Clinical trial NCT01464164
Conditions: Diamond Blackfan Anemia
Keywords: Diamond Blackfan anemia DBA Blackfan Diamond anemia Congenital pure red cell aplasia Aase-Smith II Syndrome Aase Syndrome Anemia, Congenital Pure Red Cell Aplasia, Congenital Pure Red Cell BDA Congenital Hypoplastic Anemia Erythrogenesis Imperfecta Hypoplastic Congenital Anemia Inherited Erythroblastopenia pure red cell aplasia bone marrow failure syndrome
Sponsor: Northwell Health
Start date: 2012-01-01; Completion date: 2021-04-13
Enrollment: 19 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the safety and dosing of drug Sotatercept, as a subcutaneous injection, to stimulate production of red blood cell production. To be given every 28 days for up to four doses.

Detailed description:
This study is for adult patients with Diamond Blackfan Anemia who are currently being transfused every 3- 4 weeks.

The drug will be given as a subcutaneous injection within one of three dose levels. The first dose level (0.1 mg/kg) will include 3 subjects who will receive the same dose of the drug monthly for a total of 4 doses, as long as there are no dose- limiting toxicities (DLTs). A Dose limiting toxicity is defined as inability to deliver the scheduled doses because of toxicity \>/= Grade 3, according to NCI Toxicity Grading Scale.

Once all 3 subjects have received and tolerated the low dose level, the next level will open (0.3 mg/kg)to 3 new subjects. Subjects will be monitored closely for response and side effects.

If more than 2 subjects have a dose limiting toxicity in the first dose level, then dose level -1 (0.05 mg/kg)will open, enrolling 3 more subjects. If more than 2 subjects at dose level -1, have dose limiting toxicities, the study will be discontinued. If there are no additional dose limiting toxicities, dose level -1 will be the maximum tolerated dose.

There are a total of 3 dose levels, not including dose level -1. Once the maximum tolerated dose has been reached, up to a total of 10 additional subjects will be enrolled.

Protocol Amendment: The protocol has been amended to include an additional enrollment of 20 subjects with two additional dose levels of Sotatercept (0.075 mg/kg and 0.100 mg/kg ) to be given with or without a prednisone boost.

Efficacy will be measured by response. A complete response will be determined if the subject no longer requires transfusion, while on study drug. A partial response will be measured by a reduction by 50% in need for transfusion.

Treatment modifications will be made based on evidence of side effects. Dose- escalation will be performed only if no side effects are reported and no efficacy is evidenced. Treatment will be stopped if hemoglobin is \>12 gm/dl and/ or any \>/+ grade 3 adverse event is related to sotatercept.

Study assessments will include:

* Physical exam (height, weight, vital signs and blood pressure)at screening, day 1 of each cycle and monthly for 3 months of follow up period as well as at study discontinuation.
* Additional blood pressure monitoring at day 1 of each cycle and weekly there after through cycle 4, monthly in follow up period and at study discontinuation.
* Karnofsky performance status at screening, day 1 of cycle 2 and day 1 of monthly follow up period for 3 months and study discontinuation.
* CBC reticulocyte count and ANC will be collected at day 1 of each cycle and weekly there after through cycle 4, monthly in follow up period and at study discontinuation.
* Blood chemistry, liver and kidney function will be assessed at screening, day 1 and 15 of cycle 1, day 1 of cycle 2, 3, 4 month 1 in follow up and at study discontinuation.
* Blood for iron status (serum iron, transferrin and %, ferritin) will be collected during the screening period, and at month 1 of the follow-up period as well as study discontinuation.
* Folate and B12 levels will be assessed during the screening period at day 1 of cycle 3 and again at study discontinuation.
* Urinalysis (creatinine, protein),at screening, day 15 of cycle 1, day 1 of cycles 2, 3, and 4 monthly during follow-up and at study discontinuation.
* Serum erythropoietin at screening, day 15 of cycle 1, day 1 of cycle 3, monthly during follow-up and at study discontinuation.
* FSH \& LH (everyone), DHEA \& testosterone (males only), estrogen \& estradiol (females only)at screening, day 1 of cycles 2, 3, and 4, monthly during follow- up period and at study discontinuation.
* EKG \& ECHO at screening, day 1 of cycle 3 first month of follow-up period and at study discontinuation
* Dexa Scan at screening, day 1 of monthly follow-up period and at study discontinuation
* Transfusion assessment at screening, day 1, 8, 15 and 22 of cycle 1, day 1 and 15 of cycles 2, 3, and 4, monthly during follow-up period and at study discontinuation.
* Response assessment at day 8, 15, 22 of cycle 1, day 1 and 15 of cycles2, 3, and 4, monthly for 3 months during follow-up period and at study discontinuation
* Adverse events, concomitant therapies to be assessed at day 1, 8, 15, and 22 of cycle 1, day 1 and 15 of cycles 2, 3, and 4, monthly during follow-up period and at study discontinuation
* Drug administration day 1 of cycles 1, 2, 3, and 4.

Arms: arm 1: Sotatercept to be given as a subcutaneous injection once a month for 4 consecutive months, using a dose escalation scale among 3 cohorts. \*Protocol Amendment: Two additional cohorts will be given Sotatercept 0.75mg/kg and 1 mg/kg as a subcutaneous injection once every 3 weeks. arm 2: Protocol Amendment: Two additional cohorts will be given Sotatercept 0.75mg/kg and 1 mg/kg as a subcutaneous injection once every 3 weeks along with a prednisone boost of 1 mg/kg daily for 3 weeks (max of 60 mg).
Interventions: intervention 1: Sotatercept intervention 2: Sotatercept with prednisone boost
Intervention descriptions: intervention 1: Cohort 4a: 3 patients on Sotatercept 0.75 mg/kg every 3 weeks. If the patients have no untoward events in the Patients in Dose Level 4 by the end of 3 of the 6 doses, then additional patients (Dose Level 5) will be enrolled at the next dose level:

Cohort 5a: 3 patients on Sotatercept 1 mg/kg every 3 weeks intervention 2: Cohort 4b: 3 patients on Sotatercept 0.75 mg/kg every 3 weeks with a three week prednisone boost of 1 mg/kg/day (max 60 mg). If the patients have no untoward events in the Patients in Dose Level 4 by the end of 3 of the 6 doses, then additional patients (Dose Level 5) will be enrolled at the next dose level:

Cohort 5b: 3 patients on Sotatercept 1 mg/kg every 3 weeks with a 3 week prednisone boost of 1 mg/kg/day (max 60 mg).

Protocol documents:
Prot_SAP_000.pdf: 
 
  
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Phase I/II, Open-Label Study to Determine Safety and Efficacy of  
Sotatercept (ACE-011) in Adults with  
Red Blood Cell Transfusion-Dependent Diamond Blackfan Anemia 
 
PROTOCOL NUMBER: 
ACE-011-DBA-PI-0001 
DATE PROTOCOL FINAL: 
30JUN2018 
STUDY DRUG: 
Sotatercept (ACE-011) 
INDICATION: 
Adults with Diamond Blackfan anemia and red blood 
cell transfusion dependence 
STUDY PHASE: 
Phase I/II 
BACKGROUND AND RATIONALE: 
Diamond Blackfan Anemia 
 
Diamond Blackfan anemia is a rare inherited pure red cell aplasia.  Over the past ten years 
mutations have been described in genes encoding both the small and large ribosome 
associated proteins (Draptchinskaia, 1999; Gazda, 2006; Cmejla, 2007; Farrar, 2008; Gazda, 
2008; Doherty, 2010; Landowski, 2013; Mirabello, 2014; Farrar, 2015). There is wide variability 
in clinical and biologic features, familial history, and therapeutic responses. Currently standard 
therapy includes corticosteroids, red blood cell (RBC) transfusions or hematopoietic stem cell 
transplantation (SCT) (Vlachos, 2001a).  Approximately 80% of patients have an initial 
response to corticosteroids.  Of these patients, approximately half will fail to achieve a taper to 
a tolerable steroid dose and will need to discontinue steroid therapy.  These patients and the 
20% who do not respond initially to steroid therapy must be maintained on a chronic red cell 
transfusion/iron chelation program.  Chronic transfusion/chelation therapy has considerable 
treatment-related morbidity, most notably iron overload related organ failure.  
Hematopoietic stem cell transplant has proved to be effective therapy for a select group of 
patients.  Allogeneic stem cell transplantation with a histocompatible donor has been performed 
successfully in a number of patients.  The Diamond Blackfan Anemia Registry of North America 
(DBAR) experience has been published (Vlachos, 2001b; Lipton, 2006).  However, because of 
remissions (sustained physiologically acceptable erythropoiesis for > 6 months without any 
medication or transfusion) in up to 20% of DBA patients, stem cell transplantation, regardless 


 
  
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of donor type, is not consistently offered to corticosteroid-dependent or transfusion-dependent 
DBA patients.  For many patients, the lack of a suitable donor does not allow stem cell 
transplantation as a therapeutic option, as human leukocyte antigen (HLA) matched unrelated 
donor transplants have been associated with mortality and morbidity.   
Historically the lack of truly effective and safe therapy has prompted the investigation of a 
number of other agents, including high-dose corticosteroids, immunosuppressive therapy 
(cyclosporine A and antithymocyte globulin), intravenous immunoglobulin, high-dose 
erythropoietin, interleukin-3, metoclopramide and others; however, these modalities have 
achieved, at best, anecdotal success (Vlachos, 2008). 
 
Pathophysiology 
 
Although somewhat controversial, there are data that suggest an intrinsic impairment of 
erythroid differentiation at the level of the erythroid burst-forming unit (BFU-E).  The 
consequence is a decrease in differentiated erythroid colony forming cells (CFU-E) and in 
mature RBCs.  The defect appears to be at the junction between erythropoietin (EPO)-
independent and EPO-dependent BFU-E (Ohene-Abuakwa, 2005; Da Costa, 2010).  Other 
data suggest the defect occurs later in many patients at the CFU-E/erythroblast level (Lipton, 
1986; Narla, 2011). However, most persons with DBA have increased levels of erythropoietin 
and there is no improvement in anemia with pharmacologic doses of erythropoietin. 
Many persons with DBA have mutations in genes encoding structural proteins of the small 
ribosomal subunit (Gustavsson, 1997; Willig, 1999) including RPS19, RPS7, RPS10, RPS17, 
RPS24, RPS26, and RPS 29 or large subunit RPL5, RPL11, RPL15, RPL31, and RPL35A.  
Some mutations of unknown significance are reported in other RP genes (Doherty, 2010).  
However, 25-30% of persons with DBA have no detectable RP mutation.  This suggests other 
mechanisms.  Some phenotype/genotype correlations are known relating to congenital 
abnormalities (Gazda, 2008; Quarello, 2010).   
 
