Trial Information

Randomized Phase II Trial of Individualized Adaptive Radiotherapy Using During-Treatment FDG-PET/CT and Modern Technology in Locally Advanced Non-Small Cell Lung Cancer (NSCLC)

PRIMARY OBJECTIVES:

I. To determine whether tumor dose can be escalated to improve the freedom from
local-regional progression-free (LRPF) rate at 2 years when an individualized adaptive
radiation treatment (RT) plan is applied by the use of a fludeoxyglucose F 18 (FDG)-positron
emission tomography (PET)/computed tomography (CT) scan acquired at 40-46 Gy initial dose of
RT in patients with inoperable or unresectable stage III non-small cell lung cancer (NSCLC).

II. To determine whether the relative change in standard uptake value (SUV) peak from the
baseline to the during-treatment FDG-PET/CT, defined as (during-treatment SUVpeak - baseline
SUVpeak)/baseline SUVpeak x 100%, can predict the LRPF rate with a 2-year follow up.

SECONDARY OBJECTIVES:

I. To determine whether an individualized dose escalation improves overall survival (OS),
progression-free survival (PFS), lung cancer cause-specific survival, and delays time to
local-regional progression compared to a conventional RT plan.

II. To compare the rate of severe (grade 3+ Common Terminology Criteria for Adverse Events
[CTCAE], v. 4) radiation-induced lung toxicity (RILT) defined as severe RILT pneumonitis or
clinical fibrosis.

III. To compare other severe adverse events, including grade 3+ (CTCAE, v. 4) esophagitis or
grade 2 pericardial effusions, or any grade cardiac adverse events related to chemoradiation
between a PET/CT-guided adaptive approach and a conventional RT plan.

IV. To evaluate the association of baseline 18F-fluoromisonidazole (FMISO), a PET/CT imaging
agent uptake (tumor-to-blood pool ratio) with LRPF rate (i.e., the assessment of using
baseline FMISO-PET uptake as a prognostic marker).

V. To determine if the relative change in SUVpeak from baseline to during-treatment
FDG-PET/CT and/or baseline FMISO uptake (tumor-to-blood pool ratio) predicts the
differential benefit of the adaptive therapy, i.e., the association of uptake parameters
with LRPF rate depending on the assigned treatment thus, assessing if these uptake
parameters can be useful in guiding therapies, i.e., predictive markers.

VI. To determine if other PET-imaging uptake parameters (SUVpeak during-treatment for
FDG-PET, maximum SUV, or relative change of maximum SUVs from pre- to during-treatment
FDG-PET/CT, change in metabolic tumor volume, FMISO total hypoxic volume, FMISO tumor to
mediastinum ratio, EORTC or University of Michigan/Kong's response criteria) will predict
OS, LRPF rate, and lung cancer cause-specific (LCS) survival as well as to explore the
optimal threshold for differentiating responders from non-responders.

VII. To study whether a model of combining current clinical and/or imaging factors with
blood markers, including osteopontin (OPN) [for hypoxia marker], carcinoembryonic antigen
(CEA) and cytokeratin fragment (CYFRA) 21-1 (for tumor burden), and interleukin (IL)-6
(inflammation) will predict the 2-year LRPF rate and survival better than a current model
using clinical factors and radiation dose as well as imaging factors.

VIII. To determine/validate whether a model of combining mean lung dose (MLD), transforming
growth factor beta1 (TGFβ1) and IL-8 will improve the predictive accuracy for clinical
significant RILT better comparing to the current model of using MLD alone.

IX. To explore, in a preliminary manner, whether proteomic and genomic markers in the blood
prior to and during the early course of treatment are associated with tumor response after
completion of treatment, LRPF rate, PFS, OS, and pattern of failure and treatment-related
adverse events, such as radiation pneumonitis, esophagitis, and pericardial effusion.
(exploratory)

OUTLINE: This is a multicenter study. Patients are stratified according to mean lung dose (>
14 Gy vs ≤ 14 Gy), tumor volume (≥ 200 cc vs < 200 cc), and tumor histology (squamous vs
non-squamous).

Prior to treatment, patients undergo fludeoxyglucose F 18 (FDG) positron emission tomography
(PET) and computed tomography (CT) scans at baseline and periodically during study. A subset
of patients also undergo 18F-fluoromisonidazole PET/CT scan at baseline. Patients are
randomized to 1 of 2 treatment arms:

ARM I (standard chemoradiotherapy): Patients undergo radiotherapy once daily (QD) 5 days a
week for 6 weeks. Patients also receive paclitaxel IV over 1 hour and carboplatin IV over 30
minutes once weekly for 6 weeks. Patients undergo FDG-PET/CT imaging during weeks 4-5.

ARM II (experimental chemoradiotherapy): Patients undergo image-guided radiotherapy QD 5
days a week for 3-4 weeks. Based on the week 3-4 18 FDG-PET/CT scan results, patients
undergo individualized adaptive radiotherapy for 2-3 weeks. Patients also receive paclitaxel
and carboplatin as in arm I.

CONSOLIDATION CHEMOTHERAPY: Beginning 4-6 weeks after chemoradiotherapy, patients receive
paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on day 1. Treatment repeats
every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity.

Patients may undergo whole blood, plasma, and serum samples collection at baseline and
periodically during study for metabolomics, cell death, other markers assays, and future
research studies. Primary tissue samples may be also collected.

After completion of study treatment, patients are followed up at 1 month, every 3 months for
1 year, every 6 months for 2 years, and then annually for 2 years.