safety and preliminary anti-tumor activity of tyra-300 in advanced urothelial carcinoma and other solid tumors with fgfr3 gene alterations

Conditions: Locally Advanced Urothelial Carcinoma; Metastatic Urothelial Carcinoma; Solid Tumor; Urothelial Carcinoma; Solid Tumor, Adult; Bladder Cancer; Non-muscle-invasive Bladder Cancer; FGFR3 Gene Mutation; FGFR3 Gene Alteration; Advanced Solid Tumor; Advanced Urothelial Carcinoma; Urinary Tract Cancer; Urinary Tract Tumor; Urinary Tract Carcinoma

Summary: the purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (pk), and preliminary antitumor activity of tyra-300 in cancers with fgfr3 activating gene alterations, including locally advanced/metastatic urothelial carcinoma of the bladder and urinary tract and other advanced solid tumors.

this is a single arm, multi-part, phase 1/2 global trial studying tyra-300, a novel, potent fibroblast growth factor receptor (fgfr) 3-selective tyrosine kinase inhibitor, in advanced/metastatic urothelial carcinoma of the bladder and urinary tract, that contain activating gene alterations of fgfr3. phase 1 is a dose-escalation study to evaluate the safety, tolerability, and pk of tyra-300 to determine the optimal and maximum tolerated dose (mtd) and recommended phase 2 dose (rp2d). phase 2 will evaluate the preliminary antitumor activity of tyra-300 in cancers with fgfr3 activating gene alterations, including locally advanced/metastatic urothelial carcinoma of the bladder and urinary tract and other advanced solid tumors.

Eligibility criteria:
inclusion criteria: phase 1 part a and part b * men and women 18 years of age or older. * eastern cooperative oncology group (ecog) performance status of ≤1. * histologically confirmed advanced solid tumor who have exhausted standard therapeutic options. * evaluable (part a) or measurable (part b) disease according to recist v1.1. * histologically confirmed advanced solid tumor with an eligible fgfr3 gene mutation or fusion (part b). phase 2 * men and women 18 years of age or older. * ecog performance status of 0-2 or karnofsky performance scale (kps) \>70. * at least 1 measurable lesion by recist v1.1. * histologically confirmed locally advanced/metastatic tumor in one of the following categories: * urothelial carcinoma with an eligible fgfr3 gene mutation or rearrangement who have progressed on a prior fgfr inhibitor and presence of a resistance mutation or other kinase domain mutation. * urothelial carcinoma with an eligible fgfr3 gene mutation or rearrangement who has not received a prior fgfr inhibitor. * any solid tumor with an eligible fgfr3 gene mutation or rearrangement. exclusion criteria (all phases): * has a serum phosphorus level \> upper limit of normal (uln) during screening that remains \>uln despite medical management. * any ocular condition likely to increase the risk of eye toxicity. * history of or current uncontrolled cardiovascular disease. * active, symptomatic, or untreated brain metastases. * gastrointestinal disorders that will affect oral administration or absorption of tyra-300. * females who are pregnant, breastfeeding, or planning to become pregnant and males who plan to father a child while enrolled in this study.

Keywords: bladder fgfr3 gene activation fgfr3 gene alterations fgfr3 gene fusion/rearrangement fgfr3 gene mutation fgfr3 gene translocation fgfr3 positive fibroblast growth factor receptor 3 (fgfr3) fibroblast growth factor receptor 3 alterations locally advanced cancer metastatic cancer solid tumors urothelial cancer urothelial carcinoma urinary tract cancer urinary tract tumor urinary tract carcinoma