Advanced or Metastatic Gastric Cancer

Primary objective To evaluate the overall suvival (OS) of Apatinib compared to Placebo in patients with Advanced or Metastatic Gastric Cancer(GC) Secondary objectives • To evaluate progression-free survival (PFS) • To evaluate objective response rate (ORR) • To evaluate disease control rate (DCR) • To evaluate EORTC QLQ-C30 and EORTC QLQ-STO22 • To evaluate EQ-5D-5L • To explore pharmacodynamic markers: Vascular Endothelial Growth Factor (VEGF), sVEGFR-1, sVEGFR2, sVEGFR3 • To evaluate pharmacokinetics • To evaluate the safety: Adverse events, laboratory tests, vital signs, physical examination, 12-lead ECG, ECOG performance status

Apatinib

Apatinib

Tablet

100 or 200

Primary Outcome Measure:
・ Overall Survival (OS): Time from randomization to death.
Subjects alive or lost to follow-up at the end of study (EOS)
are censored.
Secondary Outcome Measures:
・ Progression Free Survival (PFS): Time from randomization
to either radiological progression or death. Subjects alive
and free of progression at the end of study (EOS) are
censored.
・ Objective Response Rate (ORR): Percentage of subjects
with a Best Overall Response of Complete Response (CR)
or Partial Response (PR).
・ Disease Control Rate (DCR): Proportion of subjects with a
Best Overall Response of complete, partial response, or
stable disease.
・ Global health status/quality of life score according to
European Organisation for Research and Treatment of
Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQC30) and EORTC QLQ-STO22.
・ Each dimension response according to EuroQol 5-
Dimension 5-Level (EQ-5D-5L) Questionnaire.
Safety Measures:
・ Adverse events, laboratory tests, vital signs, physical
examination, 12-lead ECG, and ECOG performance status.
Exploratory Measures:
・ Pharmacodynamic marker: Vascular Endothelial Growth
Factor (VEGF), sVEGFR-1, sVEGFR2 and sVEGFR3.
・ Pharmacokinetics

Inclusion Criteria:
1. Male or female at least 18 years old or older.
2. Documented primary diagnosis of histologic- or cytologicconfirmed adenocarcinoma of the stomach or
gastroesophageal junction.
3. Patients have locally advanced unresectable or metastatic
disease that has progressed since last treatment.
4. One or more measurable or nonmeasurable evaluable
lesions per RECIST 1.1.
5. Patients should have failed or were intolerant to at least two
prior lines of standard chemotherapies with each containing
one or more of the following agents:
o Fluoropyrimidine (IV 5-FU, capecitabine, or S-1),
o platinum (cisplatin or oxaliplatin),
o taxanes (paclitaxel or docetaxel) or epirubicin,
o irinotecan,
o trastuzumab in case of HER2-positive,
o ramucirumab
Previous treatments with experimental agents (except
experimental antiangiogenic agents) alone or as part of the
first three therapy lines are allowed but not mandatory. A
maximum number of three prior therapy lines are allowed.
(For the patients whose disease recurred within 24 weeks
from the last dose of adjuvant anticancer chemotherapy, that
adjuvant anticancer chemotherapy is counted as 1 prior
chemotherapy line.)
6. Disease progression within 6 months after the last treatment.
7. Patients who have adequate bone-marrow, renal and liver
function including;
a. Hematologic: Absolute neutrophil count ≥ 1,500/mm3
,
Platelets ≥ 100,000/mm3
, Hemoglobin > 9.0 g/dL (Blood
transfusion to meet the inclusion criteria within 2 weeks is
not allowed.).
b. Renal: Creatinine clearance (according to Cockcroft-Gault
Equation or by 24 hr urine collection) > 50 mL/min and serum creatinine < 1.0 x ULN.
c. Hepatic: Serum bilirubin < 1.5 x ULN, AST and ALT ≤ 3.0 x
ULN (≤ 5.0 x UNL, if with liver metastasis).
d. Blood coagulation tests: PTT and INR ≤ 1.5 x ULN and ≤
1.5 x ULN, respectively.
e. The patient’s urinary protein should be < 2+ on dipstick or
routine urinalysis. If urine dipstick or routine analysis
indicates proteinuria ≥ 2+, then a 24-hour urine or urine
protein/creatinine ratio must be collected and must
demonstrate < 2 g of protein in 24 hours to allow
participation in the study.
8. Patients whose Eastern Cooperative Oncology Group
(ECOG) performance status are evaluated to be ≤ 1.
9. Expected survival of ≥ 12 weeks, in the opinion of the
investigator.
10.Ability to swallow the investigational product tablets.
11.Female patients of child-bearing potential must have a
negative serum or urine pregnancy test at the Screening
Visit. Females must be surgically sterile, postmenopausal for
at least 1 year prior to Screening Visit or must be using an
acceptable method of birth control ([oral, non-oral or
implantable] hormone contraceptives, intrauterine
contraceptive device or blockers and spermicides) effectively.
Abstinence is not an acceptable method of contraception for
the study.
12.Ability and willingness to comply with the study protocol for
the duration of the study and with follow-up procedures.

