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 or other intrathoracic cancers at
the Baltimore the Milwaukee or Ann Arbor 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 Cohen, Dr Beth Gore, and Dr Michelle Mierzwa (co-investigators) and our
study coordinators will ensure recruitment. The informed consent process will be done by Dr
Cohen or Gore or Dr Mierzwa or the study coordinators. 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 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 >/=70, 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 >20%. 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 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, 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.

Inclusion Criteria:

- Men and women undergoing radiation therapy to the chest for cancer at the Baltimore,
the Milwaukee, and Ann Arbor Veterans Affairs Hospital are eligible.

- Subjects who require radiation therapy to attempt to cure or to palliate their disease
will be eligible for this study.

Exclusion Criteria:

- Subjects eligible for surgical resection and who do not need radiation therapy will
not be eligible for this study.

- Subjects who must remain on ACE inhibitors, angiotensin blockers, or renin antagonists
will be excluded.