Clinical trial NCT02549937: A Multi-Center, Open-Label Study of Surufatinib (HMPL-012) in Patients With Advanced Solid Tumors
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Tumors
Keywords: biliary
pancreatic
neuroendocrine
carcinoid
PNET
EP-NET
extrapancreatic
sarcoma
soft tissue sarcoma
STS
BTC
Lead sponsor: Hutchmed
Sponsor class: INDUSTRY
First posted: 2015-09-15
Enrollment: 130
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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: 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 115 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Dose-Escalation Phase: Number of Patients With Dose-Limiting Toxicities (DLTs)
timeFrame: From the first dose of study drug (Day 1) up to Day 28 of Cycle 1
measure: Dose-Escalation Phase: Number of Patients With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
timeFrame: From the first dose of study drug (Day 1) up to approximately 90 months
measure: Dose-Expansion Phase: Arms A and D: Progression Free Survival (PFS) Rate at 16 Weeks
timeFrame: At 16 weeks
measure: Dose-Expansion Phase: Arms B and C: PFS Rate at 11 Months
timeFrame: At 11 months
Secondary outcomes:
measure: Dose-Escalation and Dose-Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of Surufatinib
timeFrame: Pre-dose and 1, 2, 4, 6, 8 hours post-dose on Days 1 and 15 of Cycle 1
measure: Dose Escalation and Dose-Expansion Phase: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Surufatinib
timeFrame: Pre-dose and 1, 2, 4, 6, and 8 hours post-dose on Days 1 and 15 of Cycle 1
measure: Dose-Escalation and Dose-Expansion Phase: Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24h) of Surufatinib
timeFrame: Pre-dose and 1, 2, 4, 6, and 8 hours post-dose on Cycle 1 Day 1
measure: Dose-Escalation and Dose-Expansion Phase: AUC Over the Dosing Interval (AUCtau) of Surufatinib
timeFrame: Pre-dose and 1, 2, 4, 6, and 8 hours post-dose on Day 15 of Cycle 1
measure: Dose-Escalation and Dose-Expansion Phase: Objective Response Rate (ORR)
timeFrame: RECIST assessments performed at screening (within 28 days before start of study treatment), Day 1 of Cycle 2, and every 8 (+/-1 week) weeks afterwards until the occurrence of disease progression, up to a maximum of 90 months
measure: Dose-Escalation and Dose-Expansion Phase: Disease Control Rate (DCR)
timeFrame: RECIST assessments performed at screening (within 28 days before start of study treatment), Day 1 of Cycle 2, and every 8 (+/-1 week) weeks afterwards until the occurrence of disease progression, up to a maximum of 90 months
measure: Dose-Escalation and Dose-Expansion Phase: Duration of Response (DoR)
timeFrame: RECIST assessments performed at screening (within 28 days before start of study treatment), Day 1 of Cycle 2, and every 8 (+/-1 week) weeks afterwards until the occurrence of disease progression, up to a maximum of 90 months
measure: Dose-Escalation Phase: Progression-Free Survival (PFS)
timeFrame: RECIST assessments performed at screening (within 28 days before start of study treatment), Day 1 of Cycle 2, and every 8 (+/-1 week) weeks afterwards until the occurrence of disease progression, up to a maximum of 53 months
measure: Dose-Expansion Phase: Time to Response (TTR)
timeFrame: RECIST assessments performed at screening (within 28 days before start of study treatment), Day 1 of Cycle 2, and every 8 (+/-1 week) weeks afterwards until the occurrence of disease progression, up to a maximum of 53 months
measure: Dose-Escalation and Dose-Expansion Phase: Maximum Percentage Change From Baseline in Tumor Size as Per RECIST v1.1
timeFrame: RECIST assessments performed at screening (within 28 days before start of study treatment), Day 1 of Cycle 2, and every 8 (+/-1 week) weeks afterwards until the occurrence of disease progression, up to a maximum of 90 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Denver
country: United States
facility: Rocky Mountain Cancer Center
state: Colorado
city: Denver
country: United States
facility: SCRI at HealthONE
state: Colorado
city: Sarasota
country: United States
facility: Florida Cancer Specialists
state: Florida
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Nashville
country: United States
facility: Tennessee Oncology
state: Tennessee
city: Dallas
country: United States
facility: Mary Crowley Cancer Research Center
state: Texas
city: Dallas
country: United States
facility: Baylor Charles A. Sammons Cancer Center
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
Study officials:
affiliation: Hutchmed
name: Marjo Hahka-Kemppinen, MD, PhD
role: STUDY_DIRECTOR
References: