Note: Descriptions are shown in the official language in which they were submitted.
WO92/10207 PCT/US91/09084
~;~ 2~ 3~
ORAL ADMINISTRATION OF ALPHA INTERFERON TO
TREAT LUNG MALIGN~NCIES
BACKGROUND OF THE INVENTION
This invention relates to pharmaceutical
compositions comprising human alpha interferon (hIFN-~)
as an active ingredient to treat lung malignancies in
mammals. The invention also relates to the use of hIFN-
~for making medicaments for treating lung malignancies in
mammals as well as to methods of treating lung
malignancies, generally referred to as lung cancer, b~
administering by oral inhalation to a mammal in need of
such treating an amount of human alpha in recombinan~ DNA
human alpha interferon (rhIFN-~) effective for such
treating.
Human alpha interferon (hIFN-3) is a naturall~
occurring mixture of at least eleven compounds including
those designated alpha-l interferon and alpha-2
interferon.
A number of alpha interferon species or
co~ponents are known and are usually designated by a
numeral and letter after the Greek letter alpha. Hu~an
alpha-l interferon is one species contemplated for use i~.
this invention as are the species designated human alpha-
2 interferons. Under USAN, recombinant DNA human alpha-2
interferons are designated Interferon Alpha-2a, whic~. car,
WO92/10207 ~ 9 ~ 3 9 3 Pcr/usgl/ogo~
-2- t~
be made as disclosed in Rubenstein, Biochem. Bioehys.
Acta (1982), 695, 5-16, and Interferon Alfa-2b.
Interferon Alfa-2b is the preferred species for use in
this invention and is a recombinant DNA human alpha
interferon (hereinafter ~rhIFN-~). Another suitable
rhIFN-n included in the acop~ of this invention is
recombinant DNA human interferon alpha-2a.
~ uman interferon alfa~2b can be produced in
bacteria and other microorganisms using recombinant DNA
techniques including those disclosed in Nagata et al.
Nature, (1980) 284, 316-329; European Patent 32,134 and
U.S. Patent No. 4,289,690. Various alpha interferon
species are disclosed in U.S. patent 4,503,03S.
It is known to administer rhIFN-~ parenterally
to treat hairy cell leukemia, AIDS-related Kaposi's
sarcoma, and hepatitis as well as intralesionally to
treat condylomate acuminata. Several groups of
investigators have documented that parenterally
administered IFN-~ does not accumulate in the
nasopharyngeal, oropharyngeal, or airway mucosa or in the
lung parenchyma in sufficient concentrations or for long
enough time periods to be effective against respiratory
virus infections.
Recently, it has been shown that non-
recombinant human leukocyte alpha-interferon (hereinafter
~hIFN-~) can be given to mammals by inhalation to
provide high local concentrations in lung and airway
mucosal tissue. Nebulized hIFN-~ inhibits viral
replication in mice tPlease give Reference). The
instillation of hIFN-~ into the bronchi of perfused
rabbit lungs has resulted in measurable serum
concentrations [V. Bocci et al., Antlviral Res. tl984)
Vol. 4, 211-220].
Intranasally administered rhIFN-~ at a dose of
5 million units/day prevented rhinovirus transmission
WO92/10207 PCT/US91/090~
~--` 23~`33~3
-3
within families (Douglas, et al, NEJM (1986), Vol. 314,
pp65-70. In one Chinese study, interferon-,~ (hIFN-~)
given both intranasally and i~traorally at a dose of 790-
1600 units/day was effective in the treatment of
influenza, respiratory syncytial viral bronchiolitis, and
asthmatic bronchitis (Jia-xiong, et al, Chin Med J.
100:162-166, 1987).
