Dose escalation and dose expansion
bleeding, neutropenia, diarrhea, toxicity, thrombocytopenia, constipation
ELECTROLYTE IMBALANCES, BLEEDING, DISEASE PROGRESSION, NEUTROPENIA, FEBRILE NEUTROPENIA, THROMBOCYTOPENIA, SOLID TUMORS, ADVERSE EVENT, HYPERTENSION
In the dose escalation phase, fruquintinib was administered sequentially in 2 successive cohorts, 3 and 5 mg PO QD on a 3/1 schedule on a 28-day cycle in a standard 3 + 3 design until the criteria for the MTD/RP2D were met. Dose-limiting toxicity (DLT)-evaluable patients must have met the following criteria: no previous anticancer therapy prior to DLT; completion of the first 28-day cycle with complete safety evaluation and reception of at least 85% of the assigned fruquintinib dose; or had a confirmed DLT during the first 28-day treatment cycle. If no more than 1 DLT occurred in the DLT observation window (Days 1–28 in Cycle 1 [C1]) among the 6 patients who received the 3 mg dose, DLT-evaluable patients were to be enrolled at the 5 mg dose level. If ≤ 1 patient experienced a DLT at the 5 mg dose level, then that dose level was declared the MTD/RP2D, and an additional 6 patients with solid tumors of any type were enrolled at the RP2D in the dose expansion phase (Cohort A). DLT assessment was only conducted for patients in the dose escalation phase.A DLT was defined as any grade 4 non-hematologic adverse event (AE); any grade 3 non-hematologic AE related to study drug with the exception of nausea/vomiting, diarrhea, constipation, hypertension, and electrolyte imbalances downgraded within 3 days with appropriate supportive treatment; grade 4 neutropenia lasting > 3 days; grade 3 febrile neutropenia; grade 4 thrombocytopenia or grade 3 thrombocytopenia associated with bleeding; or dose interruption for > 14 days due to toxicity. The MTD was defined as the highest dose at which no more than 1 of 6 patients experienced a DLT.Upon completion of dose escalation at the 3 and 5 mg dose levels and confirmation of the RP2D based on aggregated safety and PK data, additional patients were recruited in the expansion phase (Cohort A) at the RP2D to further characterize safety, tolerability, PK, and signals of clinical activity in patients with refractory solid tumors. Patients continued treatment until disease progression or any unacceptable toxicity, investigator decision to terminate therapy, or consent withdrawal.