Lirafugratinib for advanced solid tumors with an FGFR2 gene change, excluding bile duct cancer

Who can take part

• Subject is willing and able to provide informed consent for the study prior to the performance of any study-specific procedures
• Male or female subject ≥18 years of age
• Subject has a measurable disease per RECIST v1.1
• Subject has unresectable, locally advanced, or metastatic solid tumor (other than CCA) with FGFR2 f/r as detected by DNA or RNA sequencing or break-apart fluorescence in situ hybridization (defined in Appendix H), per local assessment of blood and/or tumor
• Subject has been previously (>30 days) treated with ≥1 line of systemic therapy including chemotherapy (e.g., gemcitabine/cisplatin), immunotherapy, radiation therapy, or other approved therapies
• Subject has not received prior treatment with an FGFRi
• Subject has an ECOG performance status of 0 or 1

Who cannot take part

• Subject requires treatment with a prohibited medication (Section 6.8.1) that cannot be discontinued at least 5 half-lives or 2 weeks (whichever is shorter) before the initiation of lirafugratinib
• Subject has had a major surgical procedure within 14 days of the first dose of lirafugratinib (procedures such as central venous catheter placement and tumor needle biopsy are not considered major surgical procedures). Study centers should discuss other minor surgeries with the Sponsor
• Subject has received anticancer therapy (including both systemic therapy and radiotherapy) within 14 days or 5 half-lives (whichever is shorter) and immunotherapy or other antibody therapy within 28 days prior to the first dose of lirafugratinib. Lirafugratinib may be started within these washout periods if considered by the Investigator to be safe and in the best interest of the subject, with prior Sponsor approval, provided immune-related toxicities in subjects who received previous immunotherapy have resolved to
• Subject has received locoregional hepatic therapy (e.g., transcatheter arterial chemoembolization or yttrium90) within 4 weeks prior to C1D1
• Subject has a history of another primary malignancy that has been diagnosed or required therapy within the past year. The following prior malignancies are not exclusionary: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate or breast cancer, curatively treated localized thyroid cancer, and completely resected carcinoma in situ of any site. Adjuvant hormonal therapy for previously treated breast cancer, prostate cancer, or another hormone-dependent solid tumor is not exclusionary
• Subject has documented history of and/or ongoing clinically significant ectopic mineralization/calcification
• Subject has known systemic hypersensitivity to lirafugratinib drug substance or inactive ingredients
• Subject has central nervous system (CNS) metastases or primary CNS tumor that is associated with progressive neurologic symptoms or requires increasing doses of corticosteroids to control the CNS disease. If a subject requires corticosteroids for management of CNS disease, the dose of corticosteroids must have been stable for the 2 weeks preceding C1D1. Subjects with stable or asymptomatic CNS metastases or primary CNS tumor may be eligible after consultation with the Sponsor
• Subject has received neutrophil growth factor support within 14 days of the first dose of lirafugratinib
• Subject is unwilling or unable to comply with scheduled visits, drug dosing regimen, laboratory tests, or other study procedures and study restrictions
• Pregnant female subjects, as documented by a serum beta human chorionic gonadotropin (β-hCG) pregnancy test consistent with pregnancy, obtained within 7 days prior to the first dose of lirafugratinib. Females with β-hCG values that are within the range for pregnancy but are not pregnant (false positives) may be enrolled with written consent of the Sponsor after pregnancy has been ruled out. Female subjects of nonchildbearing potential (postmenopausal for more than 1 year; bilateral tubal ligation; bilateral oophorectomy; total hysterectomy) do not require a serum β-hCG test
• Subject has prior or ongoing clinically significant disease, medical condition, surgical history, physical finding, or laboratory abnormality that, in the Investigator’s opinion, could affect the safety of the subject; alter the absorption, distribution, metabolism, or excretion of lirafugratinib; or impair the assessment of study results
• Subject has cancer other than FGFR2 f/r and has a known primary driver alteration that is amenable to approved targeted therapy (e.g., EGFR, ALK, ROS1, RET, HER2, BRAF, IDH1, KRAS). However, the subject may be eligible after consultation with the Sponsor
• Subject does not have the following adequate organ function assessments within 7 days prior to the first dose of lirafugratinib: a. Platelet count ≥75×109/L (platelet transfusion may be used to reach 75×109/L but must have been administered at least 2 weeks prior to the first dose of lirafugratinib) b. Absolute neutrophil count ≥1×109/L c. Hemoglobin ≥8 g/dL (red blood cell transfusion and erythropoietin may be used to reach 8 g/dL but must have been administered at least 2 weeks prior to the first dose of lirafugratinib) d. Aspartate aminotransferase or alanine aminotransferase <3× the upper limit of normal (ULN) if no hepatic metastases are present and <5×ULN if hepatic metastases are present e. Total bilirubin <1.5×ULN; <3×ULN, with direct bilirubin <1.5×ULN in the presence of Gilbert’s disease f. Estimated (including Cockcroft-Gault, Modification of Diet in Renal Disease [MDRD] or Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formulas [Appendix A]) or measured creatinine clearance >50 mL/min g. Serum phosphate <7.0 mg/dL (2.3 mmol/L)
• Subject has an active infection, including human immunodeficiency virus (HIV), hepatitis B virus (HBV), and/or hepatitis C virus (HCV) infectia. a. Active HIV infection is defined by positivity for HIV-1 or HIV-2 antibodies. Subjects who are HIV positive are allowed if all of the following criteria are met: CD4+ count ≥350/μL, undetectable viral load, receiving antiretroviral therapy (ART) that does not interact with lirafugratinib (subjects should be on established ART for at least 4 weeks), and no HIV/acquired immunodeficiency syndrome-associated opportunistic infection in the last 12 months (Uldrick 2017). b. Active HBV infection is defined by a positive HBV surface antigen (HBsAg) result. Subjects with a past or resolved HBV infection (defined as the presence of hepatitis B core [HBc] antibody, absence of HBsAg, and serum HBV DNA <1000 IU/mL) are eligible (Reddy 2014, Terrault 2018). Subjects with well-controlled HBV infection, indicated by presence of HBsAg with serum HBV DNA <500 IU/mL are also eligible. c. Subjects positive for HCV antibody are eligible only if the polymerase chain reaction is negative for HCV RNA
• Subject has a QT interval corrected using Fridericia’s formula >480 msec or a history of prolonged QT syndrome or Torsade de Pointes or a family history of prolonged QT syndrome
• Subject has clinically significant, uncontrolled cardiovascular disease, including congestive heart failure Class III or IV according to the New York Heart Association classification; myocardial infarction or unstable angina within the previous 6 months; uncontrolled hypertension (Grade 3 or higher); or clinically significant, uncontrolled arrhythmia, including bradyarrhythmia that may cause QT prolongation (e.g., type II second-degree heart block or third-degree heart block)
• Subject has uncontrolled comorbidity
• Female subjects, if not postmenopausal or surgically sterile, are unwilling to abstain from sexual intercourse or employ highly effective contraception during the treatment period and for at least 180 days (6 months) after the last dose of lirafugratinib. Male subjects, if not surgically sterile, are unwilling to abstain from sexual intercourse or employ highly effective contraception during the treatment period and for at least 90 days (3 months) after the last dose of lirafugratinib
• Female subjects who are breastfeeding