In man, hIFN-~ has been inhaled by patients
with advanced non-small cell lung cancer at doses up to
120 million International Units (~IUY). Kinnula et al.
discloses in the J. Interferon Res. (19B9), Vol 9, 419-23
that inhaled hIFN-~ resulted in serum concentration and
side effects (e.g. fever, headache, influenza-like
symptoms and nausea) similar to those disclosed after
systemic hIFN-~ administration as well as reversible
airflow obstruction but no activity against the lung
cancer was observed. Inhaled hIFN-f~ has also been
administered to patients suffering from bronchoalveolar
carcinoma but no activity on the bronchoalveolar
carcinoma has been demonstrated [V. Kinnula et al. J.
Interferon Res, (1988) Vol 8, Suppl. 1 pll5]
In-vitro activity of rhINF-~ A (Roferon) and
rhIFN-~D in various human tumor cell assays including
lung cancer is known [S.E. Salmon et al., ~. Clin.
Oncology (1983) Vol. I. p217-225]. Human leukocyte
interferon (hIFN-) exhibited inhibition of colony
formation of greater than 70% against only five including
2 lung tumors of the sixty-two tumor types in an ln
vitro assay (D.D. Von Hoff et al. _ancer Chemother.
harmacol. (1982), Vol. ~3, 99-103.
SUMMARY OF THE INVENTION
The present invention provides a pharmaceutical
composition for treating or preventing a lung malignancy
in a mammal which composition comprises an effective
amount of recombinant DNA human alpha interferon.
W092/~0207 PCT/US91/090~4
9~
4-- .
The present invention also provides a use of
recombinant DNA human alpha interferon for the
manufacture of a medicament for treating or preventing a
lung malignancy in a mammal.
This invention also provides a method of
treating a lung malignancy in a mammal afflicted with
such malignancy which comprises administering via oral
inhalation to such a mammal an amount of recombinant
human DNA alpha interferon effective for such treating.
This invention also provides a method of preventing a
lung malignancy in a mam~al susceptible to lung malignany
- e.g. heavy smokers of any tobacco products especially
cigars and cigarettes, which comprises administering via
oral inhalation to such a mammal an amount of recombinant
DNA human alpha interferon effective for such preventing.
DETAILED DESCRIPTION OF THE INVENTION
The term ~lung malignancy~ as used herein means
at least one of squamous cell carcinoma, large cell
carcinoma, small cell carcinoma, alveolar cell carcinoma,
bronchoalveolar carcinoma, adenocarcinoma, bronchogenic
carcinoma-in-situ, metastatic carcinoma, or sarcoma
from primary tumors outside the lung or airways.
The effectiveness of the interferon therapy of
this invention can be shown clinically in mammals, e.g.
human beings afflicted with a lung malignancy or
suspectible to a lung malignancy due to the smoking
tobacco products, especially cigarettes and/or cigars
using patients with the following entry criteria:
~ l) a Karnofskv performance status of 60%;
(2) adequate pulmonary function for undergoing the
required inhalation treatment satisfactorily as evidenced
by (a~ forced expiration volume in one second (FEVl) of
greater than or equal to 40% and (b) a forced vital
capacity (FVC) of greater than or equal to 50% of the
.. . : . .,. .,, .,., . .:. : ,..
.. -. .... .. ~ : . .
- ,. :: :, ,; : .: , - ,: - , :. -
wo 92/10207 2 ~ 9 ~ ~ ~ 3 PCT/US91/09084
f~
--5--
predicted value and; (3) no serious systemic infections
and/or fever.
The recombinant DNA human alpha interferon
(rhIFN-~) administered via oral inhalation in accordance
with this invention may be used as monotherapy or as
adjunctive therapy with other treatments e.g.,
chemotherapy or immunotherapy to treat l~ng malignancy
and prevent, inhibit andlor cure the pulmonary metastatic
spread of one or more of the types of lung malignancies
listed hereinabove. The list of conventional
chemotherapeutic agents useful in combination with alpha
interferon is disclosed by S. Wadler et al in Cancer
Research (1990), Vol 50 pp 5472-3486.
