Patients
death, tumor, melanoma, toxicity, unresectable melanoma, non-malignant disease, Gilbert’s Disease
BRAIN METASTASIS, TUMOR, HEPATIC DISORDER, MELANOMA, DISEASE, SOLID TUMORS, VIRAL INFECTION, S; HEMOGLOBIN, ONCOLOGY, LYMPHOMA, LIVER METASTASIS
Eligible patients were aged ≥ 18 years, with relapsed or refractory advanced solid tumors (excluding lymphoma but including melanoma), who had progressed on/after, or were not candidates for standard therapies or for whom no approved therapy was available (dose escalation phase and PK cohort of dose expansion phase) or who had locally advanced, metastatic, and/or unresectable melanoma which met predefined cohort-specific molecular or prior treatment criteria (dose expansion phase; Supplementary Table S1). Other key eligibility requirements included an Eastern Cooperative Oncology Group performance status ≤ 1, an expected survival time of at least 3 months, thyroid function tests consistent with stable thyroid function, a left ventricular ejection fraction of 50% or greater, as measured by echocardiogram or multiple-gated acquisition scan performed within 28 days before the first dose of tovorafenib, and suitable venous access for study-required blood sampling.Previous chemotherapy and hormone therapy were to have been completed at least 4 weeks or 4 half-lives, whichever occurred first, prior to administration of tovorafenib. Previous immunotherapy/monoclonal antibody use had to have been completed at least 4 weeks and radiation therapy at least 3 weeks prior to the administration of tovorafenib. Prior treatment with programmed cell death protein 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) monoclonal antibodies was permitted with a washout period of ≥ 6 weeks, provided there was no observed tumor shrinkage during that time relative to the previous progression scan. All associated toxicity from previous therapies had to have been resolved to ≤ grade 1 prior to administration of tovorafenib.Exclusion criteria included a history of any major disease that might interfere with safe protocol participation, inadequate organ function (absolute neutrophil count [ANC] ≤ 1500/μL; platelet count ≤ 75,000/μL; hemoglobin < 9 g/dL [hemoglobin could be supported by transfusion, erythropoietin, or other approved hematopoietic growth factors]; serum bilirubin ≥ 1.5 × upper limit of normal (ULN) or ≥ 2 × ULN if the patient was known to have Gilbert’s Disease as the only underlying hepatic disorder; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≥ 2.5 × ULN (AST and ALT ≥ 5 × ULN for patients with liver metastasis); serum creatinine ≥ 2.0 mg/dL); brain metastasis, unless previously treated with surgery, whole-brain radiation, or stereotactic radiosurgery and the disease had been stable for at least 2 months without steroid use or on a stable dose of steroids for at least 1 month prior to the first dose of tovorafenib; other active malignancy (dose expansion phase); evidence of current uncontrolled cardiovascular conditions; active bacterial or viral infection; prior investigational agents for malignant or non-malignant disease or major surgery within 28 days, or treatment with strong or moderate CYP3A/CYP2C inducers or gemfibrozil (strong CYP2C8 inhibitor) within 14 days, before the first dose of study drug. Female patients were excluded if they were pregnant or breastfeeding.