Conditions: Anemia Myelodysplastic/Myeloproliferative Neoplasm Myelofibrosis
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 56
Healthy volunteers: no

Brief summary:
This phase II trial studies the side effects of and how well sotatercept works in treating patients with myeloproliferative neoplasm-associated myelofibrosis or anemia. Sotatercept may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed description:
The goal of this clinical research study is to learn if sotatercept can help to control MPN-associated myelofibrosis and anemia. The safety of this drug will also be studied.

OUTLINE: This is a dose-escalation study.

Patients receive sotatercept subcutaneously (SC) once every 3 weeks. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients unable to achieve anemia-response after 8 cycles will be taken off study.

After completion of study treatment, patients are followed up at 1 month.

Arms:
arm 1: Patients receive sotatercept SC once every 3 weeks. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients unable to achieve anemia-response after 8 cycles will be taken off study. arm 2: patients that are already on therapy with ruxolitinib (for at least for 6 months, and on stable dose for last 2 months) will continue ruxolitinib in addition to sotatercept SC once every 3 weeks. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients unable to achieve anemia-response after 8 cycles will be taken off study.

Interventions: intervention 1: Sotatercept intervention 2: Ruxolitinib
Intervention descriptions: intervention 1: Given SC intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
PROTOCOL 2012-0534 
May 31, 2018 
 
1
 
A PHASE-2, PROSPECTIVE, OPEN-LABEL STUDY TO DETERMINE THE 
SAFETY AND EFFICACY OF SOTATERCEPT (ACE-011) IN SUBJECTS WITH 
MYELOPROLIFERATIVE 
NEOPLASM 
(MPN) 
-ASSOCIATED 
MYELOFIBROSIS AND ANEMIA 
 
 
 
 
Principal Investigator: 
 
Prithviraj Bose, M.D. 
University of Texas MD Anderson Cancer Center 
Department of Leukemia, Unit 428 
Houston, TX 77030 
Phone: 713-792-7747 
Fax: 713-794-4297 
E-mail: pbose@mdanderson.org 
 
 
 
 


PROTOCOL 2012-0534 
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2
1. 
BACKGROUND AND RATIONALE 
1.1 
Myeloproliferative Neoplasm (MPN)-Associated Myelofibrosis 
  
Myelofibrosis (MPN-associated myelofibrosis) is a rare (0.4-1.3 per 100,000 in 
Europe, Australia and USA) cancer first described in 1879 by Henck who called it 
osteosclerosis. 
MPN-associated 
myelofibrosis 
was 
classified 
as 
a 
myeloproliferative disorder (1951) and further characterized as a clonal 
proliferation of a pluripotent stem cell (1978).  There is some evidence of genetic 
transmission by a higher incidence rate in the Ashkenazi Jewish population in 
Northern Israel. Exposure to Thorotrast, industrial solvents (benzene and toluene) 
and atomic bomb radiations may be etiologic factors. The primary pathogenetic 
mechanism of proliferation of a pluripotent stem cell clone leads to ineffective 
erythropoiesis, dysplastic-megakaryocyte hyperplasia, and an increase in the ratio 
of immature granulocytes to total granulocytes. This clonal proliferation is 
characteristically accompanied by reactive bone marrow fibrosis and by extra-
medullary hematopoiesis in the spleen or other organs. Typical clinical features 
include splenomegaly, progressive anemia, and constitutional symptoms. The 
terms “myeloid metaplasia” and “extra-medullary hematopoiesis” are used 
interchangeably to describe a pathologic process of ectopic hematopoiesis that 
may occur in any organ system but primarily the liver and spleen. 
 
1.1.2 Prognosis 
 
At the molecular level, a JAK2 tyrosine kinase mutation (JAK2V617F) was recently 
described in MPN-associated myelofibrosis with mutational frequency ranging 
from 35% to 57% with 9-29% homozygosity. To date, however, the presence of 
JAK2V617F in MPN-associated myelofibrosis has not been shown to be a reliable 
prognostic variable. Presence of this mutation, change in its percent (allele burden 
modifications) during the course of treatment, and associations with outcomes may 
provide further insight into its potential use as a biologic marker to track the 
effectiveness of therapies for MPN-associated myelofibrosis. However, this is 
strictly investigational approach.  
Adverse prognostic factors for survival include older age, anemia (hemoglobin < 
10 g/dL) and receiving RBC-transfusions. The etiology for the latter finding is 
usually multi-factorial and related both to bone marrow failure and hyper-splenism. 
Poor prognosis is also correlated with leukocytosis or leukopenia, blood blasts, 
increased numbers of granulocyte precursors, thrombocytopenia, abnormal 
karyotype and hyper-catabolic symptoms. The course of the disease is variable. 
Survival from diagnosis is 2 to 20 years with median survival of about 5 years. 
Common causes of death are progressive bone marrow failure, blastic 
transformation, infection, other cancers and portal hypertension.   


PROTOCOL 2012-0534 
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3
 
1.1.3 Signs and Symptoms 
 
The clinical picture of MPN-associated myelofibrosis involves constitutional 
symptoms (e.g., cachexia, night sweats, bone pain, fatigue, fever), splenomegaly, 
anisopoikilocytosis with teardrop erythrocytes, progressive anemia, immature 
myeloid and erythroid precursors in the peripheral blood, elevated lactate 
dehydrogenase (LDH) levels, and fibrosis of the marrow (as evaluated by reticulin 
and trichrome [collagen] stains). The leukoerythroblastic picture is postulated to be 
related to both the intra-medullary sinusoidal marrow and spleen hematopoiesis.  
The disease generally occurs in adults, 70% of the subjects are >50 years of age; 
median age is 54-62 years. Anemia is apparent in 50-70% at diagnosis and 25% 
will have severe anemia with hemoglobin level < 8.0 g/dL. Splenomegaly is present 
in 85-100% of subjects at diagnosis and is massive in 10%.  Approximately one-
half of the subjects present with an elevated WBC, 28% with thrombocytosis 
(platelets >400 x 10e9/L), and 37% with thrombocytopenia (platelets <150 x 
10e9/L).   
Growth factor and cytokine variations are multiple. It is unclear whether the 
aberrations in cytokine production and in the vasculature are pathogenic or 
whether they are a non-specific reaction associated with the underlying clonal 
activity. Increased levels of basic fibroblast growth factor (bFGF) are reported in 
subjects with MPN-associated myelofibrosis. Both transforming growth factor–beta 
(TGF-β) and bFGF regulate cell growth and differentiation. In addition to their 
potent fibrogenic activity, TGF-β and bFGF regulate hematopoiesis by selective 
actions on primitive stem cells.   bFGF has been shown to augment the activity of 
stem cell factor (SCF), interleukin-3 (IL-3), granulocyte-macrophage colony 
stimulating factor (GM-CSF), andor erythropoietin on committed progenitor cells. 
Serum interleukin-6 (IL-6) has multiple biological effects, including the regulation 
of hematopoiesis, immune responses, and acute phase reactions.  IL-6 appears 
to be a potent megakaryocytic maturation factor. Other cytokines/proteins that are 
dys-regulated in MPN-associated myelofibrosis include; tumor necrosis factor-
alpha (TNF-α) and angiogenic molecules like vascular endothelial growth factor 
(VEGF). 
  
1.1.4 Treatment of MPN-associated myelofibrosis 
Two therapies are approved for MPN-associated myelofibrosis. Ruxolitinib was 
recently (November 2011) approved by US FDA and EMA for treatment of persons 
with intermediate or high-risk MPN-associated myelofibrosis, and has become 
standard first line therapy for patients with MF that have symptomatic 
splenomegaly (about 80% of patients) and/or MF-related significant systemic 
symptoms (fatigue, itching, night sweating, low grade fever, weight loss, decreased 


PROTOCOL 2012-0534 
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4
performance, bone pain, and similar). Ruxolitinib improves splenomegaly and 
constitutional symptoms in many subjects but is associated with a worsening of 
anemia. The primary clinical risks with ruxolitinib treatment are the potential 
sequelae of decreased hematopoietic proliferation attributable to the inhibition of 
growth factor pathways associated with JAK inhibition.  Dose-dependent, 
reversible thrombocytopenia has been observed in studies of patients with MF.  
Anemia and, less frequently, neutropenia have also been observed.  Increased 
rates of infection and anemia are potential risks of myelosuppression, and there 
are multiple sequelae of anemia, including the burden and risks of transfusion.   
Hydroxyurea is the most commonly used drug in the proliferative phases of the 
disease and is approved in Europe. It is a chemotherapy agent and controls 
enlarging spleen and high blood count; anemia is one of the side effects. IFNα 
produces hematologic responses and reduces splenomegaly in 30-50% of 
subjects, especially those in a proliferative phase.  However, it is often poorly-
tolerated.  Therapies for anemia include androgens and/or erythropoietin.  These 
are rarely effective and have important toxicities.  RBC-transfusions are given for 
severe anemia.  Splenectomy and/or spleen radiation are sometimes used to 
manage splenomegaly.  Splenectomy is associated with an increased risk of 
leukemia transformation in some series.  Spleen radiation can result in severe 
bone marrow suppression. No medical therapy is proved to prolong survival.  
Subjects with an intact quality of life and no threatening hematologic abnormalities, 
like erythrocytosis or thrombocytosis, are often observed without therapy. 
Advances in the pathogenesis of MPN-associated myelofibrosis are expected to 
facilitate the development of molecularly targeted therapy. In the meantime, 
current management strategies include observation for low-risk cases, ruxolitinib, 
hydroxyurea, androgens, at the intermediate and high-risk level, and allo 
transplants for high-risk disease in <5% of suitable candidates. Benefit to a subset 
of subjects is reported immune-modulating drugs (IMiDs) like thalidomide, 
lenalidomide and pomalidomide. There is an unmet medical need for 
pharmacologic therapies to improve anemia in persons with MPN-associated 
myelofibrosis. 
 
1.2 
Rationale for ACE-011 in MPN-associated myelofibrosis 
1.2.1 Background 
 
1.2.1.1 Activin Biology 
The activins (A-E) are proteins that form dimers and heterodimers.  All are part of 
the TGF-β protein super-family. The first described activin, Activin A was initially 
identified as a gonad differentiation factor involved in modulating follicle stimulating 
hormone (FSH) secretion from the pituitary (Ying, 1988).  Subsequently, the 


PROTOCOL 2012-0534 
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5
pleiotropic nature of Activin A has become more apparent (Woodruff, 1998). There 
is a growing body of data suggesting a role for activins in bone remodeling, 
specifically as a negative regulator of bone growth (Perrien, 2007). Before the two 
molecules were shown to be identical (Rivier, 1985), Activin A was also initially 
described as erythroid differentiation factor (EDF), effecting the maturation and 
differentiation of RBC’s (Murata, 1988). The mechanism(s) by which Activin A 
influences erythropoiesis remains under investigation and, in fact, there are data 
from in vitro and in vivo studies that support erythropoiesis-stimulatory (Shiozaki, 
1992; 1989) and erythropoiesis-inhibitory effects (Nakao, 1991). 
 
At the cellular level, activins bind initially to the high-affinity Type-II receptor 
(ActRIIA). The ligand-bound ActRIIA then recruits the low-affinity Type I receptor 
(ActRIA or ALK-4). The receptor hetero-complex, through its cytoplasmic protein 
kinase activity, then activates the Smad signaling cascade to eventually influence 
nuclear transcriptional factors (Chen, 2002; Mathews, 1994). Competitive binding 
of activins in the blood by the sotatercept (ACE-011) soluble fusion protein can 
result in inhibition of the ActRIIA receptor signaling pathway by impeding biological 
processes attributed to these pleiotropic proteins. 
 
The activin signaling pathway has been shown to induce terminal erythroid 
differentiation in some preclinical models.  Inhibition of activin may indirectly lead 
to increases in proliferation or differentiation of the erythroid lineage.  Based on its 
pharmacologic effects, sotatercept (ACE-011) is being developed for the treatment 
of anemia associated with a variety of disorders, such as in chronic kidney disease 
and CIA. 
 
In a retrospective study (Seder, 2009) activin immune reactivity was detected in 
about 80% of lung adenocarcinomas surveyed (N=164).  Expression ranged from 
moderate in most samples to high in about 20%. Gene expression profiling was 
also used to measure activin mRNA in 86 lung adenocarcinomas and 10 normal 
lung samples. An average of three-fold more activin transcript was detected in 
cancer tissue relative to normals samples and particularly high over-expression 
were associated with worse overall survival in stage I persons with NSCLC.   
Additionally, in the NIH “directors challenge” study for NSCLC adenocarcinoma 
(Shedden, 2008), three of 12 molecular subgroups, including the subgroup with 
the worst survival prognosis, showed over-expression of activin A. Thus, over-
expression of activin may play a role in NSCLC tumor progression. 
  


PROTOCOL 2012-0534 
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6
1.2.1.2 Sotatercept (ACE-011) 
 
Sotatercept (ACE-011) (ActRIIA-IgG1Fc) is a human fusion protein consisting of 
the extracellular domain (ECD) of activin receptor IIA (ActRIIA) linked to the human 
IgG1 Fc domain, which includes the heavy chain hinge and constant domains, CH2 
and CH3.  The ECD sequence of ActRIIA is completely conserved among 
numerous species including mouse, rat, cynomolgus monkey and humans, thus 
mouse, rat and cynomolgus monkeys have been considered relevant species for 
nonclinical evaluation of sotatercept (ACE-011). However, in order to reduce the 
potential immunogenicity of the human molecule, sotatercept (ACE-011), and to 
maximize the opportunity to maintain exposures in chronic models, a murine 
surrogate molecule was constructed by exchanging the human immunoglobulin Fc 
sequence portion of sotatercept (ACE-011) with its murine IgG2a homolog. The 
resultant construct is referred to as RAP-011 (ActRIIA-mIgG2aFc), and is 
described in the pharmacology studies below.  Both ACE-011 and RAP-011 bind 
with high affinity to activin A/B, GDF-11 and, with slightly lower affinity, to BMP-10. 
 
1.2.1.3 Pharmacology 
 
RAP-011 was evaluated in a range of animal pharmacology studies to assess the 
effects of inhibition of Activin A on the biological processes attributed to that 
regulatory protein. RAP-011 has been shown to have significant effects on the red 
cell compartment. RAP-011 treatment of mice at 10, 30 and 50 mg/kg by intra-
peritoneal injection (IP) twice per week for 3 months resulted in a 16-26% increase 
in RBC counts compared to control animals. Rats treated with sotatercept (ACE-
011) at 0.3, 3 and 30 mg/kg once per week for 3 months showed RBC increases 
of 6-15% over control animals. Finally, in cynomolgus monkeys treated with 10, 30 
or 50 mg/kg of sotatercept (ACE-011) twice per month for 3 months, there was a 
20-25% increase in RBC counts compared to control animals.  In this study, RBC 
level increases were apparent as early as 2 weeks following the initial dose of 
sotatercept (ACE-011). 
  
RAP-011 administered at 10 mg/kg to mice three days prior to administration of 
paclitaxel at 30 mg/kg was sufficient to prevent decreases in RBC parameters 
typically seen three days later. Mice receiving paclitaxel alone had decreased 
hematocrit levels from 43% to 38% three days following treatment. RAP-011 
administered three days prior to paclitaxel injection was sufficient to keep the 
hematocrit levels above 42% at three days and up to two weeks following paclitaxel 
administration. Therefore, prophylactic treatment with RAP-011 was able to 
prevent paclitaxel-induced anemia in mice. 
 


PROTOCOL 2012-0534 
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7
RAP-011 has also been shown to significantly increase bone mineral density 
(BMD) and strength in normal animals and in a variety of animal models of bone 
loss (Chantry, 2008; Lotinun, 2008; Pearsall, 2008). In a murine ovariectomy 
(OVX)-induced model of osteopenia, RAP-011 (10 mg/kg intravenous [IV], twice 
per week x 12 weeks) increased trabecular BMD > 25% in 6-12 weeks compared 
to the phosphate buffered saline (PBS)-treated controls (p<0.002).  RAP-011 
treatment was able to reverse the accelerated bone loss associated with 
ovariectomy. As expected, sham-operated (SHAM) mice (i.e., intact ovaries) 
started the study with a greater trabecular BMD than OVX mice. PBS-treated 
SHAM mice showed a 10% decrease in trabecular BMD after 12 weeks of 
treatment compared to baseline, while SHAM-RAP-011 mice had a 32% increase 
in trabecular BMD over the same period.  These data demonstrate that RAP-011 
is able to increase trabecular BMD in both the normal state and in a model of 
established bone loss. The femurs of both the RAP-011 treated OVX and SHAM 
mice showed statistically significant increases in all measured parameters of bone 
strength (i.e., maximum load, stiffness, energy, ultimate strength, and elastic 
modulus). In summary, treatment with RAP-011 produced bone of superior quality 
consistent with an anabolic agent. 
 
RAP-011 was evaluated in a mouse model of skeletal metastasis using luciferase-
tagged, human MDA-MB-231 breast cancer cells (estrogen receptor negative). 
Mice were pretreated for 2 weeks with RAP-011 (10 mg/kg, biweekly, 
subcutaneous [SC]) prior to intra-cardiac injection of tumor cells. Treatment with 
RAP-011 was continued for an additional 5 weeks following tumor implantation.  A 
parallel study was conducted to examine the effect of RAP-011 treatment, as 
described above, on survival of MDA-MB-231 bearing mice. 
 
The data suggest that RAP-011 treatment may decrease the incidence of MDA-
MB-231 metastasis to bone and may also play a role in inhibiting tumor growth in 
the bone marrow environment.  Furthermore, in the presence of tumor cells, RAP-
011 is able to prevent lytic disease through an anabolic mechanism of bone 
formation.  Lastly, treatment with RAP-011 resulted in an approximately 25% 
survival benefit in this model.   
RAP-011 was also evaluated in osteolytic bone disease of multiple myeloma.  
Multiple myeloma is associated with the development of bone disease 
characterised by increased osteoclast activity and a suppression of osteoblastic 
bone formation. Results obtained in the 5T2MM murine model demonstrated that 
RAP-011 could prevent the development of osteolytic bone disease in a 
preventative setting. 5T2MM cells promoted the development of osteolytic bone 
lesions (p<0.001), a reduction in trabecular volume (p<0.001) and cortical volume 
(p<0.005).  RAP-011 completely prevented 5T2MM-induced decreases in 
trabecular volume and number in both tibia (p<0.001 and p<0.01), femur (p<0.001 
and p<0.001) and vertebrae (p<0.01 and p<0.01) when compared to vehicle 
treated mice.  Bone volume was 19% higher in the tibia, 35% higher in the femur 


PROTOCOL 2012-0534 
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8
and 12% higher in vertebrae of RAP-011 treated mice than naïve non-tumour 
bearing mice. This study showed that, in the preclinical murine model for myeloma, 
RAP-011 stimulates bone formation by increasing osteoblast perimeter and 
number, mineralisation and bone formation rate but had no effect on osteoclast 
activity.  RAP-011 also appeared to inhibit tumor growth as demonstrated by 
decreased serum M protein, indicative of decreased tumor burden. 
 
The efficacy of RAP-011 was also examined in two orthotopic metastatic models 
of breast cancer using luciferase-tagged human MCF-7 and MDA-MB-231 breast 
cancer cells (estrogen receptor positive and negative, respectively).  Mice were 
pretreated for 2 weeks with RAP-011 (10 mg/kg, biweekly, SC) prior to the intra-
cardiac implantation of tumor cells into female nude mice.  Treatment with RAP-
011 was continued for an additional 7 weeks following tumor implantation at which 
time mice were sacrificed and assessed for tumor burden.  RAP-011 either 
modestly decreased the tumor burden (in the case of mice bearing MCF-7 tumors) 
or delayed tumor growth by approximately 3 weeks (MDA-MB-231 model) as 
measured by bio-luminescence. 
 
The ability of RAP-011 to repair osteolytic lesions caused by metastatic disease 
was investigated in mice.  In this model, MDA-MB-231-Luc cells were intratibially 
implanted in athymic nude mice to mimic bone metastasis.  Mice were treated with 
a chemotherapy regimen of paclitaxel (20 mg/kg, IP, every three days) starting 
seven days after tumor injection and continuing for the duration of the study.  On 
study day 42, mice with detectable but minimal tumor burden, as measured by 
bioluminescent imaging, were divided into two groups and treated with either 
RAP-011 (10 mg/kg, SC, biweekly) or vehicle.  Prior to dosing, μCT scans of the 
tumor bearing tibia were conducted to identify osteolytic lesions.  RAP-011 
treatment continued for four weeks (to study day 70) and a final μCT scan of the 
tibia was performed.  On study day 70 there was a trend toward decreased number 
and size of osteolytic lesions in RAP-011-treated mice compared to control 
animals.  Although osteolytic disease (most likely related to tumor burden) did 
progress in some of the treated mice, the majority of mice treated receiving RAP-
011 developed less severe or no bone lesions compared to the untreated group.  
Finally, treated animals also demonstrated an increased hematocrit, confirming the 
ability of RAP-011 to prevent CIA. To summarize, treatment with RAP-011 has the 
ability to inhibit osteolytic lesions caused by tumors and to build new bone after 
cytotoxic chemotherapy with paclitaxel. 
 
1.2.1.5 Toxicology 
 
Sotatercept (ACE-011) has been evaluated for toxicological effects in two species, 
Sprague-Dawley rats and cynomolgus monkeys.  The dose levels ranged from 0.3 


PROTOCOL 2012-0534 
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9
to 30 mg/kg in rats and from 1 to 50 mg/kg in monkeys.  These dose ranges were 
designed to support phase 1a single-dose levels of 0.01 to 3.0 mg/kg IV and phase 
1b multiple doses of 0.1 to 2 mg/kg (monthly, SC).  Weekly (rat and IV monkey 
studies) or every 2 week (SC monkey studies) dosing in animals was designed to 
provide continuous, but fluctuating serum concentrations of sotatercept (ACE-
011), which would be mimicked by a one-month dosing interval in humans. 
 
Sotatercept-related hematological (increase in RBC parameters) and 
reproductive (epididymal granulomas, testicular degeneration, decreased sperm 
counts and motility, and change in ovarian/uterine weights) findings were 
expected pharmacodynamic effects of ActRIIA signal inhibition, likely mediated 
via modulation of erythropoiesis and FSH secretion, respectively.  Unique to rats 
were adrenocortical and pancreatic findings.  Neither finding was associated with 
any clinical signs of adrenocortical (anorexia, weakness, gastrointestinal 
disturbances, serum electrolyte disturbances) or pancreatic (abnormal stool, 
weight loss) insufficiency.  Kidney findings include membranoproliferative 
glomerulonephritis and/or tubulointerstitial nephritis in rats and monkeys.  
Although assessment by immunohistochemistry demonstrated deposition of 
immunoglobulin and complement associated with glomerular changes in 
monkeys, only rare monkeys tested positive for anti-drug antibodies (ADA). 
Additionally, in a three-month toxicity study in rats, kidney findings were seen 
primarily in rats that did not exhibit an ADA response. Therefore, although anti-
sotatercept antibody deposition in the kidney cannot be ruled out as a 
contributing cause, the kidney findings are presumed to be primarily a direct 
effect of the drug. 
 
Related to the kidney findings in monkeys was the observation of perivascular 
accumulation of foamy macrophages and intimal thickening of small arteries and 
arterioles in the choroid plexus at doses of ≥ 2.6 mg/kg every 4 weeks, as well as 
mononuclear cell infiltrate at all dose levels, in the 9-month study.  Like the 
kidney, these findings were associated with deposition of immunoglobulin M 
(IgM) and complement.  Similar findings were not seen in rats. 
 
The no-observed-adverse effects levels (NOAELs) from the 3-month rat and 9-
month monkey SC studies were 3 and 1 mg/kg, respectively. Anticipated plasma 
exposure in humans at 2.0 mg/kg every 3 weeks will exceed the exposure 
attained at these NOAELs. Plasma exposures (area under the concentration 
curve [AUC]) at these doses are estimated to be approximately 0.7- and 0.3-fold, 
in rats and monkeys, respectively, that of the exposure in humans at the 
proposed maximum dose of 2.0 mg/kg. 
 


