A Phase II Trial of Apatinib in Relapsed and Unresectable High-grade Osteosarcoma After Failure of Standard Multimodal Therapy
Phase: PHASE2
Conditions: Osteosarcoma, Metastasis
Sponsor: GUO WEI

Protocol  
 
Apatinib for Advanced 
Osteosarcoma after 
Failure of Standard 
Multimodal Therapy: 
an open label phase 2 
clinical trial 
 
 

1.0 Abstract 
The prognosis of patients with recurrent or refractory osteosarcoma remains poor, 
with 5-year overall survival rates around 20%. Given the continued poor prognosis in 
this group of patients, novel treatment strategies are needed. There are no standard 
chemotherapeutic agents or targeted therapies proven to prolong survival in recurrent 
osteosarcoma. Apatinib, also known as YN968D1, is a tyrosine kinase inhibitor that 
selectively inhibits the vascular endothelial growth factor receptor-2 (VEGFR2, also 
known as KDR). It is an orally bioavailable, small molecule agent which is thought to 
inhibit angiogenesis in cancer cells; specifically, apatinib inhibits VEGF-mediated 
endothelial cell migration and proliferation thus blocking new blood vessel formation 
in tumor tissue. This agent also mildly inhibits c-Kit and c-SRC tyrosine kinases. 
Pre-clinical data suggest that apatinib may have anti-tumor activity in osteosarcoma. 
In this Phase 2 study, eligible patients between the ages of more than 16 years with 
unresected, recurrent or refractory osteosarcoma will receive apaptinib tablets 
administered daily. Progression free survival and response to therapy will be assessed. 
In addition, the tolerability and quality of life will be evaluated.  

2.0 Experimental Design Schema 
 
3.0 Goals and Objectives (Scientific Aims) 
3.1 Primary Aims 
    1.1.1 To estimate the objective response rate (ORR) at 3 month and progression 
free survival rate (PFS) at 4 month in patients with recurrent osteosarcoma who are 
administered apatinib therapy daily.  
3.2 Secondary Aims 
    3.2.1 To estimate the overall survival rate (OS), clinical benefit rate (CBR) at 6 
month, duration of response(DOR) in patients with recurrent osteosarcoma who are 
administered apatinib therapy daily. 

    3.2.2 To assess the feasibility and toxicity profile of apatinib in patients with 
recurrent or refractory osteosarcoma, pain improvement and life quality score. 
4.0 Background 
4.1 Introduction/Rationale for Development 
    The outcome of patients with newly diagnosed, localized osteosarcoma 
improved following the addition of multi-agent chemotherapy to complete surgical 
resection [1,2]. Current results in contemporary cooperative group studies reveal 
5-year event-free survival (EFS) ranging between 50-75%. [1,2] Cisplatin and 
doxorubicin are the most active agents, and standard chemotherapy includes the use 
of these two agents alone or in combination with high-dose methotrexate and/or 
ifosfamide [2,3,6]. The prognosis is poor for the 30-40% of patients who develop 
recurrent disease [3]. as well as for those with clinically detectable metastases at the 
time of initial diagnosis with 2-year survival rates of 20-30% [6,10]. 
The aggregate EFS for patients with recurrent osteosarcoma enrolled on seven 
closed Phase 2 studies from the Children’s Oncology Group (COG) or its predecessor 
groups is poor, with an overall 12% EFS at 4 months [5,7,8,9,10]. Due to the lack of 
progress seen in treatment of osteosarcoma over the past 25 years and overall poor 
prognosis for children, adolescents and young adults with recurrent or refractory 
osteosarcoma, novel treatment strategies are needed. 
The study of oncogenesis and pathobiological behavior of osteosarcoma told us 
that new blood vessel formation (angiogenesis) is fundamental to tumor growth, 
invasion, and metastatic dissemination [23]. Several groups have evaluated tumor 
microvessel density and outcome in osteosarcoma. Expression of VEGF has been 
suggested as a means of evaluating the prognostic importance of angiogenesis in 
osteosarcoma [17,18,19]. Monotherapy with second-generation broad-spectrum 
VEGF receptor tyrosine kinase inhibitors (TKIs) in sarcoma has now become an area 
of active research and application beyond gastrointestinal stromal tumors (GISTs) 
[4,14]. Within all of those preclinical experiments and clinical trials [16,18,20], the 

milestone of the treatment on advanced osteosarcoma should count on the application 
of anti-angiogenesis TKIs sorafenib on refractory cases from the Italian Sarcoma 
Group [20,22], which officially raised the 6-month progression-free survival (PFS) 
from <30-46% for the first time. However, things had seemed not to change as 
dramatically as was expected since then.  
Apatinib, also known as YN968D1, is a tyrosine kinase inhibitor that selectively 
inhibits the vascular endothelial growth factor receptor-2 (VEGFR2, also known as 
KDR)(Fig. 4.1.1). It is an orally bioavailable, small molecule agent which is thought 
to inhibit angiogenesis in cancer cells; specifically apatinib inhibits VEGF-mediated 
endothelial cell migration and proliferation thus blocking new blood vessel formation 
in tumor tissue. This agent also mildly inhibits c-Kit and c-SRC tyrosine kinases.  
 
