| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
- to assess the potential effects of trabectedin on the QT/QTc interval duration measured by electrocardiograms (ECGs) in subjects with advanced solid tumor malignancies when administered at a therapeutic dose.
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10007050 |
| E.1.2 | Term | Cancer |
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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 |
| The objective of this study is to assess the potential effects of trabectedin on the QT/QTc interval duration measured by electrocardiograms (ECGs) in subjects with advanced solid tumor malignancies when administered at a therapeutic dose. |
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| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of this study are to assess the survival, the safety and pharmacokinetics of trabectedin. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Men or women between 18 and 65 years of age, inclusive
2. Subjects with locally advanced or metastatic solid tumors who have received three or less prior lines of systemic chemotherapy will be included.
3. Subjects must have relapsed or had progressive disease following standard of care treatment with chemotherapy prior to enrollment, or intolerant to prior standard of care treatment with chemotherapy
4. Subjects who have had total prior anthracycline over 260 mg/m2 should have LVEF within normal limits, according to the institutional guidelines. A MUGA (multigated acquisition) scan or 2-d echocardiogram must be performed within 6 weeks before enrollment.
5. Blood pressure (after the subject is supine for 10 minutes) between 90 and 140 mmHg systolic, inclusive, and no higher than 90 mmHg diastolic
6. A 12-lead ECG consistent with normal cardiac conduction and function, showing:
· Sinus rhythm
· Pulse rate between 45 and 90 bpm
· QTc interval < or = 500 ms (based on the mean of 3 tracings (Fridericia corrected values))
· QRS interval of <110 ms
· PR interval <200 ms
· Morphology consistent with healthy cardiac conduction and function
7. Non-smoker (has not used any tobacco products for at least 6 months before study drug administration)
8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1
9. Adequate organ function as evidenced by the following peripheral blood counts or serum chemistry values within 7 days before Day 1:
– hemoglobin ≥ 9 g/dL
– absolute neutrophil count (ANC) ≥ 1,500/µL
– platelet count ≥100,000/µL
– serum creatinine < or = 1.5 mg/dL (< or = 132.6 µmol/L), if not then 24 hour urine creatinine clearance must be ≥ 50 mL/min
– creatine phosphokinase (CPK) < or = upper limit of normal (ULN)
10. Hepatic function variables
– total bilirubin < or = ULN. If total bilirubin is > ULN, measure indirect bilirubin to rule out Gilbert's syndrome (if indirect bilirubin is within normal range, subject is eligible)
– total alkaline phosphatase (ALP) < or =1.5 ULN, or if >1.5 ULN, ALP liver fraction or 5’ nucleotidase must be < or = ULN
– AST and ALT must be < or = 2.5 x ULN
11. Adequate recovery from surgery, at least 2 weeks from last dose of hormonal therapy, at least 3 weeks from prior chemo- or biological therapy, at least 3 weeks from receiving radiotherapy, at least 4 weeks after or a period 10 times the drug’s half life (approximately 75 days), whichever is longer, before the first dose of the study drug is scheduled from the last experimental anticancer therapy, and 6 weeks in the case of receipt of nitrosoureas or mitomycin C, provided all side effects from these therapies have resolved to grade 1 or less according to the National Cancer Institute – Common Terminology Criteria of Adverse Events (NCI_CTCAE, Version 3)
12. Must be able to receive dexamethasone or its equivalent
13. If female, must be postmenopausal (no spontaneous menses for at least 2 years), surgically sterile, abstinent, or, if sexually active, be practicing an effective method of birth control (e.g., prescription oral contraceptives, contraceptive injections, intrauterine device, double barrier method, contraceptive patch, male partner sterilization) before entry and throughout the study
14. If female of child bearing potential, must have a negative serum β-human chorionic gonadotropin (β-hCG)] pregnancy test at screening; and a negative urine pregnancy test on Day –1 of the treatment phase
15. If male, must agree to use an adequate contraception method as deemed appropriate by the investigator (e.g., vasectomy, double-barrier, partner using effective contraception) and to not donate sperm during the study and for 40 days after receiving the last dose of study drug
16. Subject must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study. Only subjects who are fully able to understand the risks, benefits, potential adverse events, and alternatives to participation, provide their consent voluntarily, and are not hospitalized involuntarily will be enrolled.
17. Subject must have received a thorough explanation of the optional pharmacogenomic research component of the study and was offered an opportunity to participate by signing the separate pharmacogenomic informed consent document.
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| E.4 | Principal exclusion criteria |
1. Subjects treated with more than three prior chemotherapy regimens (including adjuvant therapy)
2. Previous exposure to trabectedin
3. Subjects with CNS metastasis
4. Known hypersensitivity to any of the components of the trabectedin i.v. formulation or dexamethasone
5. Have heart rhythm disturbances, unusual T wave and U wave (if present) morphology, blood pressure outside of normal range, a history of cardiac failure, myocardial infarction, or cardiomyopathy, or a history of additional risk factors for torsade de pointes (e.g. heart failure, electrolyte abnormalities, family history of Long QT Syndrome)
6. Have any skin condition likely to interfere with ECG electrode placement, a history of breast implant or thoracic surgery likely to cause abnormality in electrical conduction
7. Subjects who at screening are on medication (refer to Attachment 5) that is known to prolong the QT interval or who are on CYP3A4 inhibitors or inducers. Subjects must have been off these medications for a mimumum of 5 half-lives.
8. History of or current clinically significant medical illness including (but not limited to), congestive heart failure, angina pectoris, or other cardiac disease, uncontrolled hypertension or uncontrolled arrhythmia, symptomatic brain metastases or leptomeningeal disease, significant pulmonary disease, including bronchospastic respiratory disease, uncontrolled diabetes, renal or hepatic insufficiency, thyroid disease, neurologic or psychiatric disease, infection, positive serology results for hepatitis B surface antigen (HBsAg), or hepatitis C antibodies, or any other illness that the investigator considers should exclude the subject or that could interfere with the interpretation of the study results
9. Subjects unwilling or unable to have a central catheter
10. History of illegal drug use or alcohol abuse within 6 months before study drug administration
11. If a woman, breast-feeding or planning to become pregnant during the study
12. Preplanned surgery or procedures that would interfere with the conduct of the study
13. Employee of the investigator or study center, with direct involvement in the proposed study or other studies under the direction of that investigator or study center, as well as family members of the employees or the investigator.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary pharmacodynamic endpoint will be the difference in delta-QTc at each scheduled time point. |
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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 | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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) | 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 |
| QT electrocardiogram intervals |
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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 | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | Yes |
| E.8.1.4 | Double blind | No |
| 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 |
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| 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.8.3 |
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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| 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 | Information not present in EudraCT |
| 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 |
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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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| The study is considered completed with the last visit of the last subject undergoing the study. (cfr 11.9.1) |
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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 | 0 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 26 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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