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10 
1.2.1.6 Summary of Clinical Experience 
 
1.2.1.6.1 A011-01:  A Phase-1a Study in Healthy Postmenopausal Women 
(Single- Dose) 
Sotatercept (ACE-011) was first studied in a randomized, phase 1a, single dose, 
dose escalation study in healthy, postmenopausal females (Ruckle, 2009).  
Sotatercept (ACE-011) was diluted in normal saline administered as an IV infusion 
(over approximately 1 hour) or as a SC injection on Day 1. Dose levels were 0.01, 
0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg IV and 0.03 and 0.1 mg/kg SC. A total of 48 
subjects were enrolled; 5 active and 1 placebo at each of the IV and SC dose 
levels. All subjects were followed for 4 months following a single dose 
administration.   
The pharmacokinetics (PK) of sotatercept (ACE-011) was linear. The overall mean 
exposure (AUC) was proportional to doses (0.01-3 mg/kg IV, 0.03-0.1 mg/kg SC). 
Across IV doses ranging from 0.1 through 3.0 mg/kg, the mean clearance (CL) 
ranged from 0.092 to 0.128 mL/h/kg, the volume of distribution ranged from 73.7 
to 110 mL/kg, and the mean terminal half-life in serum (t1/2, z) ranged from 23.7 to 
31.8 days, with no apparent dependence on dose.  After SC administration of 0.03 
and 0.1 mg/kg, sotatercept (ACE-011) was completely absorbed, and the mean 
t1/2, z was approximately 30 days, with no apparent dependence on dose.   
The most commonly occurring treatment-emergent adverse events (AEs; i.e., 
those occurring in more than 1 subject in any treatment group) were headache, 
infusion site reaction, injection site hemorrhage, and toothache. The majority of the 
injection site reactions and injection site hemorrhages were in the first IV cohort 
and were related to infiltration of the IV site. The majorities of treatment-emergent 
AEs was mild in severity and were judged to be unrelated to sotatercept (ACE-
011). No deaths, serious AEs (SAEs), or AEs leading to discontinuation were 
reported. Changes in RBCs, hemoglobin, reticulocytes, liver function tests, 
glucose, uric acid, amylase and lipase occurred in some subjects.  Mild, transient 
elevations in pancreas enzymes, liver enzymes, or glucose were reported as AEs 
in five subjects.   
There were no clinically significant changes from baseline in vital signs, physical 
examination, endocrine function, or electrocardiogram (ECG) data. Preservation 
of adrenal cortical function was monitored through evaluation of serum electrolytes 
(sodium 
and 
potassium 
levels) 
and 
through 
cortisol 
response 
to 
adrenocorticotropic hormone (ACTH) stimulation.   
No clinically significant findings were observed at doses up to 3.0 mg/kg IV, and 
sotatercept (ACE-011) was well tolerated in healthy, postmenopausal female 
volunteers in single dose levels up to 0.1 mg/kg SC and 3.0 mg/kg IV, the highest 
dose levels tested in this study.  
 


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11 
1.2.1.6.2  A011-02:  A Phase-1b Study in Healthy Postmenopausal Women 
(Multiple Dose) 
Sotatercept (ACE-011) was studied in a phase 1b, single-center, randomized, 
double-blind, placebo-controlled, multi-dose, dose-escalating study to evaluate the 
safety, tolerability and pharmaco-dynamics of sotatercept (ACE-011) in healthy 
postmenopausal women. Four cohorts of 10 subjects each were planned at the 
following dose levels: 0.1, 0.3, 1.0, and 2.0 mg/kg administered SC. Within each 
cohort, subjects were to be randomized to either active or placebo treatment in an 
8:2 ratio. Subjects were to receive one SC injection of sotatercept (ACE-011) or 
placebo every 28 days for a total of 4 doses. All subjects were to be followed for 
12 weeks after the last dose.   
The treatment phase of the study was terminated early after a dose-limiting 
pharmacodynamic effect was observed. While on study, one subject in the 1.0 
mg/kg cohort experienced an SAE of progressive and persistent hypertension that 
was attributed to a rapid and significant rise in hemoglobin levels, up to 20 g/dL 
and hematocrit levels, up to 57.3%. Due to symptoms of headaches, nausea, eye 
pain, dizziness and vomiting approximately one week following the second dose, 
the subject was hospitalized for monitoring and evaluation of her hypertension. 
The head MRI, fundoscopy, and ECG performed were reported as normal and 
headache symptoms resolved following corrective treatment by phlebotomy. The 
SAE resolved and the subject was discharged from the hospital the following day. 
The 
hypertension was 
monitored 
closely 
and managed 
initially 
with 
antihypertensive medication. The hypertension resolved by the end of the study 
without need of any antihypertensive medication. The subject received aspirin 
prophylactically until the end of the study and continued taking ibuprofen as 
needed for headaches. Further details can be found in the Investigator’s Brochure.   
Based on the magnitude of the hematopoietic response, the Sponsor suspended 
dose escalation to the 2.0 mg/kg dose level and further dosing in all cohorts as a 
result of this dose-limiting pharmaco-dynamic effect at the 1.0 mg/kg dose level.  
In total, 31 subjects were enrolled and treated. Dose levels of sotatercept (ACE-
011) administered included 0.1, 0.3, and 1.0 mg/kg (Cohorts 1, 2, and 3 
respectively).  All subjects randomized to active treatment in Cohort 1 received all 
4 planned doses of sotatercept (ACE-011). Due to early discontinuation of study 
drug, subjects randomized to active treatment in Cohort 2 received 3 doses of 
sotatercept (ACE-011), and subjects randomized to active treatment in Cohort 3 
received 2 doses of sotatercept (ACE-011). Subjects randomized to placebo 
treatment received between 1 and 4 doses of study treatment. In the analysis of 
the data, after the administration of the first dose, a dose and time dependent 
increase in hemoglobin, HEMATOCRIT and RBC numbers were observed (see  
Table 1 below for changes in hemoglobin levels). 
 
Table 1: 
A011-02:  A Phase-1b Study in Healthy Postmenopausal 
Women, Hemoglobin Evaluation After Different Doses of Sotatercept 


PROTOCOL 2012-0534 
May 31, 2018 
 
12 
Time Point 
Mean Change from Baseline (g/dL) 
Placebo 
N=7a 
0.1mg/kg 
N=8 
0.3mg/kg 
N=8 
1.0mg/kg 
N=8 
Baseline  
13.20 
13.11 
13.30 
12.71 
Day 8 
0.17 
0.68 
0.85 
1.21 
Day 15 
-0.27 
0.43 
0.44 
1.75 
Day 29 
0.27 
0.61 
1.21 
2.68b 
Day 36 
0.56 
0.64 
1.89 
2.96 
Day 43 
-0.02 
0.89 
1.21 
2.85 
Day 57 
0.27 
1.28 
1.64b 
2.09 
Day 64 
0.53 
1.11 
2.49 
2.21 
Day 71 
-0.10 
1.34 
2.09 
1.66 
Day 85 
0.38 
1.18b 
2.55 
1.86 
Day 92 
0.00c 
1.04 
1.60c 
3.80c 
Day 99 
-0.20 
1.21 
3.20c 
1.28c 
Day 113 
-0.02 
1.30 
1.29 
1.04 
Day 141 
0.30 
0.95 
0.34 
2.30 
Day 169 
0.20c 
0.06 
- 
2.00c 
 
a N placebo subjects with data decreases over time as a result of the early 
discontinuation of the study (i.e., there were placebo subjects in each dosing 
cohort).  There were seven placebo subjects with data at baseline, Days 8, 15, 
and 36; six subjects with data at Days 29, 43, 57, and 85; 5 subjects with data on 
Days 71 and 113; 4 subjects with data on Day 64; 3 subjects with data on Day 
141; two subjects with data on Day 99; and one subject with data on Days 92 and 
169.   
b N doses given per treatment group:  0.1 mg/kg 4 doses; 0.3 mg/kg 3 doses; 1.0 
mg/kg 2 doses.  Data beyond this study day are considered follow-up results.   
c N=1 
Other than the serious case of hemoglobin increase, no life-threatening events 
were reported.  The most notable AEs were those related to increases in 
hematologic laboratory measures in the 1.0 mg/kg dose group:  hematocrit, 
hemoglobin and RBC numbers. The AEs of increased hemoglobin and/or 
hematocrit were reported for seven of the eight subjects in this dose group.  These 
events were reported as mild or moderate elevations; all were considered probably 
related to study drug treatment.  Three of the subjects in the 1.0 mg/kg group with 
elevated Hemoglobin levels underwent phlebotomies and all Hemoglobin 


PROTOCOL 2012-0534 
May 31, 2018 
 
13 
elevations were resolved by the end of the follow-up period.  No erythroid lineage 
AEs were reported in the 0.1 or 0.3 mg/kg treatment groups.   
Paresthesia and dizziness were reported more frequently in the sotatercept (ACE-
011) groups, though the events were < G 2 and generally not considered drug 
related.  Other frequently reported events (e.g. fatigue, upper respiratory infection) 
did not appear to increase with dose and were generally mild.   
Hemoglobin levels for all subjects with elevations had returned to within normal 
limits by the end of the study.   
Adrenal cortical function was monitored through evaluation of serum electrolytes 
(sodium 
and 
potassium 
levels) 
and 
through 
cortisol 
response 
to 
adrenocorticotropic hormone (ACTH) stimulation.  All ACTH simulation test results 
were normal.   
The PK of sotatercept (ACE-011) were linear after SC administration.  Both 
AUC28d and Cmax were proportional to dose from 0.1 to 1 mg/kg following the 
first SC administration.  The t1/2, z of sotatercept (ACE-011) following the last dose 
in all three dose groups was identical, with mean t1/2, z being approximately 23 
days.  Based on the one-compartmental modeling, the mean CL/F ranged from 
3.05 to 3.90 mL/d/kg, the mean Vz/F ((apparent) volume of distribution) ranged 
from 97.47 to 103.03 mL/kg, with no apparent dependence on dose.   
Bone mineral density was assessed by dual-energy X-ray absorptiometry (DXA).  
A dose-dependent increase in the BMD of the total hip from baseline to end of 
study was observed, with a significant and rapid increase of 2.4% in the 1.0 mg/kg 
dose group, compared to a 0.7% decrease in the placebo group.  BMD results for 
lumbar spine showed slight increases of 0.4% to 1.0% from baseline to study end 
in all active treatment groups, compared with a 0.5% decrease in the placebo 
group. 
 
1.2.1.6.3  A011-04:  A Phase-2a Study in Patients with Osteolytic Lesions of 
Multiple Myeloma 
Study A011-04 is a phase-2a, multi-center, randomized, multiple-dose study to 
evaluate the safety, tolerability and efficacy of sotatercept (ACE-011) in subjects 
with osteolytic lesions of multiple myeloma (MM).  In this study, subjects were 
randomized in a 4:1 ratio to one of three dose levels of sotatercept (ACE-011) (0.1, 
0.3 and 0.5 mg/kg) or placebo, administered to subjects every 28 days by SC 
injection, for up to four doses over a 3-month period.  Sotatercept (ACE-011) was 
evaluated in combination with the anti-myeloma therapy of melphalan (4 mg/m2 on 
days 1-7), prednisolone (40 mg/m2 on days 1-7) and thalidomide (100 mg per day) 
(MPT).  The sites, Sponsor and Sponsor representatives were blinded to treatment 
assignment.  Thirty subjects were randomized and received at least one dose of 
study medication:  6 subjects received placebo, 8 subjects received 0.1 mg/kg 
sotatercept (ACE-011), 8 subjects received 0.3 mg/kg sotatercept (ACE-011), and 
8 subjects received 0.5 mg/kg sotatercept (ACE-011).  Twenty six (86.7%) subjects 


PROTOCOL 2012-0534 
May 31, 2018 
 
14 
completed the study.  One subject in the 0.1 mg/kg dose group and one subject in 
the 0.5 mg/kg dose group discontinued due to AEs.  One subject in the 0.1 mg/kg 
dose group withdrew consent and was discontinued, and one subject in the 0.3 
mg/kg dose group was discontinued at the request of the investigator.  In this study, 
50.0% of subjects were female and the mean (range) age was 60.9 (41 to 79) 
years.  The mean time since diagnosis of MM was 3.3 years, the majority of 
subjects had stage III disease at screening (83.3%) and had received prior 
chemotherapy (93.3%).  Approximately 43.3% of subjects were receiving 
bisphosphonates at screening, which continued during the study.  Fourteen out of 
24 subjects (58%) who received study treatment (sotatercept [ACE-011]) did 
receive 3 doses or more (4 out of 8 subjects in the 0.5 mg/kg dose level, 5 out of 
8 subjects in the 0.3 mg/kg dose level and 5 out of 8 subjects in the 0.1 mg/kg 
dose level). 
 
