Note: Descriptions are shown in the official language in which they were submitted.
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TITLE OF THE INVENTION
ERYTHROPOIETIN AND ANTI-TUMOR NECROSIS FACTOR ALPHA
COMBINATION THERAPY
BACKGROUND OF THE INVENTION
Erythropoietin (EPO) is a glycoprotein hormone produced by the kidney in
response to
tissue hypoxia that stimulates red blood cell production in the bone marrow.
The gene for
erythropoietin has been cloned and expressed in Chinese hamster ovary (CHO)
cells as
described in United States Patent No. 4,703,008. Recombinant human
erythropoietin (r-
HuEPO, Epoetin alfa) has an amino acid sequence identical to that of human
urinary
erythropoietin, and the two are indistinguishable in chemical, physical and
immunological tests.
Recombinant human erythropoietin acts by increasing the number of cells
capable of
differentiating into mature ~ erythrocytes, triggering their differentiation
and augmenting
hemoglobin synthesis in developing erythroblasts (SB. Krantz, Blood (1991) 77:
419-434;
BS. Beckman, M. Mason-Garcia, The Faseb Journal (1991) 5: 2958-2964).
In clinical trials to date, Epoetin alfa has been evaluated in normal subjects
as well as in
subjects with various r anemic conditions. Epoetin alfa induces a brisk
haematological
response in normal human volunteers, provided that adequate supplies of iron
are available
to support increased hemoglobin synthesis. A majority of trials have
investigated the safety
and effectiveness of Epoetin alfa in the treatment of chronic renal failure
and of anemia in
cancer.
Other trials have evaluated Epoetin alfa for the treatment of anemia
associated with
rheumatoid arthritis, prematurity, AIDS, bone marrow transplantation,
myelofibrosis, sickle
cell anemia, as a facilitator of presurgical autologous blood donation, and as
a perisurgical
adjuvant.
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Epoetin alfa is approved for sale in many countries for the treatment of
anemia in chronic
renal failure (dialysis and predialysis), anemia in zidovudine treated HIV
positive patients
(US), anemia in cancer patients receiving platinum-based chemotherapy, as a
facilitator
of autologous blood predonation, and as a perisurgical adjuvant to reduce the
likelihood
of requiring allogeneic blood transfusions in patients undergoing orthopedic
surgery.
Clinical experience has been collected over the past years to show that
Epoetin alfa can
correct anemia in cancer patients, at doses several times higher than those
shown to be
effective in renal patients. Anemia may result from the disease itself, the
effect of
concomitantly administered chemotherapeutic agents, or a combination of both.
The
condition often takes on the characteristics of the anemia of chronic disease
(ACD). ACD is
associated with erythroid hypoplasia of the bone marrow, a somewhat shortened
circulating
life of red cells and decreased bone marrow re-utilization of iron. If
erythropoietin levels are
measured, they are found to be within the normal range, but inappropriately
low for the
degree of anemia. Therefore the patient has a blunted erythropoietin response.
About 50-
60% of anemic cancer patients receiving chemotherapy responded with a
hemoglobin rise
of at least 2 g/dL to Epoetin alfa therapy given three times weekly at a dose
of 150 ILJ/kg
over a period of 12 weeks (RI. Abels, KM. Larholt, KD. Krantz, and EC. Bryant,
Pr°oceedi~2gs of the Beijing Syrnposiu~ri, Alpha Medical Press, Dayton,
Ohio, (1991) 121-
141). In a subsequent open-label dose titration study, doses up to 300 IU/kg,
were
sometimes required, demonstrating the relative resistance to the effect of
Epoetin alpha in
these patients. In three large community based studies, which enrolled over
7,000 patients
with a wide range of non-myeloid malignancies, quality of life improvements
correlated
with the change in hemoglobin from baseline. (J. Glaspy, R. Bukowski, D.
Steinberg, et
al. J. Clin. Oncol. (I997) 15:1228-34; GD. Demetri, M. Kris, J. Wade, et al.
J. Clih.
O~ccol. (1998) 16:3412-25; JL. Gabrilove, LH Einhorn, RB. Livingston, et al.
American
Society of Clinical Oncology Annual Meeting (1999) Abstract 2216). However,
patients
who did not experience an increase in hemoglobin over their baseline level did
not show
improvement in energy level, activity level, and overall quality of life. In
each of the
studies, approximately 35% of patients did not have an increase in their
hemoglobin of 2
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g/dl over baseline. Patients with progressive disease do not respond well to
epoetin alfa,
but the proportion (approximately 20%) of patients with progressive disease
does not
explain the overall rate of non-response of 35%. There is room to improve the
overall
response rate to erythropoietin in patients suffering from cancer.
