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

The study is an open-label, dose escalation clinical trial of sulfatinib orally once daily
(QD) in patients with advanced solid tumor.

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 30 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 sulfatinib dose levels at 50,100, 200, 300
and 400 mg/day.

Expansion phase:

The expansion phase will confirm the MTD with an additional 6 patients enrolled in the 400
mg/day escalation cohort. In consultation with the study investigators, observed toxicities,
tolerability, and drug exposure will be evaluated.

Approximately 30 patients will be enrolled into one of two open-label treatment arms during
this phase: at least 15 patients with advanced BTC that has progressed on standard first-line
chemotherapy will be assigned to Arm A, and at least 15 patients with advanced pNET that has
progressed on either everolimus, sunitinib, or both will be assigned to Arm B. Subjects
enrolled in this phase are to be evaluated for the safety, tolerability and pharmacokinetic
(PK) characteristics to confirm the selected sulfatinib dose.

Subjects will receive sulfatinib 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.

Inclusion Criteria:

1. Fully understand the study and voluntarily sign the informed consent form;

2. At least 18 years old;

3. 3. 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, and locally advanced or metastatic pNET that has progressed on
everolimus, sunitinib or both, during the expansion phase;

4. Evaluable or measurable disease per Response Evaluation Criteria in Solid Tumors
Version (RECIST)1.1

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

6. Expected survival of more than 12 weeks;

7. Male or female patients of child-producing potential must agree to use two methods of
the following contraceptive: condoms,intrauterine device (IUD), contraceptives (oral
or parenteral), Implanon, injectables during the study and up to 90 days post the last
day of study treatment.

Exclusion Criteria:

1. Absolute neutrophil count (ANC) of < 1.5×109/L, or platelet count of < 100 ×109/L, or
hemoglobin < 9g/dL;

2. Serum total bilirubin > 1.5 times the upper limit of normal (ULN);

3. Alanine aminotransaminase (ALT), Aspartate aminotransaminase (AST) or alkaline
phosphatase (ALP) > 2.5 ULN without hepatic metastases or ALT, AST or ALP > 5 ULN with
hepatic metastases

4. Clinically significant abnormal serum potassium (regardless of potassium agent
supplementation); serum calcium (ionic or binding to albumin post-adjusted) or serum
magnesium (regardless of magnesium agent supplementation);

5. Serum creatinine clearance < 60 ml/min on the basis of either 24-hour urine collection
or the glomerate filtration rate estimated by Cockraft-Gault equation

6. Urine protein > 2+; Patients discovered to have ≥ 1+ proteinuria on dipstick
urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate
< 1 g of protein in 24-hour urine;

7. Uncontrolled hypertension, defined as: systolic blood pressure ≥ 140 mmHg and/or
diastolic blood pressure ≥ 90 mmHg;

8. International Normalized Ratio (INR) > 1.5 ULN or activated partial thromboplastin
time (aPTT) > 1.5 ULN. Subject is currently receiving or intending to receive
anti-coagulants for therapeutic purposes. Prophylactic use of anticoagulants is
allowed.

9. 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;

10. 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.

11. 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%;

12. Mean corrected QT interval (QTc) > 480 msec or any factors that increase the risk of
QTc prolongation or risk of arrhythmic events such as hypokalaemia, congenital long QT
syndrome, family history of long QT syndrome or unexplained sudden death under 40
years of age in a next-of-kin relative.

13. Currently use medications known to cause QT prolongation or Torsades de Pointes.

14. Systemic anti-neoplastic therapies within 4 weeks prior to the initiation of
investigational treatment, including chemotherapy, radical radiotherapy,
hormonotherapy, biotherapy and immunotherapy;

15. Palliative radiotherapy for bone metastasis/lesion within 2 weeks prior to the
initiation of study treatment;

16. Strong inducers or inhibitors of CYP3A4 within 2 weeks before the first dose of study
treatment (3 weeks for St John‟s Wort).

17. Surgery prior to enrollment within 28 days prior to the initiation of study treatment
or unhealed surgical incision;

18. Toxicity from a previous anti-tumor treatment that does not return to Grade 0 or 1
(except for alopecia);

19. Known Human immunodeficiency virus (HIV) infection;

20. Known clinically significant history of liver disease, including viral or other
hepatitis, current alcohol abuse, or cirrhosis

21. Evidence of ongoing or active infection requiring intravenous antibiotics;

22. Women who are pregnant or lactating;

23. 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;

24. 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;

25. Received investigational treatment in another clinical study within 4 weeks prior to
the initiation of investigational treatment;

26. 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.