Fig.4.1.1 Schematic illustration of the possible mechanism of apatinib as the 
inhibitor of VEGFR-2. 
Apatinib was approved and launched in People’s Republic of China in 2014 as a 
subsequent-line treatment for patients with advanced gastric cancer (AGC). In 
addition, it is also currently undergoing Phase II/III clinical trials in People’s Republic 
of China for the treatment of many cancer types, such as non-small-cell lung cancer 
(NSCLC) [24], breast cancer, and hepatocellular carcinoma. These clinical trials 
demonstrate that apatinib has potential antitumor activity across a broad range of 
advanced solid tumors. Compared with other TKIs focused on anti-angiogenesis, 
Apatinib is more effective on VEGFR2 (Table.4.1.1). 

Table 4.1.1 Comparation of IC 50 in different TKIs 
target 
IC50(nM) 
Apatinib 
Sorafenib 
Sunitinib 
Pazopanib 
VEGFR-1 
70 
- 
2 
10 
VEGFR-2 
2 
90 
10 
30 
VEGFR-3 
- 
- 
17 
47 
PDGFR-b 
537 
- 
8 
84 
c-kit 
420 
68 
- 
74 
FGFR-1 
>10000 
580 
- 
- 
FLT-3 
- 
58 
- 
- 
4.2 Preclinical Studies 
Several basic studies have been dedicated to the antitumor activity of apatinib in 
vitro and in vivo. In vitro, apatinib potently suppressed the kinase activities of 
VEGFR-2, c-Kit, and c-Src, and inhibited cellular phosphorylation of VEGFR-2, 
c-Kit, and PDGFRb. Apatinib could also effectively inhibit proliferation, migration, 
and tube formation of human umbilical vein endothelial cells induced by fetal bovine 
serum, and block the budding of rat aortic ring. What’s more,  apatinib has also been 
demonstrated effective in several kinds of human cancers in vivo(Table 4.2.1). 
Encouraged by the remarkable inhibitory activity against VEGFR-2 tyrosine kinase in 
vitro, they further performed the investigation of the potential antitumor effect of 
apatinib in vivo. The results demonstrated that apatinib showed antitumor efficacy in 
vivo when administrated alone or in combination with chemotherapy against a variety 
of established tumor xenografts with good tolerance[24]. To date, the outcome of 
cancer chemotherapy still encounters two major challenges: nonspecific targets and 
multidrug resistance (MDR). In fact, more than 90% of patients with malignant 
tumors die of MDR. Apatinib could also reverse cancer MDR mediated by MDR 
protein 1 (ABCB1), MDR-associated protein 1 (MARP1), and breast cancer resistant 
protein (BCRP) through inhibiting their transport function as well[24]. Thus, apatinib 
may be useful in overcoming MDR to other conventional antineoplastic drugs. 
Table 4.2.1 Apatinib is effective in several kinds human cancers in mice. 

pharmacodynamic model 
Dose(mg/kg) 
inhibitory effect(%) 
Gastric cancer SCG-7901 
50-200 
39.3-80.7 
Colon cancer Ls174t 
50-200 
20.3-83.7 
Colon cancer HCT-116 
50-200 
41-81.2 
Colon cancer HT-29 
50-200 
37.2-74.5 
NSCLC A549 
50-200 
29.2-72.8 
NSCLC NCI-H460 
100, 200 
43.1-78.8 
Hepatic cancer H22 
50-200 
43.3-84.7 
Sarcoma S180 
50-200 
60.3-69.9 
4.3 Apatinib in Published Clinical Trials 
Apatinib has been administered to a total of 338 patients with gastric cancer, 
non-small cell lung cancer or breast cancer in 3 clinical trials. 
In a randomized, placebo-controlled, parallel-arm Phase III trial (NCT00970138), 
Li et al evaluated apatinib as a subsequent-line therapy for patients with histologically 
confirmed gastric cancer. In the trial, 144 enrolled patients were divided into three 
groups: placebo (group A), 850 mg of apatinib qd (group B), and apatinib 425 mg bid 
(group C). Progression-free survival (PFS) was the primary end point. Secondary end 
points included DCR, objective response rate, overall survival, and quality of life. The 
outcomes demonstrated that the median progression-free survival for groups A, B, 
and C was 1.40 months, 3.67 months, and 3.20 months, respectively. OS for groups A, 
B, and C was 2.50 months, 4.83 months, and 4.27 months, respectively. There were 
statistically significant differences between the apatinib groups and the placebo group 
in PFS and overall survival (P<0.001). But, there was no significant difference 
between apatinib 425 mg bid vs 850 mg qd (hazard ratio [HR]:1.22, P<0.551). These 
results illustrated that apatinib showed improved PFS and overall survival in heavily 
pretreated patients who had experienced treatment failure with two or more 
chemotherapy regimens. 
A prospective, open-label, Phase II trial by Hu et al aimed to evaluate the 
efficacy and safety of apatinib in heavily pretreated patients with metastatic  
non-triple-negative breast cancer (TNBC) (NCT01176669). In the trial, after the 