Quality of life measures improve in association with increased hemoglobin
levels in
patients with cancer related anemia. Yet approximately one-third of patients
fail to
respond to erythropoietin treatment. Among the responders, quality of life
measures
improve significantly, but do not approach those seen in healthy subjects. TNF
is
implicated in many of the processes that complicate cancer therapy, including
anemia,
fatigue, and anorexia and cachexia. Cancer related fatigue has emerged as the
most
prevalent and bothersome symptom of cancer and its treatment. (RK. Portenoy,
LM. Itri,
The Oncologist (1999) 4:1-10). It is reported by 75%-100% of patients with
cancer,
depending on the patient's diagnosis, treatment and disease status. Cancer
related fatigue
is a multi-factorial problem. However, the treatment of cancer related anemia
with
erythropoietin has emerged as a safe and effective therapy to improve quality
of life and
relieve cancer related fatigue. Therefore, modulation of TNF simultaneously
with EPO
should increase the effectiveness of EPO for increasing hemoglobin levels,
ameliorating
anemia, and increasing the Quality of life measures in cancer patients.
Tumor necrosis factor (TNF) is part of a group of inflammatory cytokines that
has been
implicated in the pathologic changes seen in a number of diseases. TNF has
been
implicated as a contributing cause of fatigue, asthenia, anorexia and cachexia
in a
number of disorders. Elevated levels of TNF were associated with post-dialysis
fatigue in
one study (AW. Dreisbach, T. Hendrickson, LA. Beezhold, et aL, Int. J. A~tif.
Organs
(1998) 21:83-6) and were seen in patients with disorders of excessive daytime
sleepiness
in another. (AN. Vgontzas, DA. Papanicolaou, EO. Bixler, et al., J. Clin.
Endrocrinol.
Metab. (1997) 82:1313-6) TNF inhibition associated with the use of thalidomide
has
been exploited to treat the anorexia and cachexia of HIV disease (PAJ.
Haslett. Sernin.
Oracol (1998) 25(6):53-7). The "procachetic" characteristics of some
inflammatory
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cytokines, and TNF in particular, were recently reviewed (JM. Argiles, FJ.
Lopez-
Soriano. Med Res Rev (1999) 19:223-48). The evidence of increased circulating
TNF
levels in cancer patients remains controversial; and, no single molecule has
yet been
identified as the mediator of cancer related cachexia. Still, TNF is an
important
candidate. An extensive review of asthenia echoes this sentiment. (DD. Von
Hoff.
Cancer Therapeutics (1998) 1:184-97).
A number of pre-clinical and clinical studies have demonstrated that TNF may
act as a
negative modulator of erythropoiesis. In murine models, there are conflicting
data
regarding the ability to abrogate TNF mediated anemia. (U. Clibon, L.
Bonewald, J.
Caro, et al. Exp Henaatol. (1990) 18:458-41; CS. Johnson, CA. Cook, P.
Furmanski, Exp
Hematol. (1990) 18:109-13). In human studies, there is an association between
circulating TNF levels and the need for increased doses of epoetin alfa in
hemodialysis
patients (M. Goiechea, J. Nartin, P. de Sequera, et al, Kidney Int (1998)
54:1337-43) and
between local production of TNF in the bone marrow of patients with the anemia
of
chronic disease secondary to rheumatoid arthritis. (M. Jongen-Lavrencic, HR.
Peeters, A.
Wognum, et al., J Rheufnatol. (1997) 24:1504-9). TNF blockade with a
monoclonal
antibody lead to improvement in the anemia of rheumatoid arthritis patients in
one study.
(D. Davis, PJ. Chrles, A. Potter, et al. Br J Rheumatol (1997) 36:950-6).
The unmet need of enhanced EPO treatment for patients who suffer from cancer
and
fatigue has been met by the present invention that describes a method to treat
patients
with a combination of EPO and an anti- Tumor Necrosis Factor alpha agent.
SUMMARY OF THE INVENTION
The present invention provides a method for the treatment of a patient,
comprising the
steps, in any order or concurrently of administering a therapeutic amount of
at least one
anti-Tumor Necrosis Factor compound and a therapeutic amount of
erythropoietin. The
present invention further provides a method for the treatment of a patient
having
malignancies, comprising the steps, in any order or concurrently of
administering a
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therapeutic amount of at least one anti-Tumor Necrosis Factor compound, a
therapeutic
amount of erythropoietin, and a therapeutic amount of an anti-tumor agent.
The methods of the present invention result in a reduced need for transfusion
and a
greater hemoglobin level in the patient. Further, the present invention
provides that
anemia may be successfully prevented or treated during the course of a
chemotherapeutic
regimen using the method of the present invention. The methods of the present
invention
result in patients that show greater quality of life, show improvement in
physical
performance and well being.
DETAILED DESCRIPTION OF THE INVENTION
The term Erythropoietin (EPO), as defined herein, refers to any molecule that
specifically
stimulates terminal differentiation of red blood cells from hematopoietic stem
cells and
stimulates production of hemoglobin. For example, but not to limit the scope
of the
current invention, EPO molecules may include small organic or inorganic
molecules,
synthetic or natural amino acid peptides, purified protein from recombinant or
natural
expression systems, or synthetic or natural nucleic acid sequences, or any
chemical
derivatives of the aforementioned. The generally preferred. form of EPO is
purified,
recombinant EPO, distributed under the trademarks of EPREXO or ERYPOO. Epoetin
alfa (EPREX", ERYPO°) is a sterile, clear, colourless, aqueous solution
for injection, that
is provided in prefilled, single-use syringes containing either 4,000 or
10,000 IIJ epoetin
alfa (a recombinant human erythropoietin) and 2.5 mg/mL human serum albumin in
0.4 mL
(4,000 IU syringe) or 1.0 mL (10,000 IU syringe) of phosphate buffer.
The term "Erythropoietin" shall include those proteins that have the
biological activity of
human erythropoietin, as well as erythropoietin analogs, erythropoietin
isoforms,
erythropoietin mimetics, erythropoietin fragments, hybrid erythropoietin
proteins,
erythropoietin receptor agonists, renal erythropoietin, brain erythropoietin,
oligomers and
multimers of the above, homologues of the above, and muteins of the above,
regardless
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of the biological activity of same, and further regardless of the method of
synthesis or
manufacture thereof including but not limited to naturally occurring,
recombinant,
synthetic, transgenic, and gene activated methods.
The term "anti-Tumor Necrosis Factor Compound" refers to drug products that
decrease
the amount of circulating, active TNFoc. The compound may achieve this by
decreasing
the amount of cellular TNFoc mRNA transcription, by decreasing mRNA
translation into
TNFoc protein, or by decreasing cellular secretion of TNFcc. Roy A. Black et
al., from
Immunex Corp., have discovered a compound that inhibits the enzyme that
releases TNF
from cell surfaces (Natur°e, 370, 218(1994)). This compound, called TNF-
a protease
enzyme inhibitor, curbs production of soluble TNF. Other suitable anti-TNFoc
compounds could work by increasing the rate of clearance or decreasing the
amount of
functional TNFa in circulation. Preferred anti-TNFcc compounds are
Thalidomide,
Pentoxifylline, Infliximab, glucocorticoids, and Etanercept. The anti-TNFoc
compounds
rnay be administered as combinations in order to maximize modulation of TNF
since
these agents acts as TNFa, inhibitors at a different points in TNF synthesis
and
pharmacokinetic activity. Pentoxifylline inhibits TNF-a gene transcription
(Doherty et
al., Surgery (St. Louis), 110:192, 1991), while thalidomide enhances TNF-oc m-
RNA
degradation (Moreira et al., 1993) and glucocorticoids such as dexamethasone
inhibit
TNF-cx m-RNA translation (Han et al., J. Exp. Med. (1990) 172:391). Infliximab
and
etanercept act by reducing the amount of circulating, active TNFcc.
Pentoxifylline (PENTOXILTM, Trental) decreases circulating TNFoc at the
Standard dose of
400 mg 3 times daily: Pentoxifylline inhibits TNF-~, gene transcription
(Doherty et al.,
Surgery (St. Louis), 110:192, 1991).
Glucocorticoids such as dexamethasone inhibit TNF-oc m-RNA translation.
Dexamethasone is administered orally, intramuscularly, or intravenously in the
dose
range of 8-40 mg (pediatric dose: 0.25-0.5 mg/kg). If given intravenously,
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dexamethasone should be given over 10-15 minutes, since rapid administration
may
cause sensations of generalized warmth, pharyngeal tingling or burning, or
acute
transient perianal and/or rectal pain. Methylprednisolone is also administered
orally,
intramuscularly, or intravenously at doses and schedules that vary from 40-500
mg every
6-12 hours for up to 20 doses.
Thalidomide (N-phthalidoglutarimide) may act by enhancing TNF-a m-RNA
degradation (Shannon et al: (1990) Amer. Societ~for Microbiology Ann. Mtg.,
Abs. U-
53). Thalidomide is given by oral administration in the range of about 30 mg
to 1500 mg
per 24 hours, preferably 200 to 500 mg per 24 hours for an adult human
weighting 70 kg.
REMICADETM (Infliximab) is a monoclonal antibody that blocks the biological
activity
of circulating TNFoc. Infliximab does not neutralize TNF(3 (lymphotoxin oc), a
related
cytokine that utilizes the same receptors as TNFoc. Remicade is supplied as a
sterile,
white, lyophilized powder for intravenous infusion. Following reconstitution
with 10 mL
of Sterile Water for Injection, USP, the resulting pH is approximately 7.2.
