Open-Label Surufatinib in European Patients With NET

The DCR was defined as the percentage of patients who achieved a best overall response (BOR) of complete response (CR), partial response (PR) or stable disease (SD) as determined by the Investigator using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. The CR was defined as disappearance of all target lesions. The PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum on study.

Time frame: RECIST assessments performed at screening (within 28 days before start of study drug), every 8 weeks for the first 24 weeks from C1D1, then every 12 weeks thereafter until the occurrence of disease progression, up to approximately 36 months

Population: The efficacy analysis set included all patients who received at least 1 dose of surufatinib and had at least 1 post-baseline tumor assessment.

Participants were administered midazolam, fexofenadine and rosuvastatin (as part of the drug cocktail) as a single dose on Day -2 (without surufatinib) and on Cycle 1 Day 15 (with surufatinib). Separate blood samples were collected for measurement of plasma concentrations of each probe substrate and surufatinib. Probe substrate of midazolam was CYP3A4, fexofenadine was P-gp and rosuvastatin was BCRP. Ratio of LS Mean for maximum plasma concentration (Cmax), area under the plasma concentration-time curve from time 0 to time of last measurable concentration (AUC0-t) and area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf) are presented as Cycle 1 Day 15/Day -2.

Time frame: Baseline (Day -2) and Cycle 1 Day 15

Population: The PK evaluable population included all patients who received at least 1 dose of the study drug and had sufficient concentration data to derive at least 1 PK parameter.

The DoR was defined as the time from the first time that the objective response reached CR or PR, whichever came first (and later confirmed), until the occurrence of PD or death. The CR was defined as disappearance of all target lesions. The PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. The PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (nadir), including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters. The appearance of 1 or more new lesions was also considered progression.

Time frame: RECIST assessments performed at screening (within 28 days before start of study drug), every 8 weeks for the first 24 weeks from C1D1, then every 12 weeks thereafter until the occurrence of disease progression, up to approximately 36 months

Population: The efficacy analysis set included all patients who received at least 1 dose of surufatinib and had at least 1 post-baseline tumor assessment. Only those patients who achieved CR or PR (responders) were included in the analysis.

The QT interval data was corrected for heart rate using 2 correction methods (Fridericia - QTcF and Bazett - QTcB). The treatment period was defined as the period from first administration of study drug up 30 days after last administration. msec=milliseconds, IFB=increase from baseline.

Time frame: From the first dose of study drug (Day 1) up to 30 days after last dose of study drug, approximately 33 months

Population: The safety analysis set included all patients who received at least 1 dose of surufatinib. Only those patients with data collected are reported.

An AE is any untoward medical occurrence in a clinical study patient temporally associated with the use of a study drug, whether or not considered related to the drug. An SAE was an AE that resulted in any of the following outcomes: death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; a congenital anomaly/birth defect or was any important medical event. TEAEs were defined as any AEs that started or worsened in severity on or after the first administration date of study drug and no later than 30 (+7) days after the last administration date of study drug or initiation of new anti-tumor therapy (whichever occurred first).

Time frame: From the first dose of study drug (Day 1) up to 30 days after last dose of study drug, approximately 33 months

Population: The safety analysis set included all patients who received at least 1 dose of surufatinib.

The ORR was defined as the percentage of patients with a BOR of CR or PR as determined by the Investigator using RECIST v1.1. The CR was defined as disappearance of all target lesions. The PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.

Time frame: RECIST assessments performed at screening (within 28 days before start of study drug), every 8 weeks for the first 24 weeks from C1D1, then every 12 weeks thereafter until the occurrence of disease progression, up to approximately 36 months

Population: The efficacy analysis set included all patients who received at least 1 dose of surufatinib and had at least 1 post-baseline tumor assessment.

Blood samples were collected at specified timepoints to obtain plasma concentrations of surufatinib at steady state on Cycle 1 Day 15.

Time frame: Cohorts A, B and C: Pre-dose and 1, 2, 3, 4 hours post-dose on Cycle 1 Day 15; Cohort D: Pre-dose and 30 minutes, 1, 2, 3, 4, 5, 6, 8 and 10 hours post-dose on Cycle 1 Day 15

Population: The pharmacokinetic (PK) analysis set included all patients who received at least 1 dose of the study drug and had at least 1 measurable plasma concentration data point for at least 1 PK analyte without protocol violations or events with potential to affect the PK concentration. Only those participants with data collected at specified timepoints are reported.

The PFS was defined as the time from the start of study drug until the first objective PD as defined by RECIST v1.1 or death, whichever came first. The PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (nadir), including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters. The appearance of 1 or more new lesions was also considered progression.

Time frame: RECIST assessments performed at screening (within 28 days before start of study drug), every 8 weeks for the first 24 weeks from C1D1, then every 12 weeks thereafter until the occurrence of disease progression, up to approximately 36 months

Population: The safety analysis set included all patients who received at least 1 dose of surufatinib.

The TTR was defined as the time from the start of study drug until the date of first documented objective response, either CR or PR (whichever was recorded first) according to RECIST v.1.1 for responders only. The CR was defined as disappearance of all target lesions. The PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.

Time frame: RECIST assessments performed at screening (within 28 days before start of study drug), every 8 weeks for the first 24 weeks from C1D1, then every 12 weeks thereafter until the occurrence of disease progression, up to approximately 36 months

Population: The efficacy analysis set included all patients who received at least 1 dose of surufatinib and had at least 1 post-baseline tumor assessment. Only those patients who achieved CR or PR (responders) were included in the analysis.