optimum dose level of 500 mg/day was recommended by Phase IIa, a Phase IIb study 
of 59 patients with metastatic TNBC was activated, with the endpoint PFS. The 
outcomes were reported that mPFS and mOS were 3.3 months and 10.6 months, 
respectively. In the 56 evaluable patients, overall response and clinical benefit rates 
were 10.7% and 25.0%, respectively. As for adverse events, the most common grade 
3/4 hematologic toxicities were thrombocytopenia (13.6%), leukopenia (6.8%), 
neutropenia (3.4%), and anemia (1.7%). The most frequent grade 3/4 nonhematologic 
toxicities were hand–foot syndrome, proteinuria, hypertension, and increased alanine 
aminotransferase.  
    A multicenter, randomized, placebo-controlled, Phase II trial by Zhang et al was 
to determine whether apatinib could improve PFS compared with placebo in patients 
with advanced nonsquamous NSCLC who failed two lines of treatment 
(NCT01270386). In the study, 135 patients were randomized in a 2:1 fashion to 
apatinib 750 mg qd vs placebo until disease progression or unacceptable toxicity. As 
expected, mPFS was 4.7 months for apatinib group vs that of 1.9 months for placebo 
group with an HR of 0.278 (P<0.0001). The response rate and DCR were also 
significantly better in apatinib arm (12.2% and 68.9%) than in placebo arm (0% and 
24.4%) (P=0.0158 and P<0.0001). Although hypertension, proteinuria, and hand–foot 
syndrome were the most frequent adverse events, they were generally mild or 
moderate in severity and were manageable. 
4.4 Dose Rationale 
Apatinib will be administered orally at a dose of 750mg/d for patients with body 
surface area (BSA) of more than 1.5m2, and 500mg/d for patients with BSA of less 
than 1.5m2. Pharmacokinetic analysis showed that the time to maximum plasma 
concentration level was ~4 hours after dose and the mean half-life was 9 hours. In 
three separate dosing groups, 500 mg (n=8), 750 mg (n=12), and 800 mg (n=8), of 28 
patients enrolled into a single dose arm, the Cmax and AUC24 values were 
dose-dependent and demonstrated variability among patients with Cmax of 1,521, 
2,379, and 2,833 ng/mL and AUC24 of 11,295, 18,172, and 21,975 ng·h/mL, 
respectively. Steady-state conditions analysis of eleven patients enrolled in the 

multidose cohort suggested no accumulation during 56 days once a day administration 
of 750 mg apatinib. 
5.0 Study Enrollment Procedures and 
Patient Eligibility 
5.1 Study Enrollment Criteria 
    Patients must be enrolled before treatment begins. The date protocol therapy is 
projected to start must be no later than 7 business days after the date of study 
enrollment.  
 The eligibility criteria listed below are interpreted literally and cannot be 
waived. All clinical and laboratory data required for determining eligibility of a 
patient enrolled on this trial must be available in the patient's medical/research record 
which will serve as the source document for verification at the time of audit. 
All clinical and laboratory studies to determine eligibility must be performed 
within 14 days prior to enrollment unless otherwise indicated. Laboratory values used 
to assess eligibility must be no older than 14 days at the start of therapy. Laboratory 
tests need not be repeated if therapy starts within 14 days of obtaining labs to assess 
eligibility. If a post-enrollment lab value is outside the limits of eligibility, or 
laboratory values are > 14 days old, then the following laboratory evaluations must be 
re-checked within 48 hours prior to initiating therapy: complete blood count (CBC) 
with differential, bilirubin, ALT and serum creatinine. If the recheck is outside the 
limits of eligibility, the patient may not receive protocol therapy and will be 
considered off protocol therapy. Imaging studies, if applicable, must be obtained 
within 2 weeks prior to start of protocol therapy (repeat the tumor imaging if 
necessary). 

5.2 Patient Eligibility Criteria 
5.2.1 Age  
Patients must be equal to or greater than 16 years of age at the time of 
enrollment. 
5.2.2 Diagnosis 
5.2.2.1 Patients must have had histologic verification of high grade osteosarcoma 
at original diagnosis or relapse. 
5.2.2.2 Patients must have measurable disease according to RECIST 1.1 (see 
Appendix 1), and have relapsed or become refractory to conventional therapy, 
unresectable. 
5.2.3 Performance Level 
Patients must have a performance status corresponding to ECOG scores 
(Appendix 2) of 0, 1 or 2, with a life expectancy >3 months. 
5.2.4 Prior Therapy 
    Patients must have fully recovered from the acute toxic effects of all prior 
chemotherapy, immunotherapy, or radiotherapy prior to entering this study. 
    5.2.4.1 Myelosuppressive chemotherapy: Must not have received within 2 weeks 
of entry onto this study (4 weeks if prior nitrosourea). 
    5.2.4.2 Biologic (anti-neoplastic agent): At least 7 days since the completion of 
therapy with a biologic agent. 
    5.2.4.3 Radiation therapy (RT): ≥ 2 weeks for local palliative RT (small port); ≥ 
6 months must have elapsed if prior craniospinal RT or if ≥ 50% radiation of pelvis; ≥ 
6 weeks must have elapsed if other substantial BM radiation. 

