Open-Label Surufatinib in European Patients With NET

Phase 2

Terminated

Conditions: Neuroendocrine Tumours
Neuroendocrine Tumour of the Lung
Small Intestinal NET

Interventions: Drug: Surufatinib

Registration Number: NCT04579679

Lead Sponsor: Hutchmed

Brief Summary: This is a Phase 2, open-label, multi-centre study of surufatinib in patients with low to intermediate grade (Grade 1 or Grade 2), well-differentiated neuroendocrine tumours (NETs).

Detailed Description: This is a Phase 2, open-label, multi-centre study of surufatinib in patients with low- to intermediate-grade (Grade 1 or Grade 2), well-differentiated NETs.

The study will enroll 4 cohorts of varying NETs, as follows:

* Cohort A - NET of lung origin

* Cohort B - NET of small bowel origin

* Cohort C - NET of non-small bowel, non-pancreas, and non-lung origin

* Cohort D - NET of any origin (DDI substudy)

All patients will be treated with oral surufatinib 300 mg QD in treatment cycles of 28 days starting on Cycle 1 Day 1.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 78

Inclusion Criteria

Has histologically or cytologically documented, locally advanced, or metastatic NET and has progressed on at least 1 prior line of therapy, but no more than 3 therapies;
Has radiologic evidence of progressive tumour within 12 months of study enrolment
Is willing and able to provide informed consent
Is ≥18 years of age
Has measurable lesions according to RECIST Version 1.1
Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Female patients of childbearing potential and male patients with partners of childbearing potential agree to use a highly effective form(s) of contraception

Key

Exclusion Criteria

Has an AE due to previous anti-tumour therapy that has not recovered to ≤CTCAE Grade 1, except alopecia and peripheral neurotoxicity with ≤CTCAE Grade 2 caused by platinum chemotherapy
Major surgery within previous 4 weeks or radiation therapy within 2 weeks prior to the start of treatment.
Prior VEGF/VEGFR-targeted therapy
Uncontrollable hypertension, defined as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg, despite antihypertensive medication
Gastrointestinal disease or condition within 6 months prior to first dose
Has a history or presence of a serious haemorrhage (>30 mL within 3 months) or haemoptysis (>5 mL blood within 4 weeks) within 6 months of first dose of study drug.
Clinically significant cardiovascular disease.
Brain metastases and/or spinal cord compression untreated with surgery and/or radiotherapy, and without clinical imaging evidence of stable disease (SD) for 14 days or longer; patients requiring steroids within 4 weeks prior to start of study treatment will be excluded.
A high risk of bleeding at screening due to tumour invasion into major vessels, such as pulmonary artery, the superior vena cava, or the inferior vena cava, as determined by investigators.
Has arterial thrombosis or deep venous thrombosis within 6 months prior to first dosing, or thromboembolic events (including stroke and/or transient ischaemic attack) within 12 months.
Has a clinically meaningful ongoing infection (eg, requiring intravenous treatment with anti-infective therapy)

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Surufatinib	Surufatinib	Cohorts A, B, and C: oral surufatinib 300 mg once daily in treatment cycles of 28 days starting at Cycle 1 Day1 Cohort D: Surufatinib 300 mg once daily in treatment cycles of 28 days starting at Cycle 1 Day and single doses of drug cocktail on Day-2 and Day 15 Cycle 1

Primary Outcome Measures

Name	Time	Method
Disease Control Rate (DCR)	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	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.

Secondary Outcome Measures

Name	Time	Method
Plasma Concentrations of Surufatinib	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	Blood samples were collected at specified timepoints to obtain plasma concentrations of surufatinib at steady state on Cycle 1 Day 15.
Number of Patients With Potentially Clinically Significant Corrected QT Interval (QTc) During Treatment	From the first dose of study drug (Day 1) up to 30 days after last dose of study drug, approximately 33 months	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.
Objective Response Rate (ORR)	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	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 to Response (TTR)	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	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.
Duration of Response (DOR)	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	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.
Progression-Free Survival (PFS)	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	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.
Cohort D: Geometric Least Squares (LS) Mean Ratio of Cytochrome P450 (CYP3A4), P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) Substrates at Cycle 1 Day 15 to Baseline	Baseline (Day -2) and Cycle 1 Day 15	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.
Number of Patients With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)	From the first dose of study drug (Day 1) up to 30 days after last dose of study drug, approximately 33 months	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).

Trial Locations

Locations (23): University of Alabama, Birmingham (UAB)
🇺🇸
Birmingham, Alabama, United States
University of California Irvine Medical Center UCIMC - H.H. Chao Comprehensive Digestive Disease Center CDDC
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Orange, California, United States
Emory University, Winship Cancer Institute
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Atlanta, Georgia, United States
Stony Brook Cancer Center
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Stony Brook, New York, United States
Houston Methodist
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Houston, Texas, United States
CHU Bordeaux
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Pessac, France
Institut Gustave Roussy
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Villejuif, France
Charite Universitatsmedizin Berlin
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Berlin, Germany
Universitaetsklinikum Erlangen
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Erlangen, Germany
Universitatsklinikum Essen, Klinik fur Endokrinologie
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Essen, Germany
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University of Alabama, Birmingham (UAB)
🇺🇸Birmingham, Alabama, United States