forager-1: a study of loxo-435 (ly3866288) in participants with cancer with a change in a gene called fgfr3

Conditions: Urinary Bladder Neoplasms; Neoplasm Metastasis; Ureteral Neoplasms

Summary: the main purpose of this study is to learn more about the safety, side effects, and effectiveness of loxo-435 by itself or when it is combined with other standard medicines that treat cancer. loxo-435 may be used to treat cancer of the cells that line the urinary system and other solid tumor cancers that have a change in a particular gene (known as the fgfr3 gene). participation could last up to 30 months (2.5 years) and possibly longer if the disease does not get worse.

this is an open-label, multi-center, phase 1 study in participants with fgfr3-altered advanced solid tumor malignancy including metastatic urothelial cancer (uc). the study will be conducted in 2 phases: phase 1a dose escalation (cohort a1) and dose optimization (cohort a2) and phase 1b dose expansion. phase 1a will assess safety, tolerability, and pharmacokinetics of loxo-435 to determine the optimal dose for further expansion. phase 1b will include 6 dose expansion cohorts to evaluate the efficacy and safety of loxo-435 as monotherapy or in combinations with pembrolizumab with or without enfortumab vedotin.

Eligibility criteria:
inclusion criteria: * have solid tumor cancer with an fgfr3 pathway alteration on molecular testing in tumor or blood sample that is deemed as actionable * cohort a1: presence of an alteration in fgfr3 or its ligands * cohort a2, b2, b3, and b5: histological diagnosis of urothelial cancer (uc) that is locally advanced or metastatic with a qualifying fgfr3 genetic alteration * cohorts b1 and b4: histological diagnosis of urothelial cancer that is locally advanced or metastatic * cohort c1: must have histological diagnosis of a non-urothelial solid tumor malignancy that is locally advanced or metastatic with a qualifying fgfr3 genetic alteration * measurability of disease: * cohort a1 and b3: measurable or non-measurable disease as defined by response evaluation criteria in solid tumors v 1.1 (recist v1.1) * cohorts a2, b1, b2, b4, b5, and c1: measurable disease required as defined by recist v1.1 * have adequate tumor tissue sample available. participants with inadequate tissue sample availability may still be considered for enrollment upon review * have an eastern cooperative oncology group (ecog) performance status of 0 or 1 for cohorts a1, a2, b3, and b5 * less than or equal to 2 for cohorts b1, b2, b4, and c1 * prior systemic therapy criteria: * cohort a1/c1: participant has received all standard therapies for which the participant was deemed to be an appropriate candidate by the treating investigator; or the participant is refusing the remaining most appropriate standard of care treatment; or there is no standard therapy available for the disease. there is no restriction on number of prior therapies. * cohort a2, b2, b3 participants must have received at least one prior regimen, and cohorts b1 and b4 participants at least 2 prior regimens, in the locally advanced or metastatic setting * there is no restriction on number of prior therapies * cohort b5: participants have not received prior systemic therapy for locally advanced or metastatic uc * fgfr inhibitor specific requirements: * cohort a1/a2/b3: prior fgfr inhibitor treatment is permitted but not required * cohort b1/b4: participants must have been previously treated with erdafitinib * cohort b2, b5, and c1: participants must be fgfr inhibitor naïve exclusion criteria: * participants with primary central nervous system (cns) malignancy * untreated or uncontrolled cns metastases * current evidence of corneal keratopathy or retinal disorder. individuals with asymptomatic ophthalmic conditions may be eligible * any serious unresolved toxicities from prior therapy * significant cardiovascular disease * prolongation of the qt interval corrected for heart rate using fridericia's formula (qtcf) * active uncontrolled systemic infection or other clinically significant medical conditions * participants who are pregnant, lactating, or plan to breastfeed during the study or within 6 months of the last dose of study treatment. participants who have stopped breastfeeding may be enrolled

Keywords: bladder cancer bladder urothelial carcinoma urinary bladder cancer urinary tract cancer renal pelvis cancer ureter cancer