5.2.4.4 Monoclonal antibodies: Must not have received any monoclonal based 
therapies within 4 weeks, and all other immunotherapy (tumor vaccine, cytokine, or 
growth factor given to control the cancer) within 2 weeks, prior to study enrollment. 
5.2.4.5 surgery completion at least 4 weeks before enrollment. 
5.2.4.6 Prior treatment (completed >2 weeks before trial entry) should include 
but not limited to standard high-grade osteosarcoma chemotherapy agents including 
doxorubicin, cisplatin, high-dose methotrexate, and ifosfamide. 
5.2.5 Organ Function Requirements 
5.2.5.1 Adequate Bone Marrow Function Defined As: 
      - Peripheral absolute neutrophil count (ANC) ≥ 1500/μL  
      - Platelet count ≥ 80,000/μL (transfusion independent) 
      - Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions) 
5.2.5.2 Adequate Renal Function Defined As: 
      - Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2 or 
      - A serum creatinine based on age/gender as follows (Table 5.2.6.2.1): 
          Table 5.2.6.2.1 Serum creatinine requirements 
 
5.2.5.3 Adequate Liver Function Defined As: 
      - Total bilirubin ≤ 2 x upper limit of normal (ULN) for age, and 
      - Aspartate Aminotransferase (AST) or Alanine Aminotransferase  
        (ALT) < 135 U/L. For the purposes of this study the ULN is defined       
        as 45 U/L.  
5.2.5.4 Adequate Cardiac Function Defined As: 
    - Shortening fraction of ≥ 27% by echocardiogram, or 
    - Ejection fraction of ≥ 50% by radionuclide angiogram. 

5.2.6 Exclusion Criteria: 
5.2.6.1 Previously exposed to other TKIs; 
5.2.6.2 Central nervous system metastasis; 
5.2.6.3 Have had other kinds of malignant tumors at the same time; 
5.2.6.4 Cardiac insufficiency or arrhythmia; 
5.2.6.5 Uncontrolled complications, such as hypertension, diabetes mellitus  
       and so on; 
5.2.6.6 Coagulation disorders; 
5.2.6.7 Urine protein≥ ++; 
5.2.6.8 Pleural or peritoneal effusion that needs to be handled by surgical        
       treatment; 
5.2.6.9 Combined with other infections or wounds. 
5.2.6.10 A history of allergic reactions attributed to compounds of similar  
       composition to apatinib. 
5.2.6.11 Pregnancy and Breast Feeding 
 
    5.2.6.11.1 Female patients who are pregnant are ineligible since there is  
             yet no available information regarding human fetal or  
             teratogenic toxicities. 
    5.2.6.11.2 Lactating females are not eligible unless they have agreed not  
             to breastfeed their infants. 
    5.2.6.11.3 Female patients of childbearing potential are not eligible  
             unless a negative pregnancy test result has been obtained. 
    5.2.6.11.4 Sexually active patients of reproductive potential are not  
             eligible unless they have agreed to use an effective        
          contraceptive method for the duration of their study participation. 
6.0 Treatment Program 
Timing of protocol therapy administration, response assessment studies, and 
surgical interventions are based on schedules derived from the experimental design or 

on established standards of care. Minor unavoidable departures (up to 72 hours) from 
protocol directed therapy and/or disease evaluations (and up to 1 week for surgery) 
for valid clinical, patient and family logistical, or facility, procedure and/or anesthesia 
scheduling issues are acceptable (except where explicitly prohibited within the 
protocol). 
6.1 Overview of Treatment Plan 
This is a single arm Phase 2 study to evaluate the use of apatinib, a small 
molecule TKI against VEGFR2. All subjects will receive apatinib 750 mg 
(BSA>1.5m2) or 500mg (BSA<1.5m2) orally once daily, given on the same time at 
half an hour after meal.  
Treatment will be discontinued if there is evidence of progressive disease or drug 
related toxicity that requires removal from therapy, as defined in Section 7.0. Therapy 
may otherwise continue. Radiographic imaging assessments of disease status obtained 
every 2 months in the first 6 months, and then every 3 months, will be compared to 
imaging done just prior to initiating therapy.  
Other therapy: Although not encouraged, subjects who achieve a partial response 
after 2 months that is confirmed after 6 months will be allowed to undergo resection 
of sites of disease or radiation and remain on protocol therapy. Apatinib therapy will 
be held 1 week before surgery and resumed when recovered from surgery but at least 
2 weeks after surgery considering the time of wound healing. Apatinib therapy will be 
continued during radiation. If the patient has not recovered from surgery within 1.5 
months the patient will go off protocol therapy. Surgery or radiation performed on 
any site of measurable disease before the end of the 6 months will render the patient 
inevaluable for disease control assessment and they will be removed from protocol 
therapy. 

6.2 Concomitant Therapy 
6.2.1 CYP3A4 inducers and inhibitors 
The use of the following medications (Appendix 3) should be discontinued prior 
to initiation of protocol therapy and should be avoided during protocol therapy if 
reasonable alternatives exist. This is not an inclusive list; please refer to other 
resources such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx or other 
frequently updated medical reference for additional information. 
6.2.2 Allowed Therapy  
6.2.2.1 No other antineoplastic agents may be given while the patient is receiving 
protocol therapy. 
6.2.2.2 Permitted therapy during this study: Allow the use of diuretics 
(hydrochlorothiazide or furosemide), ACEI (captopril or enalapril) or ARB (Losartan 
or valsartan) and other drugs alone or in combination for the treatment of 
hypertension. Allow the use of calamine, antibiotic cream (e.g. mupirocin ointment), 
hormone cream (e.g. Hydrocortisone Butyrate or Pevisone Cream) and other drug for 
external use of skin rash, desquamation. Allow the use of Granulocyte colony 
stimulating factor (granulocyte colony, stimulating factor, G-CSF), erythropoietin 
(EPO), thrombopoietin (TPO) and interleukin -11 (IL-11) to treat leukopenia, anemia 
or thrombocytopenia for salvage therapy while prophylaxis is forbidden.  
All drugs used concurrently with apatinib must be recorded in the CRF section, 
including blood transfusion, stem cell growth factors, antibiotics, analgesics and 
antidiarrheal drugs. 
6.2.3 Criteria to Continue Apatinib Therapy 
Patients are evaluated every 2 months in the first 6 months and then every 3 
months for the ability to continue apatinib therapy. They must recover from toxicities 

