| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Male and female patients age 18 years or older with histologically or cytologically confirmed advanced or metastatic NSCLC for whom standard therapy no longer exists |
|
| E.1.1.1 | Medical condition in easily understood language |
| Male and female patients age 18 years or older with histologically or cytologically confirmed advanced or metastatic NSCLC for whom standard therapy no longer exists |
|
| 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 | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 compare the PFS of patients with advanced or metastatic NSCLC, when treated with TAS-114/S-1 combination versus S-1 in patients with advanced solid tumor for which no standard therapy exists |
|
| E.2.2 | Secondary objectives of the trial |
- To investigate the OS, overall response rate (ORR), disease control rate (DCR), and duration of response (DR).
- To investigate the safety and tolerability |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| 1. Pharmacogenomic sub-study |
|
| E.3 | Principal inclusion criteria |
A patient must meet all of the following inclusion criteria to be eligible for enrollment in this study.
1. Provision of written informed consent consistent with International Council for Harmonisation
(ICH)-Good Clinical Practice (GCP) guidelines and respective local law;
2. Age ≥ 18 years old;
3. Histologically diagnosed or cytologically proven advanced or metastatic NSCLC patients, either Stage IIIB/Stage IV disease (according to Version 7 of the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology), or recurrent disease following radiation therapy or surgical resection;
4. Patients who had received at least 2 prior therapies for advanced or metastatic disease condition, including platinum doublet and pemetrexed, docetaxel, or immunotherapy, and were refractory to or unable to tolerate their last prior therapy. For patients with known epidermal growth factor receptor (EGFR) activating mutations or anaplastic lymphoma kinase translocations, and/or ROS1 rearrangements, appropriate targeted treatment should have been used. The following histological tumor types are also eligible to be included:
• Adenocarcinoma with bronchiolo-alveolar differentiation
• Large cell carcinoma
5. Tumor is locally advanced or metastatic and not suitable for surgery and radiotherapy is not indicated;
6. Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST)
criteria (Version 1.1, 2009);
7. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1;
8. Predicted life expectancy of at least 3 months;
9. Able to take medications orally;
10. Adequate organ function as defined by:
• Adequate bone marrow function: absolute neutrophil count (ANC) ≥ 1500/mm3, hemoglobin
≥ 10.0 g/dL, platelets ≥ 100,000/mm3
• Adequate liver function: Total bilirubin ≤ 1.5 × upper limit of normal (ULN), aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3 × ULN (existent liver metastases
≤ 5 × ULN)
• Adequate renal function: Calculated creatinine clearance ≥ 50 mL/min (Cockcroft-Gault Equation)
11. Women of childbearing potential (WOCBP) 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 hysterectomy, or are post-menopausal defined as
no menses for 12 months without an alternative medical cause. For both males and females, see
Section 8.7.2 for definitions of contraceptive methods considered effective for this protocol;
12. Willing and able to comply with required scheduled visits and study procedures |
|
| E.4 | Principal exclusion criteria |
A patient will be excluded from this study if any of the following criteria are met:
1. Treatment with any of the following within the specified time frame prior to the study drug administration:
• Major surgery within prior 4 weeks and minor surgery within 7 days;
• Radiotherapy for extended field within prior 4 weeks or limited field within prior 2 weeks;
• Any anticancer therapy or investigational agent within prior 3 weeks.
2. A serious illness or medical condition including but not limited to the following:
• Patients with brain or subdural metastases are not eligible unless they have completed local therapy and have discontinued the use of therapeutic corticosteroids and are stable for at least
1 month before study drug administration;
• Known leptomeningeal metastatic disease;
• Known acute or chronic active systemic infection;
• Any cardiac disease, such as myocardial infarction, unstable angina, symptomatic congestive heart failure (CHF) New York Heart Association (NYHA) class III or IV within the last
6 months. If > 6 months, cardiac function must be within normal limits and the patient must be free of cardiac-related symptoms;
• Chronic nausea, vomiting, or diarrhea considered to be clinically significant by investigator’s
discretion;
• Current or past severe lung disease (eg, interstitial pneumonia, pulmonary fibrosis, or severe emphysema);
• Pleural, peritoneal, or pericardial effusion which will require surgical intervention in the near term;
• Any history or presence of poorly controlled gastrointestinal (GI) disorders that could affect the absorption of the trial drug (eg, Crohn’s disease, ulcerative colitis);
• Known human immunodeficiency virus (HIV) or acquired immune deficiency syndrome
(AIDS)-related illness, or chronic or acute hepatitis B or C;
• Any other clinically significant acute or chronic medical or psychiatric condition or any laboratory abnormality that may increase the risk associated with study drug administration, or may interfere with the interpretation of study results;
• Poorly controlled (despite medication) or severe diabetes mellitus;
• Continuous systemic steroid administration (oral or intravenous);
• Other concurrent active cancer (synchronous double cancer or heterochronous double cancer with a disease-free interval of 3 years or shorter, excluding lesions consistent with intraepithelial cancer, ie, carcinoma in situ, or intramucosal cancer) that is assessed as cured
by local treatment.
3. Concomitant treatment with the following drugs that may interact with S-1:
• Sorivudine, brivudine, uracil, eniluracil, folinate/folinic acid, (enhance S-1 activity);
• Cimetidine, dipyridamole, and nitroimidazoles, including metronidazole and misonidazole
(may enhance S-1 activity);
• Methotrexate (may enhance S-1 activity);
• Clozapine (may increase risk and severity of hematologic toxicity with S-1);
• Allopurinol (may diminish S-1 activity);
• Phenytoin (S-1 may enhance phenytoin activity);
• Flucytosine, a fluorinated pyrimidine antifungal agent (may enhance S-1 activity);
• Coumarin-derivative anticoagulant (S-1 may enhance activity of coumarin-derivative anticoagulant);
4. Known hypersensitivity to S-1 or its metabolites (eg, 5-FU);
5. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose/galactose malabasorption since S1 contains lactose;
6. Previous use of TAS-114, S-1, and 5-FU drugs;
7. A pregnant or lactating female or possibly pregnant women, or men or women wishing to have children during the study period;
8. A judgment of the investigator that the patient is inappropriate for study participation |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression Free Survival |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Day of randomization to the start of disease progression or death (any cause), whichever occurs first |
|
| E.5.2 | Secondary end point(s) |
| Overall Survival, overall response rate, disease control rate, duration of response, safety, and tolerability |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Day of randomization to any cause of death or 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 | Yes |
| 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 | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 21 |
| 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 |
| Croatia |
| France |
| Italy |
| Japan |
| Poland |
| Spain |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| For the purpose of the final analyses, the study will be considered completed when all patients have discontinued from treatment or a minimum of 12 months from the date of the first day of treatment with TAS-114/S-1 or S-1 of the last patient enrolled or until the target number of events (deaths, n=80) is reached, whichever occurs first |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 16 |
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