An open-label, randomized, Phase IIIb trial evaluating the efficacy and safety of standard of care +/- continuous bevacizumab treatment beyond progression of disease (PD) in patients with advanced non-squamous non-small cell lung cancer (NSCLC) after first (1st)-line treatment with bevacizumab plus a platinum doublet-containing chemotherapy

Recurrent or metastatic NSCLC can be improved by some drug treatment. There
remains, however, a great need for additional treatments that will maintain the
health of patients with recurrent or metastatic NSCLC for longer periods of
time.
Bevacizumab is often combined with two chemotherapy drugs for the initial
treatment of NSCLC. At present, bevacizumab and both chemotherapy drugs are
ceased if and when NSCLC progresses (i.e. the cancer regrowth at the same
location or a cancer is found at a new location in the body (metastasis). Many
patients will then be offered new treatment with different anti-cancer drugs
(standard 2nd -line treatment) in order to reduce the growth of the cancer
cells again. Upon subsequent regrowth some patients are again offered different
anticancer drugs (3rd line treatment).

The main aim of this study is to find out if the continuation of bevacizumab,
in addition to standard 2nd & 3rd -line treatment, can help patients with NSCLC
that has progressed to live longer. The study also aims to find out if
continued bevacizumab will help patients live longer free of tumor re-growing
or spreading and if it is generally safe to use bevacizumab in combination with
standard treatment for NSCLC that has progressed.

3. TRIAL DESIGN

3.1 Overview of Trial Design
This is a two-arm, open-label, randomized, multicenter, phase IIIb trial (see
Figure 1).
Patients randomized to Arm A will receive bevacizumab 7.5 mg/kg i.v. or 15
mg/kg i.v. on Day 1 every 21 days (+/- 3 days) (to coincide with SOC treatment)
from Cycle 1 until the occurrence of an unacceptable toxicity or withdrawal of
consent (whichever occurs first). The dose of bevacizumab should be the same
dose that was administered during 1st-line and maintenance treatment.
Patients randomized to Arm B will not receive bevacizumab
All patients (Arm A and Arm B) will receive one of the following drugs as
2nd-line SOC treatment until the occurrence of an unacceptable toxicity or
withdrawal of consent (whichever occurs first):
* Erlotinib 150 mg daily taken on an empty stomach at least one hour before or
two hours after the ingestion of food
or
* Docetaxel 75 mg/m2 on Day 1 every 21 days (+/- 3 days).
or
* Pemetrexed 500 mg/m2 i.v. over 10 minutes on Day 1 every 21 days (+/- 3 days).
The 2nd-line SOC agent will be selected by the investigator prior to
randomization.
Following PD2/3, 3rd and 4th-line SOC treatment, respectively, will be chosen
by the investigator according to local practice (Section 6.4).
SOC treatment can be altered or ceased or changed for PD or unacceptable
toxicity. If SOC treatment is ceased permanently, bevacizumab treatment should
continue provided there is no unacceptable toxicity related to bevacizumab or
withdrawal of consent (see Section 4.5 for other reasons of premature
discontinuation).

Arm A: Patients will receive bevacizumab 7.5 mg/kg i.v. or 15 mg/kg i.v. on Day
1 every 21 days (+/- 3 days) in combination with SOC treatment from Cycle 1
until the occurrence of an unacceptable toxicity or withdrawal of consent
(whichever occurs first). The dose of bevacizumab should be the same dose that
was administered during 1st-line and maintenance treatment.
Arm B: Patients will receive SOC treatment without bevacizumab until
unacceptable toxicity or withdrawal of consent (whichever occurs first).
SOC treatment can be changed for toxicity or progression of disease (PD).

Standard treatment with or without bevacizumab (until progression).

Burden and risk:
The most important adverse events of bevacizumab that occur at more than 10% of
the patients are:
* High blood pressure (hypertension)
* Numbness or loss of feeling in the fingers or toes (peripheral sensory
neuropathy
* Low numbers of white blood cells (neutropenia, leucopenia) and potentially
associated with fever (febrile neutropenia)
* Low numbers of platelets (thrombocytopenia)
* Shortness of breath (dyspnea)
* Diarrhea
* Bleeding from the rectum (rectal hemorrhage)
* Nausea and vomiting
* Pain, including headache and joints pain (arthralgia)
* Alteration in speech (dysarthria)
* Constipation
* Mucosal inflammation or inflammation of the mouth (stomatitis)
* Protein in urine
* Mucocutaneous bleeding, including nose bleed (epistaxis)
* Lack of energy, weakness (asthenia, fatigue)
* Loss of appetite (anorexia)
* Fever (pyrexia)
* Runny nose (rhinitis)
* Dry skin, flaking and inflammation of the skin (exfoliative dermatitis)
* Change in skin color (skin discoloration)
* Change in the sense of taste (dysgeusia)
* Eye disorder, tearing (lacrimation increased)

Bevacizumab may also cause changes in laboratory tests carried out by your
doctor. These include: decreased blood
potassium and sodium; increased blood sugar; altered coagulation values.

Some adverse events are more common in elderly patients that in younger
patients. This is the case with arterial thromboembolic events, that can cause
a stroke or heart attack. Elderly patients also have an increased change of
leucopenia and thrombocytopenia.

Some adverse events are seen rarely or very rarely. A list of these adverse
events can be found in the patient information sheet. It is possible that
unknown adverse events occur.

Benefit:
The aim of this study is to find out if the continuation of bevacizumab, in
addition to standard 2nd & 3rd -line treatment, can help patients with NSCLC
that has progressed to live longer.