| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with stage IIIb/IV NSCLC of all histologies, who have progressed while on or following a first-line treatment and are eligible for second-line line chemotherapy |
|
| 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 |
| To compare overall survival between the ASA404 plus docetaxel group and the placebo plus docetaxel group |
|
| E.2.2 | Secondary objectives of the trial |
* To compare Progression-Free Survival (PFS) and the Overall Response Rate (ORR) per RECIST assessed by the investigators between patients receiving ASA404 or placebo in combination with docetaxel
* To assess Time to Response (CR or PR) and Duration of Response per RECIST assessed by the investigator between patients receiving ASA404 or placebo in combination with docetaxel
* To assess safety of ASA404 in combination with docetaxel
* To determine population pharmacokinetics and factors influencing systemic exposure to ASA404
* To assess physical functioning and gloval health status quality of life (QoL) as measured by the EORTC QLQ-C30 in patients receiving ASA404 or placebo in combination with docetaxel
* To assess lung cancer specific symptoms as measured by the QLQ-LC13 in patients receiving ASA404 or placebo in combination with docetaxel |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically confirmed non-small cell carcinoma of the lung of all histologies.
2. Patients who have progressed while on or following a first-line chemotherapy regimen for Stage IIIb disease (malignant pleural effusion or pericardial effusion that have been confirmed cytologically) or Stage IV disease. Patients who have received bevacizumab and/or EGFR inhibitors in first-line will be eligible
3. Age ≥ 18 years old
4. WHO Performance Status of 0-2
5. Measurable or non-measurable disease per RECIST criteria
6. Laboratory 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)
• Alkaline phosphatase ≤ 2.5 x ULN
• 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 ULN
• Electrolyte values (sodium, potassium, calcium, magnesium) within ≥1 x LLN and ≤ 1 x ULN. Patients with corrected electrolyte values are eligible
• Females of child-bearing potential must have negative serum pregnancy test (confirmation of negative urine pregnancy test within 72 hours prior to initial dosing)
7. Life expectancy ≥ 12 weeks
8. Written informed consent obtained according to local guidelines |
|
| E.4 | Principal exclusion criteria |
1. Patients having CNS metastases
2. Patients with a concurrent malignancy, or history of prior malignancy within the past three years, except for basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, treated early stage (T1a) prostate cancer or treated early stage (DCIS or LCIS) breast cancer.
3. Radiotherapy ≤ 2 weeks prior to randomization. Patients must have recovered from all acute radiotherapy-related toxicities.
4. Major surgery must be completed 4 weeks prior to starting study treatment (major surgery is defined at the investigator's discretion. Insertion of a vascular access device is not considered major or minor surgery. Patients must have recovered from all acute major surgery-related complications.
5. Treatment with all prior anti-cancer therapies ≤ 3 weeks prior to randomization (≤ 6 weeks for bevacizumab, mitomycin and nitrosoureas)
6. Concurrent use of other investigational agents and patients who have received investigational agents ≤ 4 weeks prior to randomization
7. Prior treatment with docetaxel for NSCLC in the locally advanced or metastatic first-line setting
8. Prior treatment with VDAs or tumor - VDAs
9. Any medical condition resulting in ≥ CTC grade 2 dyspnea
10. Patients with systolic BP > 160 mm Hg and/or diastolic BP > 90 mm Hg while on medication for hypertension
11. Patients with recent hemoptysis associated with NSCLC (> 1 teaspoon in a single episode within 4 weeks)
12. Patients with any one of the following:
• Patients with long QT syndrome
• Patients with a Baseline 12-lead ECG QTc of > 450 msec for men or >470 msec for women using the Fridericia (QTcF formula) measurement determined per central per central ECG evaluation report
• Congestive heart failure (NY Heart Association class III or IV)
• Patients with a myocardial infarction within 12 months of starting study treatment or with implanted cardiac pacemaker
• Unstable or poorly controlled angina pectoris, including Prinzmetal variant angina pectoris
• History of poorly-controlled labile hypertension or poor compliance with antihypertensive regimen
• History of a sustained ventricular tachycardia
* Presence of atrial tachyarrhytmia (e.g. atrial fibrillation, atrial flutter, multifocal atrial tachycardia, supraventricular tachycardia) if not effectively rate-controlled
• Any history of ventricular fibrillation or Torsades de Pointes (TdP)
• Right bundle branch block (RBBB) and either left anterior hemiblock or left posterior hemiblock (bifasicular block)
• Bradycardia defined as heart rate < 50 beats per minute
* (For China only: patients older than 70 years with evidence of myocardial ischemia by coronary artery angiography or cardiac radionucleotide imaging examination)
* (For China only: Patients with LVEF <=40%)
* any clinically significant cardiac abnormality as assessed by the investigator
13. Patients who are currently receiving treatment with any medications that have the potential to prolong QT interval or are known to have risk of causing Torsades de Pointes (See section 6.8.5.1 Table 6.3 and Appendix 2) which can not be either safely discontinued or switched to a different medication prior to starting study drug administration must be discussed with and approved by the Novartis Global clinical team prior to randomization.
14. Known allergy or hypersensitivity to docetaxel or drugs formulated with polysorbate 80
15. Peripheral sensory neuropathy with functional impairment (CTC grade 2 neuropathy, regardless of causality)
16. Pregnant or breast feeding females
17. 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.
18. Concurrent severe and/or uncontrolled medical disease
19. Significant neurologic or psychiatric disorder which could compromise participation in the study
20. Patient unwilling or unable to comply with the protocol
21. Patients receiving full-dose therapeutic oral or parenteral anticoagulation are ineligible. Patients receiving thrombolytic therapy within 10 days of starting study treatment are also ineligible. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint will be overall survival
|
|
| 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 | Yes |
| 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 | 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) | 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 210 |
| 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
|
| The final analysis will be performed when 693 events are observed. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 3 |
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