E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced or metastatic solid tumors and previously untreated gastric cancer |
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E.1.1.1 | Medical condition in easily understood language |
Tumors that are advanced or have spread to other parts of the body and stomach cancer that has not been treated before |
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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 | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065147 |
E.1.2 | Term | Malignant solid tumor |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10017758 |
E.1.2 | Term | Gastric cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
Phase Ib: to determine the maximum tolerated dose (MTD)/recommended Phase II dose and characterize the pharmacokinetics (PK) of E7050 when administered in combination with cisplatin plus capecitabine in patients with locally advanced, unresectable or metastatic solid tumors;
Phase II: to evaluate the safety and tolerability of E7050 administered in combination with cisplatin plus capecitabine compared with cisplatin plus capecitabine alone, in patients with previously untreated advanced, locally advanced, unresectable or metastatic gastric cancer. |
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E.2.2 | Secondary objectives of the trial |
Phase II: to make a preliminary assessment of the efficacy of E7050 administered in combination with cisplatin plus capecitabine, compared with cisplatin plus capecitabine alone, in patients with previously untreated, locally advanced, unresectable or metastatic gastric cancer. Efficacy will be evaluated by median time to progression (TTP), progression-free survival (PFS), proportion of PFS at Week 12, overall survival (OS), and overall response rate (ORR). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients may be entered in the study only if they meet all of the following criteria:
1. Male or female patient ≥18 years of age;
2. Histologically confirmed, unresectable, locally advanced or metastatic gastric cancer, including adenocarcinoma of the gastroesophageal junction (Phase II). For the Phase Ib portion, any unresectable, locally advanced or metastatic solid tumor;
3. At least 1 site of measurable disease by the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v. 1.1) criteria;
4. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 to 1;
5. Adequate hematologic, renal, liver, and coagulation system function as defined by laboratory values performed within 21 days prior to initiation of dosing:
Absolute neutrophil count (ANC) ≥1.5 x 109/L;
Platelet count ≥100 x 109/L;
Hemoglobin ≥9 g/dL;
Serum creatinine ≤1.5 X ULN and/or creatinine clearance ≥60 mL/min
per the Cockcroft and Gault formula;
Total serum bilirubin ≤1.5 X ULN;
Serum aspartate transaminase (AST/SGOT) or serum alanine
transaminase (ALT/SGPT) ≤2.5 X ULN, and ≤5 X ULN if liver
metastases are present. If there are bone metastases, liver-specific
alkaline phosphatase may be separated from the total and used to
assess liver function instead of total alkaline phosphatase;
PT/International normalized ratio (INR) ≤1.5 X ULN;
PTT ≤1.1 X ULN;
6. For patients with hypertension, it must be well controlled. If a patient presents with poorly controlled hypertension, defined as a mean systolic blood pressure ≥140 mm Hg or mean diastolic blood pressure ≥90 mm Hg, antihypertensive medication(s) should be initiated or adjusted with a goal to control the blood pressure <140/90 mm Hg. Blood pressure must be reassessed on 2 occasions, consecutively, that are separated by a minimum of 24 hours;
7. Male or female patients of child-producing potential must agree to use double barrier contraception, oral contraceptives, or avoidance of pregnancy measures during the study and for 90 days after the last day of treatment;
8. Females of childbearing potential must have a negative serum pregnancy test at screening;
9. Females may not be breastfeeding;
10. Ability to understand and willingness to sign a written informed consent. |
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E.4 | Principal exclusion criteria |
Patients will not be entered in the study for any of the following reasons:
1. Gastric cancer patients who have had a complete gastrectomy;
2. Patients with known HER2 over-expressing advanced or metastatic gastric cancer;
3. Prior treatment with E7050, its chemical derivatives or prior anti-c-Met therapy;
4. Prior anti-angiogenic therapy (permitted in Phase Ib);
5. For Phase Ib prior systemic therapy is allowed as long as PS and end organ function meet entry criteria;
6. For Phase II no prior palliative chemotherapy is permitted. Adjuvant or neoadjuvant chemotherapy is permitted if >12 months have elapsed between the end of adjuvant or neoadjuvant therapy and first recurrence;
