safety and anti-tumor activity of tyra-200 in advanced cholangiocarcinoma with activating fgfr2 gene alterations

Conditions: Locally Advanced Cholangiocarcinoma; Intrahepatic Cholangiocarcinoma; Solid Tumor; Metastatic Cholangiocarcinoma

Summary: the purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (pk), and preliminary antitumor activity of tyra-200 in cancers with fgfr2 activating gene alterations, including unresectable locally advanced/metastatic intrahepatic cholangiocarcinoma and other advanced solid tumors.

this is a single arm, multi-part, phase 1 clinical trial studying tyra-200, a novel, potent fibroblast growth factor receptor (fgfr) 1/2/3 tyrosine kinase inhibitor, in unresectable locally advanced/metastatic intrahepatic cholangiocarcinoma and other advanced solid tumors with activating alterations in fgfr2. part a is a dose escalation study in participants with any advanced solid tumor with fgfr/fgf pathway alterations who have exhausted approved standard therapies. part a will evaluate the safety, tolerability, and pk of tyra-200 to determine the optimal and maximum tolerated dose (mtd). part b will evaluate the preliminary antitumor activity of tyra-200 in participants with unresectable locally advanced/metastatic intrahepatic cholangiocarcinoma who have previously received an fgfr inhibitor and have fgfr2 kinase-domain mutations resistant to other fgfr inhibitors.

Eligibility criteria:
inclusion criteria: phase 1 part a * men and women 18 years of age or older. * eastern cooperative oncology group (ecog) performance status of ≤1. * any histologically confirmed advanced solid tumor with fgfr/fgf pathway alterations including fgfr gene mutations, fusions, and amplifications, as well as gene amplifications of fgfr ligands, who have exhausted or refused approved standard therapies. * evaluable disease according to recist v1.1. phase 1 part b * men and women 18 years of age or older. * eastern cooperative oncology group (ecog) performance status of ≤1. * histologically confirmed locally advanced/metastatic intrahepatic cholangiocarcinoma with a previously identified fgfr2 gene mutation or rearrangement. * must have received a prior fgfr inhibitor. participants may have received more than 1 prior fgfr inhibitor. * presence of an fgfr2 kinase domain mutation that confers resistance to previous/other fgfr inhibitors; resistance mutations should be identified by a us food and drug administration authorized/approved companion diagnostic or a clinical laboratory improvement amendments (clia) validated local test performed in a certified laboratory. * at least 1 measurable lesion by recist v1.1. exclusion criteria: * discontinued a prior anti-fgfr therapy due to significant toxicity, defined as hepatotoxicity ≥grade 3 or any grade 4 toxicity according to ctcae v5.0. * 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-200. * females who are pregnant, breastfeeding, or planning to become pregnant and males who plan to father a child while enrolled in this study.

Keywords: fgfr2 gene activation fgfr2 gene alterations fgfr2 gene fusion/rearrangement fgfr2 gene mutation fgfr2 gene translocation fgfr2 fibroblast growth factor receptor 2 (fgfr2) fibroblast growth factor receptor 2 alterations locally advanced cancer metastatic cancer solid tumors cholangiocarcinoma intrahepatic cholangiocarcinoma unresectable cholangiocarcinoma metastatic cholangiocarcinoma fibroblast growth factor receptor inhibitor