Exclusion Criteria:
1. Malignancies other than adenocarcinoma of the stomach or
gastroesophageal junction (including hematologic
malignancies) within 3 years.
(Squamous cell skin cancer or cervical carcinoma in situ
which has been cured after treatment and thyroid and
prostate cancers which are deemed by the investigator to
have little impact on the prognosis will be allowed.)
2. CNS metastases as shown by radiology records or clinical
evidence of symptomatic CNS involvement in the last 3
months prior to randomization.
3. Cytotoxic chemotherapy, surgery, immunotherapy,
radiotherapy or other targeted therapies within 4 weeks (6
weeks in cases of ramucirumab, mitomycin C, nitrosourea,
lomustine; 2 weeks in case of biopsy) prior to randomization
(Adjuvant radiotherapy given to local area for non-curative
symptom relief is allowed until 2 weeks before
randomization.).
4. Therapy with clinically significant systemic anticoagulant or
antithrombotic agents within 7 days prior to randomization
that may prevent blood clotting and, in the investigator’s
opinion, could place the subject at risk. Maximum dose of
325 mg/day of aspirin is allowed.
5. Patients who had therapeutic paracentesis of ascites (> 1L)
within the 3 months prior to starting study treatment or who,
in the opinion of the investigator, will likely need therapeutic
paracentesis of ascites (> 1L) within 3 months of starting
study treatment.
6. Previous treatment with Apatinib.
7. Known hypersensitivity to Apatinib or components of the
formulation.
8. Concomitant treatment with strong inhibitors or inducers of
CYP3A4, CYP2C9 and CYP2C19.
9. Active bacterial infections.
10.Patients with substance abuse or medical, psychological, or
social conditions that may interfere with the patient’s
participation in the study or evaluation of the study results.
Conditions include but are not limited to;
- Known history of human immunodeficiency virus (HIV)
infection.
- Active hepatitis B or C infection or chronic hepatitis B or C
infection requiring treatment with antiviral therapy or
prophylactic antiviral therapy.
11.Patients who participated, within 4 weeks prior to randomization, or are participating in any other clinical trial.
12.Pregnant or breast-feeding women.
13.History of drug or alcohol abuse within past 5 years.
14.Medical or psychiatric illnesses that, in the investigator’s
opinion, may impact the safety of the subject or the
objectives of the study.
15.History of uncontrolled hypertension (Blood pressure ≥
140/90 mmHg and change in antihypertensive medication
within 7 days prior to randomization) that is not well managed
by medication and the risk of which may be precipitated by a
VEGF inhibitor therapy.
16.Patients who have known history of symptomatic congestive
heart failure (New York Heart Association III-IV), symptomatic
or poorly controlled cardiac arrhythmia, complete left bundle
branch block, bifascicular block, or any clinically significant
ST segment and/or T-wave abnormalities, QTcF > 450 msec
prior to randomization.
17.Prior major surgery or fracture within 3 weeks prior to
randomization or presence of any non-healing wound
(procedures such as cathether placement are not considered
to be major).
18.History of bleeding diathesis or clinically significant bleeding
within 14 days prior to randomization.
19.History of clinically significant thrombosis (bleeding or clotting
disorder) within the past 3 months prior to randomization
that, in the investigator’s opinion, may place the patient at
risk of side effects from anti-angiogenesis products.
20.History of gastrointestinal bleeding, gastric stress ulcerations,
or peptic ulcer disease within the past 3 months prior to
randomization that, in the investigator’s opinion, may place
the patient at risk of side effects from anti-angiogenesis
products.
21.Myocardial infarction or unstable angina pectoris within 6
months prior to randomization.
22.History of severe adverse events, in the investigator’s
opinion, related to ramucirumab.
23.History of other significant cardiovascular diseases or
vascular diseases within the last 6 months prior to
randomization (e.g. hypertensive crisis, hypertensive
encephalopathy, stroke or transient ischemic attack [TIA], or
significant peripheral vascular diseases) that, in the
investigator’s opinion, may pose a risk to the patient on
VEGF inhibitor therapy.
24.History of clinically significant glomerulonephritis, biopsyproven tubulointerstitial nephritis, crystal nephropathy, or
other renal insufficiencies.
25.Gastrointestinal malabsorption, or any other condition that in
the opinion of the investigator might affect the absorption of
the study drug.