Trial Information

Mitigation of Radiation Pneumonitis and Fibrosis

Aim 1: To test the benefit of enalapril, an angiotensin-converting-enzyme-inhibitor, to
mitigate radiation pneumonitis and fibrosis in humans.

Subjects

Men and women undergoing radiation therapy for lung cancer at the Milwaukee Veterans Affairs
Hospital are eligible. Subjects will be recruited to this phase 2 trial after their
diagnosis of cancer and after referral to Radiation Oncology for treatment. The existence of
this study will be posted in the Radiation Oncology clinics. Dr Beth Gore (co-investigator)
and her study coordinator will ensure recruitment. The informed consent process will be done
by Dr Gore or the study coordinator, under direction of Dr Gore. Subjects who require
radiation therapy to attempt to cure or to palliate their disease will be eligible for this
study. Subjects eligible for surgical resection and who do not need radiation therapy will
not be eligible for this study. Subjects already on ACE inhibitors, angiotensin blockers, or
renin antagonists will be excluded. Use of other antihypertensives is not an exclusion
criterion. There will be no inclusion or exclusion by race or ethnic origin. Women and
minorities are eligible. Children are not eligible because children do not develop lung
cancer. Previous surgery and past or current use of chemotherapy are not exclusions.
Subjects will have a Karnofsky performance status 80, absolute neutrophils > 1000/mm^3,
platelets > 75,000/mm^3, and hematocrit > 25%. Liver and kidney function tests will be
within normal range and baseline blood pressure will be systolic > 110 mmHg sitting.
Pregnant or nursing subjects are excluded and fertile patients will use contraception. Lung
function tests including spirometry, lung volumes and diffusing capacity will be obtained as
part of standard of care for patients prior to radiotherapy, but indices from lung function
tests will not be a cause for exclusion.

The mean lung dose will be >/= 18 Gy and/or V20 >25%. Radiation will be delivered with
standard fractionation schedule of 1.8 to 2 Gy per day, 5 days per week, without planned
treatment breaks.

Experimental design

Radiation treatment starts at time 0, and is given to completion, as indicated. Enalapril or
placebo are started right after the first radiation treatment fraction and continued
thereafter. The renin-angiotensin system is tested at time 0, at three weeks, and at the
completion of radiation treatment. CT scanning is done at time 0 and every three months
thereafter for the first two years. Median survival is expected to be 18 months.

Subjects will undergo therapeutic irradiation as indicated for clinical care. They will be
enrolled to this masked, phase 2 trial at the start of radiation therapy (RT), stratified
for cancer stage, then randomized to enalapril or identical-appearing placebo. Randomization
will be done by the Department of Biostatistics, Medical College of Wisconsin, using random
number tables; the center pharmacies will be notified of the assignment to enalapril or
placebo. There will be no stratification by age, gender, lung cancer histology, or use of
chemotherapy since these do not have a consistent relation with the occurrence of RP . Use
of enalapril or placebo will not be known to the patients or their physicians during the
time of study. The medical center pharmacy will stock and provide the study drug. Study
drug, enalapril or placebo, will be started after the first fraction of the RT, at 2.5 mg by
mouth once a day and increased to 10 mg/day in weekly increments as tolerated. Routine
clinical care during the course of irradiation includes weekly or more frequent clinical
assessment and vital signs. Blood testing for kidney function and potassium will occur
within ten days after start of study drug. Additional patient visits will not occur for this
study alone. Additional blood testing will occur in usual clinical care and will also be
recorded. Routine care, independent of this study, includes CT scan chest imaging every
three months for the first two years of follow-up. The study drug will be continued for
life.

Endpoints for injury

The primary endpoint is symptomatic grade 2 or higher radiation pneumonitis, as defined by
the established criteria, within the first 4 months of irradiation. The NCI Common
Terminology Criteria Adverse Event (CTCAE) version 4.0 will be used to grade pulmonary
toxicity. CTCAE is a worldwide standard for reporting adverse events from all modalities on
cancer clinical trials. Pneumonitis is a new-onset and persistent cough requiring
anti-tussive agents and or dyspnea with effort that is unexplained by other pulmonary
illness. It may last for days to weeks. Severe cases may evolve to respiratory failure. Use
of such patient-reported symptoms is strongly recommended for cancer-related clinical
trials. Radiographic changes of RP occur in over half of subjects undergoing therapeutic
thoracic irradiation; radiographic RP will be a secondary endpoint. Classic radiographic
manifestations of RP are increased lung density within the radiation field within the first
six months after radiation therapy that is not explained by infection or cancer.
radiographic pneumonitis will be recorded by two investigators (Drs Gore and
Antonescu-Turcu, EG and AAT), using the scale reported by Guckenberger. Investigators expect
a radiographic rate of RP of 50%.