Safety:  Overall, 22 (91.7%) subjects receiving sotatercept (ACE-011) and 4 
(66.7%) subjects receiving placebo reported at least one AE.  Among subjects 
receiving sotatercept (ACE-011), AEs were reported in 87.5%, 87.5%, and 100% 
of subjects in the 0.1 mg/kg, 0.3 mg/kg, and 0.5 mg/kg dosing cohorts, 
respectively.  Treatment-related AEs (i.e., those assessed by the Investigator as 
possibly, probably, or definitely related to treatment) were reported by 21 (87.5%) 
subjects receiving sotatercept (ACE-011) and 4 (66.7%) receiving placebo.  Most 
subjects had AEs that were assessed as related to MPT:  21 (87.5%) subjects 
receiving sotatercept (ACE-011) and 4 (66.7%) subjects receiving placebo.  No 
AEs were assessed by the Investigator as related to the study medication alone 
(sotatercept (ACE-011) or placebo).  Two subjects had AEs assessed as possibly 
or probably related to study drug and possibly or probably related to MPT, one 
subject in the 0.1 mg/kg sotatercept (ACE-011) dose group (increased blood 
pressure; sudden death) and one subject in the 0.5 mg/kg sotatercept (ACE-011) 
dose group (hypertension).  Four subjects had SAEs, 1 (12.5%) subject in the 0.1 
mg/kg sotatercept (ACE-011) group and 3 (37.5%) subjects in the 0.5 mg/kg 
sotatercept (ACE-011) group.  Three subjects had SAEs that were assessed as 
treatment-related.  Of the 3 treatment-related SAEs, 2 SAEs were assessed as 
possibly related to MPT and unrelated to sotatercept (ACE-011), and 1 SAE 
(sudden death) was assessed as probably related to MPT and possibly related to 
sotatercept (ACE-011).  One subject in the 0.5 mg/kg sotatercept (ACE-011) dose 
group discontinued study drug due to episodes of atrial fibrillation assessed as 
possibly related to MPT and unrelated to sotatercept (ACE-011).   
Table 2: 
Summary of Adverse Events Reported in Greater Than or Equal 
To 5 Percent of Patients Overall 


PROTOCOL 2012-0534 
May 31, 2018 
 
15 
 
 
 Sotatercept (ACE-011) Treatment Group 
 
 
Preferred 
Terma 
Placebo 
(N=6) 
0.1 mg/kg 
(N=8) 
0.3 mg/kg 
(N=8) 
0.5 mg/kg 
(N=8) 
All Sotatercept 
 (ACE-011) 
(N=24) 
 
Any 
Grade 
Grade 
≥ 3 
Any 
Grade 
Grade 
≥ 3 
Any 
Grade 
Grade 
≥ 3 
Any 
Grade 
Grade 
≥ 3 
Any 
Grade 
Grade 
≥ 3 
Neutropenia 4 
(66.7%) 
1 
(16.7%) 
4 
(50.0%) 
2 
(25.0%) 
6 
(75.0%) 
2 
(25.0%) 
6 
(75.0%) 
3 
(37.5%) 
16 
(66.7%) 
7 
(29.2%) 
Leukopenia 
0 
0 
3 
(37.5%) 
1 
(12.5%) 
1 
(12.5%) 0 
1 
(12.5%) 
1 
(12.5%) 
5 
(20.8%) 
2 
(8.3%) 
Granulo-
cytopenia 
0 
0 
2 
(25.0%) 
1 
(12.5%) 
1 
(12.5%) 
1 
(12.5%) 
1 
(12.5%) 
1 
(12.5%) 
4 
(16.7%) 
3 
(12.5%) 
Anaemia 
0 
0 
1 
(12.5%) 
1 
(12.5%) 
1 
(12.5%) 
1 
(12.5%) 
2 
(25.0%) 
1 
(12.5%) 
4 
(16.7%) 
3 
(12.5%) 
Respiratory 
tract infection 0 
0 
1 
(12.5%) 
1 
(12.5%) 
1 
(12.5%) 0 
1 
(12.5%) 0 
3 
(12.5%) 
1 
(4.2%) 
Thrombo-
cytopenia 
0 
0 
1 
(12.5%) 0 
0 
0 
2 
(25.0%) 
1 
(12.5%) 
3 
(12.5%) 
1 
(4.2%) 
Pyrexia 
0 
0 
1 
(12.5%) 0 
1 
(12.5%) 0 
1 
(12.5%) 0 
3 
(12.5%) 0 
Blood 
pressure 
increased 
0 
0 
1 
(12.5%)
* 
1 
(12.5%)
* 
0 
0 
1 
(12.5%) 0 
2 
(8.3%) 
1 
(4.2%) 
Bronchitis 
1 
(16.7%) 0 
0 
0 
1 
(12.5%) 0 
1 
(12.5%) 0 
2 
(8.3%) 0 
Compression 
fracture 
0 
0 
0 
0 
1 
(12.5%) 0 
1 
(12.5%) 0 
2 
(8.3%) 0 
Pathological 
fracture 
0 
0 
1 
(12.5%) 0 
0 
0 
1 
(12.5%) 
1 
(12.5%) 
2 
(8.3%) 
1 
(4.2%) 
aAdverse events were those that were treatment-emergent, defined as newly 
acquired or worsened during or after administration of first dose of study 
medication.  A person with multiple occurrences of an AE counted only once 
under each preferred term.   
*Indicates the adverse event was assessed by the investigator as related (possibly, 
probably, or definitely) to study drug (sotatercept (ACE-011) or placebo).   
 
Table 3: 
Summary of SAEs Reported 


PROTOCOL 2012-0534 
May 31, 2018 
 
16 
Study 
Treatment 
Age (y) / 
Sex 
/ 
Race 
Preferred 
Term 
(Verbatim Term) 
[Severity 
/ 
Gradea] 
Study 
Dayb at 
Onset 
Outcome 
(duration) 
Relationship to 
Study 
Treatment 
0.1 mg/kg 
Sotatercept 
(ACE-011) 
and MPT 
61 / M / 
White 
Sudden 
death 
(sudden death) 
103 
Death 
Sotatercept 
(ACE-011):  
possibly 
MPT:  probably 
0.5 mg/kg 
Sotatercept 
(ACE-011) 
and MPT 
68 / M / 
White 
Pain in extremity 
(pain 
in 
leg) 
[severe / G 3] 
128 
Ongoing 
at end of 
study 
Sotatercept 
(ACE-011):  not 
related 
MPT:  not related 
 
 
Pathological 
fracture 
(pathological 
fracture of femur) 
[severe / G 3] 
130 
Ongoing 
at end of 
study 
Sotatercept 
(ACE-011):  not 
related 
MPT:  not related 
0.5 mg/kg 
Sotatercept 
(ACE-011) 
and MPT 
45 / M / 
White 
Pneumonia 
(pneumonia) 
[moderate / G 2] 
9 
Resolved 
(12 days) 
Sotatercept 
(ACE-011):  not 
related 
MPT:  possibly 
0.5 mg/kg 
Sotatercept 
(ACE-011) 
and MPT 
78 / F / 
White 
Atrial 
fibrillation 
(atrial 
fibrillation) 
[life-threatening / 
G 4] 
6 
Resolved 
(1 day) 
Sotatercept 
(ACE-011):  not 
related 
MPT:  possibly 
F= female; M = male; MPT = melphalan, prednisolone, and thalidomide; NCI 
CTCAE, v3.0 = National Cancer Institute Common Terminology Criteria for 
Adverse Events, version 3.0; y = years 
abased on NCI CTCAE, v3.0.   
bRelative to first dose of study drug.   
 
Following analysis of the central laboratory data, increases in Hemoglobin values 
were observed within 28 days after administration of the first dose of sotatercept 
(ACE-011)/placebo and sustained for ≥ 28 days from baseline at any time as 
presented in Table 4.  
  
Table 4: 
Number of Subjects with an Increase in Hemoglobin from 
Baseline at Any Time and Sustained for Greater ≥28 Days 


PROTOCOL 2012-0534 
May 31, 2018 
 
17 
Increase 
in 
Hemoglobin 
Dose Sotatercept (ACE-011)/Placebo 
0.1 
mg/kg 
N=8 
0.3 mg/kg 
N=8 
0.5 mg/kg 
N=8 
Placebo 
N=6 
Overall 
N=30 
≥ 1.0 g/dL 
4 
3 
7 
2 
16 
≥ 1.5 g/dL 
2 
3 
3 
1 
9 
≥ 2.0 g/dL 
1 
3 
2 
0 
6 
Taken together, these data, suggest a beneficial pharmaco-dynamic effect of 
sotatercept (ACE-011) on erythropoiesis in a person population with cancer CIA. 
   
A011-08: A Phase 2 Study in Women with Metastatic Breast Cancer with 
Chemotherapy Induced Anemia (Preliminary results) 
The results presented in this section are preliminary. Study A011-08 is clinically 
completed and the writing of the clinical study report is in progress. 
Study A011-08 was a phase 2, double-blind, randomized, placebo-controlled study 
to evaluate the efficacy, safety, and tolerability of sotatercept for the treatment of 
chemotherapy-induced anemia (CIA) in women with metastatic breast 
cancer.  Subjects were randomized to one of three sotatercept (0.1, 0.3, and 
0.5 mg/kg) treatment groups or to a placebo treatment group.  Planned enrollment 
included 30 subjects in each of the three sotatercept treatment groups and 15 
subjects in the placebo treatment group (2:2:2:1 ratio).  Study treatment was 
administered via subcutaneous injection every 28 days for up to 4 treatments 
(Days 1, 29, 57, and 85).  Subjects were administered concurrent treatment with a 
bone marrow suppressive chemotherapy regimen for metastatic breast cancer per 
standard of care at the study site. 
Because of changes in guidance for the treatment of CIA and a slower than 
expected rate of enrollment the study was terminated after 30 subjects 
enrolled.  All 30 received ≥1 dose of treatment:  5 subjects in the placebo cohort, 
8 subjects in the sotatercept 0.1 mg/kg cohort, 10 subjects in the sotatercept 0.3 
mg/kg cohort and 7 subjects in the sotatercept 0.5 mg/kg cohort.  29 subjects were 
white, all were female with a median age of 51 y (range, 32-74 y).  Demographic 
characteristics were similar across the cohorts. 
Fourteen subjects completed treatment.  Fourteen in the three sotatercept 
treatment groups combined and two subjects in the placebo treatment group 
prematurely discontinued study treatment.  Of the 16 subjects who withdrew during 
the treatment period, eight subjects (50.0%) discontinued due to disease 
progression, four subjects (25.0%) withdrew consent, three subjects (18.8%) 
discontinued due to an AE, and one subject discontinued because of receiving an 
ESA. 


PROTOCOL 2012-0534 
May 31, 2018 
 
18 
Of the 25 subjects in the three sotatercept cohorts combined, four received the 
planned four doses of treatment.  In the 0.1 mg/kg, 0.3 mg/kg, and 0.5 mg/kg 
treatment groups, respectively, 1/8 (12.5%), 3/10 (30.0%), and 0/7 (0.0%) subjects 
were administered all four doses of sotatercept.  Fourteen subjects in the three 
sotatercept treatment groups combined skipped and/or had at least one dose 
modification during the treatment period.  One of five (20.0%) subjects in the 
placebo treatment group was administered all four doses, and 3/5 (60.0%) subjects 
had skipped a dose and/or had a single dose modified during the treatment period. 
The primary efficacy endpoint was the rate of hematopoietic response, defined as 
the proportion of subjects with a hemoglobin increase ≥ 10 g/L from baseline for 
28 consecutive d up to 2 mo after the last dose of study treatment, in the absence 
of RBC transfusion or treatment with an ESA (Table 5). 
 
