| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced or recurrent squamous non-small cell lung cancer in patients who are candidates for platinum-based chemotherapy and who have not received prior chemotherapy for metastatic or recurrent disease. |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | PT |
| E.1.2 | Level | 8.1 |
| E.1.2 | Classification code | 10061873 |
|
| 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 feasibility of using bevacizumab plus cisplatingemcitabine
or carboplatin-paclitaxel in patients with squamous
NSCLC considered to be at major risk for pulmonary haemorrhage*,
when using preventive measures** to reduce the risk of pulmonary
haemorrhage.
*Patients considered at major risk of pulmonary haemorrhage, when
treated with bevacizumab, are defined as presenting with central tumours
of any size or peripheral tumours ≥ 2 cm in their longest diameter that
have not been previously irradiated.
**The preventive measures to reduce the risk of pulmonary haemorrhage
in patients treated with bevacizumab are:
- exclusion of patients with history of ≥ grade 2 haemoptysis (bright red
blood of at least ½ teaspoon) in the 3 months prior to inclusion in the
study
- a short course of radiation therapy 3 weeks prior to starting
chemotherapy
- delay of the first administration of bevacizumab to the second cycle of
chemotherapy. |
|
| E.2.2 | Secondary objectives of the trial |
To assess
o Overall safety and tolerability
o Best Overall Response (OR)
o Duration of Response (DR)
o Progression Free Survival (PFS) |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Age ≥ 18 years.
2. Willing and able to comply with the protocol as judged by the
investigator.
3. ECOG Performance Status of 0 or 1.
4. Life expectancy of ≥ 12 weeks at the time of inclusion.
5. Written informed consent obtained prior to any study specific
procedure.
6. Histologically or cytologically documented squamous NSCLC.
Mixed tumours should be categorised according to the predominant
cell type and the squamous cells must represent 50% or more of the
cell components. Sputum cytology alone is not acceptable.
Representative samples must be sent to Roche for central review.
Results of the review are not required prior to inclusion and treatment
of the patient.
7. Stage IIIB with malignant pleural or pericardial effusion (i.e. patients
who are not candidates for radical combined modality therapy or high-dose consolidation radiotherapy) OR stage IV (metastatic) OR
recurrent disease.
8. Patients who are candidates for treatment with platinum-based
chemotherapy as first line chemotherapy for their disease.
9. Patients in whom delaying the start of platinum-based chemotherapy
by 3 weeks is acceptable in order to allow the administration of
thoracic radiotherapy to lesions at risk of haemorrhage, when treated
with bevacizumab. This criterion is applicable to the study population
only.
10.Measurable or evaluable disease. Baseline chest CT scans and any
other chest imaging used for the assessment of lung lesions must be
sent to Roche for central review. Results of the review do not have to
be awaited for inclusion and treatment of the patients.
11. Bronchoscopic assessment available at time of inclusion into the
study to map and characterise endobronchial disease. Bronchoscopy
to be performed within 2 months prior to inclusion into the study.
12.Adequate renal function
- Serum creatinine ≤ 1.25 x ULN or calculated creatinine
clearance ≥ 50 mL/min
- Urine dipstick of 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/24 hr.
13.Adequate haematological function:
- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
- Platelet count ≥ 100 x 109/L
- Haemoglobin ≥ 9 g/dL (may be transfused to maintain or exceed
this level)
- Prothrombin International Normalized Ratio (PT_INR) < 1.5;
aPTT ≤1.5 x ULN.
14.Adequate liver function
- Total bilirubin < 1.5 x upper limit of normal (ULN)
- AST, ALT < 2.5 x ULN in patients without liver metastases; < 5
x ULN in patients with liver metastases.
15. Free of co-morbid conditions, which could affect compliance with the
protocol or the interpretation of results.
16. If female, should not be pregnant or 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 inclusion 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 |
1. Mixed, non-small cell and small cell tumours or mixed
adenosquamous carcinomas with a predominant non-squamous
non-small or small cell component.
2. Other primary tumours within the last 5 years before inclusion, except
for adequately controlled limited basal cell, squamous carcinoma of
the skin or carcinoma in situ of the cervix.
3. Prior systemic anti-tumour therapy (chemotherapy, monoclonal
antibody therapy or tyrosine kinase inhibitors).