at least possibly related to apatinib therapy to ≤ Grade 1 severity or baseline prior to 
beginning next cycle, including: 
• ANC ≥ 1500/μL 
• Platelets ≥ 80,000/μL (transfusion independent) 
• Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions) 
• Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2 or a serum 
creatinine based on age/gender as follows 
 
• Total bilirubin ≤ 2 x upper limit of normal (ULN) for age, and 
• AST or ALT < 135 U/L for the purposes of this study the ULN is defined as 45 
U/L. 
7.0 Dose Modifications for Toxicities 
7.1 Definition of Toxicities 
NOTE: Any suspected or confirmed dose-limiting toxicity should be reported to 
the Study Chair within 24 hours of site knowledge of its occurrence. Dose 
modifications are carried out according to table 7.1.1. 
Table 7.1.1 Dose modification criteria 
Level of Dose 
Group A (BSA>1.5m2) 
Group B (BSA<1.5m2) 
Initial Level 
750mg 
500mg 
Level-1 
500mg 
250mg 
Level-2 
250mg* 
0* 
*The dose for each patient can be reduced no more than 2 times. If more dose reduction is needed, 
the patient should be dropped off from the study. Apatinib therapy will continue until disease 
progression is confirmed, or unacceptable toxicity occurs.  

7.1.1 Definition of Dose-Limiting Toxicity (DLT) 
    DLT will be defined as any of the following events that are possibly, probably or 
definitely attributable to protocol therapy. Dose limiting hematological and 
non-hematological toxicities are defined differently. 
7.1.1.1 Hematological Dose Limiting Toxicity 
- Grade 4 neutropenia for > 7 days 
- Grade 4 febrile neutropenia 
- Platelet count < 25,000/μL 
- Myelosuppression that causes a delay of > 14 days 
7.1.1.2 Non-Hematological Dose-Limiting Toxicity 
Any Grade 3 or greater non-hematological toxicity, except for the following: 
- Grade3 nausea and/or vomiting of<3days duration 
- Grade3 or 4 fever <5days duration 
- Grade3 infection <5days duration 
- Grade3 rash <5days duration 
- Grade3 pruritis <5days duration 
- Grade3 fatigue <5days duration 
- Grade 3 non-hematologic laboratory abnormalities that resolve within 14 
days to Grade 1, or to initial eligibility criteria, or to baseline (if the patient 
entered the study with existing toxicity).  
- Grade 
3 
hypophosphatemia, 
hypokalemia, 
hypocalcemia, 
or 
hypomagnesemia responsive to oral supplementation. 
Any Grade 2 non-hematological toxicity that persists for ≥ 7 days and is considered 
sufficiently medically significant or sufficiently intolerable by patients that it requires 
treatment interruption will also be considered a DLT. 

7.2 Dose Modifications for Adverse Events 
    The Study Chair must be notified of any use of myeloid growth factor for 
hematologic toxicity and of any other dosage modification described below. 
7.2.1 Dose Modifications for Hematological Toxicity 
Factor 
Hematologic Toxicity 
Action 
ANCa 
  
<500/uL or <1000/uL with infection 
or fever for more than 5 days 
Reduce to a lower levelc 
PLTb 
< 75,000/μL 
Reduce to a lower levelc 
a G-CSF may be used before dose modification. 
b IL-11 or TPO may be used before dose modification. 
c Reduce to a lower level until removed from protocol therapy if dose-limiting 
toxicity recurs. 
7.2.2 Dose Modifications for Non-hematological Toxicity 
Toxity 
 
Grade 
Dose modification 
Nausea and/or vomittinga 
≥3 
Reduce to a lower level 
Elevations of 
serum AST 
and/or ALT 
≤2.5ULN 
≥3 
Reduce to a lower level 
>2.5ULNb  
≥3 
Reduce to a lower level if benefit from apatinib; 
otherwise removed from protocol therapy 
Hypertension 
≤140/90mmHg 
≥3 
Continue at former dose 
>140/90mmHgc 
≥3 
Reduce to a lower level if benefit from apatinib; 
otherwise removed from protocol therapy 
Total bilirubin>ULN at any time 
≥1 
Reduce to a lower level 
Others 
≥3 
Reduce to a lower level 
a use antiemetic drugs, including serotonin/dexamethasone/lorazepam before reduction. 
b after the use of medications to protect the liver. 
c with the use of hypotensor. 