Investigators expect almost all surviving subjects to have fibrosis by CT scanning at 6 and
12 months, and will test this as another major endpoint. Radiation fibrosis in the lung is
evident as scarring with volume loss and bronchiectasis within the radiation field at six
months or more after radiation therapy, not explained by infection or cancer. radiographic
fibrosis will be recorded and quantified by two investigators (EG, AAT). Reduction in
diffusion capacity for carbon monoxide (DLCO) correlates with pulmonary radiation fibrosis.
DLCO is obtained in all survivors at the 12 month time point, and will be compared to
baseline values as an additional secondary endpoint. The occurrence of clinical grade 2 or
higher RP, of radiographic RP and fibrosis as dichotomous variables, will be compared for
the subjects on enalapril compared to those on placebo. For RP, any image showing RP will
assign a subject to the RP group. For fibrosis, the last CT scan will be used.

Investigators will test quality of life as a secondary endpoint. The Functional Assessment
of Cancer Therapy -lung (FACT-L version 4) will be used to assess Quality of Life (QoL).
FACT-L contains four general (physical, social/family, emotional, and functional well being)
and one lung cancer specific subscale. QoL will be assessed pretreatment, and at 12 months
post treatment. Use of patient-reported data is strongly recommended for cancer-related
clinical trials.

Aim 2: To test the mechanism of mitigation by enalapril

Subjects These are the same subjects as in aim 1.

Experimental design Investigators will test the major components of the renin-angiotensin
system; angiotensinogen, plasma renin activity, and angiotensin II (ang II). These will be
measured at baseline, at three weeks after the start of irradiation, and at the completion
of irradiation. Investigators will test their mechanistic involvement by their change with
use of enalapril, in particular whether the benefit of enalapril is correlated with its
effect to lower the plasma ang II levels. Other components of the RAS, including
angiotensin (1-7), aldosterone, AcSDKP, and bradykinin will not be tested because
experimental studies have not shown them to be relevant to mitigation of normal tissue
radiation injury.

Baseline elevation of one or more of these RAS components, compared to known levels in the
normal population, may correlate with development of RP and or fibrosis in the control,
placebo group. This may permit better focused use of mitigators in the future, in only
those at risk.

Enalapril, by inhibition of ACE, will reduce plasma ang II and lead to a feedback elevation
of PRA. This will confirm adherence to drug therapy and may also correlate with its benefit.
Elevation of PRA in subjects on enalapril, but without mitigation benefit, will show that
it is ineffective, despite its adequate bioavailability.

Aim 3: To confirm that enalapril does not adversely affect cancer treatment outcomes.

Subjects These are the same subjects as in aim 1.

Experimental design Investigators will compare cancer recurrence and cancer-related survival
in subjects on enalapril versus placebo. Cancer recurrence will be assessed clinically, as
confirmed by CT imaging and or histology. The RECIST criteria will be used. Recurrence rates
and survival will be assessed by interim safety analyses during the study, and finally at
its completion. In the statistical analysis, investigators will account for the effects of
interim sampling for the safety analyses, and will adjust for patient and disease
characteristics as well as missing data. A benefit of enalapril on RP may enhance patient
survival. An adverse effect of enalapril on survival will stop this study. But a cohort of
162 veterans showed no difference in patient survival for those on ACE inhibitor compared to
those not on ACE inhibitor. Thus, investigators do not expect adverse changes in recurrence
rates or patient survival.

Expected results, potential problems, and long-term impact

Investigators expect that subjects on enalapril will have significantly less clinical and
radiographic RP and fibrosis, compared to those on placebo. Investigators expect that
subjects on placebo who develop RP and or fibrosis may have baseline elevation of AGT and
PRA compared to those who don't develop RP and or fibrosis, and that the mitigation benefit
of enalapril will correlate with its effect to increase the PRA and reduce the plasma ang II
levels. Investigators expect that enalapril will not increase cancer-related mortality, and
may even enhance overall patient survival through mitigation of radiation lung injury.