Trial Information

A Phase I/II Dose Escalation Study Using Induction Chemotherapy and Intensity-Modulated Radiation Therapy Guided by Combined CT and PET Imaging for Patients With Non-Small Cell Lung Cancer

Hypothesis and Objectives: The hypothesis that respiratory gated IMRT can escalate safely
radiation doses for NSCLC with induction chemotherapy will be tested. The intent of the
study is to determine the maximum tolerable dose of radiotherapy for NSCLC, using a novel
treatment planning technique with accelerated fractionation, given with state-of-the-art
imaging guidance.

Primary Objective:

- To establish the maximum tolerated dose of radiotherapy by assessing treatment toxicity
according to the acute RTOG grading scale.

Secondary Objectives:

- To evaluate the treatment toxicity of the combination regimen according to the chronic
RTOG grading scale;

- Quality of Life: to be assessed using the EORTC QLQ-C30 and LC13;

- To determine progression-free survival with this regimen;

- To identify partial organ tolerance doses for lung, esophagus and heart.

Schema and Methods: Eligible patients who have consented will receive two cycles of
cisplatin-vinorelbine chemotherapy. Thoracic radiotherapy will be given afterwards according
to the dose-escalating scale. Only one dose level will open at one time. Dose level 1: 84.
Gy in 35 fractions over 7 wks; Dose level 2: 79.5 Gy in 40 fractions over 6 wks; Dose level
3: 75. Gy in 40 fractions over 5 wks.

Eligibility Criteria:

- Patients with histologically-proven, by biopsy or cytology, unresected NSCLC

- Patients with AJC Stage I-III if all detectable tumors can be encompassed by radiation
therapy fields

- Patients with positive supraclavicular node (N3) or malignant pleural effusion are not
eligible.

- Age >= 18

- Karnofsky performance status >= 70

- ANC > 1.5; Plt > 100,000; Hct > 30%; AST (SGOT) < 1.5 ULN; serum creatinine < 1.5 mg/dL

- Patients must have measurable disease on the CT and PET images

- Patients must have a FEV1 > 1.0 L

- Evaluation of the total lung volume receiving 20 Gy (V20) must be < 30%; mean
esophageal dose must be < 32 Gy; and the esophageal V 55 < 28%.

- Patients must have a satisfactory IMRT plan prior to start of radiotherapy.

Statistical Considerations

Primary Endpoint: The frequency of patients developing unacceptable (grade 3 or higher)
toxicity according to the RTOG acute toxicity scale attributable to radiotherapy. Acute
radiotherapy toxicities are defined as those toxicities that occur within 90 days from the
start of radiotherapy.

Sample Size: In order to establish the maximum tolerated dose (MTD) of radiotherapy that can
be delivered using IMRT following induction chemotherapy, acceptable morbidity criteria must
be defined. Based on the Radiation Therapy Oncology Group (RTOG) 94-10, the dose limiting
toxicity (DLT: defined as a grade 3 or 4 non-hematologic toxicity) rate for this study is
determined to be 40%. After 7 evaluable patients have been followed for a minimum of 90 days
from the start of radiation therapy, patients will be evaluated with respect to treatment
morbidity. If there are no acute dose limiting toxicities in the first 5 patients (0/5),
then the current dose will be deemed to be acceptable and will be escalated. If there is 1
acute DLT observed in the first 5 patients (1/5) and no acute DLTs in the last two patients
(0/2), then the dose will be deemed to be acceptable and will be escalated. Otherwise the
current dose will be deemed to be too toxic and escalation will end. This design gives at
least 90% confidence that the true acute DLT rate at a given dose level is less than 40% and
for any given dose level, the probability of not escalating when the true toxicity rate is
40% or higher is at least 88%.

Safety Monitoring and Stoppage Rules: An SAE is any untoward medical occurrence that:

- results in death;

- is life-threatening (patient is at immediate risk of death);

- requires inpatient hospitalization or prolongation of existing hospitalization;

- results in persistent or significant disability/incapacity;

- is congenital anomaly/birth defect;

- important medical events that may not be immediately life-threatening or result in
death or hospitalization but may jeopardize the patient and may require medical or
surgical intervention to prevent one of the outcomes listed in this definition.

Reporting of SAEs is as follows:

1. Complete the Serious Adverse Event Report;

2. Fax the Serious Adverse Event Report within 24 hours of the investigator's or
designee's knowledge of the event to the attention of: Dr. Wilson Roa (780) 432-8517
(tel);(780) 432-8380 (fax) and Dr. Don Yee (403) 944-2895 (tel);(403) 283-1651 (fax);

3. Accrual may be stopped immediately as indicated upon review and confirmation of the SAE
by the two PIs.

Recruitment and Reporting: The projection rate of accrual was based on a previous
preliminary study. At this rate, it would take three months to complete accrual for each of
the 3 dose levels. A three-month waiting period is required prior to dose escalation to the
next level. Hence, an estimate of 7 months is conservatively allowed for each level,
amounting to a total of 21 months to complete accrual, treatments and waiting period for the
primary endpoint. The first manuscript on this study will be completed by the end of two
years. Analysis for the reporting treatment results will contain tabulation of all cases
entered and any excluded from analysis, with reasons for the exclusion. Respective
institutional accrual and observed endpoints of MTD, toxicity, progression-free survival and
quality of life will be analyzed.