8.0 Drug Information 
8.1 Source and Pharmacology 
Apatinib, also known as YN968D1, is a tyrosine kinase inhibitor that selectively 
inhibits VEGFR2. It is an orally bioavailable, small molecule agent which is thought 
to inhibit angiogenesis in cancer cells; specifically apatinib inhibits VEGF-mediated 
endothelial cell migration and proliferation thus blocking new blood vessel formation 
in tumor tissue. Apatinib was first synthesized by Advenchen Laboratories in 
California, USA and is being developed by Jiangsu Hengrui Medicine (China). 
Apatinib was approved by CFDA in December, 2014 for patients with late-stage 
gastric carcinoma in China.A phase IV study on safety of Apatinib started in April, 
2015. The study aims to recruit 2,000 patients 
8.2 
Pharmacokinetics  
Pharmacokinetic analysis showed that the time to maximum plasma 
concentration level was ~4 hours after dose and the mean half-life was 9 hours. In 
three separate dosing groups, 500 mg (n=8), 750 mg (n=12), and 800 mg (n=8), of 28 
patients enrolled into a single dose arm, the Cmax and AUC24 values were 
dose-dependent and demonstrated variability among patients with Cmax of 1,521, 
2,379, and 2,833 ng/mL and AUC24 of 11,295, 18,172, and 21,975 ng·h/mL, 
respectively. Steady-state conditions analysis of eleven patients enrolled in the 
multidose cohort suggested no accumulation during 56 days once a day administration 
of 750 mg apatinib. The primary routes of apatinib biotransformation include E- and 
Z-cyclopentyl-3-hydroxylation, N-dealkylation, pyridyl-25-N-oxidation, 
16-hydroxylation, dioxygenation, and O-glucuronidation after 3-hydroxylation. Nine 
major metabolites were confirmed, of which E-3-hydroxy-apatinib-O-glucuronide 
(M9-2) was the major circulating metabolite. The total recovery of the administered 
dose was 76.8% within 96 hours postdose, with 69.8% and 7.02% of the administered 
dose excreted in feces and urine, respectively.  

8.3 Adverse Effect 
The incidence of all treatment-related AE in Phase III clinical trial in gastric 
cancer was listed in table 8.3.1. 
Table 8.3.1 Incidence of Treatment-related Adverse Events 
 
8.4 Pregnancy and Lactation 
Fertility and teratology studies have not been conducted with apatinib. It is not 
known if apatinib or its metabolites is excreted in milk or can cross the placenta. For 
this reason, pregnant and nursing women should not receive apatnib. Women of 
childbearing potential and their partners who are admitted to the clinical study must 
take adequate contraceptive measures. 

8.5 Drug-drug Interactions 
    The effect of Apatnib on the absorption, metabolism, or excretion of other drugs 
has not been studied. To date, there have been no unexpected interactions observed 
between apatiniband other drugs. 
 In vitro data indicate that cytochrome P450 (CYP) 3A4 is the primary CYP 
isoenzyme involved in the metabolism of apatinib. The use of the following 
medications (Appendix 3) should be discontinued prior to initiation of protocol 
therapy and should be avoided during protocol therapy if reasonable alternatives exist. 
This is not an inclusive list; please refer to other resources such as 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx or other frequently updated 
medical reference for additional information. 
8.6 Guidelines for Administration 
   All patients will receive apatinib 750 mg (BSA>1.5m2) or 500mg (BSA<1.5m2) 
orally once daily, given on the same time at half an hour after meal. 
9.0 Criteria for Removal from Protocol 
Therapy and off Study Criteria 
9.1 Criteria for Removal from Protocol Therapy  
- Progressive disease. 
- Unacceptable toxicity due to protocol therapy (see Section 7.0).  
- Refusal of further protocol therapy by patient/parent/guardian.  
- Completion of planned therapy. 
- Physician determines it is in patient’s best interest. 
- Development of a second malignancy. 

- Repeat eligibility studies are outside the parameters required for eligibility 
- Surgery or radiation performed on any site of measurable disease before the  
  end of the 6th months. 
- Failure to recover from surgery within 6 weeks.  
- Pregnancy. 
   Patients who are off protocol therapy are to be followed until they meet the 
criteria for Off Study (see below). Follow-up data will be required unless patient is 
taken off study. 
9.2 Off Study Criteria  
   - Death. 
   - Lost to follow-up. 
   - Patient enrollment onto another study with tumor therapeutic intent. 
   - Withdrawal of consent for any further data submission. 
   - The fifth anniversary of the date the patient was enrolled on this study. 
10.0 Statistical Considerations 
10.1 Sample Size and Study Design 
There is a surprising lack of published data for PFS of patients with high-grade 
osteosarcoma that have relapsed after standard treatments. At the same time, reported 
objective responses to chemotherapy after MAPI vary widely, making this endpoint 
unsuitable in the context of patients with advanced and unresectable high-grade 
osteosarcoma. Preclinical study on osteosarcoma specimens demonstrated that 
apatinib targets were expressed and effectively inhibited by this drug in xenografts, 
providing a rationale to explore apatinib in progressing osteosarcoma patients. 
Therefore, we chose ORR at 3 month and PFS at 4 month as a primary endpoint 
rather than objective response recorded in previous trial as a point of reference. Thus, 
the trial was designed to discard a PFS at 4 month of 10% (null hypothesis) aiming to 