Diagnosis 
 
DBA diagnosis relies on several clinical and biological features.  Classic criteria are: (1) 
macrocytic, normochromic, anemia; (2) reticulocytopenia; (3) bone marrow erythroid 
hypoplasia; (4) early onset of anemia (90% present before age one year) (Alter, 1976).  


 
  
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Congenital anomalies can affect the face, arms or hands, urogenital tract, and heart.  Short 
stature and subsequent growth impairment are common.  Most affected persons have 
increased erythrocyte adenosine deaminase (Glader, 1983) and hemoglobin (Hb) F.  These 
findings are non-specific but provide supporting evidence for diagnosing non-classical DBA.  
The criteria for both classical and non-classical diagnoses have been updated (Vlachos, 2008). 
 
Therapy 
 
The two main therapeutic options are corticosteroids and RBC transfusions.  About 80% of DBA 
patients initially respond to corticosteroids.  Persons failing to respond are typically dependent 
on RBC transfusions throughout life.  Other therapies such as interleukin-3 (Bastion, 1994), 
high dose corticosteroids, cyclosporine, anti-thymocyte globulin, immunoglobulin (reviewed in 
Vlachos, 2008) and metoclopramide (Abkowitz, 2002; Leblanc, 2007), are either of unproved 
benefit and/or seem to benefit relatively few patients.  Pharmacological doses of erythropoietin 
are ineffective.  Hematopoietic stem cell transplantation is the sole cure for the hematologic 
manifestation of DBA-related anemia but is usually only considered in corticosteroid-resistant 
persons because of substantial morbidity and mortality.  Typically only transplants from HLA-
identical sibling are considered; however, recent results show marked improvement in HSCT 
from unrelated HLA-molecularly matched donors.  The best age at which to perform a transplant 
appears to be under 10 years of age (Vlachos, 2008). 
 
Activin Biology 
 
Sotatercept (ActRIIA-IgG1) is a humanized fusion-protein consisting of the extracellular domain 
of activin-receptor type IIA (ActRIIA) and the human IgG1 Fc domain.  RAP-011 is the murine 
homologue of Sotatercept.  Sotatercept and RAP-011 bind with high affinity to activin-A, 
blocking signaling through the endogenous ActRIIA-receptor.  Activin-A is an erythroid-
differentiation-factor (EDF) affecting late stages of RBC maturation (Murata, 1988). Substantial 
increases in hematocrit, hemoglobin and RBC numbers were observed in mice, rats and 
cynomolgus monkeys receiving RAP-011 or Sotatercept.  Similar changes occur in rodent 
models of chemotherapy-induced anemia and chronic kidney failure.  The mechanism(s) 
underlying these observations are not fully understood.  Some immediate effects of Sotatercept 


 
  
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appear related to changes in plasma volume.  However, long-term effects, independent of 
plasma volume, are substantial and are erythropoietin-independent. 
 
Non-Clinical Safety Studies 
 
Repeat-dose toxicology studies of Sotatercept of up to 3 and 6 months duration were done in 
rats and monkeys.  In addition, a 3-month repeat-dose study in mice was done using RAP-011.  
Sotatercept-related effects were identified in the following organs/tissues: hematologic (rat and 
monkey), reproductive (rat only), adrenals (rat only), pancreas (rat only), and kidney (rat and 
monkey).  In mice administered RAP-011, test article related effects were identified in the 
following organs/tissues:  bone marrow, brain, kidney, heart and lungs. 
Hematological (increased RBC parameters) and reproductive (epididymal granulomas, 
testicular degeneration, decreased sperm counts and motility, and changes in ovarian/uterine 
weights) findings are expected pharmacodynamic effects of ActRIIA signal inhibition.  These 
likely occur via modulation of erythropoiesis and follicle-stimulating hormone (FSH) secretion, 
respectively.  Only rats had adrenocortical (i.e., adrenal gland congestion or necrosis) and 
pancreatic (i.e., acini atrophy) findings.  Neither finding was associated with clinical signs of 
adrenocortical (anorexia, weakness, gastrointestinal or serum electrolyte disturbances) or 
pancreatic 
(abnormal stool, 
weight 
loss) 
insufficiency. 
 
Kidney 
findings 
include 
glomerulonephritis and/or tubulo-interstitial nephritis or tubular degeneration/necrosis in rats, 
monkeys and mice.  The glomerulonephritis was presumed to be from anti-Sotatercept antibody 
deposition.  In the chronic monkey study with Sotatercept and in the mouse studies using RAP-
011, kidney tubular changes were seen which did not correlate with glomerular lesions.  Tubular 
lesions without glomerular findings are not typical of anti-drug antibody deposition in the kidney 
and may represent a direct effect of Sotatercept.  Because tubular changes were observed at 
all dose levels, a second chronic monkey study using lower doses is in progress.  Mineralization 
of the choroid plexus, myocardial degeneration and alveolar histiocytosis were seen in mice 
receiving RAP-011 intra-peritoneally (IP) at doses ≥10 mg/kg.  NOAELs (No Observed Adverse 
Effect Level) from the 3-month toxicology studies of Sotatercept were noted at 3 and 30 mg/kg 
in rats and monkeys.  Plasma exposures (AUC) at these doses are estimated to be 8- and 207-
fold higher in rats and monkeys than the anticipated exposure in humans at the proposed dose 
of 0.1 mg/kg. 


 
  
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Animal Model Data 
Mice treated with RAP-011 (murine ortholog of ACE-011) respond with a rapid  increase in 
hematocrit, Hb, and RBC count (Carrancio, 2014). These effects are accompanied by an 
equally rapid stimulation of late-stage erythroid precursors in the bone marrow. RAP-011 also 
induces a significant increase in erythroid burst-forming units and erythropoietin, which could 
contribute to additional, sustained effects on RBC production. RAP-011 also was noted to have 
an effect in zebrafish models of ribosome insufficiency on RPS19 and RPS11. Treatment with 
RAP-011 restored Hb levels in these zebrafish. The beneficial effect of RAP-011 was also found 
to be synergistic with corticosteroid treatment (Ear, 2013). 
 
Clinical Data 
 
A011-01: A Phase-1a Study in Healthy, Post-Menopausal Women 
One dose of Sotatercept was given by intravenous (IV)-infusion or a subcutaneous (SC)-
injection (Ruckle, 2009).  Intravenous dose levels were 0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg.  
Subcutaneous dose levels were 0.03 and 0.1 mg/kg.  Forty-eight subjects were studied: 5 active 
subjects and 1 placebo subject at each IV and SC dose level.  All subjects were followed for 4 
months. 
Pharmacokinetics (PK) of IV Sotatercept were linear; mean exposure (AUC) was proportional 
to dose.  Mean clearance (CL) of IV doses was 0.092-0.128 mL/hr/kg, volume of distribution, 
73.7-110 mL/kg, and mean t1/2,z was 23.7-31.8 days (independent of dose).  SC Sotatercept 
was completely absorbed.  Mean t1/2, z was about 30 days (independent of dose). 
Treatment-emergent adverse events (AEs) occurring in >1 subject in any cohort were 
headache, infusion site reaction, injection site hemorrhage, and toothache.  Most injection site 
reactions and hemorrhages were in the first IV cohort and were related to infiltration.  Most 
treatment-emergent AEs were mild and judged unrelated to Sotatercept.  No deaths, serious 
AEs (SAEs) or AEs leading to study discontinuation were reported. 
 
A011-02: A Phase 1b Study in Healthy Post-Menopausal Women  


 
  
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Four cohorts of 10 subjects each were planned at 0.1, 0.3, 1, and 2 mg/kg given SC every 28 
d for 4 doses.  Subjects were randomized to Sotatercept or placebo at a 4:1 ratio within each 
cohort.  Subjects were followed for 4 months after the last dose. 
The treatment phase of the study was terminated early after a dose-limiting pharmaco-dynamic 
effect was seen. 
Thirty-one subjects received Sotatercept doses of 0.1, 0.3, and 1 mg/kg (cohorts-1, 2, and 
3)(Sherman, 2013).  All subjects randomized to active treatment in cohort-1 received the 4 
planned doses of Sotatercept.  Subjects randomized to active treatment in cohort-2 received 3 
doses of Sotatercept.  Subjects randomized to active treatment in cohort-3 received 2 doses of 
Sotatercept because of early discontinuation of the investigational product after a dose-limiting 
pharmacodynamic effect was observed.  Subjects randomized to placebo treatment received 
1-4 doses of study treatment.  Multiple doses of Sotatercept given subcutaneously produced a 
rapid and dose-dependent increase in hemoglobin evident by Day 8 in the 3 cohorts compared 
with placebo.  Mean increases in hemoglobin were 0.68, 0.85, and 1.21 g/dL in the 0.1, 0.3, 
and 1 mg/kg dose cohorts compared with 0.17 g/dL for placebo. Increases were generally 
sustained for about 2 months following the last dose.  One subject experienced a maximum 
increase of 6.4 g/dL on Day 36 after the second dose of 1 mg/kg of Sotatercept.  Similar trends 
were observed in RBCs and hematocrit. However, mean and/or median reticulocytes did not 
fluctuate significantly in Sotatercept treatment arms versus placebo subjects. 
A subject in the 1 mg/kg cohort had progressive hypertension coincident with a rapid rise in 
hemoglobin and hematocrit.  Symptoms included headache, nausea, eye pain, dizziness and 
vomiting.  Hypertension was managed with anti-hypertensive drugs and phlebotomy. The SAE 
was considered probably related to Sotatercept and resolved (see Investigator Brochure).  The 
Sponsor (Acceleron Pharma, Inc) therefore suspended escalation to the 2.0 mg/kg dose level 
and further dosing in all cohorts. 
An SAE of right knee re-injury was reported in a 50-year-old female with a prior motor vehicle 
accident in the 0.3 mg/kg cohort.  The re-injury resulted in a total right knee replacement.  The 
SAE resolved and was considered by the Investigator unrelated to Sotatercept. 
The most common AEs were those related to increases in hematological laboratory parameters 
in the 1 mg/kg cohort, including increased hemoglobin and/or hematocrit in 7 of 8 subjects.  


 
  
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These events were mild or moderate and judged probably related to Sotatercept.  Three 
subjects in the 1 mg/kg cohort had phlebotomies.  All hemoglobin and hematocrit increases 
resolved.  No erythroid-lineage AEs were reported in the 0.1 or 0.3 mg/kg cohorts.  Hemoglobin 
levels in all subjects returned to normal by study end. 
Mean AUC28d and mean Cmax were proportional to dose at 0.1-1 mg/kg following the 1st SC 
dose.  The terminal half-life (t1/2,z) of Sotatercept following the last dose in all three cohorts 
were identical, with mean of 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 ranged from 97.47 to 103.03 mL/kg and 
was dose-independent. 
Bone mineral density (BMD) was assessed by dual-energy X-ray absorption spectroscopy 
(DXA).  A dose-dependent increase in hip BMD was seen with a significant and rapid increase 
of 2.4% in the 1 mg/kg cohort compared to a 0.7% decrease in the placebo cohort.  BMD results 
for lumbar spine showed slight increases of 0.4% to 1% from baseline to study end in all cohorts 
compared with a 0.5% decrease in the placebo cohorts. 
 
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 and efficacy of Sotatercept in subjects with osteolytic lesions of multiple myeloma 
(MM)(Abdulkadyrov, 2014).  Subjects were randomized 4:1 to one of three dose levels of 
Sotatercept (0.1, 0.3 and 0.5 mg/kg) or placebo given every 28 days by SC injection for up to 4 
doses over a 3-month period.  Sotatercept was evaluated in combination with anti-myeloma 
therapy with melphalan (4 mg/m2 on days 1-7), prednisolone (40 mg/m2 on days 1-7) and 
thalidomide (100 mg per day continuously) (MPT).  Each cycle was repeated every 4 weeks for 
up to 6 cycles.  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, 8 subjects received 0.3 mg/kg 
Sotatercept, and 8 subjects received 0.5 mg/kg Sotatercept.  Twenty six (87%) subjects 
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 


 
  
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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% of subjects were female and the mean (range) age was 60.9 (41 to 79) years.  
Mean time since diagnosis of MM was 3.3 years; the majority of subjects had stage III disease 
at screening (83%) and were heavily pretreated having received up to 7  prior chemotherapy 
regimens (93%). Forty-three percent of subjects were receiving bisphosphonates at screening 
and were continued on-study. 
Fourteen subjects received  3 doses of Sotatercept (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).  Twenty-two (92%) subjects receiving Sotatercept and 4 (68%) subjects receiving 
placebo reported at least one AE. Grade 3-4 AEs, regardless of attribution, were reported in 
58% of subjects receiving Sotatercept and 17% of patients receiving placebo; no dose-related 
effect was apparent.  Most subjects had AEs that were assessed as related to MPT:  21 (88%) 
subjects receiving Sotatercept and 4 (68%) subjects receiving placebo.  No AEs were assessed 
by the Investigator as related to the study medication alone (Sotatercept 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 dose group (increased blood 
pressure; sudden death) and one subject in the 0.5 mg/kg Sotatercept dose group 
(hypertension).  Four subjects had SAEs, 1 (13%) subject in the 0.1 mg/kg Sotatercept group 
and 3 (38%) subjects in the 0.5 mg/kg Sotatercept 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, and 1 SAE (sudden death) was assessed 
as probably related to MPT and possibly related to Sotatercept.  One subject in the 0.5 mg/kg 
Sotatercept dose group discontinued study drug due to episodes of atrial fibrillation assessed 
as possibly related to MPT and unrelated to Sotatercept. 
Increased Hb levels were observed in all Sotatercept dose groups, with a trend towards a dose-
response relationship. 
Please refer to the Investigator’s Brochure for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event profile of 
Sotatercept. 


 
  
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Protocol ACE-011-MDS-001:  An Open-Label, Phase 2, Dose-Finding Study of 
Sotatercept (ACE-011) in Patients With Low- or Intermediate (Int)-1-Risk Myelodysplastic 
Syndromes (MDS) or Non-Proliferative Chronic Myelomonocytic Leukemia (CMML) and 
Anemia Requiring Transfusion 
Study ACE-011-MDS-001 is a phase 2, open-label, dose-finding, multiple-dose study to 
determine a safe, tolerable, and effective dose of Sotatercept in patients with anemia and 
International Prognostic Scoring System (IPSS)-defined Low- or Intermediate (Int)-1-risk MDS 
or non-proliferative chronic myelomonocytic leukemia (CMML).  Interim data are available and 
were presented at the 56th Annual Meeting of the American Society of Hematology (ASH) in 
December 2014 (Komrokji, 2014). Patients received subcutaneous Sotatercept at dose levels 
0.1, 0.3, 0.5, or 1 mg/kg once every 3 weeks. The primary efficacy endpoint was rate of erythroid 
hematologic improvement as defined by modified International Working Group (IWG) 2006 
criteria. The secondary endpoints included rate of achievement of RBC transfusion 
independence (TI) > 56 days and safety.  
A total of 54 MDS patients were enrolled as of the time of this interim report. Forty-six of 54 
patients (85%) had a red blood cell (RBC) transfusion burden of >4 units/56 days (high 
transfusion burden; HTB) while 8 of 54 patients (15%) had a RBC transfusion burden of < 4 
units/56 days (low transfusion burden; LTB). In this study, 30% of subjects were female and the 
median (range) age was 71 (56 to 86) years.  Median time since original diagnosis was 4 years.  
Ninety-six percent of subjects had prior use of erythropoiesis-stimulating agents. The median 
(range) red blood cell (RBC) transfusion burden was 6 (0-16) units in 8 weeks.  
One patient in the 0.5 mg/kg dose group was excluded from efficacy analysis due to protocol 
violation. Of the 53 patients evaluable for efficacy, erythroid hematologic improvement was 
achieved in 24 patients (45%): 
– 0.1 mg/kg: 0 patients (0%) (n=7) 
– 0.3 mg/kg: 4 patients (67%) (n=6) 
– 0.5 mg/kg: 8 patients (40%) (n=21) 
– 1 mg/kg: 12 patients (60%) (n=20) 


 
  
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Nineteen of 45 HTB patients (42%) responded with a reduction in transfusion burden of > 4 
RBC units/56 days. The duration of transfusion response appeared to be dose dependent. Five 
HTB patients (11%) achieved RBC-transfusion independence (TI) > 56 days. The duration of 
RBC-TI ranged from 59 to 345+ days. In the LTB group, over any 8-week transfusion-free 
period, 5 of 8 patients (63%) achieved both a mean Hb increase >1.5 g/dL sustained for >56 
days and RBC-TI >56 days. The maximum mean Hb increases ranged from 1.9 to 4.4 g/dL and 
the duration of RBC-TI ranged from 76 to 233+ days. Sotatercept was generally well tolerated. 
Three patients discontinued due to treatment-emergent adverse events (TEAEs) considered 
suspected related to Sotatercept: 1 patient with grade 2 hemolytic anemia; 1 patient with grade 
3 hypertension; and 1 patient with grade 2 muscle weakness in the 0.3, 0.5, and 1 mg/kg dose 
groups, 
respectively. 
Other 
suspected 
treatment-related 
adverse 
events 
included 
fatigue/asthenia (13%); headache (9%); decreased appetite (7%); nausea (7%); and dyspnea 
(6%). Three subjects had Grade 3-4 TEAEs, all occurring at the 0.5 mg/kg dose level: 1 patient 
had grade 3 pain in both thighs; 1 patient had grade 3 hypertension; and 1 patient had 
transformation to acute leukemia approximately 5.5 months after study treatment 
discontinuation. The investigator could not rule out a contributory role of Sotatercept. These 
data support further exploration of higher Sotatercept dose levels; longer-term treatment is 
ongoing in both HTB and LTB lower-risk MDS patients. 
 
Protocol ACE-011-B-THAL-001: An Ongoing Phase 2a, Open-Label, Dose-Finding Study 
To Determine The Safety, Efficacy, And Tolerability Of Sotatercept (Ace-011) In Adults 
With Beta-Thalassemia 
This ongoing phase 2a, multicenter, open-label, dose-finding study aims to determine a safe 
and effective dose of Sotatercept in β-thalassemia major patients with transfusion-dependent 
thalassemia (TDT), and β-thalassemia intermedia patients with TDT or non-transfusion-
dependent thalassemia (NTDT). Patients received Sotatercept 0.1, 0.3, or 0.5 mg/kg 
subcutaneously once every 3 weeks; dose escalation to 0.75 mg/kg is ongoing. Efficacy is 
assessed by haemoglobin (Hb) increase from baseline for NTDT patients and RBC transfusion 
burden reduction for TDT patients. 
Of the 25 patients enrolled, 72% had NTDT and 28% had TDT. Six NTDT patients were treated 
in each dose group (0.1, 0.3, and 0.5 mg/kg); median (range) baseline Hb was 8.7 g/dL (6.1–


 
  
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10.7), 8.3 g/dL (6.0–9.5), and 8.2 g/dL (6.4–9.3), respectively. In the first 3 cycles, Hb increases 
of ≥ 1.0 g/dL were seen in 0, 5 (83%), and 5 (83%) patients, respectively. Hb increases of ≥ 2.0 
g/dL were seen in 0, 1 (17%), and 2 (33%) patients, respectively. No appreciable transfusion 
burden reduction was seen for TDT patients in the 0.1 and 0.3 mg/kg groups; 0.5 mg/kg group 
treatment is ongoing. Increased Sotatercept exposure was associated with higher Hb increases 
in the first 3 cycles for NTDT patients (n = 17; r = 0.77, P < 0.001). Sotatercept was well 
tolerated: 19 (76%) patients remain on treatment. Three grade ≥ 2 treatment-related adverse 
events leading to discontinuation were reported; 3 patients discontinued due to lack of efficacy. 
 
