| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced or recurrent non-squamous non-small cell lung cancer |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10059515 |
|
| 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 assess the safety profile of bevacizumab when combined with standard chemotherapy as first-line treatment of advanced or recurrent non-squamous NSCLC. In particular, the incidence of serious adverse events (SAEs) related to bevacizumab and the incidence of specific AEs (serious and non-serious) such as hypertension, proteinuria, wound healing complications, gastrointestinal perforations, arterial and venous thomboembolic events, haemoptysis, CNS bleeding, other haemorrhages and CHF will be investigated. |
|
| E.2.2 | Secondary objectives of the trial |
To assess the efficacy of bevacizumab as measured by TTP and OS.
To assess the safety of bevacizumab in patients who develop CNS metastases during the treatment period.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients included in the study should have the following criteria:
1. Written informed consent (informed consent document to be approved by the institution’s Independent Ethics Committee and patient consent obtained prior to any study-specific procedure)
2. Age ≥18 years
3. Able to comply with the protocol
4. Histologically or cytologically documented inoperable, locally advanced (Stage IIIb with supraclavicular lymph node metastases or malignant pleural or pericardial effusion), metastatic (Stage IV) or recurrent NSCLC other than squamous cell (tumours of mixed histology should be categorized by the predominant cell type)
5. ECOG PS 0-2
6. Life expectancy ≥12 weeks
7. Adequate haematological function
- Absolute neutrophil count (ANC) ≥1.5 x 10[9]/L AND
- Platelet count ≥100 x 10[9]/L AND
- Haemoglobin ≥9 g/dL (may be transfused to maintain or exceed this level)
8. Adequate liver function
- Total bilirubin <1.5 x ULN AND
- Asparagine aminotransferase (AST), alanine aminotransferase (ALT) <2.5 x ULN in patients without liver metastases; <5 x ULN in patients with liver metastases
9. Adequate renal function
- Serum creatinine ≤1.25 x ULN or calculated creatinine clearance ≥50 mL/min AND
- Urine dipstick for proteinuria <2+. Patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate ≤1 g of protein in 24 hours
10. INR ≤1.5 and PTT ≤1.5 x ULN within 7 days prior to enrolment
11. If female, should not be pregnant or be breast-feeding. Women with an intact uterus (unless amenorrhoeic for the last 24 months) must have a negative serum pregnancy test within 28 days prior to enrolment into the study. If a serum pregnancy test is not performed within 7 days prior to the first dose of bevacizumab, a confirmatory urine test (within 7 days prior to the first dose of bevacizumab) is required.
|
|
| E.4 | Principal exclusion criteria |
Patients with any of the following will be excluded from study entry:
1. Mixed, non-small cell and small cell tumours or mixed adenosquamous carcinomas with a predominant squamous component
2. History of haemoptysis, defined as bright red blood of at least half a teaspoon in the 3 months prior to enrolment
3. Evidence of tumour invading major blood vessels on imaging. The investigator or the local radiologist must exclude evidence of tumour that is fully contiguous with, surrounding, or extending into the lumen of a major blood vessel (e.g. pulmonary artery or superior vena cava)
4. Evidence of CNS metastases, even if previously treated. If suspected, the patient should be scanned within 28 days prior to enrolment to rule out CNS metastases
5. Neoadjuvant/adjuvant chemotherapy within 6 months prior to enrolment
6. Radiotherapy within 28 days prior to enrolment
7. Major surgery (including open biopsy), significant traumatic injury within 28 days prior to enrolment or anticipation of the need for major surgery during study treatment
8. Minor surgery, including insertion of an indwelling catheter, within 24 hours prior to the first bevacizumab infusion
9. Current or recent use of aspirin (>325 mg/day)
10. Current or recent (within 10 days of first dose of bevacizumab) use of full-dose oral or parenteral anticoagulants or thrombolytic agent for therapeutic purposes. Prophylactic use of anticoagulants is allowed
11. History of evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding
12. Uncontrolled hypertension (systolic >150 mmHg and/or diastolic >100 mmHg)
13. Clinically significant (i.e. active) cardiovascular disease for example CVA (≤6 months before enrolment), myocardial infarction (≤6 months before enrolment), unstable angina, CHF NYHA Class ≥II, serious cardiac arrhythmia requiring medication during the study and might interfere with regularity of the study treatment, or not controlled by medication
14. Non-healing wound, active peptic ulcer or bone fracture
15. History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months of enrolment
16. Women with an intact uterus (unless amenorrhoeic for the last 24 months) not using effective, non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile). Men who do not agree to use effective contraception during the study and for a period of 60 days following the last administration of bevacizumab
17. Treatment with any other investigational agent, or participation in another clinical trial within 28 days prior to enrolment
18. Known hypersensitivity to bevacizumab and any of its excipients, and any of the chemotherapies
19. Evidence of any other disease, neurological or metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment-related complications.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The incidence of SAEs related to bevacizumab and the incidence of specific AEs (serious and non-serious) such as hypertension, proteinuria, wound healing complications, arterial and venous thomboembolic events, haemoptysis, CNS bleeding, other haemorrhages, gastrointestinal perforations and CHF, are considered as primary endpoints. (ECOG PS 2 patients will be analysed separately.) |
|
| 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 | No |
| 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 | 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 300 |
| 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
|
| 1 year after the last patient is enrolled, or when all patients have died. |
|
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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