Each single-
use vial contains 100 mg Infliximab, 500 mg sucrose, 0.5 mg polysorbate 80,
2.2 mg
monobasic sodium phosphate and 6.1 mg dibasic sodium phosphate. No
preservatives
are present. Data from a study of single intravenous infusions of 1, 5, 10 or
20 mg/kg
show a direct and linear relationship between the dose administered and the
maximum
serum concentration (C,nax) and area under the concentration-time curve. The
volume of
distribution at steady state (Vd), clearance and mean residence time are
independent of
the administered dose. Infliximab has a prolonged terminal half-life and is
predominantly
distributed within the vascular compartment. A single infusion of the
recommended dose
of 5 mg/kg resulted in a median CmaX of 118 ~glmL, a median Vd equal to 3.0
liters and a
terminal half life of 9.5 days.
ENBRELTM (etanercept) is a dimeric fusion protein consisting of the
extracellular ligand-
binding portion of the human 75 kilodalton (p75) tumor necrosis factor
receptor (TNFR)
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linked to the Fc portion of human IgGl. The Fc component of etanercept
contains the
CH2 domain, the CH3 domain and hinge region, but not the CH1 domain of IgGl.
Etanercept is produced by recombinant DNA technology in a Chinese hamster
ovary
(CHO) mammalian cell expression system. It consists of 934 amino acids and has
an
apparent molecular weight of approximately 150 kilodaltons. ENBRELTM is
supplied as
a sterile, white, preservative-free, lyophilized powder for parenteral
administration after
reconstitution with 1 mL of the supplied Sterile Bacteriostatic Water for
Injection, USP
(containing 0.9% benzyl alcohol). Following reconstitution, the solution of
ENBRELTM
is clear and colorless, with a pH of 7.4 ~ 0.3. Each single-use vial of
ENBRELTM
contains 25 mg etanercept, 40 mg mannitol, 10 mg sucrose, and 1.2 mg
tromethamine.
ENBRELTM is administered as a single subcutaneous (SC) injection.
It is readily apparent to those skilled in the art that a wide variety of
malignancies are
treatable according to the methods of the present invention.
Such tumor types include, but are not limited to, solid tumors, hematological
tumors,
sarcomas, carcinomas, neoplasms, as well as tumors of the breast, Non-
Hodgkin's
Lymphoma, myeloma, Hodgkin's lymphoma, leukemia, colon, rectal, colo-rectal,
stomach, gastrointestinal, ovarian, lung, pancreas, and prostate.
It is readily apparent to those skilled in the art that a wide variety of non-
platinum and
platinum containing anti-tumor agents are suitable for use in the methods of
the present
invention. Platinum containing anti-tumor agents include, but are not limited
to,
cisplatin, and cis-dichlorodiammineplatinum. Non-platinum containing anti-
tumor agents
include, but are not limited to, cyclophosphamide, fluorouracil, epirubicin,
methotrexate,
vincristine, doxorubicin, bleomycin, and etoposide.
Quality of life is usually affected by malignancy, e.g., due to the underlying
disease, effects
of therapy and the psychological burden of coping with cancer. Fatigue is the
most
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frequently reported symptom in cancer patients and impairs significantly their
quality of life
(ML. Winningham, LM. Nail, M. Barton Burke, et al., Oncol Nursing Forum (1994)
21:
2.3-34) Anemia contributes to fatigue and to the reduction in quality of life.
The effects on
fatigue (FACT An) and quality of life (ECOG performance score, Cancer Linear
Analogue
Scale, SF36) of early intervention and/or treatment of anemia with the
combination therapy
of EPO + anti-TNFa can be alleviated with concurrent use of EPO + anti-TNFoc
during
chemotherapy.
The following examples illustrate the present invention without, however,
limiting the
same thereto.
EXAMPLE 1
A Randomized, Controlled Trial of Epoetin Alfa and Etanercept
OVERVIEW OF STUDY DESIGN
The study will be a double-blind, randomized, placebo controlled trial. After
initial evaluation for eligibility, cancer patients with treatment related
anemia will
be assigned in a 1:1 randomization to receive either epoetin alfa plus placebo
(Regimen A) or epoetin alfa plus etanercept (Regimen B). Patients who do not
achieve an increase in hemoglobin of 1 g/dl without transfusion after four
weeks
of treatment will receive an increased dose epoetin alfa during weeks 5-8.
Patients on Regimen A (epoetin alfa + placebo) who do not achieve an increase
in hemoglobin of 2 g/dl over baseline by week 9 will be crossed over to
Regimen
B in an 8 week open label extension phase. Patients on Regimen B who do not
achieve a 2 g/dl increase in hemoglobin over baseline by week 9 will be taken
off
study. Responding patients will continue on their assigned treatment and
blinding
will be maintained for 16 weeks.
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All patients must have received at least one course of chemotherapy and be
scheduled to receive a minimum of 8 weeks of additional chemotherapy after
study enrollment. Measures of Quality of Life (QoL), executive function, and
weight will be obtained at study entry and at weeks 9 and 17 or at the time of
withdrawal from the study. Hematologic parameters will be measured bi-weekly.