7. Known central nervous system lesions, except for asymptomatic non-progressing, treated brain metastases. Treated brain metastases are defined as having no evidence of progression or hemorrhage, as ascertained by clinical examination and brain imaging (MRI or CT) during the Screening period. Treatment for brain metastases must have been completed at least 4 weeks prior to Day 1 and may include whole brain radiotherapy, radiosurgery (RS; Gamma Knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician. Dexamethasone must be discontinued at least 3 weeks prior to Day 1;
8. History of other malignancies except: (1) adequately treated basal or squamous cell carcinoma of the skin; (2) curatively treated, a) in situ carcinoma of the uterine cervix, or b) prostate cancer, or c) superficial bladder cancer; or (3) other curatively treated solid tumor with no evidence of disease for ≥3 years;
9. Received treatment in another clinical study within the 30 days prior to commencing study treatment or patients who have not recovered from side effects of an investigational drug to Grade ≤1, except for peripheral neuropathy (Grade 1 and Grade 2 are permitted) and alopecia;
10. Are currently receiving any other anti-cancer treatment;
11. Palliative radiotherapy is not permitted throughout the study period. Prior palliative radiotherapy within 30 days prior to commencing study treatment;
12. CTCAE Grade ≥3 peripheral neuropathy (Grade 1 and Grade 2 are permitted);
13. Patients with known dihydropyrimidine dehydrogenase deficiency;
14. Patients with clinically significant hearing loss that may be further diminished by treatment with cisplatin plus capecitabine (significance of hearing loss to be determined by the Investigator);
15. Serious non-healing wound, ulcer, bone fracture, or have undergone a major surgical procedure, open biopsy, or significant traumatic injury within the 21 days prior to commencing study treatment. Minor surgery such as Portacath placement or skin biopsy is permitted if ≥7 days have passed;
16. History of bleeding diathesis or coagulopathy;
17. History of bleeding varices;
18. Active hemoptysis (defined as bright red blood of ½ teaspoon or more) within the 30 days prior to study entry;
19. Clinically significant gastrointestinal bleeding (bleeding requiring procedural intervention, eg, variceal banding, transjugular intrahepatic portosystemic shunt procedure, arterial embolization, topical coagulation therapy) within 6 months prior to first dose;
20. History of untreated deep venous thrombosis within the past 6 months (eg, calf vein thrombosis), or history of portal vein thrombosis;
21. Refractory nausea and vomiting, malabsorption, significant bowel resection, or any other medical condition that would preclude adequate absorption or result in the inability to take oral medication;
22. Significant cardiovascular impairment (history of congestive heart failure New York Heart Association [NYHA] Grade >2, unstable angina or myocardial infarction within the past 6 months, or serious cardiac arrhythmia);
23. Uncontrolled ascites, requiring drainage at least twice per week;
24. Any history of cerebral vascular accident, transient ischemic attack, or Grade ≥2 peripheral vascular disease unless they have had no evidence of active disease for at least 6 months prior to randomization;
25. Patients with organ allografts requiring immunosuppression;
26. Known positive human immunodeficiency virus (HIV), known hepatitis B surface antigen, or active hepatitis C positive;
27. History of hypersensitivity reactions to cisplatin or capecitabine;
28. Hypersensitivity to E7050 and/or E7050 chemical derivative;
29. Have any medical condition that would interfere with the conduct of the study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary exploratory efficacy endpoint will be the median time-to-progression (TTP), within treatment group, defined as time from the date of randomization of a patient until the date of first documented progression of such patient’s disease based on Investigator assessments according to RECIST (v. 1.1). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Date of first documented progression of such patient's disease based on Investigator assessments according to RECIST or (2) the date of such patient's death due to any cause. |
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E.5.2 | Secondary end point(s) |
Secondary exploratory efficacy endpoints include median progression-free survival (PFS), proportion of PFS at Week 12, overall survival (OS), and overall response rate (ORR), within treatment group. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 12 for proportion of PFS |
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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 | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
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 |
Russian Federation |
Ukraine |
United Kingdom |
United States |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |