Clinical trial NCT00452023
Conditions: Myeloproliferative Disorders
Keywords: Myeloproliferative Disorders Essential Thrombocythemia Polycythemia Vera Pegasys IFN-alpha2a Pegylated-Interferon Alpha-2A PEG-IFNa-2a
Sponsor: M.D. Anderson Cancer Center
Start date: 2005-04-07; Completion date: 2023-05-26
Enrollment: 83 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical research study is to see if Pegasys (IFN-alpha2a) can help to control the disease in patients with ET, PV, AMM/MF, and Ph-negative CML. The safety of this treatment will also be studied.

Detailed description:
IFN-alpha2a has been used for the treatment of a variety of disorders (such as hepatitis C). IFN-alpha2a is a drug that may affect the way infections and malignant diseases develop.

Before treatment starts, you will have blood (around 2 teaspoons) and bone marrow samples collected. To collect a bone marrow sample, an area of the hip or chest bone is numbed with anesthetic and a small amount of bone marrow is withdrawn through a large needle. These samples will be used for tests to confirm the diagnosis of the disease. Women who are able to have children must have a negative blood pregnancy test.

During treatment, you will receive IFN-alpha2a as an injection under the skin once a week. You (or your caregiver) will be taught how to give the injections, and you will receive treatment on an outpatient basis.

Treatment will continue (injections once a week) as long as the disease does not get worse.

If the disease gets worse or you experience any intolerable side effects, you will be taken off the study and your doctor will discuss other treatment options with you.

During treatment you will have blood (around 1 teaspoon) collected every other week for 2 months, then once every 1 or 2 months for a year, then every 3 months. You will also have bone marrow samples collected every 3 to 6 months during the first year of treatment. After the first year of treatment, bone marrow samples will be collected only when your doctor feels they are needed. The blood and bone marrow samples will be used for tests to check on the response to therapy.

This is an investigational study. IFN-alpha2a has been approved by the FDA for the treatment of hepatitis C and is commercially available. However the use of IFN-alpha2a in this study is investigational. The commercial prepartion of IFN-alpha2a(Pegasys) will be used in this study. Up to 280 participants will take part in this study. All will be enrolled at M. D. Anderson.

Arms: arm 1: Starting dose 90 microgram (mcg) injection under the skin once a week. arm 2: Starting dose 450 microgram (mcg) injection under the skin once a week. arm 3: Starting dose 360 microgram (mcg) injection under the skin once a week. arm 4: Starting dose 270 microgram (mcg) injection under the skin once a week. arm 5: Starting dose 180 microgram (mcg) injection under the skin once a week.
Interventions: intervention 1: IFN-alpha2a
Intervention descriptions: intervention 1: Starting dose 90 microgram (mcg) injection under the skin once a week

Protocol documents:
Prot_SAP_000.pdf: 
DM03-0109 
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PEG IFN-alpha2a (Pegasys®) therapy in patients with chronic 
myeloproliferative diseases (excluding Philadelphia chromosome 
positive chronic myeloid leukemia).DM03-0109 
 
1.0 Hypothesis 
 
PEG IFN-a2a (Pegasys®) is an effective and tolerable 
treatment for patients with essential thrombocythemia 
(ET) and polycythemia vera (PV).  
  
 
2.0 Objectives 
2.1 
The primary objective of this study is to determine 
the efficacy of PEG IFN-α2a in patients with 
chronic myeloproliferative diseases: ET and PV. 
 
2.2 
The secondary objective is to evaluate the 
toxicities of PEG IFN-α2a in patients with these 
disorders.  
 
2.3 
The tertiary objective is to evaluate pertinent 
morphologic and molecular characteristics of 
these diseases before and during the therapy with 
PEG IFN-α2a. 
 
3.0 Background and Rationale 
3.1 The Diseases and Current Treatment 
 
ET, and PV are chronic myeloproliferative diseases, 
which are clinically defined entities within the broad 
category of chronic myeloid disorders.  Because the 
clonal process originates at the stem-cell level, with 
retention of cellular differentiating capacity, chronic 
myeloproliferative diseases are characterized by bone 
marrow panhyperplasia and accumulation of mature 
myeloid cell lines.  Currently, specific disease 
classification is based on the predominant pattern of 
myeloid-cell proliferation and the presence or absence of 
reactive bone-marrow fibrosis, with or without 
extramedullary hematopoiesis (Tefferi et al.).  
Thrombocytosis and absolute erythrocytosis are 
prerequisites for the diagnosis of ET and PV, 
respectively.  Life expectancy in ET approaches that of 
an age- and sex-matched control population, and median 


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survival exceeds 15 years in young patients with PV.  
Nevertheless, these disorders are considered incurable 
and treatment is directed at reducing morbidity and 
preventing life-threatening complications.  Vasomotor 
disturbances (headaches, dizziness, acral dysesthesia, 
erythromelalgia, visual symptoms), thrombohemorrhagic 
events, and the risk of transformation into acute myeloid 
leukemia or AMM/MF characterize the clinical course of 
both ET and PV (Tefferi et al.). 
 
Vasomotor symptoms may occur in up to one-third of the 
patients and are usually controlled with aspirin.  Bleeding 
complications, in the absence of platelet anti-aggregant 
therapy, are infrequent (< 1% pt/yr) and usually 
inconsequential.  In contrast, thrombotic complications 
are more frequent and may even be fatal, especially in 
PV. In both ET and PV significant proportion of patients 
experience a thrombotic episode either before (10%-
15%) or at diagnosis (10%-20%).  During follow-up, the 
risk of thrombosis in both ET and PV depends on the 
patient's age and previous history of thrombosis (Rozman 
et al.). In comparison to a control population adequately 
matched for age, sex, and cardiovascular risk factors, 
patients with ET were found to be at a significantly 
increased risk for thrombosis (1% v 7% pt/yr).  The risk 
was highest for patients older than 60 years (15% pt/yr) 
and for those with a previous history of thrombosis (31% 
pt/yr).  The thrombogenic effects of advanced age and 
history of previous thrombosis were confirmed by other 
large studies.  Therefore, patients with ET who are older 
than 60 years and/or have a history of previous 
thrombosis are considered ‘high-risk for thrombosis’.  
Additional risk factors may include the presence of 
cardiovascular risk factors, especially smoking.  The 
degree of thrombocytosis or platelet-function 
abnormalities has not been correlated with thrombotic 
risk. 
 
In one of the largest retrospective studies ever conducted 
in patients with PV, thrombosis was observed in 19% of 
1213 patients followed up for a median of 5.3 years.  
Thrombotic risk was correlated with advanced age (> 4% 
pt/yr for patients older than 60 years versus 1.8% pt/yr for 
those younger than 40 years) and a history of 
thrombosis.  These and other risk factors for thrombosis 
(treatment with phlebotomy alone, increased phlebotomy 


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requirement) were previously identified during the original 
Polycythemia Vera Study Group studies.  Similar to the 
observation in ET, the absolute platelet count was not 
predictive of a thrombotic episode (Silverstein et al.). 
 
3.1.1 
ET 
 
Transformation into acute myeloid leukemia or AMM/MF 
is rare in ET (< 2% in most large series).  Therefore, 
treatment efforts in ET should strive to reduce thrombotic 
events in high-risk-for thrombosis patients without 
increasing the intrinsically low risk of leukemic 
transformation.  To that effect, a recent randomized study 
of high-risk-for-thrombosis patients with ET demonstrated 
that treatment with hydroxyurea, compared with no 
myelosuppressive therapy, resulted in a significant 
decrease in thrombotic events (3.6% v 24% during a 
median follow-up of 27 months).  Follow-up was too short 
to assess risk of leukemic transformation (Tefferi, 
Silverstein and Hoagland). 
 
Acute myeloid leukemia has been reported in ET in the 
presence or absence of antecedent chemotherapy.  In 
nonrandomized studies of patients with ET, acute 
myeloid leukemia was reported to develop after treatment 
with both alkylating and nonalkylating agents.  Some 
case reports have underscored the significant risk of 
acute myeloid leukemia associated with long-term use of 
hydroxyurea in ET.  Regardless, the leukemogenic 
potential of hydroxyurea is generally believed to be lower 
than that of alkylating agents.  As such, the risk-benefit 
ratio favors the use of hydroxyurea therapy in high-risk-
for-thrombosis patients with ET older than 60 years.   
 
The choice of a platelet-lowering agent in younger 
patients who are at risk for thrombosis is currently a 
matter of controversy (Fenaux et al., Nand et al.). 
Anagrelide is an oral imidazoquinazolin derivative that is 
used to treat ET. Because anagrelide has an anticyclic 
AMP phosphodiesterase activity (and accordingly inhibits 
platelet aggregation in humans), the drug initially was 
tested for its potential use as a platelet antagonist.  
However, initial human studies at relatively low doses 
revealed a potent but reversible thrombocytopenic 
activity.  To date, this thrombocytopenic effect has been 
observed only in humans and occurs at plasma 


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concentrations that are much lower than those capable of 
inhibiting platelet aggregation.  Functional platelet 
abnormalities have not been observed with doses 
currently used to treat thrombocytosis. 
 
Most of the side-effects of anagrelide observed in 
humans and animals are cardiovascular and stem from 
the direct peripheral vasodilatory effect and positive 
inotropic activity of the drug.  The vas odilatory effect is 
believed to be the underlying cause of headache, which 
is the most frequent side-effect (occurring in more than 
one third of patients receiving treatment).  Other side-
effects related to the vasodilatory effect include fluid-
retention or edema (24%), dizziness (15%), and postural 
hypotension, occurring at high single-dose levels.  The 
cardiac effects include palpitations or forceful heart beats 
(27%), tachycardia and other arrhythmias (<10%), and 
congestive heart failure (2%).  Less common side-effects 
include diarrhea, abdominal pain, nausea and transient 
rash.  Rarely observed events with treatment have 
included hyperpigmentation of the lower extremity, 
pulmonary fibrosis, and abnormal liver function tests.  In 
one small study of 20 patients with ET treated with 
anagrelide, eight patients experienced side-effects and 
treatment with the drug was discontinued in six patients. 
Therefore, anagrelide therapy should be avoided in 
patients with heart disease, and the drug should be given 
carefully to elderly patients.  In addition, although 
anagrelide has no mutagenic activity, it is currently not 
advised for use during pregnancy (Anagrelide study 
group). 
 
3.1.2 
PV 
 
All patients with PV require phlebotomy, with the goal of 
keeping the hematocrit less than 45% in men and 42% in 
women.  This maneuver prolongs survival by decreasing, 
but not abolishing, the risk of thrombosis.  The residual 
risk of early thrombosis (33%) is reduced further by 
supplementing phlebotomy with myelosuppressive 
therapy (10%).  In contrast, the addition of chemotherapy 
has not been shown to decrease the risk of 
transformation into acute myeloid leukemia (< 2%) or 
myelofibrosis with myeloid metaplasia (9%) observed in 
patients receiving treatment with phlebotomy alone.  
Instead, some of the currently available 


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myelosuppressive agents have been shown to increase 
the risk of leukemic transformation to 11% (chlorambucil), 
8% (radiophosphorus), 7% (pipobroman), or 6% 
(hydroxyurea).  On the basis of these observations, 
hydroxyurea is currently recommended as a supplement 
to phlebotomy for patients with PV who are at risk for 
thrombosis. 
 
The goal of therapy in PV is not only to prevent 
thrombosis but also to reduce the risk of transformation 
into acute myeloid leukemia or AMM/MF.  As such, new 
therapeutic agents need to be explored in both ‘low-risk’ 
and ‘high-risk’ patients with PV.  ‘Low-risk’ patients with 
PV remain at an increased risk for thrombosis and 
transformation into acute myeloid leukemia or AMM/MF.  
Regardless, it currently is assumed that the risk-benefit 
ration favors treatment with phlebotomy alone in this 
group of patients.  Such an assumption may not hold true 
when the specific agents are considered that are less 
leukemogenic than alkylating agents or radiophosphorus 
(Silverstein et al.). 
 
In ‘high-risk’ patients with PV the decision to institute a 
myelosuppresive agent should take into account not only 
the potential benefit in preventing thrombosis but also the 
risk of inducing therapy-related acute myeloid leukemia 
and the possible negative impact on pregnancy. The 
leukemogenic potential of the currently preferred agent, 
hydroxyurea, appears to be lower than that of alkylating 
agents or radiophosphorus.  However, several studies 
have suggested that in comparison with phlebotomy 
alone, the long-term use of hydroxyurea may be 
associated with an increased risk of the development of 
myelodysplastic syndrome or acute myeloid leukemia.  
Therefore, in ‘high-risk’ patients younger than 60 years, 
interferon-α may be considered a reasonable alternative 
to hydroxyurea as a myelosuppresive agent.  Specifically, 
interferon-α may be considered for ‘high-risk’ young 
women who may be pregnant or are of childbearing age 
and for control of refractory pruritus. 
 
Anagrelide is a nonmyelosuppressive, selective platelet-
lowering agent.  The decrease in thrombotic risk 
associated with PV has been shown only with the use of 
myelosuppressive agents.  However, the degree of 
thrombocytosis has not been correlated with thrombotic 


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risk in PV.  Therefore, no theoretical rationale currently 
exists to encourage the use of anagrelide in PV (Berk et 
al.). 
 
3.2  
Interferon as a Therapeutic Agent in 
Myeloproliferative Diseases 
 
The precise mechanism of action of interferon-α in the 
chronic myeloproliferative disease has not been 
established clearly, but it largely appears to be the result 
of an antiproliferative effect on hematopoietic progenitor 
cells from which the abnormal clone arises.  Dose-
dependent suppression of progenitor cells has been 
demonstrated in vivo and in vitro and it affects both 
normal and clonal progenitors.  However, there is 
evidence for a selective action on clonal progenitor cells.  
In patients with ET treated with interferon-α, the decrease 
in platelet count has been associated with a significant 
decrease in the number and size of bone-marrow 
megakaryocyte progenitors (CFU-M).  Similarly, a 
significant decrease in erythroid (BFU-E) and 
granulocyte-macrophage (CFU-GM) progenitors was 
associated with the elimination of the need for 
phlebotomy in patients with PV treated with interferon-α.  
This synchronous decrease in both circulating mature 
hematopoietic cells and progenitor cells is consistent with 
an inhibitory effect on the progenitors as the mechanism 
of controlling thrombocytosis and erythocytosis (Partaneu 
et al.). 
 
Earlier work by our group at MDACC revealed that 
interferon-α could suppress excessive thrombocytosis in 
Ph-positive CML (Talpaz et al. 1983).  Subsequent 
reports confirmed the platelet-lowering activity of 
interferon-α in chronic myeloproliferative diseases.  
Numerous investigators have since reported on the 
therapeutic effects of interferon-α in ET.  These include 
platelet-reduction (up to 80% - 100% response rate), 
resolution of splenomegaly and control of disease-
associated symptoms.  Also, several authors have 
reported sustained, unmaintained remissions following 
discontinuation of long-term interferon-α therapy.  
Remission induction doses ranged from 3 to 5 million 
units per day given subcutaneously, with an average 
response time of 12 weeks.  Maintenance doses were 
lower, consistent with a decrease in bone-marrow 


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megakaryocyte mass seen with continuous interferon-α 
therapy.  Interferon-α is not know to be leukemogenic or 
teratogenic, and it does not cross the placenta.  
Consequently, treatment with interferon-α may be 
considered during pregnancy. 
 
Preliminary reports on interferon-α as a new therapy for 
PV appeared in the late 1980s.  Subsequent studies 
confirmed the benefits of interferon-α in PV, which 
include induction of complete hematologic remission (up 
to 70% - 80% response rate) and resolution of disease-
associated symptoms and/or splenomegaly.  It is now 
thought that interferon-α antagonizes the action of 
platelet-derived growth factor (PDGF) in addition to its 
direct effect on erythroid progenitors (Silver RT).  
Inhibition of PDGF may be effective in MF as well.  
Doses used to obtain these responses varied between 4 
and 27 million units subcutaneously per week, with an 
average maintenance does of 3 million units three times 
a week.  One of the major benefits of interferon-α therapy 
in PV has been the ability to control refractory pruritus 
(75% response rate) and to improve quality of life.  
Recent reports suggest that interferon-α may have the 
potential to suppress the abnormal clone in PV, 
analogous to its ability to induce cytogenetic remission in 
CML.  Eradication or suppression of the malignant clone 
has major implications for altering the natural history of 
PV, with its inherent risk of transformation into leukemia 
or myelofibrosis (Lewis et al.). 
 
