| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Refractory metastatic gastric cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic gastric cancer refractory to treatment |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10007050 |
| E.1.2 | Term | Cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
|
| E.2.2 | Secondary objectives of the trial |
• Progression-free survival (PFS) based on Investigator assessment of radiologic images
• Safety and tolerability
• Overall response rate (ORR)
• Disease control rate (DCR)
• Time to deterioration of Eastern Cooperative Oncology Group (ECOG) performance status to score of 2 or higher
• Quality of life (QoL) (EORTC QLQ-C30 and QLQ-STO22) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A patient must meet all of the following inclusion criteria to be eligible for enrollment in this
study:
1. Has provided written informed consent.
2. Has histologically confirmed non-resectable, metastatic gastric adenocarcinoma including adenocarcinoma of the gastroesophageal (GE) junction as defined by the American Joint Committee on Cancer (AJCC) staging classification (7th ed., 2010). Documentation of histology of the tumor (primary or metastasis) will be required prior to enrollment. Gastroesophageal junction involvement must be documented by endoscopic, radiologic, surgical or pathology report.
3. Has previously received at least 2 prior regimens (at least 1 cycle per regimen) for advanced disease and were refractory to or unable to tolerate their last prior therapy:
a. Prior regimens must have included a fluoropyrimidine, platinum, and either a taxaneand/ or irinotecan-containing regimen; patients whose tumors are HER2-neu-positive (HER2+) must have received prior anti-HER2+ therapy if available.
b. Patients have progressed based on imaging during or within 3 months of the last administration of their last prior regimen.
c. Patients who have withdrawn from their last prior regimen due to unacceptable toxicity warranting discontinuation of treatment and precluding retreatment with the same agent prior to progression of disease will also be eligible to enter the study.
d. Patients who have received postoperative adjuvant chemotherapy and radiotherapy, and had recurrence during or within 6 months of completion of the adjuvant chemotherapy are allowed to count the adjuvant therapy as one prior regimen for advanced disease. Patients who have received pre- and post-operative adjuvant chemotherapy, and had recurrence during or within 6 months of completion of the adjuvant chemotherapy are allowed to count the adjuvant therapy as one prior regimen only if the same regimen was administered both pre- and post-operatively.
4. Has measureable or nonmeasurable disease as defined by RECIST 1.1 criteria.
5. Is able to take medications orally (ie, study drug must not be administered via a feeding tube).
6. Is ≥18 years of age (≥20 years for patients in Japan).
7. Has an ECOG performance status of 0 or 1 at time of randomisation
8. Has adequate organ function as defined by the following criteria:
a. Absolute neutrophil count (ANC) of ≥1,500/mm3 (ie, ≥1.5 × 10(9)/L by International Units [IU]).
b. Platelet count ≥100,000/mm3 (IU: ≥100 × 10(9)/L).
c. Hemoglobin value of ≥9.0 g/dL prior to randomization based on measurements obtained 2 weeks or more after last transfusion received.
d. Aspartate aminotransferase (AST; SGOT) and alanine aminotransferase (ALT; SGPT) ≤3.0 × upper limit of normal (ULN); if liver function abnormalities are due to underlying liver metastasis, AST (SGOT) and ALT (SGPT) ≤5 × ULN.
e. Total serum bilirubin of ≤1.5 × ULN (except for Grade 1 hyperbilirubinemia due solely to a medical diagnosis of Gilbert’s syndrome).
f. Serum creatinine ≤1.5 mg/dL.
9. Is willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
10. Women of childbearing potential must have a negative pregnancy test (urine or serum) within 7 days prior to starting the study drug. Both males and females must agree to use effective birth control during the study (prior to the first dose and for 6 months after the last dose) if conception is possible during this interval. Female patients are considered to not be of childbearing potential if they have a history of tubal ligation or hysterectomy or are post-menopausal with a minimum of 1 year without menses. For both males and females, definitions of contraceptive methods considered effective, and frequency of pregnancy testing for this protocol should be consistent with local laws and regulations. |
|
| E.4 | Principal exclusion criteria |
Exclude a patient from this study if any of the following conditions are observed:
1. Has a serious illness or medical condition(s) including, but not limited to the following:
a. Other concurrently active malignancies excluding malignancies that are disease free for more than 5 years or carcinoma-in-situ deemed cured by adequate treatment.
b. Known brain metastasis or leptomeningeal metastasis.
c. Active infection (ie, body temperature ≥38°C due to infection) including active or unresolved pneumonia/pneumonitis.
d. Intestinal obstruction, pulmonary fibrosis, renal failure, liver failure, or cerebrovascular disorder.
e. Uncontrolled diabetes.
f. Myocardial infarction within 12 months prior to randomization, severe/unstable angina, symptomatic congestive heart failure New York Heart Association (NYHA) class III or IV
g. Gastrointestinal hemorrhage (Grade ≥3) within 2 weeks prior to randomization.
h. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, or chronic or acute hepatitis B or hepatitis C.
i. Patients with autoimmune disorders or history of organ transplantation who require immunosuppressive therapy.
j. Psychiatric disease that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results.
2. Has had treatment with any of the following within the specified time frame prior to randomization:
a. Major surgery within prior 4 weeks (the surgical incision should be fully healed prior to study drug administration).
b. Any anticancer therapy within prior 3 weeks.
c. Extended field radiation within prior 4 weeks or limited field radiation within prior 2 weeks.
d. Any investigational drug/device received within prior 4 weeks.
3. Has previously received TAS-102.
4. Has unresolved toxicity of greater than or equal to CTCAE Grade 2 attributed to any prior therapies (excluding anemia, alopecia, skin pigmentation, and platinum-induced neurotoxicity).
5. Is a pregnant or lactating female.
6. Is inappropriate for entry into this study in the judgment of the Investigator. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint – Overall Survival
Survival is the primary endpoint of this study and is defined as the time from the date of randomization to the death date. In the absence of death confirmation or for patients alive as of the OS cut-off date, survival time will be censored at the date of last study follow-up, or the cutoff date, whichever is earlier.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The OS cut-off date used for the primary analysis will be based on the date of the 384th death in the study. With the OS cut-off date being event driven, for operational efficiency, the cut-off date for all other study endpoints will be fixed at close proximity of the OS cut-off date, when the milestone is nearing completion. |
|
| E.5.2 | Secondary end point(s) |
Key Secondary Efficacy Endpoint - PFS
Progression free survival is defined as the time from the date of randomization until the date of the investigator-assessed radiological disease progression or death due to any cause. Patients who are alive with no disease progression as of the analysis cut-off date will be censored at the date of the last tumor assessment. Patients who receive non-study cancer treatment before disease progression, or patients with clinical but not radiologic evidence of progression will be censored at the date of the last evaluable tumor assessment before the non-study cancer treatment
is initiated. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Patients who are alive with no disease progression as of the analysis cut-off date will be censored at the date of the last tumor assessment. Patients will have a CT scan every 8 weeks until disease progression. |
|
| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Study becomes open-label if the primary endpoint of the study is met (Protocol section 9.3) |
|
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 100 |
| 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 |
| Belarus |
| Belgium |
| Czech Republic |
| France |
| Germany |
| Ireland |
| Israel |
| Italy |
| Japan |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Spain |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
|
| The end of study is defined as completion of safety follow-up for the last patient who discontinues study treatment, including patients who are switched to open-label TAS-102 after completion of final analysis. |
|
| 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 | 1 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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