| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| This phase III trials is conducted world-wide in order to demonstrate safety and efficacy of ASA404 in combination with a paclitaxel-carboplatin chemotherapy in the treatment of patients with stage IIIb/IV NSCLC who are eligible for a first line chemotherapy. The study population will consist of patients with NSCLC of all histologies eligible for first-line therapy. |
|
| 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 | 10066490 |
| E.1.2 | Term | Progression of non small cell lung cancer |
|
| 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 primary objective is to compare the overall survival (OS) of patients receiving ASA404 or placebo in combination with paclitaxel and carboplatin for first-line treatment of stage IIIb/IV NSCLC. |
|
| E.2.2 | Secondary objectives of the trial |
- To compare the OS of patients with non-squamous NSCLC receiving ASA404 or placebo in combination with paclitaxel and carboplatin
- To compare the OS of patients with squamous NSCLC receiving ASA404 or placebo in combination with paclitaxel and carboplatin |
|
| 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 |
- sub-study of ECG with correlating PK at selected sites will be closely examined in 150 patients
- exploratory biomarker research studies will be conducted as a sub-study to this protocol |
|
| E.3 | Principal inclusion criteria |
1. Histologically confirmed non-small cell carcinoma of the lung. (Histological or
cytological specimens must be collected via surgical biopsy, brushing, washing or core
needle aspiration of a defined lesion. Sputum cytology is not acceptable.)
2. Newly diagnosed Stage IIIb disease (malignant pleural effusion or pericardial effusion that have been confirmed cytologically) or Stage IV disease
3. No prior systemic antineoplastic treatment for Stage IIIb/IV non-small cell carcinoma of the lung (Prior neoadjuvant or adjuvant chemotherapy for earlier stage I/II NSCLC is allowed if 12 months or more prior to Baseline visit)
4. Age ≥ 18 years old
5. WHO Performance Status of 0-1
6. Measurable or non-measurable disease per RECIST criteria (Post-text suppl 1)
7. Lab values within the range, as defined below, within 2 weeks of randomization:
• Absolute neutrophils count (ANC) > 2.0 x 109/L
• Platelets ≥ 100 x109/L
• Hemoglobin ≥ 10 g/dL
• Serum creatinine ≤ 1.5 x ULN (≤ 120 micro mol/L)
• Serum bilirubin ≤ 1.5 x ULN (≤ 25 micro mol/L)
• Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN (≤ 5 x
ULN if liver metastases)
• International Normalized Ratio (INR) or Prothrombin Time (PT) < 1.5 x
IULN
• Electrolyte values (potassium, calcium, magnesium) within > 1 x LLN and < 1 x
ULN. Patients with corrected electrolyte values are eligible. See Section 6.8.1 &
7.3.4.3.
• Females of child-bearing potential must have negative serum pregnancy test
(confirmation of negative urine pregnancy test within 72 hours prior to initial dosing).
8. Life expectancy ≥ 12 weeks
9. Written informed consent obtained according to local guidelines |
|
| E.4 | Principal exclusion criteria |
1. Patients having CNS metastases (Patients having any clinical signs of CNS metastases
must have a CT or MRI of the brain performed to rule out CNS metastases in order to be
eligible for study participation. Patients who have had brain metastases surgically
removed or irradiated with no residual disease confirmed by imaging are allowed.).
2. Patients with a history of another primary malignancy ≤ 5 years, with the exception of
non-melanoma skin cancer or cervical cancer in situ.
3. Radiotherapy ≤ 2 weeks prior to randomization. Patients must have recovered from all
radiotherapy-related toxicities.
4. Major surgery ≤ 4 weeks prior to randomization or minor surgery ≤ 2 weeks prior to randomization. Major surgery is defined by the use of general anesthesia, however endoscopic examinations with diagnostic intent are not considered major surgery. Insertion of a vascular access device is exempt from this exclusion criteria. Patients must have recovered from all surgery-related complications.
5. Concurrent use of other investigational agents and patients who have received
investigational agents ≤ 4 weeks prior to randomization
6. Prior exposure to Tumor-VDAs or other vascular targeting agents (anti-VEGF, anti-VEGF
receptor agents, anti-EGFR agents [bevacizumab, cetuximab, etc.])
7. Pleural effusion that causes ≥ CTC grade 2 dyspnea
8. Patients with systolic BP > 160 mm Hg and/or diastolic BP >90 mm Hg
9. Patients with recent hemoptysis associated with NSCLC (>1 teaspoon in a single episode
within 4 weeks)
10. Patients with any one of the following:
• Patients with long QT syndrome
• Patients with a Baseline 12-lead ECG QTc of >450 msec per central evaluation
• Congestive heart failure (NY Heart Association class III or IV)
• Patients with a myocardial infarction within 12 months of study entry
• Unstable or poorly controlled angina pectoris, including Prinzmetal variant angina
pectoris
• History of labile hypertension or poor compliance with anti-hypertensive regimen
• History of a sustained ventricular tachycardia
• Any history of ventricular fibrillation or Torsades de Pointes
• Right bundle branch block and left anterior hemiblock (bifasicular block)
• Bradycardia defined as heart rate <50 beats per minute
11. Concomitant use of drugs with a risk of causing Torsades de Pointes
12. Known allergy or hypersensitivity to platinum-containing drugs, taxanes, other drugs formulated in Cremophor EL (polyoxyethylated castor oil) or any known excipients of these drugs.
13. Peripheral sensory neuropathy with functional impairment (CTC grade 2 neuropathy, regardless of causality)
14. Pregnant or breast feeding females
15. Women of child bearing potential or sexually active males, unwilling or unable to use the required highly effective method(s) of contraception for both sexes while receiving treatment and for at least 6 months after the discontinuation of study treatment.
16. Concurrent severe and/or uncontrolled medical disease (i.e. uncontrolled diabetes, chronic
renal disease, chronic liver disease, confirmed diagnosis of HIV infection or active
uncontrolled infection).
17. Significant neurologic or psychiatric disorder which could compromise participation in the
study
18. Patient unwilling or unable to comply with the protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall survival (OS) - time from the date of randomization to the date of death due to any cause, or the last date the patient was known to be alive (censored observation) at the date of the data cutoff for the final analysis. |
|
| 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 | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Stratification by NSCLC histology and gender |
|
| 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
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Yes |
| 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 |
|
| 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
| |
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 6 |
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