reach a PFS at 4 month of 30% or higher (alternative hypothesis). Using Simon’s 
optimum two-stage design and setting α-error at 0·05 and β-error at 0·10, the presence 
of at least six successes in the 17 patients enrolled in the first stage allowed the trial to 
proceed to the second stage in which 20 more patients were needed to be enrolled for 
the minimum total of 37 patients. 
10.2 Statistical Analysis 
The intention-to-treat analysis included all patients who received at least one 
dose of apatinib. The population assessable for treatment activity comprised all 
patients for whom at least one disease assessment (either clinical or radiological) was 
done. The primary endpoint was analysed in the intention-to-treat population. We 
estimated survival endpoints according to the Kaplan- Meier method, with 95% CIs. 
RECIST overall responses and disease control were calculated and reported with 95% 
CIs. We investigated the effect of P-ERK1/2 and P-RPS6 expression by comparing 
survival outcomes with the two-sided Mantle-Cox log-rank test, Fisher’s exact test, 
and the Mantel-Haenszel odds ratio (OR) estimate. We compared baseline versus 
on-treatment PAS and BPI scores with a paired student’s t test. We computed all 
statistics with IBM SPSS Statistics (version 20) and GraphPad Prism (version 5). 
10.2.1 Evaluability for Disease Control and Response 
10.2.1.1 Which Patients will be Considered Evaluable for RECIST Response: 
Any eligible patient who receives at least one dose of apatinib will be considered 
evaluable for response with the following exception: if a patient receives non-protocol 
anti-cancer therapy during the response evaluation period after the patient is 
considered as having a partial or complete response but prior to confirmation of this 
status by tumor imaging and before progressive disease is noted, the individual will 
be considered inevaluable for the response endpoint. Further, patients who stop 
apatinib after the 1st evaluation because of toxicities or death will be considered 
evaluable for the response evaluation and will be counted as non-responders for the 
response endpoint. 

10.2.2.2 Which Patients Will Be Considered Evaluable for Disease Control 
Success: 
Any eligible patient who receives at least one dose of apatinib will be considered 
evaluable for response with the following exception: if a patient receives non-protocol 
anti- cancer therapy during the first two months of therapy is considered as having a 
partial or complete response but prior to confirmation of this status by tumor imaging 
and before progressive disease is noted, the individual will be considered inevaluable 
for the disease control success endpoint. 
10.2.2.3 Which Patients Will be Considered a Disease Control Success: 
Any patient who is evaluated free of all detectable disease (complete response) 
or is considered as having a partial response after two months of therapy or is 
considered as having stable disease (‘at least stable disease’) after three months of 
therapy. 
10.2.2.4 Which Patients Will be Considered Not a Disease Control Success: 
Any evaluable patient who does not meet the criteria for disease control success 
(complete response, partial response or stable disease) will be considered to not have 
experienced disease control success. 
In particular, any patient who dies because of treatment-related toxicity during 
the first three months since starting treatment will be considered not to have 
experienced disease control success. Also, any patient who is eligible, receives one 
dose of apatinib and is lost to follow-up at (for example) the end of the second 
(complete response, partial response) or third months will be considered not a disease 
control success (stable disease). 
Patients who are not evaluable for both disease control and response evaluation 
may be replaced for the purposes of the statistical rule. 
10.2.2 Evaluability for Toxicity 
Tolerability of apatinib - An eligible patient will be considered for toxicity 
monitoring if one of the following occurs: (1) complete two months of apatinib prior 
to receiving non-protocol anticancer therapy; (2) die on protocol therapy for a reason 
considered possibly, probably or likely related to apatinib; or (3) are removed from 

protocol therapy because of an adverse experience possibly, probably or likely related 
to apatinib. A toxicity- evaluable patient will be considered in the analysis during the 
interval from study enrollment until the termination of protocol therapy. A 
toxicity-evaluable patient will be considered to have experienced an excessive 
toxicity event if: (1) the patient dies on protocol therapy for a reason considered 
possibly, probably or likely related to; or (2) experiences a dose-limiting toxicity 
(DLT). DLTs will be as defined in Section 7.1.1 of the protocol: 
The analytic unit for monitoring for excessive toxicity will be the patient-month: 
Each 2 months where the patient receives apatinib and does not receive non-protocol 
anticancer therapy will be considered in the analysis. If there is overwhelming 
evidence that the dose selected for this trial has a per-2 months-DLT probability of 
more than 30%, we will identify the regimen to a toxicity profile that may require 
modification of the regimen. We will use a Bayesian rule to monitor for excessive 
toxicity. We will assume a beta prior to distribution with α=0.6 and β=1.4. If this 
posterior probability of the chance of DLT is at least 30% exceeds 80%, we will 
identify the regimen to a toxicity profile that may require modification of the regimen. 
11.0 Evaluation Criteria 
11.1 Common Terminology Criteria for Adverse Events 
(CTCAE) 
    This study will utilize version 4.0 of the CTCAE of the National Cancer Institute 
(NCI) for toxicity and performance reporting. A copy of the CTCAE version 4.0 can 
be downloaded from the CTEP website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm) or 
Appendix 4.    Additionally, toxicities are to be reported on the appropriate case 
report forms. 