These preliminary data suggest Sotatercept every three weeks increases serum Hb in β-
thalassemia and MDS patients, improving anemia; these effects appear to be dose-dependent. 
Sotatercept may provide clinical benefit with a favorable safety profile. Our DBA patients have 
already completed 0.1, 0.3 and 0.5 mg/kg/dose every 4 weeks for 4 cycles. The patients have 
had no Grade 4 toxicities. We are now amending this study to increase the dose further and 
increase the interval to every 3 weeks like the patients with beta-thalassemia and 
myelodysplastic syndrome have been receiving and tolerating with a positive response. 
 
 
OBJECTIVES: 
 
Primary Objective(s) 
 
Determine a safe and effective dose of Sotatercept in adults with DBA and RBC 
transfusion dependence 
Secondary Objective(s) 
 
Determine time to response 
 
Determine response duration 
 
Evaluate the safety profile of Sotatercept in adults with DBA and RBC transfusion 
dependence 
Exploratory Objective(s): 
 
Evaluate effects of Sotatercept on bone densitometry 
 
ENDPOINTS: 


 
  
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Primary Endpoint(s): 
 Complete response (CR):  transfusion-independent and Hb > 9 gm/dL  
 Partial response (PR): increase in transfusion interval from baseline and Hb < 9 gm/dL 
with an increase in reticulocyte count  
Secondary Endpoint(s): 
 
Time to response 
 
Response duration 
 
Safety (type, frequency, and severity of adverse events and relationship to Sotatercept 
[according to the currently active minor version of National Cancer Institute (NCI) 
Common Terminology for Adverse Events (CTCAE) version 4.0]). 
Exploratory Endpoint(s): 
 
Improvement of bone density as measured by bone densitometry (DEXA scan) 
 
INDICATION: 
 
Adults with DBA and red blood cell transfusion dependence. 
 
STUDY DESIGN: 
 
This study is a single-center, phase I/II, open-label, dose-escalation study to determine a safe 
and effective dose of Sotatercept in adults with DBA and RBC-transfusion-dependence. Three 
cohorts have already completed 0.1, 0.3 and 0.5 mg/kg/dose every 4 weeks for 4 cycles. The 
patients have had no Grade 4 toxicities. Thus this study will increase the dose further and 
increase the interval between the doses to that which patients with beta-thalassemia and 
myelodysplastic syndrome have been receiving and tolerating with a positive response.  
Cohorts of 3 subjects will receive Sotatercept starting with a dose of 0.75 mg/kg (dose level 4).  
Subsequent dose levels are specified in Table 1.  Subjects will receive Sotatercept SC once 
every 21 days for up to 6 doses.  The subsequent cohorts may begin after and only after all 3 
subjects in the previous cohort have completed 28 days following their 4th dose of Sotatercept 
(or last dose if Sotatercept is not discontinued for safety reasons) and safety has been 
determined to proceed.  Non-responders at lower dose-levels may receive Sotatercept at the 
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Definition of Recommended Dose: 
 
The recommended dose of Sotatercept is defined as the lowest dose level determined safe and 
effective.  The dose levels to be evaluated in this study are listed below (Table 1): 
Table 1:  Sotatercept Dose Levels 
Dose Level 
Dose 
Frequency 
Status 
Dose Level 1 
0.1 mg/kg 
Every 4 weeks 
Completed 
Dose Level 2 
0.3 mg/kg 
Every 4 weeks 
Completed 
Dose Level 3 
0.5 mg/kg 
Every 4 weeks 
Completed 
Dose Level 4 
0.75 mg/kg 
Every 3 weeks 
This study 
Dose Level 5 
1 mg/kg 
Every 3 weeks 
This study 
 
Dose: 
 
Three dose levels of Sotatercept have already been studied (0.1, 0.3 and 0.5 mg/kg).  Dose 
selection was based on safety and exposure-response data from study A011-04 where subjects 
received up to 4 treatments of Sotatercept at 0.1, 0.3, or 0.5 mg/kg.  Sotatercept was safe and 
exposure-dependent increases in hemoglobin were observed.  There was no relationship 
between increased blood pressure, Sotatercept maximum concentration and maximum 
hemoglobin increase (Report A011-04-CP).  Further increased dose levels have been used in 
beta-thalassemia and myelodysplastic syndrome without untoward side effects and with good 
response. This study has not had a response to the initial three doses and has had no significant 
side effects. Therefore, the study is now amended to two new dose levels of 0.75 mg/kg and 1 
mg/kg. Also the previous dose levels were given every 4 weeks. New studies have shown 
increased effectiveness at every 3 week dosing. Thus the 4th and 5th dose levels will be given 
every 3 weeks.    
 
Also as noted above there are data that corticosteroids are synergistic with the ortholog of 
Sotatercept. Aside from red cell transfusion, corticosteroids are a mainstay of treatment for 
DBA. Patients may respond to high doses of corticosteroids and then be weaned to a lower 
dose. The transfusion dependent patients may have been responsive in the past and “lost” their 


 
  
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response due to an intercurrent illness or some other unknown trigger. We postulate that 
patients who had a response in the past may respond to Sotatercept if given a priming dose of 
steroids concurrently. We therefore will stratify patients with regards to their ability to take a 
standing ‘start-up’ dose of corticosteroids as follows: 
a- If a patient has no contraindication to corticosteroid therapy (as noted below), then the 
patient will start prednisone 1 mg/kg/day (max of 60 mg daily) for 3 weeks concurrent with 
first dose of Sotatercept. At the second dose (3 weeks later) the prednisone will be weaned 
to 0.67 mg/kg/day (max 40 mg daily) for 4 days and then 0.33 mg/kg/day (max 20mg daily) 
for 3 days. The prednisone will be discontinued 1 week after the 2nd dose of Sotatercept. 
b- If a patient has a contraindication to corticosteroid therapy (as noted below), then the patient 
will begin Sotatercept without any concurrent prednisone treatment. 
c- A patient is deemed to have a contraindication to corticosteroid therapy if he/she has a 
history of cataracts, glaucoma, pathologic fractures, diabetes mellitus, or steroid psychosis. 
d- A patient can opt out of the steroid arm if he/she has had other untoward steroid effects and 
would otherwise refuse participation in the trial if steroids were mandatory. 
 
The trial will therefore be structured as such: 
The first patients (Dose level 4) will be stratified by whether they can tolerate a course of 
Prednisone and be divided into:  
   Cohort 4a: 3 patients on Sotatercept 0.75 mg/kg with Prednisone 
   Cohort 4b: 3 patients on Sotatercept 0.75 mg/kg without Prednisone  
If the patients have no untoward events in the Patients in Dose Level 4 by the end of 3 of the 6 
doses, then additional patients (Dose Level 5) will be enrolled at the next dose level: 
   Cohort 5a: 3 patients on Sotatercept 1 mg/kg with Prednisone  
   Cohort 5b: 3 patients on Sotatercept 1 mg/kg without Prednisone 
Recruitment to Dose Level 5 can proceed independently for each of the cohorts, i.e. once the 
patients in Cohort 4a have completed 3 of the 6 doses without untoward events, patients can 
be enrolled into Cohort 5a, even if not all the patients have been recruited to Cohort 4b.   
 


 
  
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Dose Escalation / De-escalation Rules 
 
The study follows a sequential dose-escalation design.  The decision of whether to open Dose 
Level 5 will be made once the last of three subjects at Dose Level 4 completes the 3rd dose of 
Sotatercept and safety has been determined to proceed.  The following dose-escalation rules 
will be used: 
 
3 subjects are entered into each cohort at Dose Level 4 (0.75 mg/kg); 
 
If no subject experiences a dose-limiting toxicity (DLT) by the 3rd dose of Sotatercept, 
Dose Level 5 (1 mg/kg) is opened; 
 
If 1 of 3 subjects in a cohort in Dose Level 4 has a DLT, 3 more subjects are enrolled 
into that cohort at the same Dose Level 4. 
 
If there are no additional DLTs by the 3rd dose, Dose Level 5 is opened. 
 
If ≥ 2 subjects in a cohort at Dose Level 4 have a DLT (other than an increase in 
hemoglobin), that cohort will be discontinued. 
 
The cohort without DLT and with an appropriate Hb response will be chosen to be the 
maximum tolerated dose (MTD). 
 
Up to a total of 8 additional subjects will be entered into the MTD. 
 
Definition of Dose-Limiting Toxicity 
 
A DLT is defined as: 
 
Inability to deliver the scheduled doses because of toxicity.  These subjects should be 
discontinued from the Treatment Period and continue in the Follow-Up Period for 1 
month from their last dose; OR 
 
Any toxicity  Grade 3; 
Should a subject leave the study before completing 3 doses of Sotatercept during the treatment 
period for reasons other than a DLT, one (1) additional subject will be added to that dose level. 
 
Dose Modifications 
 
At each dose level the 2nd or 3rd doses can be delayed in case of hypertension > Grade 2 and/or 
sustained increase of hemoglobin  2 gm/dL from the previous dose except those attributed to 
RBC transfusions.  Table 2 lists guidelines for dose modifications: 


 
  
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* Dose delay of Sotatercept is defined as a dose not administered > 4 days from the planned 
dosing dated due to Hb ≥ 10 gm/dL, hypertension ≥ SBP 150 mmHg and DPB ≥ 100 mmHg 
and/ or Sotatercept related toxicity.  
 


 
  
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Table 2 provides guidelines for dose modifications: 
Table 2:          Dose Modification, Dose Reduction and Dose Delay Guidelines 
NCI CTCAE 
Toxicity Grade 
Event 
Action 
≥ Grade 2 
Hypertension 
Dose delaya 
Hold until resolved < Grade 2 
 Grade 3 
Other non-hematological AEs 
Dose delay a 
Hold until resolved  Grade 1 
  
Hemoglobin (Hb)  
  
If Hb ≤ 12.5 g/dLb  and: 
  
  
- Δ Hb < 2g/dL at Day 21 
from last dose 
Continue dosing following 
schedule at the same Dose 
Level. Hypertension should be 
< Grade 2. 
  
- Δ Hb > 2g/dL at Day 21 
from last dose 
Dose Reduce to the Previous 
Dose Level. Hypertension 
should be < Grade 2. 
  
