A Multi-Center, Open-Label Study of Surufatinib (HMPL-012) in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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Primary Objective Dose Escalation: To evaluate the safety and tolerability of surufatinib in patients with advanced solid tumors and to determine the maximum tolerable dose (MTD) or recommended phase II dose (RP2D). Primary Objective Dose Expansion: To evaluate the anticancer activity of surufatinib in patients with advanced Biliary Tract Cancer (BTC), patients with advanced pancreatic neuroendocrine tumors (pNETs), patients with locally advanced, unresectable, metastatic extra-pancreatic neuroendocrine tumors (EP-NETs), and patients with soft tissue sarcomas (STS) treated at a dose of 300 mg QD. Secondary Objective: To evaluate the pharmacokinetic profile of multiple dose surufatinib in patients with advanced solid tumors and to evaluate the anti cancer activity of surufatinib in patients with advanced solid tumors.

Detailed Description
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The study is an open-label, dose escalation and expansion clinical trial of surufatinib orally once daily (QD) in patients with advanced solid tumors. The study consists of two phases: Dose escalation phase - A 3+3 design will be used for this portion of the study. Approximately 15 to 35 evaluable patients will be enrolled. The actual number of patients depends on the Dose-limiting toxicity (DLT) situation as well as the RP2D dose level reached in this trial. The trial will approximately evaluate five surufatinib dose levels at 50,100, 200, 300 and 400 mg/day. Expansion phase: Approximately 105 patients will be enrolled into one of four open-label treatment arms during this phase: at least 30 patients with advanced BTC that has progressed on standard ﬁrst-line chemotherapy will be assigned to Arm A, at least 15 patients with advanced pNET that has progressed on either everolimus, sunitinib, or both will be assigned to Arm B, at least 15 patients with advanced EP-NET that has progressed on everolimus will be assigned to Arm C, and at least 45 patients with Soft Tissue Sarcoma will be assigned to Arm D. Subjects enrolled in this phase are to be evaluated for the safety, tolerability and pharmacokinetic (PK) characteristics to confirm the selected surufatinib dose. Subjects will receive surufatinib daily treatment continuously with every 28-day treatment cycle until disease progression, death, or intolerable toxicity at the investigator's discretion for a favorable benefit to risk balance.

Official Title
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A Multi-Center, Open-Label, Clinical Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Surufatinib (HMPL-012), Previously Named Sulfatinib in Advanced Solid Tumors

Conditions
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Tumors

Intervention / Treatment
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* Drug: surufatinib


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Fully understand the study and voluntarily sign the informed consent form; At least 18 years old; Histologically or cytologically documented, locally advanced or metastatic solid malignancy of any type during the dose escalation phase, that has progressed on available standard systemic therapy, and for whom no effective therapy or standard of care exists; and locally advanced or metastatic BTC that has progressed on standard ﬁrst-line chemotherapy; locally advanced or metastatic pNET that has progressed on everolimus, sunitinib or both; locally advanced or metastatic EP-NET that has progressed on everolimus; advanced STS that has progressed on at least one line of standard therapy or refused standard frontline cytotoxic chemotherapy during the expansion phase; Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Exclusion Criteria: Hypertension that is not controlled by antihypertension medication, defined as: systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg; History or presence of digestive tract diseases, including active gastric/duodenal ulcer or ulcerative colitis, or active hemorrhage of an unresected gastrointestinal tumor, or an evaluation by investigators of having any other condition that could possibly result in gastrointestinal tract hemorrhage or perforation; History or presence of serious hemorrhage , hemoptysis or hematemesis within 3 months or a thromboembolic event (including Deep Vein Thrombosis (DVT), stroke and/or transient ischemic attack) within 6 months; Patients with squamous Non Small Cell Lung Cancer (NSCLC) should be excluded; Clinically significant cardiovascular disease, including but not limited to, acute myocardial infarction within 6 months prior to enrollment, severe/unstable angina pectoris or coronary artery bypass grafting, New York Heart Association Class III/IV congestive heart failure, ventricular arrhythmias requiring treatment or left ventricular ejection fraction (LVEF) < 50%; Systemic anti-neoplastic therapies within 4 weeks prior to the initiation of investigational treatment, including chemotherapy, radical radiotherapy, hormonotherapy, biotherapy and immunotherapy; Palliative radiotherapy for bone metastasis/lesion within 2 weeks; Known Human immunodeficiency virus (HIV) infection; Known clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis; Women who are pregnant or lactating; Brain metastases and/or spinal cord compression untreated with surgery and/or radiotherapy, and without clinical imaging evidence of stable disease for 14 days or longer; Subjects requiring steroids within 4 weeks prior to start of study treatment will be excluded; Inability to take medication orally, dysphagia or an active gastric ulcer resulting from previous surgery or a severe gastrointestinal disease, or any other condition that investigators believe may affect absorption of the investigational product; Received investigational treatment in another clinical study within 4 weeks prior to the initiation of investigational treatment; Other disease, metabolic disorder, physical examination anomaly, abnormal laboratory result, or any other condition that investigators suspect may prohibit use of the investigational product, affect interpretation of study results, or put the patient at high risk.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Escalation 50 mg<br>Escalation cohort at 50 mg/day | Drug: surufatinib<br>* orally once daily (QD) in patients with advanced solid tumor.<br>* Other names: sulfatinib;|
| Experimental: Escalation 100mg<br>Escalation cohort at 100 mg/day | Drug: surufatinib<br>* orally once daily (QD) in patients with advanced solid tumor.<br>* Other names: sulfatinib;|
| Experimental: Escalation 200 mg<br>Escalation cohort at 200 mg/day | Drug: surufatinib<br>* orally once daily (QD) in patients with advanced solid tumor.<br>* Other names: sulfatinib;|
| Experimental: Escalation 300 mg<br>Escalation cohort at 300 mg/day | Drug: surufatinib<br>* orally once daily (QD) in patients with advanced solid tumor.<br>* Other names: sulfatinib;|
| Experimental: Escalation 400 mg<br>Escalation cohort at 400 mg/day | Drug: surufatinib<br>* orally once daily (QD) in patients with advanced solid tumor.<br>* Other names: sulfatinib;|
| Experimental: Expansion<br>Subjects will receive RP2D surufatinib daily treatment continuously with every 28-day treatment cycle. Four expansion cohorts will enroll BTC, pNET, EP-NET, and STS patients, respectively. | Drug: surufatinib<br>* orally once daily (QD) in patients with advanced solid tumor.<br>* Other names: sulfatinib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of DLT | The primary outcome during dose escalation will be the incidence rate of DLTs | From date of enrollment through end of Cycle 1, up to 28 days | 
| Progression Free Survival (PFS) rate | The primary outcome during dose expansion will be the PFS rate for each cohort | From date of enrollment to progression or death up to 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| maximum plasma concentration calculated with Blood samples | Blood samples will be taken to measure the levels of study drug. | within 30 days after the first dose | 
| time to reach maximum concentration calculated with Blood samples | Blood samples will be taken to measure the levels of study drug | within 30 days after the first dose | 
| Objective response rate | the proportion of subjects who have a Complete Response or Partial Response | within 30 days after the last dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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biliary, pancreatic, neuroendocrine, carcinoid, PNET, EP-NET, extrapancreatic, sarcoma, soft tissue sarcoma, STS, BTC