All measurements should be made within 3 days prior to a subsequent course of
chemotherapy. Assessments of tumor response will be made at enrollment, with
subsequent assessments at weeks 9 and 17 or at the time of withdrawal from the
study.
STUDY POPULATION
General Considerations
The specific inclusion and exclusion criteria for enrolling subjects in this
study
are described in the following sections. Exceptions to these
inclusion/exclusion
criteria should occur infrequently and should be discussed in advance with the
Ortho Biotech medical monitor. If an exception is agreed upon and a subject is
allowed to participate, the medical monitor will send confirmation to the site
acknowledging the exception. This confirmation form or letter is to be kept
with
the case report forms (CRFs) both at the site and at the sponsor.
Inclusion Criteria
Subjects must satisfy the following criteria before entering the study:
~ Histologically proven breast or lung cancer
~ Prior chemotherapy <_ 1 course
~ No evidence of progressive disease at study entry
~ Treatment related anemia (must have started chemotherapy
prior to study entry) with hemoglobin >_ 8 g/dl and <_ 12 g/dl
~ Age >_ 18 years
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~ Iron replete (transferrin saturation of >_ 20% and serum
ferritin >_ 100 ng/ml)
~ ECOG Performance status of 0-1 (see Appendix X) as
determined by the investigator of designee.
~ Life expectancy of at least 6 months
~ Scheduled to receive at least an 8 weeks of chemotherapy
~ Understands and signs informed consent
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from
participating in the study:
~ Prior chemotherapy > 1 course
~ Use of biological response modifiers or cytokines within 30
days of study entry
~ Diagnosis of rheumatoid arthritis, inflammatory bowel
disease, or any disease for which etanercept may be
primary therapy
~ Chronic infection within 30 days of study entry
~ Active infection at study entry
~ Acute infection within 7 days of study entry
~ Brain metastases
~ Uncontrolled seizures
~ Uncontrolled hypertension
~ Transfusion within 2 months of study entry
~ Iron deficiency or other nutritional anemia
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~ Active hemolytic anemia
~ Bleeding
~ Known hypersensitivity to mammalian cell-derived
products
~ Known hypersensitivity to human albumin
~ Prior treatment with epoetin alfa or any investigational
erythropoietin within 8 weeks of study entry
~ Significant medical disease other than cancer
~ Second malignancy, other than basal cell carcinoma of the
skin, within 5 years of study entry
~ Use of corticosteroids other than for occasional use for
anti-emesis or pre-treatment for a medication
~ Advanced or poorly controlled diabetes mellitus
~ Pregnant or lactating woman
RANDOMIZATION AND BLINDING
Overview
Randomization will be used to avoid bias in the assignment of patients to
treatment, to increase the likelihood that subject attributes are evenly
balanced
across groups, and to enhance the validity of comparisons across treatment
groups. Investigators and patients will be blinded to the identity of
etanercept
and placebo to enhance the validity of comparisons that are subject to
observer
bias or the placebo effect (e.g. - QoL end points). EPO will be given to all
patients in an open label manner. Patients will be assigned randomly to each
treatment regimen.
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PROCEDURES
Pre-Randomization Phase (Baseline)
The following evaluations and procedures are to be performed within 14 days
prior to randomization unless otherwise specified. All laboratory tests and
QoL
and cognitive measures must be performed prior to the start of the first
chemotherapy course after randomization.
~ Patient demographics
~ ECOG Performance Status as rated by the investigator or
designee
~ Tumor assessment using the NCI RECIST Criteria within
14 days prior to randomization
~ Chemotherapy, radiation and surgery history
~ Weight measured fully dressed except for shoes on the
same scale to be used throughout the study
~ Clinical laboratory tests
~ Hemoglobin, hematocrit, MCV, absolute
reticulocyte count, white blood cell count with
differential and platelet count within 3 days prior to
randomization
~ Iron studies: ferritin, total iron binding capacity
(TIBC), transferrin saturation, serum iron,
transferrin receptor levels
~ RBC folate and vitamin Bi2 levels
~ BUN, creatinine
~ AST, ALT, total bilirubin
~ Serum TNFa and anti-TNFcc levels
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~ FACT-An, Linear Analog Scale Assessment (LASA),
CLOX and EXIT 25 within 3 days prior to the
administration of chemotherapy
~ Transfusion history
~ Signed informed consent
Subjects will be assigned to treatment groups based on a computer-generated
randomization schedule. The randomization will be balanced by using permuted
blocks and will be stratified by center and type of cancer. Based on this
randomization code, the study drug will be packaged and labeled for each
subject. [Subject numbers] [Medication code numbers] will be preprinted on the
study drug labels and assigned sequentially as subjects qualify for the study
and
are randomized to treatment.
To maintain the blind, the etanercept or placebo drug container will have a
two-part, tear-off label with directions for use and other information on each
part.