Table 5: 
Primary Efficacy Analysis:  Subjects with Hemoglobin Increase 
from Baseline of ≥10 g/L for 28 Consecutive Days – Per Protocol Set, Central 
Laboratory Results (Study A011-08) 
 
 
Sotatercept Treatment Group 
 
Placebo 
(N=5) 
0.1 mg/kg 
(N=5) 
0.3 mg/kg 
(N=9) 
0.5 mg/kg 
(N=4) 
All 
Sotatercept 
(N=18) 
Responder 
1 (20.0%) 0 
3 (33.3%) 2 (50.0%) 5 (27.8%) 
Non-responder 
4 (80.0%) 5 (100%) 6 (66.7%) 2 (50.0%) 13 (72.2%) 
Five of 18 subjects in the three sotatercept (0.1, 0.3, and 0.5 mg/kg) treatment 
groups combined responded.  One of five subjects in the placebo group 
responded.  Response rates among subjects in the sotatercept 0.3 mg/kg (33%) 
and 0.5 mg/kg (50%) treatment groups were greater than those in the sotatercept 
0.1 mg/kg (0%) and placebo (20%) treatment groups, and suggest a possible 
dose-response relationship. 
 
Among the 13 subjects in the three sotatercept treatment groups combined who 
were non-responders, five subjects skipped a dose and/or had at least one dose 
reduced during treatment.  Four had achieved a hemoglobin increase ≥1 g/dL and 
one subject achieved an elevated hemoglobin of ≥ 11 g/dL   Mean changes from 
baseline hemoglobin levels during the 28-day period after the first dose are 
presented in Figure 1.  Mean changes from baseline hemoglobin levels during the 
28-day period after the first dose in subjects in the sotatercept 0.1 mg/kg group 
were similar to those in the placebo group.  Mean increases in hemoglobin during 
that period in the sotatercept 0.3 mg/kg and 0.5 mg/kg groups were greater those 
in the sotatercept 0.1 mg/kg and placebo treatment groups, and support a 
sotatercept dose-response relationship. 


PROTOCOL 2012-0534 
May 31, 2018 
 
19 
 
Figure 1: 
Mean Change from Baseline Hemoglobin during 28 Days 
Following First Treatment – All Subjects, Central Laboratory Results (Study 
A011-08) 
 
Note: Subjects were administered their assigned treatment on Day 1. 
 
Mean changes from baseline hemoglobin over the extended period from first dose 
to 28 days after the last dose are presented in Figure 2.  Increases in Hemoglobin 
concentrations were achieved in all sotatercept treatment groups.  Mean changes 
in Hemoglobin during the 28-day period showed greater increases in Hemoglobin 
concentrations among subjects in the sotatercept 0.3 mg/kg and 0.5 mg/kg groups 
than those of subjects in the sotatercept 0.1 mg/kg and placebo treatment groups, 
and provide additional evidence of a dose-response relationship. Mean increases 
following repeated doses of sotatercept declined over the 28-day interval between 
treatments.   
Figure 2: 
Mean Change from Baseline Hemoglobin during Period from 
First Dose to 28 Days Following the Last Treatment – All Subjects, Central 
Laboratory Results (Study A011-08) 


PROTOCOL 2012-0534 
May 31, 2018 
 
20 
 
Note: Subjects were administered their assigned study treatment on Days 1, 
29, 57, and 85. 
Assessments of safety in this study were consistent with the known safety profile 
of sotatercept.  Overall, 20 of 25 (80.0%) subjects in the three sotatercept 
treatment groups combined and all five (100%) subjects in the placebo treatment 
group reported ≥ 1 AE.  Most AEs were assessed by the investigator as unrelated 
to study treatment.  There were no hypertension or thromboembolic events 
reported as AEs in subjects administered sotatercept. 
Observed increases in Hemoglobin, hematocrit, and RBCs and decreases in FSH 
were consistent with results from prior clinical studies and are consistent with the 
known pharmacologic profile of sotatercept.  There were no notable differences 
between treatment groups in the emergence of Grade 3 or 4 toxicities.  Five of 
seven subjects in the sotatercept 0.5 mg/kg group demonstrated shifts in 
creatinine from normal (at baseline) to Grade 1 (worst post baseline value).  All 
observations of creatinine concentrations in the other treatment groups remained 
within the normal range.  Mean changes in vital signs were generally small with no 
trends over time over treatment groups.  There were no clinically significant 
abnormal findings on ECG, and no notable differences among treatment groups in 
QTc. 
The results of this study suggest that sotatercept is safe and demonstrates 
hematopoietic activity when administered as repeated doses of 0.1, 0.3, or 
0.5 mg/kg administered SC every 28 days for the treatment of CIA in subjects with 
metastatic breast cancer.  These findings are consistent with a robust 


PROTOCOL 2012-0534 
May 31, 2018 
 
21 
hematopoietic response following each repeated treatment of sotatercept at doses 
of 0.3 or 0.5 mg/kg, but also indicate that responses decline during the intervals 
between repeated treatments.  These data suggest that a shorter dosing interval 
might result in a more sustained hematopoietic response and provide a rationale 
for a dosing interval of less than 28 days. 
 
ACE-011-MDS-001: A phase 2 dose-ranging study of sotatercept for the 
treatment of patients with anemia and low- or intermediate-1 risk 
myelodysplastic syndromes or non-proliferative chronic myelomonocytic 
leukemia (Preliminary results) 
This is an ongoing open-label, randomized, phase 2, parallel dose-ranging, 
multicenter study of sotatercept for the treatment of patients with anemia 
(hemoglobin ≤ 9.0 g/dL requiring transfusion of ≥ 2 units of RBCs in the 84 days 
prior to enrollment) and low- or intermediate-1 risk myelodysplastic syndromes or 
non-proliferative chronic myelomonocytic leukemia (CMML). Patients received 
subcutaneous sotatercept at dose levels of 0.1, 0.3, 0.5, or 1.0 mg/kg once every 
3 weeks. 
 
A preliminary safety analysis from this ongoing Celgene-sponsored MDS study 
(Komrokji 2014) indicates that administration of sotatercept is generally well-
tolerated at the dose levels tested (N=54, as of May 22, 2014). 
 
ACE-011-REN-001: Safety and hemoglobin effect of the first 28-day dose 
cycle of sotatercept 0.7 mg/kg compared with lower doses and placebo for 
correction of anemia in hemodialysis subjects (Interim analysis) 
 
This is ongoing randomized, single-blind, placebo-controlled, sequential dose-
escalation study in subjects with end-stage kidney disease on hemodialysis.  
At the end of the first dose cycle, home blood pressure (BP) measurements 
revealed small changes from baseline in systolic BP (SBP) and diastolic BP (DPB) 
that were generally similar in magnitude in subjects receiving placebo or 
sotatercept 0.3, 0.5, and 0.7 mg/kg in the safety population (N=23) (Figure 3).  
 
During the 225-day, long-term treatment phase, home BP measurements showed 
no consistent or dose-dependent change from baseline among subjects in any of 
the treatment groups (N=17). 
 
In order to ensure the safety of the study subjects, this protocol includes the 
monitoring of blood pressure and hemoglobin, and treatment discontinuation 
rules in order to mitigate the risk of blood pressure increases. 


PROTOCOL 2012-0534 
May 31, 2018 
 
22 
 
Figure 3. Change from baseline in home blood pressure (BP) at the end of 
dose cycle 1. 
 
 
Potential Risks for Human Use 
Nonclinical studies to determine the safety of sotatercept (ACE-011) have been 
conducted in cynomolgus monkeys and Sprague-Dawley rats.  Many of the 
observed effects in these studies were as a result of the expected biologic activity 
of TGF-β superfamily inhibition and can be summarized as a dose-dependent 
decrease in sperm count and motility secondary to FSH suppression as well as 
reversible increases in RBC parameters due to the effects on erythroid 
differentiation factor (activin).   
The most significant toxicity findings are listed below:   
Hematological findings (increase in RBC parameters – RBCs, hemoglobin, 
hematocrit) were observed across all studies.  Associated with the increase in RBC 
parameters were increases in reticulocytes and decreases in mean corpuscular 
hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC).  
The increase in RBC parameters is an anticipated effect of sotatercept (ACE-011) 
treatment and is being targeted as a therapeutic intervention for conditions 
associated with anemia.   


PROTOCOL 2012-0534 
May 31, 2018 
 
23 
In the 6- and 9-month monkey studies, glomerulonephritis and/or tubulointerstitial 
nephritis were observed in monkeys administered ≥ 10 mg/kg administered 
subcutaneously (SC) every 2 or 4 weeks.  At 2.6 mg/kg administered SC every 4 
weeks for 9 months, kidney findings were limited to a single incidence of 
tubulointerstitial nephritis.  The NOAEL in the 9-month study was considered to 
be 1 mg/kg every 4 weeks.  Serum exposure in monkeys at the 1 mg/kg dose is 
estimated to be ~0.9-fold the projected serum exposure in humans at the 
maximum dose of 2 mg/kg every 3 weeks proposed in humans.  In the single- 
and multiple-dose studies in healthy postmenopausal women, there have been 
no changes in serum chemistry or urinalysis profiles suggestive of kidney injury. 
Subjects administered sotatercept should be monitored closely. 
In the 9-month monkey study, treatment-related findings in the choroid plexus 
included:  peri-vascular accumulations of foamy macrophages and intimal 
thickening of small arteries and arterioles primarily at 10 mg/kg administered every 
2 weeks as well as an increased incidence of small, focal aggregates of 
mononuclear inflammatory cells at all dosages.  Findings at 1 mg/kg were limited 
to mononuclear cell infiltrates and were not adverse.   
Anti-drug antibodies (ADA) have been observed in toxicology studies.  Adrenal 
gland congestion or necrosis was observed in rats but not in monkeys.  The finding 
was more pronounced in female rats and appeared following either one month of 
IV dosing or 3 months of SC dosing.  Although the current data suggest adrenal 
toxicity may be specific to rats, the relevance of the adrenal findings to humans is 
uncertain.   
Elevations in liver enzymes (alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], and/or alkaline phosphatase) and triglycerides, were 
observed sporadically in rats and monkeys receiving sotatercept (ACE-011).  
There were no histological correlates in the liver, and often a dose-response 
relationship was not observed.  The relevance of these findings to sotatercept 
(ACE-011) treatment is uncertain; however, liver enzymes will continue to be 
monitored in this study.   
Pregnancy and Lactation 


PROTOCOL 2012-0534 
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24 
Because of the potential for effects on hormones in the pituitary, including FSH, 
in addition to possible direct effects on fetus, there may be potential indirect 
effects on the fetus.  Delays in fetal development (decreased fetal weights and 
delays in ossification) were observed at doses ≥ 15 mg/kg (1.6-fold of the 
projected exposure at the maximum proposed human dose of 2.0 mg/kg every 3 
weeks).  In addition, at 50 mg/kg (3.8-fold the exposure at the maximum 
proposed human dose), there was an increase in late fetal death coupled with an 
overall increase in post implantation loss and a reduction in live litter size, as well 
as an increase in the incidence of developmental variations of supernumerary 
ribs with corresponding increases and decreases in thoracic and lumbar 
vertebrae, respectively.  No fetal malformations were observed in this study at 
dosages up to 50 mg/kg. The NOAEL for embryofetal development effects was 5 
mg/kg (~1.0-fold the projected exposure at the maximum proposed human dose 
of 2.0 mg/kg every 3 weeks) based on reduced fetal weights and associated 
delays in ossification.    
− In an embryo-fetal development study in rabbits, post-implantation 
loss was increased and average litter size and live fetuses were 
reduced at 15 and 50 mg/kg. In addition, fetal body weights were 
reduced in all sotatercept dosage groups. Abortions occurred in 
one rabbit in the 5 mg/kg dosage group and two rabbits in the 50 
mg/kg dosage group. Based on these findings, an NOAEL was not 
identified in this study and was therefore less than 5 mg/kg (1.0-fold 
the exposure at the maximum proposed human dose of 2.0 mg/kg 
every 3 weeks). 
− Precautions should still be taken to protect females of childbearing 
potential.  Nonclinical studies on breast milk have not been done.   
− If sotatercept (ACE-011) is taken during pregnancy, a teratogenic 
effect in humans cannot be ruled out.  Therefore, all sotatercept 
(ACE-011) protocols describe pregnancy prevention requiring 
females of child-bearing potential to use highly effective methods of 
birth control.  In addition, since it is unknown if sotatercept (ACE-011) 
is found in breast milk, breast feeding is prohibited in all protocols.   
Fertility 
− In male rats, sperm granulomas and testicular degeneration were 
observed histologically.  In addition, sperm analysis revealed a 
reduction in sperm counts and motility as well as sperm 
fragmentation in isolated animals (2/10 males) at doses of 30 mg/kg 
IV. Sperm fragmentation was also noted in 2/5 males administered 
10 mg/kg IV at the end of the recovery period.  Overall, there was 
some evidence of recovery (motility similar to controls) at the end of 
the 4-week recovery period.  There was no evidence of a treatment-
related impact on reproductive organs (testes, ovary, uterus) of 
monkeys in the toxicity studies; however, the monkeys on these 


