Phase I study of concurrent with involved-field thoracic radiotherapy for inoperable non-squamous cell lung cancer, followed by both concurrent and maintenance Bevacizumab

The treatment of choice in patients with locally-advanced non-small cell lung
cancer is chemo-radiotherapy. However, novel measures are clearly needed to
improve both survival and local control as median survival in patients treated
by concurrent chemo-radiotherapy alone was 22.2 months, and the local failure
rate of 22% [Albain 05]. The dismal long-term prognosis for these patients
with stage III disease has prompted intensive efforts to find new therapeutic
modalities that will provide survival improvements.

In randomized phase III clinical trials, the humanised anti-VEGF monoclonal
antibody bevacizumab (Avastin) has shown a survival advantage in patients with
metastatic lung, colo-rectal and breast cancer. Preclinical studies show that
the combination of Avastin and radiation enhances radiation response and local
tumor control.Safety data is patients undergoing thoracic radiotherapy and
concurrent Avastin in a necessary step before incorporating this novel agent
into phase II and III trials of chemo-radiation with Avastin.

Primary objectives

To establish the safety and tolerability of
1. two doses of bevacizumab 7.5 mg/kg administered every 3 weeks with
concurrent thoracic radiotherapy to 66 Gy;
2. concurrent (7.5 mg/kg) and maintenance (15 mg/kg) bevacizumab during, and
following, completion of thoracic radiotherapy to 66 Gy

Secondary objectives

1. Correlate all observed toxicity with dose-volume histograms of irradiated
normal organs.
2. Explore surrogate tumor end-points that may correlate with the efficacy of
combined treatment with anti-VEGF targeted therapy
3. Estimate the objective tumor response after radiotherapy and concurrent
bevacizumab based on RECIST criteria

A single-centre, open-label, non-comparative, dose-finding phase I trial of
thoracic radiotherapy with bevacizumab and a stepwise (4-level) cohort
design.Patients will receive 2 cycles of induction chemotherapy prior to
radiotherapy and concurrent bevacizumab, which will commence 3 weeks after the
last administration of chemotherapy. Any cisplatin-based doublet combination
will be accepted as an induction regime

Level 1: 66Gy (maximum permitted cord dose *32 Gy) + concurrent bevacizumab
Level 2: 66Gy (maximum permitted dose *36 Gy) + concurrent bevacizumab At least
3 patients will be treated at each level and each will be followed-up for at
least 3 months before the next level.
Level 3: 66 Gy (maximum permitted cord dose *36 Gy) + concurrent Bevacizumab
followed by maintenance bevacizumab until either disease progression or a
maximum of 1 year
Level 4: 66 Gy (maximum permitted cord dose *40 Gy) + concurrent Bevacizumab
followed by maintenance bevacizumab until either disease progression or a
maximum of 1 year

see study design (above)

During the radiotherapy, patients will receive 2 infusions of Avastin at
intervals of 3 weeks, and Avastin will be repeated every 3 weeks after
radiation for a maximum period of 12 months, in the absence of disease
progression.

There are no preclinical data to suggest that the expected incidence of
radiation-induced toxicities, mainly esophagitis and radiation pneumonitis,
will be increased by the proposed combined treatment. On the other hand, the
median survival of the study patients is less than 17.2 months despite
high-dose chemo-radiotherapy and novel approaches are clearly indicated. As
Avastin has been shown to improve survival in patients with metastatic
non-small cell lung cancer, the relative risks with combined therapy is
possible less that for agents without systemic activity.