Toxicity and cost are major obstacles to the use of 
interferon-α therapy.  The adverse dropout rate has been 
approximately 17% and 20% among treated patients with 
ET or PV, respectively.  Upon initiation of therapy, most 
patients experience a transient influenza-like syndrome 
associated with fever and chills, myalgias, headache, and 
arthralgias.  Premedication with acetaminophen is usually 
helpful in ameliorating these acute side-effects.  Chronic 
side-effects include fatigue, nausea, anorexia, weight-
loss, diarrhea, increased liver transaminase, altered 
mental status, and depression.  Also, the exacerbation or 
development of autoimmune disease, including 
autoimmune thyroiditis, immune-mediated hemolytic 
anemia or thrombocytopenia, and symmetric 
polyarthropathy in patients receiving long-term interferon-
α therapy has been described (Silver RT). 


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Early studies with the long acting pegylated interferon-α 
suggest that this agent induces significantly less side 
effects while it is probably more active. We conducted a 
pilot study of PEG-interferon α-2b (PEG Intron) in 
patients with ET.  Patients with a history of persistent 
(greater than 2 months) platelet counts > 600 x 109/L, 
with hyperplasia of bone marrow megakaryocytes in the 
absence of an alternate identifiable cause of 
thrombocytosis were eligible. Patients were required to 
have either thrombo-hemorrhagic signs and/or symptoms 
in a previously untreated patient; persistence of thrombo-
hemorrhagic signs and/or symptoms in a patient 
receiving anagrelide, interferon-α, or hydroxyurea; or 
intolerance to anagrelide, interferon-α, or hydroxyurea. 
The initial PEG-interferon α-2b dose was from 1.5 to 4.5 
µg/kg/week subcutaneously with subsequent dose 
adjustments as indicated by response and adverse 
events. Eleven patients (9 female, median age 54 years 
(range 26-69) were treated. PEG-interferon α-2b rapidly 
controlled platelet counts and resolved symptoms in all 
patients. The median duration of PEG-interferon α-2b 
therapy on study was 9 months (4-17). No patient had 
signs or symptoms of thrombosis or hemorrhage while on 
study. Ten (91%) patients were in CR after 2 months of 
therapy, 11 (100%) after 4 months. One patient 
discontinued therapy at 4 months because of persistent 
Grade 3 fatigue and a second at 5 months because of 
anxiety and depression.  Thus, we believe that PEG-
interferon α-2b has significant activity in patients with ET 
(Alvarado et al.) 
 
3.3  
Angiogenesis in Myeloproliferative Diseases 
 
The putative role of angiogenesis in the neoplastic 
phenotype was first described thirty years ago (Folkman). 
Over the last decade, advances in molecular, 
cytogenetic, and cellular techniques have highlighted the 
powerful prognostic and therapeutic implications of the 
angiogenic process as it relates to human malignancy.  
Most of the early work focused on identification, 
quantification, and implication of vascularity on the 
biology and clinical behavior of solid tumors 
(Scappaticci). More recently, malignant hematologic 
disorders have been studied and the importance of bone 
marrow vascularity (angiogenesis) on the natural history 


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and possible therapy of these diseases is beginning to 
emerge (Thomas, Kerbel and Folkman).   
 
One of the earliest reports describing the role of 
angiogenesis in a hematologic malignancy examined 
bone marrow from children with ALL (Perez-Ataye et al.). 
Median microvessel density was significantly higher in 
the bone marrow of patients with ALL compared to 
normal controls. Studies of microvessel density have 
been duplicated in patients with AMM/MF, CML, ET, 
acute myeloid leukemia (AML), myelodysplastic 
syndrome (MDS), and chronic lymphocytic leukemia 
(CLL): bone marrow from patients with these diseases all 
demonstrated statistically higher levels of vascular 
density compared with normal bone marrow (Thomas, Di 
Raimondo et al.).  
 
The molecular and cellular mechanisms responsible for 
the angiogenic process are becoming better understood. 
As a substitute for microvessel density, other surrogate 
markers are being explored, particularly serum or plasma 
levels of known angiogenic factors. Vascular endothelial 
growth factor (VEGF) remains one of the most potent 
positive regulators of endothelial cell proliferation that has 
been described.  New data suggest some overlap 
between endothelial and hematopoietic cells, and the 
possibility that angiogenic factors may also play a role in 
the growth and proliferation of hematopoietic cells 
(Kerbel and Folkman, Albitar). To understand the role of 
VEGF in the neoplastic process, studies have correlated 
serum levels in patients with a variety of solid human 
malignancies and clinical outcome (Scappaticci). Similar 
studies are emerging in patients with hematologic 
malignancies (Thomas, Albitar, Di Raimondo et al.).  For 
example, VEGF was first identified as a possible 
paracrine growth factor in patients with AML (Fiedler et 
al.), and was shown to be an independent predictor of 
outcome in patients with AML (Aguayo et al.). Our recent 
study found increased expression of VEGF in marrow 
cells from patients with CML and the high VEGF levels 
correlated with poor outcome of patient with chronic 
phase CML (Verstovsek et al.). In addition, we found high 
levels of VEGF receptor 1 and 2 in CML patients.  While 
levels of receptor expression did not correlate with any 
particular disease phase, there was a statistically 
significant correlation between higher levels of VEGF-R2 


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expression and prognosis.  These findings support 
VEGF-R2 over-expression as an independent prognostic 
indicator for shortened survival in patients with chronic 
phase CML.  Similarly, a number of studies found not 
only increased bone marrow microvessel density but also 
increased circulating angiogenic factors in other 
myeloproliferative diseases (ET, PV, MF) (Di Raimondo 
et al., Musolino et al.). Finally, the levels of circulating 
angiogenic factors are being used in the assessment of 
efficacy of anti-angiogenic therapy: for example, 
circulating levels of VEGF have been correlated with 
thalidomide’s efficacy in hematological diseases.   
 
Interferon-α has been shown to have antiangiogenic 
effects (reviewed in Kerbel and Folkman). The first 
evidence that interferon-α had anti-endothelial activity 
was reported in 1980 when it was found to inhibit the 
motility of vascular endothelial cells in vitro in a dose-
dependent and reversible manner, and subsequently 
found to inhibit angiogenesis in vivo. Experimental 
studies in mice showed that the anti-angiogenic efficacy 
of interferon-α is optimal at low doses and declines at 
higher doses. The first use of anti-angiogenic therapy in 
humans was in 1988 when pulmonary hemangiomatosis 
in 12-year old boy was successfully treated with daily low 
dose interferon-α. New blood-vessel growth in 
proliferating haemangiomas has been associated with 
increased expression of angiogenic factor called 
fibroblast growth factor (FGF) and interferon-α has been 
shown to downregulate FGF expression in human cancer 
cells. There is now evidence that interferon-α therapy in 
CML may be successful at least in part due to its 
antiangiogenic properties as angiogenic factors are 
suppressed in treated patients (Di Raimondo et al.). 
 
 
4.0 Background Drug Information 
4.1 Interferons 
 
The interferons are a family of naturally occurring, small 
proteins with molecular weights of approximately 15,000 
to 21,000 daltons.  Although first described by Isaacs and 
Lindermann (Isaacs et al.) as substances produced by 
virally infected cells that could induce resistance in other 
cells to lytic virus infections, they are produced and 
secreted by virtually all eukaryotic cells in response to 


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viral infections or to various biologic and synthetic 
inducers.  Three major classes of interferons have been 
identified: alfa, beta, and gamma.  These classes are not 
homogenous, and each may contain several different 
molecular species of interferon.  For example, at least 14 
genetically distinct human alfa interferons have been 
identified thus far. 
 
The genes for a number of these proteins have been 
cloned, and recombinant forms of interferon α, including 
interferon α-2a and interferon α-2b, have undergone 
extensive clinical investigation.  To date, interferon  has 
been approved in numerous countries for the treatment 
of chronic hepatitis B and C (CHC), hairy-cell leukemia, 
AIDS-related Kaposi’s sarcoma, condylomata acuminata, 
renal cell carcinoma, malignant melanoma, chronic 
myelogenous leukemia, basal cell carcinoma, non-
Hodgkin’s lymphoma, multiple myeloma, cutaneous T-
cell lymphoma (mycosis fungoides), chronic delta 
hepatitis and laryngeal papillomatosis.  Interferon α is 
also being used in combination with a multiplicity of 
chemotherapeutic agents in the investigational treatment 
of a variety of malignancies and in combination with 
ribavirin, amantadine, mycophenolate mofetil, and 
nonsteroidal anti-inflammatory drugs in the 
investigational treatment of patients with CHC. 
 
Current treatment regimens require frequent 
administration of interferon α.  Treatment intervals may 
range from three times per week to as often as once daily 
for periods of several months to a year or longer.  The 
frequency of interferon α administration is determined by 
therapeutic requirements of the disease (daily for certain 
oncology indications and three times weekly for virology 
indications) and the pharmacokinetic properties of the 
protein.  In various studies, the reported terminal 
elimination half-life for interferon α ranges from 4 to 10 
hours, with peak serum concerntrations occurring at 3 to 
8 hours following intramuscular or subcutaneous 
administration, there is little or no detectable interferon α 
remaining in the serum.  Thus, frequent administration of 
interferon α has been considered necessary for sustained 
efficacy.  Furthermore, treatment with interferon α results 
in several dose-dependent side effects that cause 
difficulties associated with frequent administration.  The 
typical acute toxicity profile that tends to occur after every 


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injection includes flu-like symptoms of fever, chills, 
headache, myalgia, and dizziness. 
 
4.2  
Rationale for Use of PEG IFN-α2a 
 
Subject compliance with daily interferon α dosing during 
the prolonged treatment course of therapy is an important 
factor for achieving clinical benefit.  In general, despite 
the absence of direct comparisons, anti-tumor efficacy 
appears inferior in those studies where the median 
interferon α dose delivered is less than 3.6 MIU/m2/day.  
Similarly, trials performed in Ph-positive CML suggest 
that an increased AUC, with associated prolonged tumor 
exposure to the interferon α effect, may be more critical 
than peak interferon α levels in mediating an anti-
leukemic effect.  Early discontinuation of interferon α due 
to toxicity could adversely affect a patient’s ability to 
achieve a response.   
 
If the same clinical benefit can be achieved with a long-
acting interferon α, the requirement for multiple injections 
will be reduced and result in great subject convenience.  
Given the pharmacokinetics and pharmacodynamics of 
PEG IFN-α2a and preliminary assessments of tolerability, 
PEG IFN-α2a may widen the therapeutic index for 
conventional interferon- and offer an improved risk 
benefit ratio. 
 
4.3  
PEG IFN-α2a 
 
PEGs are amphiphilic polymers of ethylene glycol of 
varying average molecular weights that can be covalently 
attached to proteins.  Modification of proteins with PEG 
has resulted in increased serum half-life and reduced 
immunogenicity for a number of proteins.  The properties 
of pegylated proteins vary with the number of PEG 
molecules attached per protein molecule and the 
structure (e.g., linear or branched) and average 
molecular weight of the PEG polymer.  A number of 
proteins used for patient therapy have now been modified 
with PEG and evaluated clinically.  All of these pegylated 
proteins have increased half-lives relative to the 
unmodified proteins.  Pegylated proteins are also less 
immunogenic or nonimmunogenic. 
 


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Hoffmann-La Roche has developed a modified form of 
interferon α-2a, pegylated interferon α-2a (PEG IFN-α2a, 
Pegasys), which is chemically modified by the covalent 
attachment of a 40K branched methoxy polyethylene 
glycol moiety. Compared with interferon α-2a, PEG-IFN 
α-2a exhibits sustained absorption, decreased systemic 
clearance, and an approximately tenfold increase in 
serum half-life. The biological activity of PEG IFN-α2a, as 
measured by 2,5-OAS activity, is similarly prolonged, 
resulting in a significantly improved pharmacodynamic 
response compared with interferon α-2a. 
Pharmacokinetic and pharmacodynamic data obtained 
from animals (rat and monkey), phase I studies in healthy 
volunteers, and phase II and III studies in patients with 
chronic hepatitis C (CHC) indicate that PEG IFN-α2a 
injected once a week has the potential for superior 
efficacy as compared with interferon α-2a injected three 
times a week. The adverse effect profile to date is similar 
to that observed with interferon α-2a. A phase I 
ascending dose study in patients with renal cell 
carcinoma has been completed, and the dose being used 
in the phase II study is 450  µg. Enrollment in a phase I 
study in patients with Ph-positive CML has been 
completed. Although a true MTD was not reached, the 
dose used in phase III CML study was also 450 µg. 
 
4.4  
Pharmacokinetics of PEG IFN-α2a 
 
The structure of the PEG moiety directly affects the 
clinical pharmacology of PEG-IFN α-2a. Specifically, the 
size and branching of the 40 kDa PEG moiety define the 
absorption, distribution, and elimination of PEG-IFN α-2a.  
The pharmacokinetics of PEG-IFN α-2a were studied in 
healthy subjects and hepatitis C infected patients.  
Absorption of PEG-IFN α-2a was sustained, peak serum 
concentrations were reached 72 to 96 hours after dose 
administration, and measurable concentrations were 
seen within 3 to 6 hours of a single dose.  Dose 
proportional increases in AUC and Cmax were seen in 
patients who received once weekly doses of PEG-IFN α-
2a.  The absolute bioavailability was 84% and was similar 
to that seen with IFN α-2a. 
 
The systemic clearance was about 100 mL/h, which was 
100-fold lower than that of interferon α-2a.  After an 


DM03-0109 
September 16, 2019 
Page 14 
intravenous dose, the terminal half-life was about 60 
hours, compared to 3 to 4 hours for standard interferon.  
The terminal half-life after subcutaneous dosing was 
longer (about 80 hours, range of 50 to 140 hours).  After 
intravenous dosing, the steady-state volume of 
distribution was 6 to 14 liters.  Based on studies in rats, 
the drug is distributed to the liver, kidney, and bone 
marrow as well as being highly concentrated in the blood. 
 
Metabolism is the main clearance mechanism for PEG-
IFN α-2a. The kidneys eliminated less than 10% of a 
dose as the intact PEG-IFN α-2a.  The metabolic profile 
of PEG-IFN α-2a has not been fully characterized.  
Studies in rats showed that the PEG moiety remained 
attached as the protein portion was metabolized. The 
metabolic products of PEG-IFN α-2a (including the PEG 
moiety attached to the metabolized interferon) were 
excreted in the urine and bile.  In rats, the half-life of the 
radiolabeled PEG moiety was about 10 days and, thus, 
within about 40 days the PEG moiety was eliminated 
from the body. 
 
In patients with CHC, steady-state serum concentrations 
increased twofold to threefold compared with single-dose 
values and reached steady state within 5 to 8 weeks of 
once weekly dose administration. Once steady state was 
achieved, there was no further accumulation of PEG-IFN 
α-2a.  The peak to trough ratio after 48 weeks of 
treatment was about 1.5 to 2.0.  PEG-IFN α-2a serum 
concentrations were sustained throughout the 1-week 
dose interval (168 hours). 
 
4.5  
Preclinical Studies with PEG IFN-α2a  
 
The pharmacologic and immunomodulatory properties of 
PEG IFN-α2a relative to those of interferon α-2a were 
evaluated in both in vitro and in vivo studies. Since the 
biological activity of interferon α-2a is species restricted, 
these studies were performed using cells (bovine, 
human) or animals (cynomolgus monkeys) in which 
interferon α-2a is active. The following were the main 
observations: 
 
• 
PEG IFN-α2a  retains both the antiviral and 
antiproliferative activities of unmodified 


DM03-0109 
September 16, 2019 
Page 15 
interferon α-2a, although usually with lower 
specific activity. 
• 
PEG IFN-α2a  causes less of an immunogenic 
response in mice than interferon α-2a. 
• 
PEG IFN-α2a  is immunogenic in monkeys, as 
was anticipated based on the immunogenicity of 
interferon α-2a in monkeys, but this observation is 
not considered predictive of the immunogenic 
potential of PEG IFN-α2a  in humans. 
 