PROTOCOL 2012-0534 
May 31, 2018 
 
25 
studies, were too immature to fully assess the potential impact on 
reproductive organs. The NOAEL for reproductive effects (testicular 
or ovarian) was 1 mg/kg IV.  Serum exposure (AUC0-28d) in rats at 
the NOAEL was estimated to be ~ 10,940 µg∙hr/mL, ~ 0.5-fold the 
projected serum exposure in humans at the maximum proposed 
dose of 2.0 mg/kg every 3 weeks (estimated AUC0-28d ~ 20,928 
μg∙hr/mL).   
− In summary, in view of the potential risks sotatercept (ACE-011) 
treatment has on fertility, sotatercept (ACE-011) is targeted toward 
person groups for whom the potential benefits outweigh the 
perceived risks.   
Because of the potential risks sotatercept treatment has on fertility, sotatercept 
was first studied in healthy postmenopausal in two completed phase-1 clinical 
trials. In addition, due to the potential for effects on hormones in the pituitary, levels 
of growth hormone, ACTH, and thyroid stimulating hormone (TSH) were monitored 
closely in the phase 1 studies.   
Completed studies in humans carried out in postmenopausal females showed a 
dose-dependent decrease in circulating levels of FSH, with mean levels in the 
multi-dose study in the two higher dose groups remaining below baseline at study 
end. No effect of sotatercept on growth hormone, ACTH, TSH or kidney was 
observed.   
To date, anti-sotatercept binding antibodies were detected in approximately 6.3% 
(9 of 143) of evaluable subjects receiving sotatercept, with one-third (3 of 9) of 
them having pre-existing positive titers before the start of sotatercept treatment.  
Preliminary review of data available, including AEs, SAEs, and laboratory results, 
did not show immune mediated allergic effect or other safety consequence.   
Please refer to the Investigator Brochure for further detailed information on the 
available pharmacology, toxicology, drug metabolism, clinical studies and AE 
profile of sotatercept.   
1.2.1.7. 
Potential Risks of the Combination of Ruxolitinib and 
Sotatercept 
 


PROTOCOL 2012-0534 
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26 
RUXOLITINIB AND SOTATERCEPT APPEAR NOT TO HAVE OVERLAPPING  
SIDE EFFECTS IN CLINICAL STUDIES CONDUCTED SO FAR. THEREFORE, 
A COMBINATION OF RUXOLITINIB AND SOTATERCEPT IS NOT 
EXPECTED TO RESULT IN ANY NEW CLINICALLY RELEVANT ISSUES. OF 
NOTE, AS PER THE DESIGN OF THE STUDY, ONLY PATIENTS THAT ARE 
ON RUXOLITINIB FOR AT LEAST FOR 6 MONTHS, AND ON STABLE DOSE 
FOR THE LAST 2 MONTHS, WOULD POTENTIALLY BE ELIGIBLE FOR 
PARTICIPATION IN THIS STUDY, WHERE SOTATERCEPT WOULD BE 
ADDED TO THEIR THERAPEUTIC REGIMEN. 


PROTOCOL 2012-0534 
May 31, 2018 
 
27 
2.0 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Objective 
Determine safety and efficacy of sotatercept as therapy for persons with 
MPN-associated myelofibrosis and anemia 
2.2 
Endpoints 
2.2.1 Primary 
Safety  
Anemia response  
 
2.2.2 Secondary 
 
Time to anemia response 
 
Duration of anemia response 
 
 


PROTOCOL 2012-0534 
May 31, 2018 
 
28 
3.0 
INVESTIGATIONAL PLAN 
3.1. 
Design 
Phase-2, open-label study to determine safety and efficacy of sotatercept in 
persons with MPN-associated myelofibrosis and anemia 
 
Screening Phase: 
Potential subjects will enter screening and be evaluated for the inclusion and 
exclusion criteria for the Treatment Period of this study. The screening period will 
not last more than 28 days (except for bone marrow biopsy which can be done 
within 6 months). The assessments and procedures that will be performed during 
screening are outlined in Appendix: Schedule of Events. Screening assessments 
will include an informed consent, medical history, transfusion history for previous 
84 days, review of prior MF-directed medications, complete physical exam, vital 
signs, ECOG performance status assessment, complete blood count (CBC) with 
differential, serum chemistries, erythropoietin level, 12-lead ECG, bone marrow 
biopsy and aspirate to confirm diagnosis, spleen and liver measurements, and 
pregnancy test in females of childbearing potential (FCBP) will have to be 
obtained.1  
 
Treatment Period: 
Subjects meeting study-entry-criteria will be enrolled and receive sotatercept. 
Twenty-one days is considered one cycle of therapy.  Subjects may be taken off 
study after 8 cycles if there is no anemia-response.  Those patients experiencing 
clinical benefit may remain on study treatment as long as they derive benefit in the 
judgment of treating physician, in the absence of disease progression or toxicity 
warranting discontinuation of therapy.   
 
Initially patients not on any therapy for MF, will be assigned alternately into two 
treatment cohorts of 5 subjects each: (1) 0.75 mg/kg dose SC every 3 weeks; and 
(2) 1.0 mg/kg dose SC every 3 weeks.  Response will be analyzed after each cycle, 
starting with cycle 5 of therapy. The cohort with at least one responder (out of 5 
treated patients) will be expanded with an additional 15 subjects. If none of the 5 
subjects in a cohort responds by cycle 8, enrollment into that cohort may be closed. 
If a cohort is closed for lack of efficacy, ongoing subjects in the cohort may have 
their dose changed to that of the other cohort dose, if there was a response in the 
other cohort.  If there is no responder in either cohort additional dose cohorts of 5 
subjects each may be considered at lower or higher doses of sotatercept (this will 
require protocol amendment); the same rules for cohort expansion will apply. After 
the 5th subject in each cohort has been evaluated for response, then a cohort-
 
1 A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy 
or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months 
(i.e., has had menses at any time in the preceding 24 consecutive months). 


PROTOCOL 2012-0534 
May 31, 2018 
 
29 
summary will be completed and submitted to the IND Office’s Clinical Research 
monitor. 
 
Separate cohort for patients that are already on therapy with ruxolitinib (for at least 
for 6 months, and on stable dose for last 2 months) will be enrolled. These patients 
will be given 0.75 mg/kg dose of sotatercept SC every 3 weeks and the same 
statistical analysis for efficacy will apply as described for cohorts above. 
Specifically, response will be analyzed after each cycle, starting with cycle 5 of 
therapy. If there is at least one responder out of 5 treated patients, this cohort will 
be expanded with an additional 15 subjects. If none of the first 5 subjects in this 
cohort responds by cycle 8, enrollment into the cohort may be closed. 
 
Study assessments and serial measurements of safety and efficacy will be 
performed as outlined in Appendix: Schedule of Assessments. All scheduled visits 
will have a ±4-day window unless otherwise stated. Vital signs will be measured at 
the start of each cycle but monitoring of blood pressure may be done at home on 
non-dosing days. Blood pressure will be measured at a minimum every week for 
first 3 weeks during cycles 1-5. Patients will be instructed to call treating physician 
and his staff if systolic blood pressure [SBP] ≥ 140 or diastolic blood pressure 
[DBP] ≥ 90. In the absence of clinically significant changes in blood pressure after 
5 cycles of treatment, monitoring frequency may decrease to once per cycle at the 
investigator’s discretion. Hematologic parameters will be measured at a minimum 
every week for first 3 weeks during courses 1-5, then every 2-3 weeks thereafter. 
Serum chemistry parameters, including erythropoietin level, will be measured at 
minimum every 3-6 weeks.  
 
 
Blood samples will be collected for assessment of antidrug antibody (ADA) and 
pharmacokinetics (PK) in all subjects as described in Appendix: Instruction for 
collection of samples for sotatercept ADA and PK. The sample will be collected 
prior to administration of sotatercept on the first day of cycles 1-5, then every other 
cycle for cycles 7-12 (i.e., cycles 7, 9 and 11), then every 6 months for cycles 12+; 
samples will be stored in Dr. Verstovsek’s laboratory at MD Anderson Cancer 
Center. Upon completion of clinical study, ADA samples will be shipped to QPS, 
LLC in Newark, DE; PK samples will be shipped to supporter of the study, Celgene 
Corporation.  
 
Occasional missed PK and ADA samples not completed due to patient schedule 
will not be considered as deviations. 
 
An unscheduled visit can occur at any time during the study.  The date for the visit 
and any data resulting there from will be recorded on the appropriate source.  
Source documents for these unscheduled visits must be maintained. At treatment 
discontinuation, subjects will undergo off study evaluations as outlined in 
Appendix: Schedule of Assessments. In addition, a safety assessment will be done 


PROTOCOL 2012-0534 
May 31, 2018 
 
30 
approximately 30 days post the last dose of study drug (the person will be 
contacted by the PI or his staff to assess for AE’s). 
Women of childbearing potential and men must agree to using medically approved 
contraceptive measure for at least 112 days following the last dose of sotatercept 
(ACE-011), Males must agree to use a latex condom or non-latex condom NOT 
made of natural (animal) membrane during any sexual contact with females of 
childbearing potential or a pregnant female while participating in the study and for 
at least 112 days following the last dose of sotatercept (ACE-011), even if he has 
a vasectomy. The two methods of reliable contraception must include one highly 
effective method (i.e. intrauterine device [IUD], hormonal [birth control pills, 
injections, or implants], tubal ligation, or partner’s vasectomy) and one additional 
effective (barrier) method (i.e. latex condom, diaphragm, cervical cap).  Females 
of childbearing potential (FCBP) must be referred to a qualified provider of 
contraceptive methods if needed.  
Males must tell the doctor right away if his partner becomes pregnant or suspects 
pregnancy. 
3.1.1 Investigational Drug 
 
Celgene Corporation will supply sotatercept to study-subjects at no charge. 
Sotatercept clinical drug product will be provided as a lyophilized powder 
(lyophilized ACE-011 drug product process 3 Formula). The clinical drug product 
consists of sotatercept in 10 mM citrate buffer, pH 5.8, 8% sucrose, and 0.02% 
polysorbate-80.  It is supplied as a lyophilized powder in labeled, rubber stopper, 
3-mL glass vials. The recommended storage temperature for sotatercept 
lyophilized drug product is 2°C to 8°C.  Prior to administration, the lyophilized drug 
product is reconstituted with 1 mL water for injection.  The reconstituted drug 
product consists of a 50 mg/mL solution of sotatercept.  The reconstituted 
sotatercept should be used immediately after reconstitution, and if not used 
immediately, the reconstituted sotatercept, in its original package, may be held for 
up to 6 hours at 2°C to 8°C. Once the reconstituted drug product is drawn into a 
syringe, it should be administered immediately (within one hour from the time it 
was drawn). The total hold time of the reconstituted drug product, including the 
hold time in a syringe, must not exceed 6 hours. Accurate recording of all study 
drug administration (including dispensing and dosing) will be made in the 
appropriate source documents.   
The Investigator or designee is responsible for taking an inventory of each 
shipment of study drug received, and comparing it with the accompanying study 
drug accountability form. The study staff will verify the accuracy of the information 
on the form, sign and date it, retain a copy in the study file, and return a copy to 
Celgene or its representative. At the study site, all investigational study drugs will 
be stored in a locked, safe area to prevent unauthorized access. Celgene will 
instruct the Investigator on the return or destruction of unused study drug.  If any 


PROTOCOL 2012-0534 
May 31, 2018 
 
31 
study drug is lost or damaged, its disposition should be documented in the source 
documents.  Study drug will be destroyed per MDACC destruction policies. 
Treatment Administration and Schedule 
Sotatercept should be given every 3 weeks as a SC injection to subjects at the 
clinical site and will be documented in the source record. SC injections will be given 
in the upper arm, abdomen, or thigh. Each subject will return to the site on each 
scheduled clinic visit. All adverse events/toxicities are to be graded according to 
the Common Terminology Criteria for Adverse Events (CTCAE Version 4.0). In a 
case of clinically relevant grade 4 drug-related toxicity, therapy will be stopped and 
person’s participation in a study discontinued. In other instances, any sotatercept-
related adverse event that may have occurred has to resolve to ≤ grade 2 for the 
next scheduled injection to be given. Delay in giving sotatercept because of drug-
related adverse effects is ≤ 56 days; after that patient will have to be taken off the 
study. Once the therapy restarts, 21-day cycles will resume.  
 