The tear-off section of the label will contain a concealed area identifying
the
study drug (e.g., active or placebo) and will be removed and attached to the
subject's CRF when the drug is dispensed. The second part of the label will
remain affixed to the study drug container and will contain all identifying
information except for the identity of the drug contained. The study drugs
will be
identical in appearance and will be packaged in identical containers.
Under normal circumstances, the blind should not be broken. The blind should
be
broken only if specific emergency treatment would be dictated by knowing the
treatment status of the subject. In such cases, the investigator must contact
the
sponsor. If the investigator is unable to contact the sponsor, the
investigator may
in an emergency determine the. identity of the treatment by exposing the
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concealed area of the label attached to the subject's CRF. Individual code
breaks
by the investigator will normally result in withdrawal of the subject from the
trial.
The date, time, and reason for the unblinding must be documented on the
appropriate page of the CRF (Study Completion Information) and the sponsor
must be informed as soon as possible.
The randomization schedule will not be revealed to study subjects, parents or
guardians, investigators and clinical staff, or site managers until all
subjects have
completed the double-blind phase of the trial.
To allow for the cross-over of non-responding patients randomized to EPO
alone,
the investigator will call the study sponsor with the week 9 hemoglobin
results.
If a patient is a non-responder, the study sponsor will inform the
investigator of
the patient's treatment assignment. Patients who do not respond to EPO + STAN
(Regimen B) will proceed to Off Study Evaluation procedures. Non-responding
patients treated on EPO + placebo (Regimen A) will be treated with EPO +
ETAN for an additional 8 weeks in an open label extension phase. Non-
responding patients treated with EPO+ETAN who subsequently respond indicate
synergistic action of the anti-tumor necrosis factor agent with EPO Compauison
of the response of patients treated with EPO or with EPO+ETAN will further
indicate synergistic action of the combination therapy.
DOUBLE-BLIND TREATMENT PHASE
During this phase patients should remain blinded to study-related test
results prior to the completion of each set of OoL and cognitive measures.
The treating physician may provide laboratory results as soon as the forms
are completed for that visit.
For patients receiving every three week chemotherapy, evaluations should be
completed at least 3 days following the end of the last dose of chemotherapy.
For
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patients receiving every four week chemotherapy, evaluations should be
completed within 3 days prior to the scheduled chemotherapy course.
Week 3
~ ECOG Performance Status as rated by the investigator or
designee
~ Weight measured fully dressed except for shoes on the
same scale to be used throughout the study
~ Clinical laboratory tests
~ Hemoglobin, hematocrit, MCV, absolute
reticulocyte count, white blood cell count with
differential and platelet count
~ Iron studies: ferntin, total iron binding capacity
(TIBC), transferrin saturation, serum iron,
transferrin receptor levels
~ Serum TNFoc and anti-TNFa levels
~ Transfusion history
Week 5
ECOG Performance Status as rated by the investigator or
designee
~ Chemotherapy, radiation and surgery history
~ Weight measured fully dressed except for shoes on the
same scale to be used throughout the study
~ Clinical laboratory tests
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~ Hemoglobin, hematocrit, MCV, absolute
reticulocyte count, white blood cell count with
differential and platelet count Iron studies: ferritin,
total iron binding capacity (TIBC), transferrin
saturation, serum iron, transfernn receptor levels
~ Serum TNFoc and anti-TNFa, levels
~ Transfusion history
Week 9
This evaluation will serve as the Off Study Evaluation for Non-responders on
Regimen B
~ ECOG Performance Status as rated by the investigator or
designee
~ Tumor assessment using the NCI RECIST Criteria (see
Appendix X) within 14 days
~ Chemotherapy, radiation and surgery history
~ Weight measured fully dressed except for shoes on the
same scale to be used throughout the study
~ Clinical laboratory tests
~ Hemoglobin, hematocrit, MCV, absolute
reticulocyte count, white blood cell count with
differential and platelet count
~ Iron studies: ferritin, total iron binding capacity
(TIBC), transferrin saturation, serum iron,
transferrin receptor levels
~ RBC folate and vitamin B12 levels
~ BUN, creatinine
AST, ALT, total bilirubin
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~ Serum TNFa and anti-TNFa levels
~ FACT-An, Linear Analog Scale Assessment (LASA),
CLOX and EXIT 25 within 3 days prior to the
administration of chemotherapy
~ Transfusion history
Responding patients on both regimes will continue on their assigned treatment
and be evaluated through week 17 as follows.