The antiproliferative effects of PEG IFN-α2a and 
interferon α-2a were compared in an in vitro assay 
against a series of tumor cell lines, including a CML line 
(K562), four renal cell carcinoma cell lines (ACHN, A-
498, G-402 and Caki-1), and four malignant melanoma 
cell lines (HS-294-T, A-375, SK-MEL-28 and SK-MEL-3). 
The data demonstrate that PEG IFN-α2a  maintains 
antiproliferative activity against this range of human 
tumor cells. As in vitro models cannot account for the 
pharmacokinetic advantage of PEG IFN-α2a, the most 
appropriate assessment would be in vivo models, in 
which this potential benefit of the molecule should be 
observed. The in vivo antitumor effects of PEG IFN-α2a  
were evaluated in nude mice bearing human tumor 
xenografts. Nude mice were injected with tumor cells 
subcutaneously and tumors were allowed to grow until 
well-established tumors were present. Treatment with 
either PEG IFN-α2a  once per week or unmodified 
interferon α-2a three times per week was administered sc 
in the opposite flank from the tumor for 4 to 6 weeks. The 
total weekly doses for PEG IFN-α2a and interferon α-2a 
were equivalent. In A-498–bearing nude mice, treatment 
with 100 g of interferon α-2a three times per week 
significantly inhibited growth of this tumor compared with 
untreated controls. In animals treated with 300 µg 
(measured as micrograms of interferon α-2a) of PEG 
IFN-α2a once per week, PEG IFN-α2a was more active 
than interferon α-2a in inhibiting tumor growth and also 
resulted in tumor regression. In similar experiments using 
two other renal cell carcinoma cell lines (ACHN and Caki-
1), a clear trend toward increased activity of PEG IFN-
α2a over interferon α-2a was found but without the 
statistical significance seen with A-498. In conclusion, 
PEG IFN-α2a shows marked antitumor activity when 


DM03-0109 
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administered to nude mice bearing human renal cell 
carcinoma tumor xenografts.  
 
4.6  
Clinical Studies in Healthy Volunteers 
 
PEG IFN-α2a  was administered by subcutaneous 
injection to 92 healthy volunteers in a phase I double-
blind study. Volunteers received single ascending doses 
of 45, 135 or 270 µg of PEG IFN-α2a or 3 MIU (15 µg) or 
18 MIU (90 µg) of unmodified interferonα -2a. Results 
showed that: 
 
• 
PEG IFN-α2a had a more favorable 
pharmacokinetic profile than interferon α-2a, with 
decreased clearance and a serum t½ 
approximately 10-fold higher. 
• 
PEG IFN-α2a had an improved pharmacodynamic 
profile as compared with interferon α-2a, as 
measured by a prolonged elevation of 2’5’-
oligoadenylate synthetase following single-dose 
administration.  
• 
The safety and tolerability profiles of PEG IFN-α2a  
are similar to those of interferon α-2a. Neutropenia 
was more frequent and more marked in PEG IFN-
α2a  treated patients, but neutrophil counts 
recovered in all cases in less than two weeks 
following drug administration. 
 
4.7 Clinical Studies in Chronic Hepatitis C (CHC) 
 
In a phase II dose-finding study in patients with non-
cirrhotic CHC, doses of 45, 90, 180 and 270 µg of PEG 
IFN-α2a once weekly vs 3 MIU interferon α-2a tiw were 
evaluated in an ascending dose design. The side effect 
profile was similar to the adverse events observed with 
interferon α-2a, and a dose of 180 µg has been found 
acceptable in patients with CHC. At the 270 µg dose 
level, 18 of 40 patients required dose modification; 
however, for patients with CHC a neutrophil count of less 
than 1.0 x 109 /L was considered dose limiting. There 
were no cases of neutropenic sepsis. A second phase II 
study has been conducted in 268 cirrhotic patients, and 
two phase III studies in 1170 patients with CHC have 
been completed; all studies used Roferon-A as a 
comparator. In total, data have been generated in 995 
hepatitis patients treated with doses of 45 µg (20 pts), 90 


DM03-0109 
September 16, 2019 
Page 17 
µg (116 pts), 135 µg (215 pts), 180 µg (604 pts), or 270 
µg (40 pts) PEG IFN-α2a. Results showed that: 
 
Results from a Phase II PEG IFN-α2a ascending dose 
study confirm the optimal dose of PEG IFN-α2a for the 
treatment of CHC to be 180 µg once weekly.  Sustained 
virologic response was 36% in CHC patients without 
cirrhosis treated with this dose.  These results also 
confirm significant improvements in liver histology for 
patients treated with either PEG IFN-α2a or standard 
interferon α2a  therapy.  Pharmacokinetic data from a 
Phase III multinational study further support the once 
weekly 180 µg dose of PEG IFN-α2a for the treatment of 
CHC. 
 
Results from a Phase II PEG IFN-α2a pharmacokinetics 
study confirm the feasibility of similar once-weekly PEG 
IFN-α2a dosing in CHC patients with cirrhosis as in 
healthy volunteers and noncirrhotic hepatitis C patients.   
 
One Phase III PEG IFN-αa study reports virologic 
sustained responses of 39% in CHC patients without 
cirrhosis (28% in CHC patients with Genotype 1 infection) 
when treated with 180 g PEG IFN-α2a once weekly for 
48 weeks.  A second Phase III study reports virologic 
sustained responses of 38% in previously untreated CHC 
patients with or without cirrhosis treated with either 135 g 
or 180 g of PEG IFN-2a once weekly for 48 weeks.  
Sustained virologic response among CHC patients with 
Genotype 1 infection were 22% and 19% following 180 g 
and 135 g of PEG IFN-α2a once weekly for 48 weeks, 
respectively. Additionally, histologic improvement 
(defined as  2-point improvement from baseline on post-
liver biopsy) occurred in 58% and 48% of patients treated 
once-weekly with 180 g and 135 g of PEG IFN-α2a, 
respectively. 
 
A Phase II/III PEG IFN-α2a study reports virologic 
sustained responses of 30% in difficult-to-treat CHC 
patients with cirrhosis when treated with 180 µg PEG 
IFN-α2a once weekly for 48 weeks.  Study results also 
confirm statistically significant improvements in both liver 
histology and quality of life for patients treated with 180 
µg PEG IFN-α2a when compared with standard 
interferon α2a therapy. 


DM03-0109 
September 16, 2019 
Page 18 
 
The overall frequency and types of adverse events, 
laboratory abnormalities and drug discontinuations 
reported during a 48-week course of PEG IFN-α2a 
therapy administered once weekly, appear similar to that 
of a 48-week course of interferon α2a therapy 
administered three times a week.  Adverse events 
included fatigue, headache, myalgia, arthralgia, flu-like 
symptoms, nausea, vomiting, injection site reactions, 
fever, chills, diarrhea, alopecia, abdominal pain, 
depression, irritability, insomnia, rigors, dizziness and 
anorexia. Laboratory abnormalities included neutropenia, 
thrombocytopenia, abnormal ALT values, hypothyroidism 
and hyperthyroidism. The incidence of premature 
withdrawals for adverse events and laboratory 
abnormalitites were similar between the PEG IFN-α2a 
dose groups and the interferon α-2a group 
(approximately 10%).  
 