The recombinant DNA human alpha interferon
(~rhIFN-a~) is administered by oral inhalation in
accordance with this invention as a pharmaceutical
composition containing rhIFN-~ which may be dissolved or
dispersed in a pharmaceutically acceptable carrier
suitable for use in a nebulizer and/or a metered dose
inhaler. Pharmaceutically acceptable carriers include,
for example, water, saline, ethanol and the like which
form a rhIFN-a solution or suspension suitable for
administration via oral inhalation in accordance with
this invention. If desired, the rhIFN-a pharmaceutical
composition useful in this invention may also contain
minor amounts of non-toxic auxiliary substances such as
melting agents, emulsifying agents, preservatives,
stabilizers, and pH buffering agents. The preparation of
these pharmaceutical compositions is well known to those
skilled in the art; see for example Remington's
Pharmaceutical Sciences Mack Publishing Co., Easton PA
15th Edition (1975).
A preferred rhIFN-a pharmaceutical composition
for use in accordance with this invention is the Intron~
A brand of interferon available as a solution from
WO 92/10207 93 Pcr/us9l/09084
Schering-Plough Corporation, Kenilworth, New Jersey.
This commercially available Intron A rhlFN-~ composition
contains glycine, di- and mono- basic sodium phosphate as
a buffer and serum albumin. Other preferred rhIFN-2
pharmaceutical compositions include any sterile isotonic
aqueous solution, e.g. physicological phosphate-buffered
saline at pH 7.3 which may also contain pharmaceutically
acceptable non-toxic auxiliary agents such as stabilizers
and/or a surfactants and the desired amount of rhIFN-~.
The concentratioh of rhIFN-~ in the pharmaceutical
composition may be adjusted by dilution with 0.9~ saline
solution before administration via oral inhalation. The
oral inhalation of drugs by use of nebulizers and metered
dose inhalers is well known. See for example Remington,
ibid, at chapter 99, pages 1910-1912. Useful nebulizers
include the Spira Electro 4 nebulizer, manufactured by
Hameenlinman Tyoleskus, Hameenlinna, Finland, whose use
is disclosed by Kinnula et al. in the J. of Interferon
Research (1989) Vol. 9 at p420. Useful metered dose
inhalers as well as drug delivery systems that help
deliver oral aerosolized medications from metered dose
inhalers to the lungs include INHAL-AID and INSPIREASE
drug delivery systems available from Schering-Plough
Corporation, Kenilworth, New Jersey, U.S.A, for as well
as those disclosed in the Physicians Desk Reference, 1990
Edition, for use with bronchodilators. The output of the
nebulizer or metered dose inhaler for use in this
invention should consistently and reliably produce
particles and/or droplets having a mass median
aerodynamic diameter (M.M.A.D.) above about 0.5 ~icrons,
pre~erably having a M.M.A.D. above about 0.5 and less
than about 8 microns and more preferably having a M.M.A.D
above about 0.5 to about 5.0 microns. Orally inhaled
particles and/or droplets containing rhIFN-2 having a
M.M.A.D in the range of above about 0.5 to less than
WO92/10207 ~ 9 ~ 3 ~ 3 PCT/US91/ogo~
7-
about 8 microns are suitable for deposition on the
peripheral airways and lungs and thus maximize the
beneficial effects of inhaled rhIFN-~. Droplets and
particles having a M.M.A.D. greater than 8 microns become
impacted in the upper airways; and thosa having a
M.M.A.D. less than about 0.5 microns tend to behave liXe
a gas and are exhaled. However, droplets and/or
particles of rhlFN-~ ~aving the preferred M.M.A.D. have a
high surface energy and tend to agglomerate. The
addition of a surfactant preferably a non-volatile liquid
soluble in the propellant used in nebulizers or metered
dose inhalers is desirable to lessen such agglomeration.