Please note: ‘CTCAE v4.0’ is understood to represent the most current version of 
CTCAE v4.0 as referenced on the CTEP website (ie, v4.02 and all subsequent 
iterations prior to version 5.0). 
11.2 Response Criteria for Patients with Solid Tumors 
    For the purposes of this study, patients should be evaluated for response 
following Months 2, 4 and 6 and following every 3rd month thereafter. Patients who 
have a RECIST response (CR or PR) at Month 6 will have confirmatory imaging after 
Month 8. 
Response and progression will be evaluated in this study using the new 
international criteria proposed by the revised Response Evaluation Criteria in Solid 
Tumors (RECIST) guideline (version 1.1) (Appendix 1). Changes in the largest 
diameter (unidimensional measurement) of the tumor lesions and the shortest 
diameter in the case of malignant lymph nodes are used in the RECIST criteria. 
11.2.1 Disease Parameters 
11.2.1.1 Measurable disease: Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 
20 mm by chest x-ray, as ≥ 10 mm with CT scan, or ≥ 10 mm with calipers by 
clinical exam. All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
11.2.1.2 Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline 
and in follow-up, only the short axis will be measured and followed. 
11.2.1.3 Non-measurable disease: All other lesions (or sites of disease), 
including small lesions (longest diameter <10 mm or pathological lymph nodes with 
≥10 to <15mm short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 

cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable. 
Note: Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable nor 
non-measurable) since they are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred for 
selection as target lesions. 
11.2.1.4 Target lesions: All measurable lesions up to a maximum of 2 lesions per 
organ and 5 lesions in total, representative of all involved organs, should be identified 
as target lesions and recorded and measured at baseline. Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be representative 
of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest 
lesion does not lend itself to reproducible measurement in which circumstance the 
next largest lesion which can be measured reproducibly should be selected. A sum of 
the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes 
are to be included in the sum, then only the short axis is added into the sum. The 
baseline sum diameters will be used as reference to further characterize any objective 
tumor regression in the measurable dimension of the disease. 
11.2.1.5 Non-target lesions: All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be identified as 
non-target lesions and should also be recorded at baseline. Measurements of these 
lesions are not required, but the presence, absence, or in rare cases unequivocal 
progression of each should be noted throughout follow-up. 
11.2.2 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler 
or calipers. All baseline evaluations should be performed as closely as possible to the 

beginning of treatment and never more than 2 weeks before the beginning of the 
treatment. 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless the 
lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
11.2.2.1 Clinical lesions: Clinical lesions will only be considered measurable 
when they are superficial (eg, skin nodules and palpable lymph nodes) and ≥ 10 
mm diameter as assessed using calipers (eg, skin nodules). In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the 
lesion, is recommended. 
11.2.2.2 Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung. However, CT is 
preferable. 
11.2.2.3 Conventional CT and MRI: This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. If 
CT scans have slice thickness greater than 5 mm, the minimum size for a measurable 
lesion should be twice the slice thickness. MRI is also acceptable in certain situations 
(eg, for body scans). 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and 
temporal resolution; however, there are many image acquisition variables involved in 
MRI, which greatly impact image quality, lesion conspicuity, and measurement. 
Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is 
performed, the technical specifications of the scanning sequences used should be 
optimized for the evaluation of the type and site of disease. Furthermore, as with CT, 
the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence. It is beyond the 
scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters 
for all scanners, body parts, and diseases. Ideally, the same type of scanner should be 
used and the image acquisition protocol should be followed as closely as possible to 
prior scans. Body scans should be performed with breath-hold scanning techniques, if 
possible. 

11.2.2.4 Ultrasound: Ultrasound is not useful in assessment of lesion size and 
should not be used as a method of measurement. Ultrasound examinations cannot be 
reproduced in their entirety for independent review at a later date and, because they 
are operator dependent, it cannot be guaranteed that the same technique and 
measurements will be taken from one assessment to the next. If new lesions are 
identified by ultrasound in the course of the study, confirmation by CT or MRI is 
advised. If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
11.2.2.5 Endoscopy, Laparoscopy: The utilization of these techniques for 
objective tumor evaluation is not advised. However, such techniques may be useful to 
confirm complete pathological response when biopsies are obtained or to determine 
relapse in trials where recurrence following complete response (CR) or surgical 
resection is an endpoint. 
11.2.2.6 Cytology, Histology: These techniques can be used to differentiate 
between PR and CR in rare cases (eg, residual calcification in tumor types, where 
known residual benign calcifications can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment when the measurable tumor has met criteria for response 
or stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
11.2.3 Response Criteria 
11.2.3.1 Evaluation of Target Lesions 
    Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
    Partial Response (PR): At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum diameters.  
Progressive Disease: At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the baseline 

sum if that is the smallest on study). In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at least 5 mm. (Note: the 
appearance of one or more new lesions is also considered progression). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
11.2.3.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes must be non-pathological in 
size (<10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits 
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. Unequivocal progression 
should not normally trump target lesion status. It must be representative of overall 
disease status change, not a single lesion increase. 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 
11.2.3.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). The patient's 
best response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
For Patients with Measurable Disease (ie, Target Disease) 

 
11.2.4 Duration of Response 
11.2.4.1 Duration of overall response: The duration of overall response is 
measured from the time measurement criteria are met for CR or PR (whichever is first 
recorded) until the first date that recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively documented. 
11.2.4.2 Duration of stable disease: Stable disease is measured from the start of 
the treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements. 
12.0 Appendix 
Appendix 1 RECIST 1.1 
Appendix 2 ECOG scores 

Appendix 3 CYP3A4 inducers and inhibitors 
Appendix 4 CTCAE version 4.0 
Appendix 5 EORTC QLQ C-30 
Adverse Effect of apatinib from company 
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