4.8 Clinical Studies in Renal Cell Carcinoma (RCC) 
 
A phase I/II dose-finding study in advanced or metastatic 
RCC is fully recruited. Twenty-seven patients had been 
entered into the phase I portion of this study and dosed in 
cohorts of six patients with once weekly PEG IFN-α2a 
180 µg, 270 µg, 360 µg, 450 µg or 540 µg. Dose limiting 
toxicities occuring at 540 µg PEG IFN-α2a included 
elevated liver transaminases (1 patient with grade 3 
ALT), and fatigue (1 patient with grade 3 fatigue). For this 
reason, the MTD was determined to be 540 µg, and the 
dose chosen to be taken forward into further 
development is 450 µg, which has been well tolerated for 
3 months or more. Forty additional patients have now 
been entered into the Phase II portion of the study at the 
dose of 450 µg. Three patients have stopped treatment 
for safety reasons: thrombocytopenia (180 µg), increased 
alkaline phosphatase (450 µg) and GI 
bleeding/sepsis/seizure, unrelated to treatment (450 µg). 
Most patients in the RCC study are tolerating PEG IFN-
α2a well. The types of adverse events have been similar 
in nature to that of unmodified α-interferons. Adverse 
event reports are available for 66 patients, and the most 
frequently occurring (>5%) adverse events include: 
fatigue, fever, chills, myalgia, nausea, headache, 
decreased appetite, back pain, dizziness and diarrhea. 
Changes in laboratory values have generally been mild to 


DM03-0109 
September 16, 2019 
Page 19 
moderate, and are consistent with those expected with 
the use of alpha interferons. The most important 
laboratory abnormalities have been elevations in 
transaminase levels, ranging from minor increases to 
grade 3 ALT elevations experienced by three patients in 
the highest dose group tested. These elevations have 
returned to near baseline either on treatment or after 
holding a dose. Other laboratory abnormalities include 
mild to moderate decreases in white cells, neutrophils, 
lymphocytes, platelets and hemoglobin over the first few 
weeks of treatment. The only notable instance of 
hematological toxicity is one patient who experienced 
neutropenia and developed pneumonia beginning on the 
third day after the first 180 µg PEG IFN-α2a injection. 
Twenty-seven patients have discontinued treatment due 
to progressive disease. Efficacy assessments are 
available from the first 27 patients entered in the study. 
Five of the 27 phase I patients have demonstrated 
confirmed partial response (18.5%); 12 patients 
completed the 6-month study and 10 continued treatment 
in a maintenance phase. 
 
4.9 
 
Prior Clinical Experience with PEG IFN-α2a in 
Hematological Diseases 
 
4.9.1 
Safety of PEG-IFN -α2a in the Treatment of 
Ph-positive CML:  Study NO15764 
 
Study NO15764 is a phase I, open-label, nonrandomized, 
dose-escalation trial of the safety and efficacy of PEG 
IFN-α2a in Ph-positive CML.  A total of 43 patients 
received either PEG-IFN α-2a monotherapy (three at 270 
µg and six each at 360, 450, 540 or 630 µg) or PEG-IFN 
α-2a plus cytosine arabinoside (ara-C) combination (six 
at 450 µg of PEG-IFN α-2a plus 10 mg of ara-C, six at 
540 µg of PEG-IFN α-2a plus 10 mg or ara-C, and four at 
540 µg of PEG-IFN α-2a  plus 20 mg of ara-C).  The 
PEG-IFN α-2a doses were given once weekly.  The ara-C 
doses were given daily.  However, for patients in the 540-
µg PEG-IFN α-2a plus 20-mg ara-C group, ara-C was 
given only on 10 days a month. 
 
All patients from all treatment groups had one or more 
adverse events.  The types of adverse events were 
similar to those seen with α-interferons.  The most 
frequently observed adverse events included fatigue, 


DM03-0109 
September 16, 2019 
Page 20 
headache, rigors, myalgia, decreased appetite, diarrhea, 
nausea, night sweats, pyrexia, and injection site pain or 
irritation. 
 
As of November 20, 2001, four patients had died.  One 
patient treated with 450 µg of PEG-IFN -α2a died of 
lymphoma.  The reasons for the other three deaths (one 
from the PEG-IFN -α2a 270-µg group and two from the 
PEG-IFN -α2a 630-µg group were not specified.  These 
three deaths occurred 5, 14, and 16 months after 
treatment ended, and were assumed to had been related 
to the underlying disease. 
 
A total of 19 serious adverse events were reported in 13 
patients.  All treatment groups had at least one patient 
who experienced a serious adverse event.  The serious 
adverse events that were reported included 
thrombocytopenia, transfusion reaction, gastroenteritis, 
herpes simplex, viral infection, unevaluable reaction 
(pregnancy in spouse), pyrexia, device failure, hernia 
repair, lymphoma, dehydration, diarrhea, liver fatty, blood 
bilirubin increased, weakness, pleuritic pain, and 
atherosclerosis.  About two-thirds of the serious adverse 
events were possible, probably, or remotely related to the 
study drug and usually needed dose reduction or, in a 
few cases, premature treatment discontinuation.  
However, most of these serious adverse events resolved 
without sequelae. 
 
A total of 12 patients withdrew from the study for safety-
related reasons.  Four of the six patients with 540 µg of 
PEG-IFN α-2a plus 10 mg of ara-C withdrew, while none 
of the patients treated with 360 µg of PEG-IFN or 540 µg 
of PEG-IFN α-2a plus 20 mg of ara-C withdrew for safety 
related reasons.  One or two patients from each of the 
remaining treatment groups withdrew for safety-related 
reasons.  Of the 12 patients whose treatment was 
discontinued prematurely for safety reasons, eight 
patients were withdrawn for adverse events including 
irritation of the buccal mucosa, lymphoma, mucositis and 
pruritic rash, fatigue, leg pain, neuropathy, and weakness 
of the lower extremities; and four patients were 
withdrawn for laboratory abnormalities including 
thrombocytopenia, elevated liver enzymes, abnormal 
liver function tests, and elevated bilirubin. 
 


DM03-0109 
September 16, 2019 
Page 21 
4.9.2 
Safety of PEG-IFN α-2a in the Treatment of 
Ph-positive CML:  Study NO16006 
 
Study NO16006 is a phase III, randomized, open-label, 
parallel-arm, multicenter trial comparing the efficacy and 
safety of PEG-IFN α-2a and interferon α-2a in patients 
with recently diagnosed Ph-positive CML never treated 
with interferons.  Patients have been randomly assigned 
to receive subcutaneous injection of either 450 µg of 
PEG-IFN α-2a once weekly or 9 MIU of interferon α-2a 
daily (titrated upward from a starting dose of 3 MIU daily) 
for up to 12 months.  Responders to treatment may 
continue treatment for an additional year.  As of 
November 19, 2001, 71 and 74 patients who received 
PEG-IFN α-2a and interferon α-2a, respectively, had 
safety data available. 
 
Eight-five percent and 77% of patients treated with PEG-
IFN α-2a and interferon α-2a, respectively, had one or 
more adverse events.  The most common adverse 
events from both treatment groups were similar to those 
seen with interferon treatment, such as pyrexia, myalgia, 
fatigue, rigors, diarrhea, nausea, arthralgia, headache, 
appetite decreased, and anorexia.  Most of these events 
occurred more frequently in the PEG-IFN α-2a-treated 
patients than in the interferon α-2a-treated patients. 
 
Two patients from each treatment group have died.  
CML, aggravated general condition, and thrombotic 
thrombocytopenic purpura each led to the death of one 
patient.  The reason for the fourth death was not 
specified. 
 
Fourteen percent of patients treated with PEG-IFN α-2a 
and 15% of patients treated with interferon α-2a had 
experienced serous adverse events.  About one-third of 
the reported serious adverse events were possibly, 
probably, or remotely related to the study drug and 
required dose reduction or premature treatment 
discontinuation.  However, most of these serious adverse 
events resolved without sequelae.  For the PEG-IFN α-
2a-treated patients, serious adverse events were 
reported more often as general disorders and disorders 
of blood and the lymphatic system; for the interferon α-
2a-treated patients, serious adverse events were 
reported more often as general disorders, 


DM03-0109 
September 16, 2019 
Page 22 
musculoskeletal, connective tissue, and bone disorders, 
and cardiac disorders. 
 
Six PEG-IFN α-2a-treated patients (8%) and eight 
interferon α-2a-treated patients (11%) withdrew because 
of adverse events or laboratory abnormalities.  For the 
PEG-IFN α-2a treatment group, the safety reasons for 
patient withdrawal included acute hip pain, 
thrombocytopenia, very high WBC counts, and low 
neutrophil and platelet counts and low hemoglobin 
concentration.  For the interferon α-2a treatment group, 
the safety reasons for patient withdrawal included 
myalgia, depression, anaphylaxis, femoral head necrosis, 
and positive chest x-ray and flu-like syndrome. 
  
4.10 
Rationale for Dosage Selection 
 
The PEG-IFN dose for this phase II study has been 
selected based on safety results, the maximum tolerated 
dose (MTD) determined in the phase I study in patients 
with  Ph-positive CML, in combination with ara-C (Talpaz 
et al. 2000), and a minimum of 3 months safety data from 
the patients taking the projected phase III dose. In the 
phase I RCC study, the MTD was 540 µg, therefore the 
dose used in the phase II portion of that study is 450 µg. 
Patients in the phase I CML study have shown 
neutropenia and elevated transaminases starting at 540 
µg, although a formal MTD has not been declared, even 
at the dose of 630 µg. When given once weekly, 450 µg 
of PEG-IFN α-2a is the dose that is considered to deliver 
the best balance between 
immunostimulatory/antiproliferative effect and long-term 
tolerability.  To increase safety of the medication, the 
starting dose, will be 90µg and may be increased to 
doses of 180µg, 270µg, 360µg, and 450µg provided 
patients do not experience significant side effects. 
 
4.11 
Update of study results as of 01/15/2009 and 
plans 
 
At present the study has accrued 40 patients with PV and 
36 patients with ET.  Most patients had extensive prior 
therapies with hydroxurea and anagrelide and all 40 
patients with PV had phlebotomies.  With a median 
folllowup of 24 months on Pegasys therapy, the overall 
hematologic repsonse rate was 81% with PV (complete 


DM03-0109 
September 16, 2019 
Page 23 
in 78%) and 92% with ET (complete in 86%).  These 
results are the best ever achieved with any form of 
therapy in PV and ET.  In addition, measuring JAK2 
V617F mutations, we observed complete molecular 
responses in 12% of patients and any molecular 
response in 53% of patients.  Side effects were 
accetable.  At the Pegasys dose of 90 mcg weekly Grade 
3 neutropenia was observed in only 8% of patients and 
other side effects (fatigue, dizziness, depression) in only 
4% of patients each.  These findings are a true 
therapeutic breakthrough in the managment of PV and 
ET and have been also reproduced by investigators in 
France (Kiladjian et.al Blood 112;3065,2008) who 
reported with Pegasys therapy in 40 patients with PV a 
CHR in 78%, a complete molecular response in 24%, 
and a major molecular response in 69%.   
 
Hoffman-LaRoche, the Company, declined to expand the 
study and provide free drug.  Our results suggest this is 
the best available treatment for these patients.  We would 
like to expand the study and continue therapy  with 
Pegasys commercial preparation.  We propose to include 
up to 100 patients with PV and 100 patients with ET.  
This will allow a more precise estimate of hematologic 
and molecular response with long term follow up, a better 
estimate of long term survival and toxicity profiles, and a 
treatment of patients on protocol which affords better 
care by our leukemia experts and allows future analyses 
of data in a large cohort including an evaluation of 
prognostic factors that determin molecular response and 
long term outcome.  Our data was presented at ASH 
2008 (Quintas-Cardama, Blood 112:653, 2008). 
 
 
Update September, 2019 
Sixteen patients remain on study for a median of 12 
years (range 11 - 13).  All patients are on a stable dose 
of pegylated interferon with normal blood counts.  None 
of the patients have experience drug-related adverse 
reactions in 9  years.  Changes in the protocol reflect 
standard of care monitoring of patients in long term 
complete hematologic remission.  This study represents 
the longest follow up of patients with ET or PV treated 
with pegylated interferon. 
 


DM03-0109 
September 16, 2019 
Page 24 
 
5.0 Patient Eligibility Criteria 
5.1 Inclusion Criteria 
 
• Following diagnoses:  
 
--ET:  Patients with PLT > 600 x109/l documented 
in the past 12 months; hyperplasia of 
marrow megakaryocytes in the absence of 
identifiable cause of thrombocytosis and in 
the absence of Ph chromosome. Patients 
with ET and lower PLT will be eligible if 
attributable to prior ET therapy. 
--PV: Patients should have Hb >/= 15g/dl (except 
if patient is having phlebotomies done or is 
taking hydroxyurea)  and documented past 
diagnosis 
 
• Performance status < 2 (ECOG scale; see Appendix 
A). 
• Age greater than 18 years since disease is extremely 
rare in younger age group. 
• Adequate liver function: total bilirubin of < 2.0 mg/dl  
(except for patients with Gilbert’s Syndrome) and 
AST (SGOT) or ALT (SGPT) < 3 X ULN (or < 5 X 
ULN if considered due to tumor), and renal 
function (serum creatinine < 2.0 mg/dl) 
• Signed informed consent indicating that patients are 
aware of the investigational nature of this study in 
keeping with the policies of the M.D. Anderson 
Cancer Center.  The only acceptable consent form 
is the one approved by the M.D. Anderson Cancer 
Center IRB.  
• Willingness and ability to comply with the 
requirements of the protocol for the duration of the 
study. 
• Patients must have been off chemotherapy for 1 week 
prior to beginning Pegasys and have recovered 
from the toxic effects of that therapy.  Patients 
may have received hydroxyurea or anagrelide 
immediately before study entry, and may continue 
into therapy if treating physician determines that 
this is in the best interest of the patient. 
 
5.2 Exclusion Criteria 
• Pregnant or lactating women. 


DM03-0109 
September 16, 2019 
Page 25 
• Patients with prior history of another malignancy or 
concurrent malignancy, except for the following: 
basal cell carcinoma of the skin, carcinoma in situ 
of the cervix, or other malignancies if the patient is 
disease free >3 years. 
• Patients with history of ischemic retinopathy. 
• 
Patients with history of severe cardiac disease: 
NYHA Functional Class III or IV, myocardial 
infarction within 6 months, uncontrolled ventricular 
tachyarrythmias or unstable angina. 
• 
Patients with history of medically significant 
psychiatric disease if not controlled, especially 
endogenous depression (does not include reactive 
depression post-cancer diagnosis), psychosis and 
bipolar disease. 
• Patients with seizure disorders requiring 
anticonvulsant therapy. 
• 
Patients with known infection with HBV, HIV, or 
other active systemic infection. 
• Patients with known autoimmune disease except for 
rheumatoid arthritis. 
• Patients with renal disease on hemodialysis. 
• 
Patients taking continuous or chronic high-dose 
systemic steroids; if discontinued, there must be a 
minimum washout period of one month before 
study drug is begun. 
• 
Patients with known hypersensitivity to PEG-IFN 
α-2a or its components. 
 
6.0 Treatment Plan 
6.1 Start of Therapy 
 
This is a Phase II (activity), non-randomized, open-label 
study. All patients will be registered  in the Clinical 
Oncology Research Database (CORE) at MD Anderson 
Cancer Center after the informed consent is signed. 
Medication will be dispensed to patients from MD 
Anderson Pharmacy. 
 
• PEG-IFN α-2a will be given subcutaneously once 
weekly and may be self-administered. 
• Starting dose of PEG-IFN α-2a is 90 micrograms 
subcutaneously weekly. 
• Treatment will be given as long as it benefits the 
patient (see section 9.1) 
 


DM03-0109 
September 16, 2019 
Page 26 
The patient may be given the first injection in the clinic or 
may be taught self-injection techniques for self-
administration at home, if the patient and investigator feel 
comfortable with this arrangement. Patients not able to 
return to MD Anderson Cancer Center  for injection 
teaching may receive teaching from their local physician.  
Prior to receiving multi-dose vials, patients local 
physician will be provided with a letter explaining the 
teaching needs of the patients along with a teaching 
documentation form (see appendix I).The teaching 
documentation form must be completed and returned to 
MD Anderson Cancer Center prior to the patient 
receiving study drug in multi-dose vials. PEG-IFN α-2a 
will be provided as either ready-to-use solution in single 
use glass vials or as multi-dose vials. Contents require 
no mixing before use.  
 