~ he effective amount of rhIFN-~ ~or treating
and/or preventing a lung malignancy in accordance with
this invention is a dosage range of rhIFN-~ of about l x
lO6 international units (IU) to about l x lOll IU,
preferably about l x lO6 IU to about 5 x lOlO IU, and
more preferably about l x lO6 IU to about 2 x lOlO IU.
The rhINF-~ maybe administered daily in single or divided
doses.
Based on the judgment of the attending
clinician, the amount of rhIFN-~ administered and the
treatment regimen used will, of course, be dependent on
the age, sex and medical history of the patent being
treated, the severity of the specific lung malignancy and
the tolerance of patient to the treatment regimen as
evidenced by local toxicity (e.g. nasal irritation and/or
bleeding) and by systemic side effects (e.g. fever,
malaire pancytopenia, CNS depression, qastrointestinal
irritation and elevated liver enzymes).
The following is a description of the clinical
protocol to be utilized for treating and preventing lung
malignancies.
:' ' ': . .,~ ;. ':' . , ,,': ''.
:,:.
W092/~0207 PCT/US91/090
stud~ Design
Prior to snrollment, all patients are throughly
examined and their disease clinically staged using chest
x-rays, computerized tomography, EXG, hematologic and
blood chemistries. Clotting studies including total
fibrinogen determination, PTT, PT, TT, and fibrin
degradation products are conducted. Xarnofsky
performance status, pulmonary function includi~g peak
expiratory flow (PEF), ~orced expiratory volume in one
second (FEVl), and forced vital capacity (FVC) are -
measured. Subjective and objective symptoms including
the number and severity of coughing bouts, shortness of
breath, pain and coughing-up of blood as well as body
temperature, blood pressure, and heart rate are measured.
Serum rhIFN-~ Concentrations
Serum rhIFN-~ concentrations are determined by
use of commercially available immunoradiometric assays
(Abbott Diagnotics and Centocor, respectively) or by
vesicular stomatitis virus (VSV) plaque reduction in HEp2
cultures. Measurement are performed before inhalation
and 2hr, 5hr, lOhr, 15hr and 24 hr after inhalation.
ToxicitY Evaluation and Response Criteria
Each patient is vigorously monitored for early
signs of toxicity as well as radiographic evidence of
clinical effectiveness throughout the treatment course
and on a regular basis thereafter. Methods of evaluation
include frequent physician examination, a regular
schedule for performance of laboratory procedures
including hematologic and serum chemistries pulmonary
function and clotting studies. Radiographic studies
include chest x-rays and CT scans as appropriate.
Toxicity is graded in accordance with the Work Health
Organization's recommendations for grading of acute and
~. . : :., . : ., :: , . - . . , :.
WO92/10207 2 ~ 9 ~ 3 J 3 PCT/US91/09084
~.,
_g_
subacute toxicity. Performance status is graded from
zero to four wit~ complete disability being defined as
four. Tumor response is determined by means of serial
radiographic studies. Areas of referenced tumors are
determined by multiplication of the longest diameter by
the greatest perpendicular diameter. Complete response
would be then defined as the disappearance of all
measurable disease determined by observation separated by
at least four weeks with the appearance of no new lesions
within the radiation portal. Partial response is a 50%
decrease in the referenced tumor mass and stable disease
would be defined as a less than 50% decrease in tumor
size, or less than 25~ increase. A tumor growth larger
than 25% is considered progressive disease.
Other response criteria include relief of
subjective and objective symptoms especially a
significant reduction in (l) the number and severity of
coughing bouts (2) the shortness of breath, and (3)
coughing-up of blood. Weight gain, increase in pulmonary
capacity, exercise capacity and reduction in adjuntive or
comcomitant cancer therapies would also indicate
effective treatment.
Symptoms and objective side effects of rhIFN-a
therapy including changes in body temperature, airflow
obstructure and flu-like symptom are also measured.
A reduction in tumor growth and/or lung
malignancy by administering by oral inhalation rhIFN-a to
patients in need of`such administer is expected.
. ~ . , "
: , - : : : :: ::.::
,,