4. Prior radiotherapy for the treatment of the patients’s current stage of
disease (stage IIIB with pleural or pericardial effusion, stage IV or recurrent disease). Patients who have received radiotherapy
to the chest as a part of the treatment of an earlier stage of disease are
eligible if the last fraction of radiotherapy was administered at least
4 weeks prior to inclusion into the study. Palliative radiotherapy for
the relief of metastatic bone pain allowed prior to inclusion
into the study, providing
- No more than 30% of marrow-bearing bone has been irradiated
- The last fraction of radiotherapy has been administered within
4 weeks prior to inclusion.
5. Patients at high-risk for radiation pneumonitis (high V20 values) or
unable to tolerate radiotherapy, as per investigator’s assessment. This
criterion applies to the study population only.
6. History of ≥ grade 2 haemoptysis (bright red blood of at least
½ teaspoon) in the 3 months prior to inclusion into the study.
7. Evidence of tumour invading major blood vessels on imaging. The
investigator or the local radiologist must exclude evidence of tumor
that is fully contiguous with, surrounding, or extending into the lumen
of a major blood vessel (e.g. pulmonary artery or superior vena cava).
8. History or evidence of inherited bleeding diathesis or coagulopathy
with the risk of bleeding.
9. Current or recent (within 10 days of first dose of bevacizumab) use of
aspirin (> 325 mg/day) or other NSAID with anti-platelet activity or
treatment with dipyramidole, ticlopidine, clopidogrel (>75 mg/day)
and cilostaz.
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 (as opposed to prophylactic) purposes. At inclusion, exploratory population only.
11. Increased risk of gastrointestinal perforation, hypertension, wound
healing complications, thromboembolism or haemorrhage (for
thromboembolism and haemorrhage increased risk relates to risks
other than NSCLC).
12. Clinically serious (as judged by the investigator) non-healing wound,
peptic ulcer or bone fracture.
13. History of abdominal fistula, gastrointestinal perforation, or
intra-abdominal abscess within 6 months of inclusion.
14. Evidence of spinal cord compression or brain metastases. A CT or
MRI of the brain must be performed within 4 weeks prior to inclusion
into the study.
15.History or evidence, upon physical/neurological examination, of CNS
disease unrelated to cancer, unless adequately treated with standard
medical therapy.
16.Major surgical procedure, open biopsy or significant traumatic injury
within 28 days prior to inclusion, or anticipation of the need for major
surgery during the course of the study treatment.
17.Minor surgical procedures within 24 hours prior to inclusion.
18. Uncontrolled hypertension (systolic > 150 mmHg and/or
diastolic > 100 mmHg) or clinically significant (i.e. active)
cardiovascular disease: CVA/stroke (≤ 6 months prior to inclusion),
myocardial infarction (≤ 6 months prior to inclusion), unstable
angina, New York Heart Association (NYHA) Grade II or greater
congestive heart failure, or serious cardiac arrhythmia requiring
medication.
19.Active infection requiring i.v. antibiotics at inclusion.
20.Women with an intact uterus (unless amenorrhoeic for the last
24 months) not using effective, non-hormonal means of contraception. 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.
21. Current or recent (within 30 days of inclusion) treatment with
another investigational drug or participation in another investigational
study.
22. Evidence of any other disease, metabolic or psychological
dysfunction, physical examination finding or clinical laboratory
finding giving reasonable suspicion of a disease or condition that
contraindicates the use of an investigational drug, or that may affect
patient compliance with study routines, or places the patient at high
risk from treatment related complications.
23. Known hypersensitivity to any excipients of bevacizumab
formulation or to the chosen chemotherapy regimen
(cisplatin-gemcitabine or carboplatin-paclitaxel).
24.Hypersensitivity to Chinese hamster ovary cell products or other
recombinant human or humanised antibodies. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Rate of grade ≥3 bevacizumab related pulmonary haemorrage in the study population. |
|
| 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 | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| 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
| 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.8.6 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 | Information not present in EudraCT |
| 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 of the primary endpoint, the rate of grade ≥ 3 bevacizumab-related
pulmonary haemorrhages, will be performed after all patients have:
- completed a maximum of 12 months of treatment with bevacizumab
- or have stopped study treatment earlier because of disease progression or
unacceptable toxicity
- or have withdrawn from study treatment
AND have been followed up for 60 days after their last administration of bevacizumab. |
|
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
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