If Hb > 12.5 g/dLb ≤ 14g/dLb  for less than 
4 weeksc, and: 
 
 
- Δ Hb < 2g/dL at Day 21 from 
last dose 
Dose delay for up to an 
additional 12 weeks until Hb < 
12.5 g/dL, and hypertension < 
Grade 2; continue dosing at 
the same dose level. 
 
 
- Δ Hb > 2g/dL at Day 21 from 
last dose 
Dose delay for up to an 
additional 12 weeks until Hb < 
12.5 g/dL, ΔHb<2 g/dL and 
hypertension < Grade 2, AND 
one Level Dose reduce to the 
previous dose level. 
  
If Hb > 14g/dLb sustained for 4 
weeks (confirmed by laboratory 
assessment)c 
Discontinue treatment 
  
If a subject experiences  ≥ 3 Dose 
Reductions 
Discontinue treatment 
a Dose delay of Sotatercept is defined as a dose not administered > 4 days from the planned dosing date due to 
Hb > 12.5g/dL and/or hypertension ≥ Grade 2 according to NCI CTCAE criteria and/or Sotatercept-related 
toxicity ≥ Grade 3. 
b Based on the pre-transfusion/pre-treatment Hb value at the time of re-treatment. 
c If Hb > 12.5 g/dL, Hb measurement should occur every week. 
If dosing of a subject is delayed for more than 12 weeks (up to a maximum of 15 weeks delay 
from the previous dose administered), the treatment should be discontinued. 


 
  
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Treatment Discontinuation 
 
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product and/or from the study: 
• 
Hb > 14 g/dL (not influenced by transfusions), sustained for ≥ 4 weeks, confirmed by 
weekly assessments. 
• 
Hypertension DLT as defined below. 
• 
Any other (i.e., excluding Hb and hypertension) treatment-related (suspected) toxicity ≥ 
Grade 3. 
• 
Treatment-related (suspected) toxicity ≤ Grade 2 that delays treatment by more than 3 
months. 
• 
Adverse event that, in the judgment of the investigator, may cause severe or permanent 
harm or that rules out continuation of treatment. 
• 
Hypersensitivity reaction to Sotatercept. 
• 
Withdrawal of consent. 
• 
Death. 
• 
Lost to follow-up. 
• 
Pattern of significant noncompliance. 
• 
Completed study, per protocol (6 complete cycles of 21 days each).  Subjects who have 
a sustained Hb increase or a decreased transfusion burden by end of Cycle 6 but for a period 
less than or equal to 8 consecutive weeks (potential late responders) may continue treatment 
for up to an additional two cycles (Cycles 7-8) for the purpose of meeting response criteria.   
The reason for treatment discontinuation should be recorded in the CRF and in the source 
documents. 
 
Closure of the Study 
Celgene reserves the right to terminate this study at any time for reasonable medical or 
administrative reasons. Any premature discontinuation will be appropriately documented 
according to local requirements (eg, IRB, regulatory authorities, etc.). 
In addition, the investigator or Celgene has the right to discontinue a single site at any time 
during the study for medical or administrative reasons such as: 


 
  
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• 
Unsatisfactory enrollment; 
• 
GCP noncompliance; 
• 
Inaccurate or incomplete data collection; 
• 
Falsification of records; 
• 
Failure to adhere to the study protocol. 
 
 
SCHEDULE OF STUDY ASSESSMENTS: 
 
See Table 4 
 
PHASE OF DEVELOPMENT: 
 
Phase I/II study 
 
SUPPORT:  
 
Celgene 
86 Morris Avenue 
Summit, NJ 07901 USA 
 
STUDY PRODUCT: 
 
SOTATERCEPT (ACE-011) 
DESCRIPTION OF STUDY TREATMENTS 
Description of Investigational Product(s) 
Process III Clinical Drug Product - Lyophilized Powder: 
 
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 stoppered, sealed, 3-mL glass vials. 
 
The recommended storage temperature for Sotatercept lyophilized drug product is 2°C 
to 8°C. 
o Prior to administration, the lyophilized drug product is reconstituted with 1 mL 
water for injection (WFI).  The reconstituted drug product consists of a 50 
mg/mL solution of Sotatercept.  The reconstituted Sotatercept, in its original 


 
  
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container closure system, 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 
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. 
 
Sotatercept lyophilized product will be shipped to the investigational site with a 
TempTale monitor in an appropriate nomadic shipper. 
Shipping / TempTales 
All shipments include instructions for the TempTale device within the shipper. All TempTales 
are to be stopped immediately upon receipt and unpacking of the shipment. Follow the 
TempTale Instruction Sheet in the shipper for handling of the temperature monitoring device.  
 
If the TempTale does not have an alarm bell showing in the screen, the IP was shipped 
and received in the appropriate temperature range.  The temperature parameters 
should be checked and documented on the TempTale instruction sheet and the IP 
would be ready for use. 
 
Please note: if the alarm bell is showing on the TempTale display upon receipt of 
shipment and stopping of the TempTale, please store the material appropriately and 
quarantine it from use.  Notify Celgene of the excursion right away and await 
confirmation that the IP is acceptable for use or is to be returned or destroyed. 
Sotatercept Preparation and Administration 
The clinical staff will fill out the following information on the Sotatercept Drug Accountability 
Log (see Appendix 8) on the dosing day: 
 
Date 
 
Visit 
 
Subject Number 
 
Subject Initials 
 
Dose 
 
Number of mLs used 
 
Lot Number 
 
Time Drug Removed from Refrigerator/Freezer (24 hr clock) 
 
Time Subject Dosed (24-hour clock) 
 
The site personnel will confirm the lot # (for Sotatercept), the number of vials used, and the total 
volume of Sotatercept given and record this information in the source documents and in the 
pharmacy records. 
 
Preparation of Sotatercept for Subcutaneous Dosing 
Investigational Product (ACE-011) Preparation  
 
Process III Clinical Drug Product- Lyophilized: On the day of dosing, the 
pharmacist/designee will: 


 
  
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 
Pull the appropriate vial(s) from the refrigerator and allow the vial to equilibrate to room 
temperature. 
 
Add 1 mL WFI (Sterile Water for Injection) to a Lyophilized ACE-011 vial  
 
Let the vial sit at room temperature ~2 minutes  
 
Gently invert the vial to dissolve powder that may have gotten into the stopper/neck 
 
Gently swirl the vial for ~10 seconds (NOTE: Do not shake and avoid prolonged or 
vigorous agitation). Allow the vial to sit at room temperature for ~ 3 minutes. This 
procedure will produce a clear 50 mg/mL solution for administration 
 
The reconstituted Sotatercept drug product is a clear to slightly yellowish opalescent 
solution.) 
 
Note 1:  The reconstituted ACE-011, in its original container closure system, may be held 
for up to 6 hours at 2°C to 8°C.  
Note 2:  Once the reconstituted drug product is drawn into a syringe, it should be 
administered within one hour from the time it was drawn.   
Note 3:  The total hold time of the reconstituted drug product, including the hold time in a 
syringe, must not exceed 6 hours. 
 
 
1 mL syringes should be utilized for dispensing.  Syringes need to measure up to 0.01 
mL so that dose reductions can be accurately measured. 
 
Subcutaneous injections should be given in the following order as needed:  1) right 
upper arm, 2) left upper arm, 3) right upper thigh, 4) left upper thigh, 5) abdomen.   
 
Sufficient care should be taken so that the injection is not given intramuscularly or 
intravenously.   
 
If a dose volume is required to be split into more than 1 syringe (>1 mL dose 
requirement), then the volumes should be split into similar or equal volumes of 1 mL or 
less.  For example, a subject requiring a 1.25 mL injection volume, that volume will be 
split into 2 syringes (one syringe can contain 0.62 mL and one syringe can contain 0.63 
mL). 
Treatment Administration and Schedule 
Sotatercept will be administered as a SC injection to subjects by the study staff at the clinical 
site and will be documented in the study source record.  Subcutaneous injections will be given 
in the upper arm, abdomen, or thigh. 
Dose-escalation to the next dose level will be performed only if no side effect is reported AND 
if no efficacy is evidenced at the current dose level. 
For treatment discontinuation, please refer to Section: Dose Escalation / De-escalation Rules 
Selection of Dose for the Study 
Sotatercept administered as a single dose up to 3.0 mg/kg was previously demonstrated to be 
safe and to have durable effects on markers of bone formation and resorption as well as red 
blood cells following a single IV administration.  A dose-limiting pharmacodynamic effect of 
Sotatercept with increases in hemoglobin, hematocrit and RBCs was established in healthy 


 
  
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post-menopausal women at the 1.0 mg/kg dose level following multiple SC administration.  
This study will further delineate the hematopoietic profile of Sotatercept in subjects with 
Diamond Blackfan anemia. 
Selection and Timing of Dosing for Each Subject 
Subjects will be enrolled and receive their first dose of Sotatercept on study Day 1.  Sotatercept 
administration should occur no sooner than 3 days after RBC transfusion. Up to a total of 6 
doses will be administered every 21 days during the Treatment Period. Dose delay of 
Sotatercept from the planned dosing may occur due to Hb ≥ 10 g/dL, hypertension ≥ SBP 150 
mmHg and DPB ≥ 100 mmHg and/or Sotatercept related toxicity.   
 