Sotatercept will be held if there is an increase in hemoglobin level to ≥11.5 g/dL 
and may restart if/when hemoglobin level decreases to ≤11.0 g/dL. Once therapy 
restarts 21-day cycles resume.  
3.3 
Inclusion and Exclusion Criteria 
 
Subjects are to be assessed for suitability for entry into the study based on the 
following inclusion and exclusion criteria. 
3.3.1 Key Inclusion criteria 
Subjects must meet the following inclusion criteria: 
1. MPN-associated myelofibrosis; 
2. Anemic patient OR RBC-transfusion-dependent patient   
3. ≥18 years of age 
4. ALT (SGPT) and AST (SGOT) ≤ 2.5x upper limit of normal (ULN), or ≤ 4x 
ULN (if upon judgment of the treating physician, it is believed to be due to 
extramedullary hematopoiesis [EMH] related to MF) 
5. Direct bilirubin ≤ 1.5 x ULN; or ≤ 2x ULN (if upon judgment of the treating 
physician, it is believed to be due to extramedullary hematopoiesis related 
to MF) 
6. Creatinine clearance > 50 mL/min. 
7. Treatment-related toxicities from prior therapies must have resolved to 
Grade ≤ 1 
8. Women of childbearing potential and men must agree to using medically 
approved (i.e., mechanical or pharmacological) contraceptive measure for 
at least 112 days following the last dose of sotatercept (ACE-011), Males 
must agree to use a latex condom or non-latex condom NOT made of 
natural (animal) membrane during any sexual contact with females of 


PROTOCOL 2012-0534 
May 31, 2018 
 
32 
childbearing potential or a pregnant female while participating in the study 
and for at least 112 days following the last dose of sotatercept (ACE-011), 
even if he has a vasectomy. 
9. For cohort of patients that are already on ruxolitinib therapy: on therapy with 
ruxolitinib for at least for 6 months, and on stable dose for last 2 months, 
before starting therapy with sotatercept 
3.3.2. Key Exclusion Criteria 
 
1. Serious medical condition or psychiatric illness that would prevent, (as 
judged by the treating physician) the subject from signing the informed 
consent form or any condition including the presence of laboratory 
abnormalities, which places the subject at unacceptable risk if he/she were 
to participate in the study or confounds the ability to interpret data from the 
study; 
2. Pregnant or lactating female; 
3. Known positive for human immunodeficiency virus-1 (HIV-1), or active 
infection with hepatitis-B or -C;  
4. Use of any MPN-associated myelofibrosis-directed therapy within 2 weeks 
prior to study Day 1 (other than Ruxolitinib at a stable dose for patients in 
the combination cohort as stated in inclusion criteria). 
5. Symptomatic congestive heart failure (New York Heart Association 
Classification >Class II), unstable angina, or unstable cardiac arrhythmia  
6. Prior sotatercept   
7. Major surgery within 4 weeks prior to Day 1  
8. Severe allergic or anaphylactic reactions or hypersensitivity to recombinant 
proteins or excipients in the investigational product 
9. Uncontrolled hypertension (systolic blood pressure [SBP] ≥ 140 or diastolic 
blood pressure [DBP] ≥ 90).   
3.7 Concomitant therapy   
3.7.1 Recommended concomitant therapy 
All supportive measures consistent with optimal subject care will be given 
throughout the study.  Packed red blood cell transfusions are allowed when 
necessary.  Growth factor use (including erythropoietin) is not allowed with the 
exception of the use of filgrastim (G-CSF) or pegfilgrastim, which is permitted at 
the investigators discretion when used to treat febrile neutropenia or grade 3-4 
prolonged neutropenia.   
3.7.3. Prohibited concomitant therapy 
Concomitant use of growth factors (including erythropoietin and excluding G-CSF 
and pegfilgrastim), cytotoxic chemotherapeutic agents (e.g. hydroxyurea), or 


PROTOCOL 2012-0534 
May 31, 2018 
 
33 
other experimental drug or therapy for myelofibrosis while the subject is on study 
is prohibited. Chronic use (>2 weeks) of greater than physiologic doses of a 
corticosteroid agent (dose equivalent to >10 mg/day of prednisone) is not 
permitted during the study. Anagrelide is allowed to be used during the study to 
control elevated platelet count. 
3.8 Discontinuation of Study Treatment 
Subjects should have blood pressure (systolic and diastolic) measured after 
approximately 10 minutes seated, before each dose of study drug. If SBP ≥140 
mmHg or DBP ≥90 mmHg, blood pressure should be re-checked. If unable to 
control it, dosing should be postponed (Table 6).  
 
Treatment with study drug is to be discontinued when any of the following occurs: 
• Lack of therapeutic effect  
• Adverse event(s) which in the judgment of the PI may cause severe or 
permanent harm or which rule out continuation of study drug. 
• Hypertension (Table 6) 
• Withdrawal of consent 
• Lost to follow-up 
• Death 
• Suspected pregnancy 
 
Table 6. Management of hypertension 
 
Event 
Action 
Hypertension  
 
 
-If Systolic blood pressure (SBP) 
≥140 OR Diastolic BP (DBP) ≥ 90 
mm Hg AND SBP increase ≥ 20 
mmHg over baseline OR DBP 
increase ≥ 20 mmHg over baseline 
Dose delay (no more than 2 dose delays allowed) 
Hold until resolved  
SBP and DBP should be < 140 and < 90 mmHg 
Initiation of  anti-hypertension is allowed after one 
week if the BP is Systolic blood pressure (SBP) ≥140 
OR Diastolic BP (DBP) ≥ 90 mmHg AND SBP 
increase ≥ 20 mmHg over baseline OR DBP increase 
≥20 mmHg over baseline 
 
-If 2 Dose delays due to BP increase, 
ie SBP ≥140 OR DBP ≥ 90 mmHg 
AND SBP increase ≥ 20 mmHg over 
baseline OR DBP increase ≥ 20 
mmHg over baseline 
Dose delay until SBP and DBP should be < 140 and < 
90 mmHg 
 
 
 
-If SBP > 160 mmHg OR DBP > 100 
mmHg, sustained (ie confirmed by 
two measurements within 7 days) 
Discontinue treatment 
 


PROTOCOL 2012-0534 
May 31, 2018 
 
34 
4.0 Serious Adverse Event reporting  
4.1 Serious Adverse Event Reporting (SAE)  
 
An adverse event or suspected adverse reaction is considered “serious” if, in the 
view of either the investigator or the sponsor, it results in any of the following 
outcomes: 
 
• Death 
• A life-threatening adverse drug experience – any adverse experience that 
places the patient, in the view of the initial reporter, at immediate risk of death 
from the adverse experience as it occurred. It does not include an adverse 
experience that, had it occurred in a more severe form, might have caused 
death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
• A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug 
abuse (21 CFR 312.32). 
• Important medical events as defined above, may also be considered 
serious adverse events. Any important medical event can and should be 
reported as an SAE if deemed appropriate by the Principal Investigator 
or the IND Sponsor, IND Office. 
• All events occurring during the conduct of a protocol and meeting the 
definition of a SAE must be reported to the IRB in accordance with the 
timeframes and procedures outlined in “The University of Texas M. D. 
Anderson Cancer Center Institutional Review Board Policy for Investigators 
on Reporting Unanticipated Adverse Events for Drugs and Devices”. Unless 
stated otherwise in the protocol, all SAEs, expected or unexpected, must be 
reported to the IND Office, regardless of attribution (within 5 working days of 
knowledge of the event). 
• All life-threatening or fatal events, that are unexpected, and related to the 
study drug, must have a written report submitted within 24 hours (next 
working day) of knowledge of the event to the Safety Project Manager in the 
IND Office.  
• Unless otherwise noted, the electronic SAE application (eSAE) will be 
utilized for safety reporting to the IND Office and MDACC IRB.  
• Serious adverse events will be captured from the time of the first 
protocol-specific intervention, until 30 days after the last dose of drug, 


PROTOCOL 2012-0534 
May 31, 2018 
 
35 
unless the participant withdraws consent. Serious adverse events must 
be followed until clinical recovery is complete and laboratory tests have 
returned to baseline, progression of the event has stabilized, or there 
has been acceptable resolution of the event. 
• Additionally, any serious adverse events that occur after the 30 day time 
period that are related to the study treatment must be reported to the 
IND Office. This may include the development of a secondary 
malignancy.  
 
Reporting to FDA: 
• Serious adverse events will be forwarded to FDA by the IND Sponsor 
(Safety Project Manager IND Office) according to 21 CFR 312.32.  
 
It is the responsibility of the PI and the research team to ensure serious 
adverse events are reported according to the Code of Federal 
Regulations, Good Clinical Practices, the protocol guidelines, the 
sponsor’s guidelines, and Institutional Review Board policy. 
 
Leukemia Guidelines for AE reporting will be followed.  
 
Adverse Events and Protocol specific data will be entered into PDMS/CORe. 
PDMS will be used as the electronic case report form.  
 
4.1.1 Expedited reporting by investigator to Celgene 
 
Investigator Communication with Supporting Companies: 
Serious adverse events (SAE) are defined above.  The investigator must inform 
Celgene in writing using a Celgene SAE form, MD Anderson SAE form, or 
MEDWATCH 3500A form of any SAE within 24 hours of being aware of the event.  
The written report must be completed and supplied to Celgene by facsimile within 
24 hours/1 business day.  The initial report must be as complete as possible, 
including an assessment of the causal relationship between the event and the 
investigational product(s), if available.  Information not available at the time of the 
initial report (e.g., an end date for the adverse event or laboratory values received 
after the report) must be documented on a follow-up report.  A final report to 
document resolution of the SAE is required.  The Celgene tracking number (ACE-
011-MPN-associated myelofibrosis-PI-0005) and the institutional protocol number 
should be included on SAE reports (or on the fax cover letter) sent to Celgene.  A 
copy of the fax transmission confirmation of the SAE report to Celgene should be 
attached to the SAE and retained with the person records. 
 
The Celgene Study Identifying number:  ACE-011-MPN-associated 
myelofibrosis-PI-0005 should be written on the top of the form. 


PROTOCOL 2012-0534 
May 31, 2018 
 
36 
Celgene Drug Safety Contact Information: 
Celgene Corporation      
Global Drug Safety and Risk Management    
Connell Corporate Park      
300 Connell Dr.  Suite 6000     
Berkeley Heights, NJ  07922        
Fax:  
(908) 673-9115 
E-mail:  
drugsafety@celgene.com 
 
4.1.2 Pregnancies 
 
Pregnancies and suspected pregnancies (including a positive pregnancy 
test regardless of age or disease state) of a female subject or the female 
partner of a male subject occurring while the subject is on study drug, or 
within 30 days of the subject’s last dose of study drug, are considered 
immediately reportable events.  Study drug is to be discontinued 
immediately and the subject instructed to return any unused portion of the 
study drug to the investigator(s).  The pregnancy, suspected pregnancy, or 
positive pregnancy test must be reported to the Celgene Safety immediately 
by phone and facsimile using the SAE Report Form. 
The female should be referred to an obstetrician-gynecologist experienced 
in reproductive toxicity for further evaluation and counseling. 
The Investigator(s) will follow the female subject until completion of the 
pregnancy, and must notify Celgene Safety of the outcome of the pregnancy 
as a follow-up to the initial SAE report. 
If the outcome of the pregnancy meets the criteria for immediate 
classification as a SAE (i.e., spontaneous or therapeutic abortion [any 
congenital anomaly detected in an aborted fetus is to be documented], 
stillbirth, neonatal death, or congenital anomaly [including that in an aborted 
fetus]), the Investigator(s) should follow the procedures for reporting SAEs 
(i.e., report the event to Celgene Safety by telephone and facsimile within 
24 hours of the Investigator’s knowledge of the event). 
In the case of a live “normal” birth, Celgene Safety should be advised by 
telephone and facsimile within 24 hours of the Investigator’s knowledge of 
the event. 
All neonatal deaths that occur within 30 days of birth should be reported, 
without regard to causality, as SAEs.  In addition, any infant death after 30 
days that the Investigator(s) suspects is related to the in utero exposure to 
the study drug should also be reported to  Celgene Safety  by telephone 
and facsimile within 24 hours of the Investigators’ knowledge of the event. 


