A Multi-Center, Open-Label Study of Surufatinib (HMPL-012) in Patients With Advanced Solid Tumors
- Registration Number
- NCT02549937
- Lead Sponsor
- Hutchmed
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 130
- 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
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Escalation 50 mg surufatinib Escalation cohort at 50 mg/day Escalation 200 mg surufatinib Escalation cohort at 200 mg/day Escalation 100mg surufatinib Escalation cohort at 100 mg/day Escalation 300 mg surufatinib Escalation cohort at 300 mg/day Expansion surufatinib 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. Escalation 400 mg surufatinib Escalation cohort at 400 mg/day
- Primary Outcome Measures
Name Time Method Dose-Escalation Phase: Number of Patients With Dose-Limiting Toxicities (DLTs) From the first dose of study drug (Day 1) up to Day 28 of Cycle 1 A DLT was defined as any of the following toxicities determined by the Investigator to have a reasonable possibility of being related to surufatinib. Adverse events (AE) were graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Any Grade 4 non-hematological toxicity; any Grade 3 non-hematological toxicity except for nausea/vomiting, diarrhea, constipation, electrolyte imbalances, or transient hypertension downgraded within 3 days with appropriate supportive treatment; Grade 4 neutropenia lasting \>7 days; Grade 3 febrile neutropenia (absolute neutrophil count \<1.0 × 10\^9/liter (L) with a single temperature of \>38.3 degree Celsius (°C) or a sustained temperature of \>=38°C for more than 1 hour; Grade 4 thrombocytopenia or \>=Grade 3 thrombocytopenia associated with tendency to bleed; dose interruption or delay for \>14 days due to toxicity; any life-threatening complication or abnormality not covered in NCI CTCAE v. 4.03.
Dose-Escalation Phase: 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 approximately 90 months An AE was any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a drug or other protocol-imposed drug, regardless of attribution. An SAE was an AE that resulted in any of the following outcomes: was fatal; was life threatening; required or prolonged inpatient hospitalization; resulted in persistent or significant disability/incapacity; a congenital anomaly/birth defect in a neonate/infant born to a female patient or female partner of a male patient exposed to the study drug(s); was considered a significant medical event by the Investigator. 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).
Dose-Expansion Phase: Arms A and D: Progression Free Survival (PFS) Rate at 16 Weeks At 16 weeks The tumor response was determined according to the international Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 guideline. PFS is defined as the time (in months) from the start date of study medication (Day 1) until the date of objective disease progression as defined by RECIST Version 1.1 or death (by any cause in the absence of progression), whichever occurred earlier. PFS rate probability at 16 week was estimated. Progression is defined by RECIST v1.0 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 or appearance of 1 or more new lesions.
Dose-Expansion Phase: Arms B and C: PFS Rate at 11 Months At 11 months The tumor response was determined according to the RECIST v1.1 guideline. PFS is defined as the time (in months) from the start date of study medication (Day 1) until the date of objective disease progression as defined by RECIST Version 1.1 or death (by any cause in the absence of progression), whichever occurred earlier. PFS rate probability at 11 months was estimated. Progression is defined by RECIST v1.0 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 or appearance of 1 or more new lesions.
- Secondary Outcome Measures
Name Time Method Dose Escalation and Dose-Expansion Phase: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Surufatinib Pre-dose and 1, 2, 4, 6, and 8 hours post-dose on Days 1 and 15 of Cycle 1 Plasma samples were collected to determine Tmax of surufatinib. The PK parameters were determined by non-compartmental analysis.
Dose-Escalation and Dose-Expansion Phase: Objective Response Rate (ORR) 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 The ORR was defined as the percentage of patients achieving a complete response (CR) or partial response (PR) as confirmed best overall response (BOR) as determined by the Investigator using RECIST v1.1. The BOR was defined as the best response recorded from the start of study treatment until documented RECIST version 1.1 progression, death, or withdrawal of consent. 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.
Dose-Escalation and Dose-Expansion Phase: Maximum Percentage Change From Baseline in Tumor Size as Per RECIST v1.1 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 Percentage change in tumor size was determined for patients with measurable disease at baseline and was derived at each visit by the percentage change in the sum of the diameters of target lesions compared to baseline, mean of maximum percentage change is presented. Baseline was defined as the last evaluable tumor assessment result obtained prior to the administration of study drug (including unscheduled assessments).
Dose-Escalation and Dose-Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of Surufatinib Pre-dose and 1, 2, 4, 6, 8 hours post-dose on Days 1 and 15 of Cycle 1 Plasma samples were collected to determine Cmax of surufatinib. The pharmacokinetic (PK) parameters were determined by non-compartmental analysis.
Dose-Escalation and Dose-Expansion Phase: AUC Over the Dosing Interval (AUCtau) of Surufatinib Pre-dose and 1, 2, 4, 6, and 8 hours post-dose on Day 15 of Cycle 1 Plasma samples were collected to determine AUCtau of surufatinib. The PK parameters were determined by non-compartmental analysis.
Dose-Escalation and Dose-Expansion Phase: Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24h) of Surufatinib Pre-dose and 1, 2, 4, 6, and 8 hours post-dose on Cycle 1 Day 1 Plasma samples were collected to determine AUC0-24h of surufatinib. The PK parameters were determined by non-compartmental analysis. Data from pre-dose to 8 hours post-dose were extrapolated to obtain the AUC0-24 data.
Dose-Escalation and Dose-Expansion Phase: Disease Control Rate (DCR) 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 The DCR was defined as the percentage of patients who achieved a CR, PR or stable disease (SD) as confirmed BOR 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. 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.
Dose-Escalation and Dose-Expansion Phase: Duration of Response (DoR) 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 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.
Dose-Escalation Phase: Progression-Free Survival (PFS) 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 The PFS was defined as the time from the start date of study drug until the date of objective PD as assessed by the Investigator using RECIST version 1.1 or death (by any cause in the absence of progression).
Dose-Expansion Phase: Time to Response (TTR) 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 The TTR was defined as the time from the start of study drug until first documented response (and later confirmed) according to RECIST v.1.1 for responders only.
Trial Locations
- Locations (12)
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Rocky Mountain Cancer Center
🇺🇸Denver, Colorado, United States
Tennessee Oncology
🇺🇸Nashville, Tennessee, United States
City of Hope Comprehensive Cancer Center
🇺🇸Los Angeles, California, United States
SCRI at HealthONE
🇺🇸Denver, Colorado, United States
Florida Cancer Specialists
🇺🇸Sarasota, Florida, United States
Mount Sinai Hospital
🇺🇸New York, New York, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Mary Crowley Cancer Research Center
🇺🇸Dallas, Texas, United States
Baylor Charles A. Sammons Cancer Center
🇺🇸Dallas, Texas, United States
Fondazione IRCCS Istituto Nazionale dei Tumori
🇮🇹Milano, Italy
Virginia Cancer Specialists, PC
🇺🇸Fairfax, Virginia, United States