived from the individual disease stages Ta and T1. We show that sufficient molecular heterogeneity exists within the separate stages to allow subclassification and that this is more clinically meaningful for stage T1 disease than that derived from all NMIBCs. This provides improved biological understanding and identifies subtypes of T1 tumors that may benefit from chemo- or immunotherapy.
Phase 1/2 Trial Results of a Large Surface Area Microparticle Docetaxel for the Treatment of High-Risk Nonmuscle-Invasive Bladder Cancer. [2022]We investigated the safety, preliminary efficacy, and immune effects of large surface area microparticle docetaxel (LSAM-DTX) administered by direct injection after transurethral resection of bladder tumor (TURBT), and by intravesical instillation in high-risk nonmuscle-invasive bladder cancer.
Intravesical VAX014 Synergizes with PD-L1 Blockade to Enhance Local and Systemic Control of Bladder Cancer. [2022]Emerging clinical evidence indicates that the combination of local administration of immunotherapy with systemic immune-checkpoint blockade targeting the PD-1/PD-L1 pathway improves response rates in select solid tumor indications; however, limited clinical experience with this approach exists in advanced bladder cancer patients. VAX014 is a novel bacterial minicell-based, integrin-targeted oncolytic agent undergoing clinical investigation for intravesical (IVE) treatment of nonmuscle-invasive bladder cancer. Here, we demonstrated that the antitumor activity of VAX014 following IVE administration was dependent upon CD4+ and CD8+ T cells in two syngeneic orthotopic bladder tumor models (MB49 and MBT-2). PD-L1 upregulation was found to be an acquired immune-resistance mechanism in the MB49 model, and the combination of VAX014 with systemic PD-L1 blockade resulted in a significant improvement in bladder tumor clearance rates and development of protective antitumor immunologic memory. Combination treatment also led to enhanced systemic antitumor immune responses capable of clearing distal intradermal tumors and controlling pulmonary metastasis. Distal tumors actively responding to combination therapy demonstrated a phenotypic shift from regulatory T cell to Th1 in intratumoral CD4+ T cells, which was accompanied by a higher percentage of activated CD8+ T cells and higher IFNγ. Finally, VAX014's target integrins α3β1 and α5β1 were overexpressed in tumor biopsies from advanced-stage bladder cancer patients, as well as in both the MB49 and MBT-2 orthotopic mouse models of bladder cancer. These collective findings provide a rationale for the clinical investigation of VAX014 and systemic PD-1/PD-L1 blockade in advanced-stage bladder cancer.
Hsa_circ_0003221 facilitates the malignant development of bladder cancer cells via resulting in the upregulation of DHCR24 by targeting miR-892b. [2022]This research concentrated on the biological effects and special mechanism of circ_0003221 in bladder cancer (BLCA).
PemBla: A Phase 1 study of intravesical pembrolizumab in recurrent non-muscle-invasive bladder cancer. [2023]This study aimed to investigate the anti-PD-1 inhibitor pembrolizumab as a potential agent for use in non-muscle-invasive bladder cancer (NMIBC) by conducting a Phase 1 safety run-in study to assess the safety and tolerability of intravesical pembrolizumab after transurethral resection of the bladder tumour (TURBT).