Week 13
~ ECOG Performance Status as rated by the investigator or
designee
~ Clinical laboratory tests
~ Hemoglobin, hematocrit, MCV, absolute
reticulocyte count, white blood cell count with
differential and platelet count
~ Iron studies: ferritin, total iron binding capacity
(TIBC), transferrin saturation, serum iron,
transferrin receptor levels
Serum TNFa and anti-TNFa levels
~ Transfusion history
~ Determination of response: non-responders already on
60,000 U/week proceed to Off Study Evaluation
Week 17
~ Proceed to Off Study Evaluation
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OPEN LABEL EXTENSION PHASE FOR NON-RESPONDERS IN REGIMEN A
Week 13
~ ECOG Performance Status as rated by the investigator or
designee
~ Clinical laboratory tests
~ Hemoglobin, hematocrit, MCV, absolute
reticulocyte count, white blood cell count with
differential and platelet count
~ Iron studies: ferritin, total iron binding capacity
(TIBC), transferrin saturation, serum iron,
transfernn receptor levels
~ Serum TNFa and anti-TNFoc levels
~ Transfusion history
Week 17
~ Proceed to Off Study Evaluation
OFF STUDY EVALUATION
~ ECOG Performance Status as rated by the investigator or designee
~ Tumor assessment using the NCI RECIST Criteria within 14 days
~ Chemotherapy, radiation and surgery history
~ Weight measured fully dressed except for shoes on the same scale
to be used throughout the study
~ Clinical laboratory tests
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~ Hemoglobin, hematocrit, MCV, absolute reticulocyte
count, white blood cell count with differential and platelet
count
~ Iron studies: ferritin, total iron binding capacity (TIBC),
transfenin saturation, serum iron
~ BUN, creatinine
~ AST, ALT, total bilirubin
~ Serum TNF and anti-TNF levels
~ FACT-An, Linear Analog Scale Assessment (LASA), CLOX and
EXIT 25 within 3 days prior to the administration of
chemotherapy
~ Transfusion history
DOSAGE AND ADMINISTRATION
~imen A (EPO + Placebo)
EPO will be started at a dose of 40,000 U per week given SC, without regard to
the timing of chemotherapy. If at the evaluation prior to the week 5 dose the
hemoglobin has not increased by at least 1 g/dl over the baseline value, the
dose
of EPO will be increased to 60,000 U per week for weeks 5-8. If the hemoglobin
increases by at least 2 g/dl over baseline at the time of the week 9
evaluation, the
patient will be considered a responder. Responders will continue to receive
the
dose of EPO given during weeks 5-8 until week 16. Non-responders will be
offered the opportunity to receive EPO + ETAN in an 8 week open label
extension.
Placebo injections will be given at a dose of 1 ml SC, at a site separate from
the
EPO site, on days 1 and 4 of each week (day 1 is counted as the day the EPO
and
placebo are given together). The patient should receive two doses of placebo
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during week 8, prior to the week 9 evaluation. Responders will continue to
receive placebo in a blinded manner through week 16. Two placebo injections
should be given in week 16, prior to the off study evaluation. Non-responders
will be offered the opportunity to receive EPO + STAN in an 8 week open label
extension.
Regimen B (EPO + ETAN)
EPO will be started at a dose of 40,000 U per week given SC, without regard to
the timing of chemotherapy. If at the evaluation prior to the week 5 dose the
hemoglobin has not increased by at least 1 g/dl over the baseline value, the
dose
of EPO will be increased to 60,000 U per week for weeks 5-8. If the hemoglobin
increases by at least 2 g/dl over baseline at the time of the week 9
evaluation, the
patient will be considered a responder. Responders will continue to receive
the
dose of EPO given during weeks 5-8 until week 16. Non-responders will proceed
to the Off Study Evaluation at week 9.
ETAN injections will be given at a dose of 25 mg (1 ml) SC, at a site separate
from the EPO site, on days 1 and 4 of each week (day 1 is counted as the day
the
EPO and ETAN are given together). The patient should receive two doses of
ETAN during week 8, prior to the week 9 evaluation. Responders will continue
in ETAN through week 16. Two ETAN injections should be given during week
16 and prior to the off study evaluation. Non-responders will proceed to the
off
study evaluation at week 9.
Open label phase for non-responders on Regimen A
To assess the effectiveness of ETAN in overcoming resistance to EPO, placebo
will be replaced with ETAN at week 9 for patients who are non-responders in
Regimen A. The following doses of EPO and ETAN will be given during weeks
9-16 in these patients:
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(1) Patients on an EPO dose of 60,000 Ulweek at week 8 will continue on that
dose for weeks 9-12. ETAN will be given at a dose of 25 mg SC, at a site
separate from the EPO site, on days 1 and 4 of each week (day 1 is counted as
the
day the EPO and placebo are given together). ETAN will be started on the day
of
the week 9 EPO dose and continue until 2 doses are given during week 12. If
the
evaluation at week 13 indicates at least a 1 g/dl increase in hemoglobin over
the
week 9 value or a 2 g/dl increase over the baseline value, then the patient
will be
considered a responder and continue on study through week 16. ETAN should
continue until 2 doses are given in week 16. The patient then will proceed to
the
Off Study Evaluation. If the patient is a non-responder at week 13, then the
patient will proceed to the Off Study Evaluation.