For guidelines on dose modifications and dose delays see:  Dose Modifications 
Treatment / Study Discontinuation 
For guidelines on Discontinuations see sections:  Treatment Discontinuation and Study 
Discontinuation 
Method of Treatment Assignment 
All subjects who qualify for the study will be enrolled into the study and receive up to 6 doses 
of Sotatercept.  A unique multi-digit subject identification number will be manually assigned by 
the site staff to each subject entering the Treatment Period. 
Packaging and Labeling 
The label(s) for IP will include Supporter name, address and telephone number, the protocol 
number, IP name, dosage form and strength (where applicable), amount of IP per container, 
lot number, expiry date (where applicable), medication identification/kit number (if applicable), 
dosing instructions, storage conditions, and required caution statements and/or regulatory 
statements as applicable.  Additional information may be included on the label as applicable 
per local regulations. 
Investigational Product Accountability and Disposal  
Accountability for Sotatercept is the responsibility of the Investigator.  Investigational clinical 
supplies must be received by a designated person at the clinical site and kept in a secure and 
temperature-controlled location.  The investigational site must maintain accurate records 
demonstrating dates and amounts of Sotatercept received, to whom it was administered 
(subject-by-subject accounting), and accounts of any Sotatercept accidentally or deliberately 
destroyed or returned.  Accurate recording of all IP administration will be made in the 
appropriate section of the subject’s CRF and source documents.  Unless otherwise notified, 
all vials of Sotatercept, both used and unused, must be saved for drug accountability.  The 
used vials may be discarded, per the institution’s standard practice, after drug accountability 
has been completed by the monitor.  The Investigator must return all unused vials of 
Sotatercept to the Supporter at the end of the study, or the Sotatercept may be destroyed at 
the clinical site with the permission of the Supporter.  For either scenario, the outcome must 


 
  
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be documented on the drug accountability log.  The Supporter will provide direction for the 
outcome of all unused vials. 
Celgene will instruct the Investigator on the return, disposal and/or destruction of IP 
Investigational Product Compliance. 
The Investigator or designee is responsible for accounting for all IP that is administered during 
the course of the study. 
 
 
STUDY POPULATION:  
Inclusion Criteria 
 
1.  18 years of age. 
2. DBA diagnosed according to the Diamond Blackfan anemia criteria (Vlachos, 2008) 
(Appendix 2). 
3. RBC transfusion-dependence (defined as  2 units of RBC per 28 days averaged over 
12 weeks prior to study entry) (Gale, 2010) (Appendix 2). 
4. Creatinine clearance > 30 ml/min.     Renal function assessed by calculated creatinine 
clearance as follows (see Appendix 7: Cockcroft-Gault estimation of CrCl). 
5. Karnofsky performance scale score > 70 (Appendix 3). 
6. Females of childbearing potential participating in the study are to use highly effective 
methods of birth control during study participation and for 6 weeks following the last dose 
of Sotatercept.  Females of childbearing potential must have a negative serum or urine 
β-HCG pregnancy test within 3 days prior to the start of Sotatercept given on Day 
1.  Subjects must be counseled concerning measures to be used to prevent pregnancy 
and potential toxicities prior to the first dose of Sotatercept.  A female of childbearing 
potential is a sexually mature woman who has not undergone a hysterectomy or bilateral 
oophorectomy; or who has not been postmenopausal for at least 24 consecutive months 
(i.e., who has had menses at some time in the preceding 24 months). 
7. Males must agree to use a latex condom during any sexual contact with females of 
childbearing potential while participating in the study and for 16 weeks following the last 
dose of Sotatercept, even if he has undergone a successful vasectomy.  Subjects must 
be counseled concerning measures to be used to prevent pregnancy and potential 
toxicities prior to the first dose of Sotatercept. 


 
  
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8. Agreement to adhere to the study visit schedule, understand and comply with all protocol 
requirements. 
9. Disease free of prior malignancies for >5 yrs with the exception of currently treated basal 
cell carcinoma, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix 
or breast. 
10. Understand and sign a written informed consent. 
 
Exclusion Criteria 
 
1. SGOT > 5X ULN, SGPT >5X ULN or bilirubin > 5X ULN. 
2. Heart disease (New York Heart Association classification of ≥ 3 [Appendix 5]). 
3. Uncontrolled hypertension.  If hypertension is considered clinically stable, systolic blood 
pressure (SBP) must be < 150 mmHg or diastolic blood pressure (DBP) must be              < 
100 mmHg. 
4. Treatment with another investigational drug or device <8 weeks pre-study entry. 
5. History of severe or severe anaphylactic reaction or hypersensitivity to recombinant 
proteins or excipients in investigational product.  
6. Pregnant or lactating females. 
 
 
 
STUDY DURATION: 
 
Each subject will be on the study for approximately 8 months (including the Screening Period, 
the Treatment Period, and the Follow-Up Period) (see Table 4).  The Treatment Period is 
approximately 16 weeks with a post-treatment Follow-Up Period of approximately 16 weeks 
from the subject’s last dose of Sotatercept.  Subjects who discontinue from the Treatment 
Period early will still continue to the Follow-Up Period for 16 weeks from the last dose of 
Sotatercept. 
 
NUMBER OF STUDY SITES: 
 
This is a single center study. 
Subjects will receive the treatment at: 


 
  
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Cohen Children’s Medical Center of New York 
Northwell Health  
Campus of: 
The Feinstein Institute for Medical Research 
Clinical Research Center  
350 Community Drive 
Manhasset, NY 11030 
 
 
EFFICACY EVALUATION: 
 
Responses are defined as shown in Table 3 below.  Response must be documented for ≥ 84 
consecutive days (3 months). 
Table 3:  Response 
Response 
 
Transfusions 
 
 
None 
Reduced 
Complete response (CR) 
 
X 
 
Partial response (PR) 
 
 
X 
(50% decrease) 
 
SAFETY EVALUATION: 
 
Side effects will be recorded at each follow-up visit. 
Side effects will be graded according to the NCI-CTCAE (currently active minor version 4) 
(Appendix 6). 
All serious adverse events will be reported to Cohen Children’s Medical Center of New York 
and to Celgene. 
 
TREATMENT MODIFICATIONS: 
           
 
Dose-escalation will be performed only if no side effect is reported AND if no efficacy is 
evidenced (see above). 
 
Treatment will be stopped:  
o if hemoglobin is >14 gm/dL 
o any ≥ Grade 3 adverse event related to Sotatercept 


 
  
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Adverse events and/or Serious Adverse events:  
Monitoring, Recording and Reporting of Adverse Events 
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may 
appear or worsen in a subject during the course of a study. It may be a new intercurrent 
illness, a worsening concomitant illness, an injury, or any concomitant impairment of the 
subject’s health, including laboratory test values (as specified by the criteria below), 
regardless of etiology. Any worsening (i.e., any clinically significant adverse change in the 
frequency or intensity of a pre-existing condition) should be considered an AE.  A diagnosis or 
syndrome should be recorded on the AE page of the CRF rather than the individual signs or 
symptoms of the diagnosis or syndrome.  
An overdose, accidental or intentional, whether or not it is associated with an AE, or abuse, 
withdrawal, sensitivity or toxicity to an investigational product should be reported as an AE.  If 
an overdose is associated with an AE, the overdose and adverse event should be reported as 
separate terms. 
All subjects will be monitored for AEs during the study.  Assessments may include monitoring 
of any or all of the following parameters:  the subject’s clinical symptoms, laboratory, 
pathological, radiological or surgical findings, physical examination findings, or other 
appropriate tests and procedures. 
All AEs will be recorded by the Investigator from the time the subject signs informed consent 
to 16 weeks after the last dose. AEs and serious adverse events (SAEs) will be recorded on 
the AE page of the CRF and in the subject’s source documents.  All SAEs must be reported to 
Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the event by 
facsimile, or other appropriate method, using the SAE Report Form, or approved equivalent 
form. 
Serious Adverse Event (SAE) Definition  
A serious adverse event is one that at any dose (including overdose): 
 
Results in death 
 
Is life-threatening1 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability or incapacity2 
 
Is a congenital anomaly or birth defect 
 
Is an important medical event3 
 
1“Life-threatening” means that the subject was at immediate risk of death at the time of the serious 
adverse event; it does not refer to a serious adverse event that hypothetically might have caused death 
if it were more severe. 
2“Persistent or significant disability or incapacity” means that there is a substantial disruption of a 
person’s ability to carry out normal life functions. 


 
  
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3Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in situations where none of the outcomes listed above occurred.  Important medical events 
that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the other outcomes listed in the definition above 
should also usually be considered serious.  Examples of such 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.  A new 
diagnosis of cancer during the course of a treatment should be considered as medically important.  
Adverse Event Reporting 
Toxicity will be scored using CTCAE Version 4.0 for toxicity and adverse event reporting.  A copy of 
the CTCAE Version 4.0 can be downloaded from the CTEP homepage (http://ctep.info.nih.gov).  All 
appropriate treatment areas should have access to a copy of the CTCAE Version 4.0.  All adverse 
clinical experiences, whether observed by the investigator or reported by the patient, must be 
recorded, with details about the duration and intensity of each episode, the action taken with respect 
to the test drug, and the patient’s outcome.  The investigator must evaluate each adverse experience 
for its relationship to the test drug and for its seriousness. 
 
The investigator must appraise all abnormal laboratory results for their clinical significance.  If any 
abnormal laboratory result is considered clinically significant, the investigator must provide details 
about the action taken with respect to the test drug and about the patient’s outcome. 
Pregnancies 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of 
age or disease state) of a female subject occurring while the subject is on IP (Investigational 
Product), or within (insert time-frame which must be at least 28 days of the subject’s last dose 
of IP), are considered immediately reportable events. IP is to be discontinued immediately. 
The pregnancy, suspected pregnancy, or positive pregnancy test must be reported to 
Celgene Drug Safety immediately by facsimile, or other appropriate method, using the 
Pregnancy Initial Report Form, or approved equivalent form. The female subject should be 
referred to an obstetrician-gynecologist, preferably one experienced in reproductive toxicity 
for further evaluation and counseling. 
 
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form, or approved equivalent 
form. If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic 
abortion), the Investigator should report the abnormal outcome as an AE. If the abnormal 
outcome meets any of the serious criteria, it must be reported as an SAE to Celgene Drug 
Safety immediately by facsimile, or other appropriate method, within 24 hours of the 
Investigator’s knowledge of the event using the SAE Report Form, or approved equivalent 
form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, within 24 hours of the Investigator’s 
knowledge of the event using the SAE Report Form, or approved equivalent form. 


 
  
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Male Subjects 
If a female partner of a male subject taking investigational product becomes pregnant, the 
male subject taking IP should notify the Investigator, and the pregnant female partner should 
be advised to call their healthcare provider immediately. 
 
Celgene Drug Safety Contact Information: 
Celgene Corporation 
Global Drug Safety and Risk Management 
86 Morris Avenue 
Building S12 
Summit, New Jersey 07901 
Fax:  
(908) 673-9115 
E-mail:  
drugsafety@celgene.com 
Investigator Reporting Responsibilities (IND TRIALS ONLY) 
The conduct of the study will comply with all FDA safety reporting requirements.   
IND Annual Reports 
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, that an annual 
report is provided to the FDA within 60-days of the IND anniversary date.  21 CRF 312.33 
provides the data elements that are to be submitted in the report.  The Annual Report should 
be filed in the study's Regulatory Binder, and a copy provided to Celgene Corporation as a 
supporter of this study as follows. 
 
