| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced or Metastatic Gastric Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Stomach cancer, also known as gastric cancer developing from the lining of the stomach. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the overall suvival (OS) of Apatinib compared to Placebo in patients with Advanced or Metastatic Gastric Cancer (GC) |
|
| E.2.2 | Secondary objectives of the trial |
• 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 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female at least 18 years old or older.
2. Documented primary diagnosis of histologic- or cytologic-confirmed 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
o nivolumab
o pembrolizumab
Previous treatments with experimental agents (except experimental antiangiogenic agents) alone or as part of the first three prior therapy lines are allowed but not mandatory. A maximum number of three prior therapy lines are allowed, unless nivolumab or pembrolizumab was used in a prior line, for which case a maximum of four 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 (no other medical cause involved) or must be using an acceptable method of birth control effectively. Acceptable methods of birth control include hormone contraceptives [oral, non-oral, or implants], intrauterine contraceptive device or Intrauterine Contraceptive System that are approved or certified in Japan or applicable country. Other intrauterine contraceptive device, contraception double barrier methods such as condom, sponge, cervical cap and diaphragm with spermicides, if locally determined to be effective outside of Japan, may be considered as acceptable.
12. Ability and willingness to comply with the study protocol for the duration of the study and with follow-up procedures.
|
|
| E.4 | Principal 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. Patients are eligible if metastases have been treated and have returned to neurologic baseline or are neurologically stable (except for residual signs or symptoms related to the CNS treatment).
3. Cytotoxic chemotherapy, surgery, immunotherapy, radiotherapy or other targeted therapies within 3 weeks (4 weeks in cases of ramucirumab, mitomycin C, nitrosourea, lomustine; 1 week 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 or chronic hepatitis B or C infection or requiring treatment with antiviral therapy or prophylactic antiviral unless evidence of viral suppression has been documented and the patient will remain on appropriate antiviral therapy throughout.
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 > 450/470 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, biopsy-proven 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall Survival (OS): Time from randomization to death. Subjects alive or lost to follow-up at the end of study (EOS) are censored. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
・ 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 QLQ-C30) and EORTC QLQ-STO22.
・ Each dimension response according to EuroQol 5-Dimension 5-Level (EQ-5D-5L) Questionnaire.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Measured on an ongoing basis as per flow chart |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 29 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| France |
| Poland |
| Romania |
| Germany |
| Italy |
| Russian Federation |
| Ukraine |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| A treatment cycle is composed of 28 days (4 weeks) and the study treatment will be continued until the death of the subject or discontinuation of the study treatment due to disease progression, intolerable toxicity or subject’s withdrawal of consent. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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