(2) Patients on an EPO dose of 40 000 Ulweek at week ~ will continue that dose
through for weeks 9-12. ETAN will be given at a dose of 25 mg SC, at a site
separate from the EPO site, on days 1 and 4 of each week (day 1 is counted as
the
day the EPO and placebo are given together). The first dose of ETAN will be
given on the day of the week 9 EPO dose and continue until 2 doses are given
during week 12. If the evaluation at week 13 indicates at least a 1 g/dl
increase in
hemoglobin over the week 9 value, or a 2 gldl increase over the baseline
value,
then the patient will continue on study through week 16 at the same dose of
EPO.
ETAN should continue until 2 doses are given during week 16 EPO. The patient
then will proceed to the Off Study Evaluation. If the patient is a non-
responder at
week 13, then the EPO dose will be increased to 60,000 U/week and the patient
will continue on study through week 16. ETAN should continue until 2 doses are
given during week 16 EPO. The patient then will proceed to the Off Study
Evaluation.
Dose adjustment of EPO
If the hemoglobin is >_ 13 g/dl on 2 consecutive evaluations, EPO should be
withheld until the hemoglobin drops to 12 g/dl. EPO should then be resumed at
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75% of the last dose given before discontinuation. If the hemoglobin increases
by > 1.3 g/dl in a 2 week period, EPO should be continued at 75% of the
previous dose.
Patients who develop sepsis
All study medication should be discontinued in patients who develop sepsis
while
on study. The Study Completion/Early Withdrawal form should be completed
and the study sponsor informed immediately.
Administration of EPO
Epoetin alfa 40,000 U/ml should be brought to room temperature and drawn up
into a plastic syringe immediately prior to administration by SC injection
according to standard techniques. The EPO and ETAN/placebo may be given at
the same time on day 1 of each week, but should be administered at separate
sites. Each vial of EPO should be used only once. The maximum injection
volume per site is 2 ml.
Administration of ETAN
Study medication (ETAN/placebo) should be reconstituted with 1 ml of the
supplied sterile bacteriostatic water for injection, USP (0.9% benzyl
alcohol). The
diluent should be slowly injected into the vial. Some foaming may occur. To
avoid excessive foaming, do not shake or agitate vigorously. Swirl gently
until
dissolution occurs, usually over less than 5 minutes. The solution should be
clear
and colorless. The medication should then be drawn up into a plastic syringe
and
administered SC as soon as possible after reconstitution. New injections
should
be given at least 1 inch from an old site and never into areas where the skin
is
tender, bruised, hard or red. Prior to injection of the study medication, Part
2 of
the two-part vial label is to be attached to the subject's case report form
after
entry of the subject's initials and number, and the date of study medication
administration. Each vial of study medication should be used only once.
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Iron
Iron deficiency may develop during the use of EPO and may limit the efficacy
of
EPO if left untreated. If laboratory evidence of iron deficiency develops
during
the study, the patient should be given 150-200 mg of elemental iron per day.
The
appropriate formulation of the iron supplement is left to the discretion of
the
treating physician.
CONCOMITANT THERAPY
Patients may be transfused with packed red blood cells when judged to be
necessary by the physician of record. A hemoglobin level should be obtained at
the time the type and cross-match specimen is drawn. The pre-transfusion
hemoglobin value, along with the number of units used and the total volume
transfused, should be recorded in the case report form.
All concomitant therapy administered during the study will be recorded on the
case report form. The use of androgens or hematinic agents (folate, B i2)
other
than iron is prohibited during the study. The use of corticosteroids, other
than
occasional use as a pre-medication or an anti-emetic is prohibited during the
study.
The sponsor must be notified in advance (or as soon as possible thereafter) of
any
instances in which prohibited therapies are administered.
EFFICACY EVALUATIONS
The primary endpoints to be evaluated in this study are as follows:
1. a comparison of the proportion of patients in each regimen who achieve a
response by week 9
2. a comparison of the change in scores on QoL measures in each regimen
between Baseline, week 9 and Off Study in responders, and using an intent
to treat analysis of all patients
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3. the proportion of non-responders in Regimen A who show a response at
week 13 and week 17 when crossed over to the EPO + ETAN arm (Regimen
B)
4. a comparison of the proportion of patients in each regimen who experience
significant weight loss.
EFFICACY AND DISEASE STATUS EVALUATION CRITERIA
1 Response is defined as a 2g/dl or greater increase in the hemoglobin
when compared to the Baseline value.
1 Significant wei h~ t loss will be defined as Off Study Weight divided by
Baseline Weight less than 0.90.
1 Disease status will be defined according the current version of the
RECIST Criteria issued by the National Cancer Institute.
The following measurement tools will be used in this study:
~ Linear Analog Scale Assessment
~ Fact-An
~ CLOX: An Executive Clock Drawing Task
~ EXIT 25: The Executive Interview.
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