 
Celgene Corporation 
 
Attn: Medical Development 
 
86 Morris Avenue 
 
Summit, NJ  07901 
 
Tel: (908) 673-9000 
 
All adverse experience reports must include the patient number, age, sex, weight, severity of reaction 
(e.g. mild, moderate, severe), relationship to drug (e.g. probably related, unknown relationship, 
definitely not related), date and time of administration of test medications and all concomitant 
medications, and medical treatment provided.   The investigator is responsible for evaluating all 
adverse events to determine whether criteria for “serious” and as defined above are present.  The 
investigator is responsible for reporting adverse events to Celgene as described below. 


 
  
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Expedited Reporting by Investigator to Celgene 
Serious adverse events (SAE) are defined above.  The investigator must inform Celgene in 
writing using a Celgene 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-DBA-PI-0001) 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 patient records. 
Report of Adverse Events to the Institutional Review Board 
The principal Investigator is required to notify his/her Institutional Review Board (IRB) of a serious 
adverse event according to institutional policy.   
Investigator Reporting to the FDA 
Serious adverse events (SAEs) that are unlisted/unexpected, and at least possibly 
associated to the drug, and that have not previously been reported in the Investigators 
brochure, or reference safety information document should be reported promptly to the Food 
and Drug Administration (FDA) by telephone or by fax.  Fatal or life threatening SAEs that 
meet the criteria for reporting to the FDA must be reported to the FDA within 7 calendar days 
after awareness of the event.  All other SAEs that meet the criteria for reporting to the FDA 
must be reported to the FDA within 15 calendar days after awareness of the event.  A clear 
description of the suspected reaction should be provided along with an assessment as to 
whether the event is drug or disease related.    
Adverse event updates/IND safety reports 
Celgene shall notify the Investigator via an IND Safety Report of the following information: 
 
Any AE associated with the use of drug in this study or in other studies that is both serious and 
unexpected. 
 
Any finding from tests in laboratory animals that suggests a significant risk for human subjects 
including reports of mutagenicity, teratogenicity, or carcinogenicity. 
 
The Investigator shall notify his/her IRB/EC promptly of these new serious and unexpected AE(s) or 
significant risks to subjects. 


 
  
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The Investigator must keep copies of all AE information, including correspondence with Celgene and 
the IRB/EC, on file.  
 
 
STATISTICS: 
 
All subjects who received at least one dose of study drug will be included for safety and efficacy 
analysis. Demographics and baseline characteristics will be summarized by dose levels.  
Primary Endpoint(s): 
 Complete Response and Partial Response Rate will be summarized by dose level.  
Secondary Endpoint(s): 
 Time to response is defined as the time from the first dose to the first date when the 
CR/PR criteria was met. If a subject does not have CR/PR, subject will be censored on 
the date of last laboratory assessment. Time to response will be listed by subject and 
dose level. Kaplan-Meier method will be used to estimate the median time to response 
by dose level. 
 Duration of response is for CR/PR subjects only and is defined as the time from the first 
date that CR/PR criteria were met (e.g. the day following the last RBC transfusion) to the 
date when CR/PR criteria were not met (e.g. start date of next RBC transfusion). 
 All adverse events (including non-serious and serious) will be summarized by dose 
levels.  Key laboratory results will be summarized using CTC grade by dose levels. 
 
 
SAMPLE SIZE: 
 
Planned number of subjects is approximately 20. 
 
 
 


 
  
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Table 4:  Schedule of Study Assessments:  
Procedures 
Screening 
Period* 
Treatment Period 
Follow-Up Period 
Study 
DC 
 
Cycle 1 
Cycle 2 
Cycle 4 
Cycle 5 
Cycle 6 
Post-
Rx 1 
Post-
Rx 2 
Post-
Rx 3 
Post-
Rx 4 
Wk-4 to 
Wk0 
Wk0a 
(±1d) 
Wk1 
(±1d) 
Wk2 
(±1d) 
Wk3 
(±2d) 
Wk6 
(±2d) 
Wk9 
(±2d) 
Wk12 
(±2d) 
Wk15 
(±2d) 
Wk19 
(±7d) 
Wk23 
(±7d) 
Wk27 
(±7d) 
Wk 31 
Obtain subject 
informed consent form 
 
- 
- 
 
- 
- 
 
- 
- 
- 
- 
- 
 
Assess 
inclusion/exclusion 
criteria 
 
- 
- 
 
- 
- 
 
- 
- 
- 
- 
- 
 
Obtain medical subject 
history 
 
- 
- 
 
- 
- 
 
- 
- 
- 
- 
- 
 
Record prior 
treatments and 
procedures (including 
transfusion history) 
 
- 
- 
- 
- 
- 
 
- 
- 
- 
- 
- 
 
Physical examination 
 
 
- 
- 
 
 
 
 
 
- 
- 
- 
 
Vital signs including, 
blood pressure; weight 
for treatment period 
only; height at 1st visit 
only 
- 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 3 


 
  
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Procedures 
Screening 
Period* 
Treatment Period 
Follow-Up Period 
Study 
DC 
 
Cycle 1 
Cycle 2 
Cycle 4 
Cycle 5 
Cycle 6 
Post-
Rx 1 
Post-
Rx 2 
Post-
Rx 3 
Post-
Rx 4 
Wk-4 to 
Wk0 
Wk0a 
(±1d) 
Wk1 
(±1d) 
Wk2 
(±1d) 
Wk3 
(±2d) 
Wk6 
(±2d) 
Wk9 
(±2d) 
Wk12 
(±2d) 
Wk15 
(±2d) 
Wk19 
(±7d) 
Wk23 
(±7d) 
Wk27 
(±7d) 
Wk 31 
Karnofsky 
performance status 
(Appendix 4) 
 
- 
- 
- 
 
 
 
 
 
- 
- 
- 
 
 
Hematology b * 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood chemistry, 
Hepatic function, 
Kidney function c * 
 
 
 
- 
 
 
 
 
 
- 
- 
- 
 
 
FSH & LH (males & 
females) 
_ 
 
- 
- 
- 
- 
 
- 
- 
- 
- 
- 
- 
Testosterone (males 
only) 
_ 
 
- 
- 
- 
- 
 
- 
- 
- 
- 
- 
- 
Estrogen & estradiol 
(females only) 
_ 
 
- 
- 
- 
- 
 
- 
- 
- 
- 
- 
- 
Menstrual status 
(females only) 
 
- 
- 
- 
- 
- 
 
 
- 
- 
- 
- 
- 
Pregnancy Test d * 
 
- 
- 
- 
- 
- 
 
- 
- 
- 
- 
- 
- 
Cycle 3 


 
  
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Procedures 
Screening 
Period* 
Treatment Period 
Follow-Up Period 
Study 
DC 
 
Cycle 1 
Cycle 2 
Cycle 4 
Cycle 5 
Cycle 6 
Post-
Rx 1 
Post-
Rx 2 
Post-
Rx 3 
Post-
Rx 4 
Wk-4 to 
Wk0 
Wk0a 
(±1d) 
Wk1 
(±1d) 
Wk2 
(±1d) 
Wk3 
(±2d) 
Wk6 
(±2d) 
Wk9 
(±2d) 
Wk12 
(±2d) 
Wk15 
(±2d) 
Wk19 
(±7d) 
Wk23 
(±7d) 
Wk27 
(±7d) 
Wk 31 
ECHO (within one 
year prior to 
enrollment, to be 
repeated if clinically 
indicated) 
 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
 
- 
DEXA scan (within 
one year prior to 
enrolment, to be 
repeated if clinically 
indicated) 
 
- 
- 
- 
- 
- 
- 
- 
 
- 
- 
- 
 
 
Transfusion 
Assessment e 
 
 
- 
- 
 
 
 
 
 
 
 
 
 
Response 
Assessment 
- 
- 
 
- 
 
 
 
 
 
 
 
 
 
Adverse Events 
- 
 
 
- 
 
 
 
 
 
 
 
 
 
Concomitant therapies 
/ procedures 
- 
 
 
- 
 
 
 
 
 
 
 
 
 
Administer study drug 
- 
 
- 
- 
 
 
 
 
 
- 
- 
- 
- 
Cycle 3 


 
  
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*Historical clinical laboratory evaluations performed for routine medical evaluation within 28 days (prior to signing study consent) are 
acceptable for study entry. 
a: All D1 assessments are to be done prior to Sotatercept administration. 
b: Hematology laboratory evaluations (RBC count, hemoglobin, hematocrit, reticulocyte count, WBC, ANC, and platelet count) will be 
collected at Screening, at subsequent visits during the Treatment and Follow-Up Periods, and at Study Discontinuation visit, as 
referenced in the schedule above.  Any laboratory evaluations may be repeated more frequently if clinically indicated.  
c: Serum chemistry laboratory evaluations (sodium, potassium, chloride, CO2 (bicarbonate), calcium, magnesium, phosphorus, BUN, 
creatinine, glucose, albumin, total protein, alkaline phosphatase, bilirubin [total and direct], AST, and ALT) will be collected at 
Screening, and at days referenced in the schedule above.  Any laboratory evaluations may be repeated more frequently if clinically 
indicated.  
d: Females of childbearing potential:  A female of childbearing potential is a sexually mature woman who has not undergone a 
hysterectomy or who has not been postmenopausal for at least 24 consecutive months (i.e., who has had menses at some time in the 
preceding 24 months).  A serum or urine beta-HCG test (which must be negative) must be performed not more than 3 days from the 
start of Sotatercept administration (Study D1) once the subject.  Subjects must agree to use highly effective methods of birth control 
during study participation and for at least 16 weeks following the last dose of Sotatercept.  Subjects must be counseled concerning 
measures to be used to prevent pregnancy and potential toxicities prior to the first dose of Sotatercept.  Pregnancy tests will be 
performed according to the above schedule during study participation.   
e: Subjects must have documented transfusion history for > 12 weeks before inclusion/initiation of treatment. 
 