PROTOCOL 2012-0534 
May 31, 2018 
 
37 
If the female is found not to be pregnant, any determination regarding the 
subject’s continued participation in the study will be determined by the 
Investigator. 


PROTOCOL 2012-0534 
May 31, 2018 
 
38 
5.0 
STATISTICS 
5.1 
Overview 
This is a phase-2 open-label, non-comparative study to determine safety and 
efficacy of sotatercept in persons with MPN-associated myelofibrosis and anemia.  
Efficacy will be assessed as anemia-response.   Two dose cohorts (0.75 and 1.0 
mg/kg) will be studied in patients not on any MF-directed therapy. Additional cohort 
of MF patients, currently on therapy with ruxolitinib (for at least for 6 months, and 
on stable dose for last 2 months) will be studied.  Up to 60 persons will be enrolled 
(20 per cohort), at a rate of 1 subjects per month. Additional patients may be 
enrolled in case of early discontinuation (˂8 cycles of therapy given) due to 
unrelated reasons (i.e. replacement patients). The study is not designed for 
statistical comparisons between the dose cohorts.   
5.2 
Datasets to be analyzed 
All subjects receiving ≥1 dose of sotatercept are evaluable for safety.  
5.3 
Statistical Methodology 
5.3.1 Primary Endpoint 
The primary endpoints are safety and anemia-response.  Primary analysis of a 
response for each dose cohort will be performed once all 20 patients have been 
accrued to that dose cohort and treated for at least 5 cycles (unless therapy is 
stopped in a given patient earlier due to toxicity). 
5.3.2 Study-Design 
This is an open-label, 2 dose level trial to evaluate the efficacy and safety of 
sotatercept in patients with MPN-associated myelofibrosis (PMF or post ET/PV 
MF) and significant anemia. Clinical efficacy will be assessed as anemia- 
response with a target rate of greater than or equal to 30% at either dose level. 
Initially patients not on any MF-directed therapy will be assigned to two different 
treatment groups alternatively: 5 patients will be treated with 0.75 mg/kg dose SC 
every 3 weeks, and 5 patients will be treated with 1.0 mg/kg dose SC every 3 
weeks. Assignment of the following 15 patients per dose level (if both dose levels 
require expansion) will be done alternatively. Each 3-week period will be defined 
as one cycle. Additional cohort of MF patients, currently on therapy with 
ruxolitinib (for at least for 6 months, and on stable dose for last 2 months) will be 
studied: these patients will be treated with 0.75 mg/kg dose SC every 3 weeks of 
sotatercept. Same design will be applied to this cohort of patients: if there is at 
least one responder out of 5 treated patients, this cohort will be expanded with an 
additional 15 subjects. 
 
5.3.3 Interim Futility and Safety Monitoring 
 


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39 
The method of Thall, Simon, Estey (1995, 1996) as extended by Thall and Sung 
(1998) will be used for interim futility and safety monitoring.  
 
5.3.3.1 Futility Monitoring: 
We assume a non-informative beta (0.6, 1.4) prior for the anemia-response rate 
and we will apply the following futility stopping rule for each dose cohort separately. 
The futility stopping rule will be applied every 5 patients, starting with the 5th patient 
per dose cohort. Specifically, we will stop enrollment to a dose cohort if at any time 
during the study,  
 
Pr{anemia-response rate > 30% | data from patients evaluated} <  0.05 
 
In other words, if at any time during the study, we determine that there is less than 
5% chance that the anemia-response rate for a given dose cohort is greater than 
30%, we will stop enrollment into that dose cohort.  Stopping boundaries 
corresponding to this probability criterion are as follows:  
[# of patients with anemia-response/ # of evaluable patients] </= 0/5, 1/15, 2/20.  
 
The operating characteristics corresponding to this stopping rule is as follows: 
True anemia-response 
rate 
Prob(early stopping) 
0.05 
0.90 
0.1 
0.70 
0.2 
0.37 
0.3 
0.18 
0.4 
0.08 
0.5 
0.03 
 
At the end of the trial, if for a given dose cohort, Pr (anemia-response rate > 30% 
| data) >0.95, then that dose cohort will be considered a success. If a dose cohort 
is closed at the interim for a lack of efficacy, ongoing patients from that treatment 
group may have their dose regimen changed to the other treatment group (if there 
was a response in the other cohort).  
 
With a total of 20 patients in a dose cohort, if we observe 6 confirmed responders, 
the 95% credible interval will be (0.132, 0.502).  
 
5.3.4. Safety evaluation  
Data from all subjects who receive ≥1 dose of study drug are included in the safety 
analysis. Severity of the toxicities will be graded according to the NCI CTCAE v4.0 
whenever possible.  Toxicity is defined as an adverse event and classified as 
possibly, probably, or definitely related to study drug. Such adverse events will be 
recorded by the PI in a database. The maximum grade for each type of toxicity will 
be recorded for each subject, including start/stop dates, and frequency tables for 
each group will be reviewed to determine toxicity patterns. 


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40 
 
Toxicity Stopping Rule: 
For safety monitoring, we define toxicity as any Grade 4 non-hematologic 
adverse event that is considered to be at least possibly related to treatment. We 
assume a non-informative beta prior (0.4, 1.6), which has a mean of 20%; and 
we will apply the following toxicity stopping rule-in each dose cohort separately. 
For practical reasons, we will monitor the toxicity in cohort of 5. Specifically, we 
will stop a dose cohort if  
 
Pr{toxicity rate > 20% | data from patients evaluated} >0.85 
 
In other words, if we determine that there is more than 85% chance that the 
toxicity rate is greater than 20% in a given dose cohort, that dose cohort, will be 
terminated.  In addition, the higher dose cohort will be stopped once the lower 
dose cohort is terminated according to the above stopping rule. Stopping 
boundaries for each dose cohort corresponding to this probability criterion are as 
follows:  
[# of patients with Grade 4 non-hematologic AEs/ # of evaluable patients] >/=3/5, 
4/10, 5/15, 7/20.   
 
The operating characteristics corresponding to this toxicity stopping rule is as 
follows: 
True overall toxicity 
rate 
Prob(early stopping) 
0.05 
0.002 
0.1 
0.024 
0.2 
0.206 
0.3 
0.530 
0.4 
0.808 
 
5.3.5.  Analysis Plan 
 
The primary analysis will be based on the intent-to-treat (ITT) principle. Patients 
who drop off the study early before being able to be evaluated for the 84-day 
interval will not be counted as having anemia response 
 
Anemia response is a composite endpoint defined as an increase in 
hemoglobin (hemoglobin response; defined below) in a subject with anemia 
(anemic patient as defined below) OR becoming RBC-transfusion-
independent in a subject who is RBC-transfusion-dependent (defined 
below): 


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41 
1. Hemoglobin-response is defined as an increase in hemoglobin level of 
≥1.5 g/L (compared to baseline) on every determination consecutively for 
a ≥84 d interval, without RBC-transfusions. 
2.  
RBC-transfusion-independence is defined as no RBC-transfusion in any 
“rolling” 84 day interval during the treatment period, in patients who were 
RBC-transfusion dependent at enrollment. 
 
Definitions: 
Anemic patient is defined for the purpose of this protocol as 1. a patient with a 
hemoglobin level <10 g/L on every determination over 84 days before study-entry, 
without RBC-transfusions, and 2. a patient with a hemoglobin level <10 g/L that is 
receiving RBC-transfusions periodically but not meeting criteria for transfusion-
dependent patient as defined below.  The baseline hemoglobin value for these 
subjects is the lowest hemoglobin level during the antecedent 84 days.  
RBC-transfusion-dependent patient is defined as a patient with an RBC-
transfusion-frequency of ≥2 units PRBC/28 days averaged over 84 days 
immediately pre-study-entry.  There must not be any consecutive 42 days without 
an RBC-transfusion during this interval 
 
Secondary Endpoints 
Duration of response: duration of response is defined as the date at which the 
subject’s objective status is first noted to be a response, to the date progression 
is documented (if one has occurred) or to the date of last follow-up (for those 
subjects who have not progressed). 
Time to response: The time to response is defined as interval from 1st dose of study 
drug to 1st day of a response. Non-responders are censored on the last evaluation 
date.  
The distribution for each of these event-time variables (duration of response and 
time to response) will be estimated by Kaplan-Meier curves.  
 
 


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42 
6.0 
REGULATORY CONSIDERATIONS 
6.1 
Institutional Review Board/Ethics Committee approval 
The protocol for this study has been designed in accordance with the general 
ethical principles outlined in the Declaration of Helsinki.  The review of this protocol 
by the IRB/EC and the performance of all aspects of the study, including the 
methods used for obtaining informed consent, must also be in accordance with 
principles enunciated in the declaration, as well as ICH Guidelines, Title 21 of the 
Code of Federal Regulations (CFR), Part 50 Protection of Human Subjects and 
Part 56 Institutional Review Boards. 
The Investigator will be responsible for preparing documents for submission to the 
relevant IRB/EC and obtaining written approval for this study.  The approval will be 
obtained prior to the initiation of the study. 
The approval for both the protocol and informed consent must specify the date of 
approval, protocol number and version, or amendment number. 
Any amendments to the protocol after receipt of IRB/EC approval must be 
submitted by the Investigator to the IRB/EC for approval.  The Investigator is also 
responsible for notifying the IRB/EC of any serious deviations from the protocol, or 
anything else that may involve added risk to subjects. 
Any advertisements used to recruit subjects for the study must be reviewed and 
approved by the IRB/EC prior to use. 
6.2 
Informed consent 
The PI must obtain informed consent of a subject or his/her designee prior to any 
study related procedures as per GCPs as set forth in the CFR and ICH guidelines. 
Documentation that informed consent occurred prior to the subject’s entry into the 
study and the informed consent process should be recorded in the subject’s source 
documents.  The original consent form, signed and dated by the subject and by 
the person consenting the subject prior to the subject’s entry into the study, must 
be maintained in the medical records.  
6.3 
Subject confidentiality 
Celgene affirms the subject’s right to protection against invasion of privacy.  In 
compliance with United States federal regulations, Celgene requires the 
Investigator to permit Celgene’s representatives and, when necessary, 
representatives of the FDA or other regulatory authorities to review and/or copy 
any medical records relevant to the study in accordance with local laws. 
Should direct access to medical records require a waiver or authorization separate 
from the subject’s statement of informed consent, it is the responsibility of the 
Investigator to obtain such permission in writing from the appropriate individual. 


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43 
6.4 
Study records requirements 
The PI must ensure that the records and documents pertaining to the conduct of 
the study and the distribution of the study drug, that is copies of eCRF and source 
documents (original documents, data, and records [e.g., hospital records; clinical 
and office charts; laboratory notes; memoranda; subject’s diaries or evaluation 
checklists; pharmacy dispensing records; recorded data from automated 
instruments; copies or transcriptions certified after verification as being accurate 
copies; microfiches; photographic negatives, microfilm, or magnetic media; x-rays; 
subject files; and records kept at the pharmacy, at the laboratories, and at medico-
technical departments involved in the clinical study; documents regarding subject 
treatment and study drug accountability; original signed informed consents, etc.]) 
be retained by the Investigator for as long as needed to comply with national and 
international regulations (generally 2 years after discontinuing clinical development 
or after the last marketing approval).  The PI agrees to adhere to the 
document/records retention procedures by signing the protocol. 
6.5 
Premature discontinuation of study 
6.5.1 Single center 
The responsible local clinical Investigator, MDACC as well as Celgene have the 
right to discontinue this study at any time for reasonable medical or administrative 
reasons in any single center.  Possible reasons for termination of the study could 
be but are not limited to: 
Unsatisfactory enrollment with respect to quantity or quality. 
Inaccurate or incomplete data collection. 
Falsification of records. 
Failure to adhere to the study protocol. 
6.5.2 Study as a whole 
Celgene and MDACC reserve the right to terminate this clinical study at any time 
for reasonable medical or administrative reasons. 
Any possible premature discontinuation would be documented adequately with 
reasons being stated, and information would have to be issued according to local 
requirements (e.g., IRB/EC, regulatory authorities, etc.). 


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