Trial Information

Phase II Study of the Efficacy and Safety of a Radiotherapy Dose Complement in the Treatment of Hypoxic Lesions Identified by F-miso PET/CT in Patients With Stage III Non-small-cell Lung Cancer (NSCLC) Not Amenable to Curative Surgical Resection Who Are Candidate for Curative Radio-chemotherapy

Background This phase II study will assess the efficacy and safety of a radiotherapy dose
complement (boost) in the treatment of hypoxic lesions, measured by F-miso PET/CT, in
patients with stage III NSCLC not amenable to surgery and candidate for chemoradiotherapy.

There is a strong theoretical rationale supporting a radiotherapy dose increase in patients
with hypoxic pulmonary tumour. F-miso PET enables in vivo identification and localisation of
hypoxic tumoral areas, which constitute a target for an increased total dose of radiation
therapy. Preliminary studies in head and neck cancers have demonstrated the feasibility and
support the medical benefit of this novel approach. To date, no studies investigating
non-small-cell lung cancer patients have been performed.

Given the methodological constraints, we propose a Gehan plan optimizing the number of
subjects to be enrolled and the budget.

The project team has been working on imaging of radiotherapy targets for NSCLC for many
years within a research group identified by the French National Cancer Institute (INCa) in
2005, and part of the axis 3 of Northwest Canceropole (Prof. Gregoire - Prof. Lartigau -
Prof. Vera)2. This project was presented at an EORTC meeting "Imaging and radiotherapy"
(organised by Dr. Nestlé) on May 28th 2010. It has been approved by the President of ESTRO
(Prof. Gregoire) and the members of SFMN (French Society of Nuclear Medicine) and of the
SFRO (French Society of Radiation Oncology) during an "Imaging and Hypoxia" Meeting in
September 8th, 2010.

The aim of the study is to assess the efficacy and safety of a radiotherapy dose complement
(boost) in this difficult medical condition for which only limited treatment options are
available.

Objective(s) of the clinical study Main objective: to evaluate the rate of local control
after dose complement in hypoxic lesions [maximum dose without the fraction of total lung
volume receiving more that 20 Gy exceeding 30% of the lung (V20)], as determined by F-miso
PET/CT.

Secondary objectives:

- 3 months and 1 year toxicity

- Percentage of patients for whom the RT dose could be increased

- Simultaneous variation of the glucose metabolism and hypoxia during radiotherapy

- Predictive value on 1-year survival probability of the variations in glucose metabolism
and hypoxia during radiotherapy

Main inclusion criteria

- Patients with stage III non-small-cell lung cancer candidate for curative
radio-chemotherapy

- The final inclusion is granted after completion of a dosimetric study confirming that
the dose objectives (minimum dose of 60 Gy in 99% of target volume) and constraints to
organs at risk can be achieved.

Main assessment criteria

- Percentage of local control as evaluated by CT (RECIST criteria) and FDG PET/CT at 3
months

Assessment criteria for hypoxia Visual analysis: centralized via SFMN net with 3 blinded
readers within 8 days (Richin, JCO 2006). Definition of hypoxia and decision about boost
dose.

Quantitative analysis: hypoxic fraction determined retrospectively (secondary endpoints and
ancillary study). The Gross Target Volume (GTV) will be delineated on FDG PET/CT images
using an adaptive method (Vauclin, PMB 2009). The contour of the GTV will be copied onto
F-miso PET images after registration. Voxels with a signal to noise ratio greater than 1.2
will be considered as the hypoxic volume.

Experimental plan Assumption: to increase the local control rate at 3 months from 17% to
40%. A two-staged Gehan plan will be implemented. The assumption of therapeutic efficacy is
π = 0.4 - In the first stage, 6 patients will receive a radiotherapy dose boost on the
hypoxic lesions. If no local control is observed in these 6 patients, the trial will be
stopped (power 0.95). In a second stage, the number of patients to be included will be
determined according to the number of local controls in stage 1, the desired precision being
set to ε = 0.10 (n=19 maximum).

Number of subjects required 60 patients with significant uptake on FDG-PET imaging after
neo-adjuvant chemotherapy (75 pre-inclusion) will be included. Only half of these 60
patients (30) are expected to be definitely eligible with F-miso PET identifying hypoxic
areas. Out these 30 eligible patients, we assume that 5 will not be evaluable, so that a
total of 25 evaluable patients will be assessable.