6.2 Dose Escalation and Dose Reduction 
 
 
Dose Level 
Dose of Pegasys in micrograms SQ 
weekly 
+4 
450 mcg 
+3 
360 mcg 
+2 
270 mcg 
+1 
180 mcg 
0(starting dose) 
90 mcg 
-1 
45 mcg 
-2 
45 mcg every other week 
 
 
Any patient who experiences grade 1 or 2 adverse event 
(see NCI-CTC guidelines, appendix C) should be 
maintained on the assigned dose if possible. Treatment 
should be put on hold if a patient experiences any of the 
following: 
 
 
• grade 3-4 laboratory abnormalities 
• grade 3-4 constitutional toxicity  
 


DM03-0109 
September 16, 2019 
Page 27 
 
Dose adjustments may be made at the discretion of the 
treating physician. 
 
Questionable cases should be resolved by clinical 
judgment of the investigator. 
 
7.0 Pretreatment evaluation 
The pre-treatment evaluation will be aimed at 
confirming/establishing the diagnosis.  The evaluation will 
consist of a through assessment of the following  tests: 
and will be done within a month of enrollment in the study 
(unless noted otherwise): 
 
•A complete primary evaluation with physical 
examination 
•CBC, platelet counts, differential 
•Serum creatinine, bilirubin, SGPT 
•Pregnancy test (if of child bearing potential) 
•Βone marrow aspiration and biopsy; cytogenetic studies; 
if not done in the last 3-6 months  
 
 
 
 
8.0 Evaluation During Study 
• 
Follow up visits at MD Anderson every 3-6 months 
with review of symptoms and physical exam for 
the first year, then every 6-12 months and 
thereafter approximately once yearly or at the 
discretion of the treating physician.  
 
• 
CBC, platelets, differential, creatinine, bilirubin, 
and SGPT are recommended  twice per year or at 
the discretion of the treating physician. 
 
• 
Thyroid function tests are recommended once per 
year or  at the discretion of the treating physician. 
• 
Bone marrow aspiration and biopsy every 3-6 
months during the first year, then if needed; 
cytogenetics once when in complete remission if 
abnormal prior to therapy.  
 
 
 
 
8.1 Monitoring of Patients on Study 


DM03-0109 
September 16, 2019 
Page 28 
 
Patient will be given instructions and the M.D. Anderson 
contact name (principal investigator/MD Anderson 
Leukemia staff treating physician), phone, and fax 
numbers.  The patient’s local doctor will be identified, 
contacted, and the protocol details discussed. 
 
All therapy will be given under the care of the patient’s 
local doctor and MD Anderson Leukemia staff treating 
physician. The patient’s local doctor should contact the 
MD Anderson Leukemia staff treating physician before 
any dose modifications are considered, and the 
modifications should be initiated only by the MD 
Anderson Leukemia staff treating physician or principal 
investigator, and complications will be dictated at each 
follow-up visit. 
 
From past experience, it is recognized that treatment 
provided in collaboration with patient’s local doctor 
outside MD Anderson may occasionally result in some 
difficulties such as 1) not performing tests as required, 2) 
not sending results of tests or updates of patient courses, 
3) and not informing on toxicities and hospitalizations. 
This type of therapy is already broadly practiced in the 
community. Therefore: 1) we will discuss with the 
patient’s local doctor about the protocol and doses, 2) we 
will make significant efforts (contact at least twice and 
document) to retrieve the information (tests, toxicities, 
hospitalizations), and 3) we will document all the 
information on follow-up visits.  Since information may 
still be missing in one or more components in some 
patients (e.g. missing CBC or SMA-7, missing drug 
administration record), these types of difficulties will be 
collected and documented in the patient’s medical 
record. This will reflect the oncology community practice 
of the program. 
 
9.0 Criteria for Response and Toxicity 
9.1 Criteria for Response 
 
9.1.1 
ET 
CR = Reduction of PLT to <440x109/l and disappearance 
of thromboembolic events, without the use of anagrelide 
or hydroxyurea 
 


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PR = Reduction of PLT by 50% but still >440x109/l or 
reduction of thromboembolic events by 50%, without the 
use of anagrelide or hydroxyurea 
 
9.1.2 
PV 
CR = Normalization of Hb (< 15.0g/dl), no phlebotomies 
needed, and disappearance of splenomegaly by 
palpation, without the use of anagrelide or hydroxyurea 
 
PR = A 50% reduction in phlebotomies rate or 
splenomegaly reduced by 50% by palpation, without the 
use of anagrelide or hydroxyurea 
 
9.2 Toxicity 
 
 
 
10.0 Criteria for Removal from the Study 
Subjects have the right to withdraw from the study at any 
time for any reason. An excessive rate of withdrawals 
can render the study uninterpretable; therefore, 
unnecessary withdrawal of subjects should be avoided. 
Should a subject decide to withdraw, all efforts will be 
made to complete and report the observations as 
thoroughly as possible. Criteria for discontinuation of 
therapy include: 
 
• 
Clearly documented progressive disease 
(increasing requirement for blood transfusion, 
increasing spleen size, increasing platelet or white 
blood cell count, increasing frequency of 
phlebotomies, or frequency of thromboembolic 
events) or no response  (see section 9.1) within 6 
months from the start of the therapy on a given 
dose (i.e. continuously on the same dose level of 
PEG-IFN α-2a). Caution: Patient without response 
after 3 months on a given dose should have the 
dose escalated if possible (see section 6.2); if no 
response when on the escalated dose for 6 
months, then therapy should stop. 
• Severe toxicities not responding to dose adjustments 
(see section 6.2) 
• Non-compliance to protocol requirements (see section 
5.0) 


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• 
Development of other conditions for which, in the 
Investigator’s opinion, it is in the subject’s best 
interest to be withdrawn from the study. 
 
11.0 Statistical Considerations 
11.1 
This is a phase II trial of  PEG IFN-a2a 
(Pegasys®) as a treatment for ET and PV.  In each 
disease, a response rate of 35% or more would be 
accepted as evidence for a good efficacy to be further 
pursued in this disease subsets in larger randomized or 
combination studies.  Therefore, in each disease 
category, the study will stop if response is 07, < 1/11, 
<2/15.  Otherwise it will accrue 80 patients to better 
define the response and toxicity profiles.  Also, in the 
total study group, a severe toxicity rate of <20% is 
allowed.  Therefore, the study will also stop if severe 
toxicity is observed in >7/15, 11/30, 15/45. 
 
11.2 
Update of statistical considerations as of 
1/15/2009 
 
Experience in 76 patients has shown very high response 
rates of 78% to 86% in ET and PV.  This expansion of 
the study is to provide patients with the best available 
treatment, Pegasys, at an optimal dose schedule, in the 
context of a study using the commercial drug.  Up to 100 
patients with ET and 100 patients with PV will be treated.  
This will allow for 1) a large scale capture of more precise 
response data (hematologic, molecular), 2) detailed 
analysis of side effects, 3) evaluation of longer term 
prognosis and survival, and 4) analysis of potential 
prognostic factors associated with molecular response.  
Such analyses will be conducted using standard 
analytical methods. 
 
12.0 Reporting Requirements 
 
 
 
12.1 
Serious Adverse Events will be reported per institutional 
policy.  Adverse events will be reported in the medical 
record. 
 
 
 
 
 
See Appendix G 
 
 
12.2 
The research protocol includes adequate plans to protect 
identifiers from improper use. HIPAA Identifiers (name, medical record number) 


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will be collected but will be replaced by study numbers in the analytical file; complete 
confidentiality will be maintained during this retrospective evaluation, manuscript 
preparation, and submission. 
 
 
(a) The research protocol includes an adequate plan to destroy the 
identifiers at the earliest opportunity consistent with conduct of the 
research. Identifiers (name, medical record number) will be collected but 
will be replaced by study numbers in the analytical file; Complete 
confidentiality will be maintained during this retrospective evaluation, 
manuscript preparation, and submission. Identifiers will be destroyed within 
1 year of publication 
 
 
(b) The research protocol includes adequate written assurances that the PHI 
will not be reused or disclosed to any other person or entity, or for other 
research. 
Complete confidentiality will be kept during this retrospective evaluation, manuscript 
preparation, and submission.  This data will not be used for any other purpose and 
will not be reused or disclosed to any other person or entity, or for other research. 
 
Anonymized information will be retained by the investigator in locked files or 
password protected databases 
 
2. The research could not practicably be conducted without access to and use of 
the PHI. Access and use of PHI is essential to conducting this study and meeting the 
study objectives. 
 
 
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