 
 


 
  
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Appendix 1 
Selected Bibliography 
 
Abdulkadyrov KM, Salogub GN, Khuazheva NK, Sherman ML, Laadem A, Barger R, 
Knight R, Srinivasan S, Terpos E. Sotatercept in patients with osteolytic lesions of multiple 
myeloma. Br J Haematol 2014 Jun;165(6):814-23. 
 
Abkowitz JL, Schaison G, Boulad F, et al. Response of Diamond-Blackfan anemia to 
metoclopramide: evidence for a role for prolactin in erythropoiesis. Blood 2002; 100:2687-
2691. 
 
Ball SE, McGuckin CP, Jenkins G, Gordon-Smith EC. Diamond-Blackfan anaemia in the 
U.K.: analysis of 80 cases from a 20-year birth cohort. Br J Haematol 1996;94:645-653 
Bastion Y, Bordigoni P, Debré M, Girault D, Leblanc T, Tchernia G, Ball S, McGuckin C, 
Gordon-Smith EC, Békassy A, et al. Sustained response after recombinant interleukin-3 in 
diamond blackfan anemia. Blood 1994 Jan 15;83(2):617-8. 
Cappellini MD, Forni GL, Origa R, Marcon A, Balocco M, Laadem A.  Interim results from a 
phase 2a, open-label, dose-finding study to determine the safety, efficacy, and tolerability 
of Sotatercept (ace-011) in adults with beta-thalassemia. Presented at the VIII Congresso 
Nazionale S.I.T.E. in Genova on October 9-11, 2014. 
Carrancio S, Markovics J, Wong P, Leisten J, Castiglioni P, Groza MC, Raymon HK, Heise 
C, Daniel T, Chopra R, Sung V.  An activin receptor IIA ligand trap promotes erythropoiesis 
resulting in a rapid induction of red blood cells and haemoglobin. Br J Haematol 2014 
Jun;165(6):870-82.  
Cmejla R, Cmejlova J, Handrkova H, Petrak J, Pospisilova D. Ribosomal protein S17 gene 
(RPS17) is mutated in Diamond-Blackfan anemia. Hum Mutat 2007; 28(12):1178-82. 
Da Costa L, Moniz H, Simansour M, Tchernia G, Mohandas N, Leblanc T. Diamond-
Blackfan anemia, ribosome and erythropoiesis. Transfus Clin Biol 2010 Sep;17(3):112-9. 
Diamond LK, Wang WC, Alter BP. Congenital hypoplastic anemia. Adv Pediatr 1976; 
22:349-78. 
Doherty L, Sheen MR, Vlachos A, et al. Ribosomal protein genes RPS10 and RPS26 are 
commonly mutated in Diamond-Blackfan anemia. Am J Hum Genet 2010 Feb 
12;86(2):222-8. Epub 2010 Jan 28. 
Draptchinskaia N, Gustavsson P, Andersson B, Pettersson M, Willig TN, Dianzani I, Ball S, 
Tchernia G, Klar J, Matsson H, Tentler D, Mohandas N, Carlsson B, Dahl N. The gene 
encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia. Nat Genet 
1999; 21(2):169-75. 


 
  
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Dussiot M, Maciel TT, Fricot A, Chartier C, Negre O, Veiga J, Grapton D, Paubelle E, 
Payen E, Beuzard Y, Leboulch P, Ribeil JA, Arlet JB, Coté F, Courtois G, Ginzburg YZ, 
Daniel TO, Chopra R, Sung V, Hermine O, Moura IC. An activin receptor IIA ligand trap 
corrects ineffective erythropoiesis in β-thalassemia. Nat Med 2014:398-407.  
Ear J, Huang H, Tehrani Z, Sung V, Daniel T, Chopra R, Lin S. RAP-011 efficiently 
rescues erythropoiesis in zebrafish models of Diamond Blackfan anemia. Presented at the 
55th Annual Meeting of the American Society of Hematology (ASH); New Orleans, LA, 
USA; December 7–10, 2013. 
Farrar JE, Nater M, Caywood E, McDevitt MA, Kowalski J, Takemoto CM, Talbot CC Jr, 
Meltzer P, Esposito D, Beggs AH, Schneider HE, Grabowska A, Ball SE, Niewiadomska E, 
Sieff CA, Vlachos A, Atsidaftos E, Ellis SR, Lipton JM, Gazda HT, Arceci RJ. Abnormalities 
of the large ribosomal subunit protein, Rpl35a, in Diamond-Blackfan anemia. Blood 2008; 
112(5):1582-92. 
Farrar JE, Quarello P, Fisher R, O'Brien KA, Aspesi A, Parrella S, Henson AL, Seidel NE, 
Atsidaftos E, Prakash S, Bari S, Garelli E, Arceci RJ, Dianzani I, Ramenghi U, Vlachos A, 
Lipton JM, Bodine DM, Ellis SR. Exploiting pre-rRNA processing in Diamond Blackfan 
anemia gene discovery and diagnosis. Am J Hematol 2014 Oct;89(10):985-91. 
Gale RP, Barosi G, Barbui T, Cervantes F, Dohner K, Dupriez B, et. al. What are RBC-
transfusion-dependence and –independence. Leuk Res 2010 Aug 5. 
Gazda HT, Grabowska A, Merida-Long LB, Latawiec E, Schneider HE, Lipton JM, Vlachos 
A, Atsidaftos E, Ball SE, Orfali KA, Niewiadomska E, Da Costa L, Tchernia G, Niemeyer C, 
Meerpohl JJ, Stahl J, Schratt G, Glader B, Backer K, Wong C, Nathan DG, Beggs AH, 
Sieff CA. Ribosomal protein S24 gene is mutated in Diamond-Blackfan anemia. Am J Hum 
Genet 2006; 79(6):1110-8. 
Gazda HT, Sheen MR, Vlachos A, Choesmel V, O'Donohue MF, Schneider H, Darras N, 
Hasman C, Sieff CA, Newburger PE, Ball SE, Niewiadomska E, Matysiak M, Zaucha JM, 
Glader B, Niemeyer C, Meerpohl JJ, Atsidaftos E, Lipton JM, Gleizes PE, Beggs AH. 
Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal 
thumbs in Diamond-Blackfan anemia patients. Am J Hum Genet 2008; 83(6):769-80. 
Glader BE, Backer K, Diamond LK. Elevated erythrocyte adenosine deaminase activity in 
congenital hypoplastic anemia. N Engl J Med 1983; 309(24):1486-90. 
Gustavsson P, Skeppner G, Johansson B, et al. Diamond-Blackfan anaemia in a girl with a 
de novo balanced reciprocal X;19 translocation. J Med Genet 1997;34:779-782. 
 
Komrokji R, Garcia-Manero G, Ades L, Laadem A, Vo B, Prebet T, Stamatoullas A, Boyd 
T, Delaunay J, Steensma DP,  Sekeres MA, Beyne-Rauzy O, Zou J, Attie KM, Sherman 
ML, Fenaux P, List AF.  An Open-Label, Phase 2, Dose-Finding Study of Sotatercept 
(ACE-011) in Patients With Low- or Intermediate (Int)-1-Risk Myelodysplastic Syndromes 
(MDS) or Non-Proliferative Chronic Myelomonocytic Leukemia (CMML) and Anemia 


 
  
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Requiring Transfusion. Presented at the 56th Annual Meeting of the American Society of 
Hematology (ASH); San Francisco, CA, USA; December 6–9, 2014. 
 
Landowski M, O'Donohue MF, Buros C, Ghazvinian R, Montel-Lehry N, Vlachos A, Sieff 
CA, Newburger PE, Niewiadomska E, Matysiak M, Glader B, Atsidaftos E, Lipton JM, 
Beggs AH, Gleizes PE, Gazda HT. Novel deletion of RPL15 identified by array-
comparative genomic hybridization in Diamond-Blackfan anemia. Hum Genet 2013 
Nov;132(11):1265-74.  
 
Leblanc TM, Da Costa L, Marie I, Demolis P, Tchernia G. Metoclopramide treatment in 
DBA patients: no complete response in a French prospective study. Blood 2007; 
109:2266-2267. 
Lipton JM, Atsidaftos E, Zyskind I, Vlachos A.  Improving clinical care and elucidating the 
pathophysiology of Diamond Blackfan anemia: an update from the Diamond Blackfan 
Anemia Registry. Pediatr Blood Cancer 2006; 46(5):558-64. 
Lipton JM, Kudisch M, Gross R, Nathan DG. Defective erythroid progenitor differentiation 
system in congenital hypoplastic (Diamond-Blackfan) anemia. Blood 1986; 67(4):962-8.  
Liu JM, Ellis SR. Ribosomes and marrow failure: coincidental association or molecular 
paradigm? Blood 2006 Jun 15;107(12):4583-8. 
 
Mirabello L, Macari ER, Jessop L, Ellis SR, Myers T, Giri N, Taylor AM, McGrath KE, 
Humphries JM, Ballew BJ, Yeager M, Boland JF, He J, Hicks BD, Burdett L, Alter BP, Zon 
L, Savage SA. Whole-exome sequencing and functional studies identify RPS29 as a novel 
gene mutated in multicase Diamond-Blackfan anemia families. Blood 2014 Jul 
3;124(1):24-32. 
Murata M, Onomichi K, Eto Y, Shibai H, and Muramatsu M.  Expression of erythroid 
differentiation factor (EDF) in Chinese hamster ovary cells.  Biochem Biophys Res 
Commun 1988; 151: 230-5. 
Narla A, Vlachos A, Nathan DG. Diamond blackfan anemia treatment: past, present, and 
future. Semin Hematol 2011; 48(2):117-23. 
Ohene-Abuakwa Y, Orfali KA, Marius C, Ball SE. Two-phase culture in Diamond Blackfan 
anemia: localization of erythroid defect. Blood 2005 Jan 15;105(2):838-46. 
Perrien DS, Akel NS, Edwards PK, et. al.  Inhibin A is an endocrine stimulator of bone 
mass and strength.  Endocrinology 2007; 148: 1654-65. 
Quarello P, Garelli E, Carando A, Brusco A, Calabrese R, Dufour C, Longoni D, Misuraca 
A, Vinti L, Aspesi A, Biondini L, Loreni F, Dianzani I, Ramenghi U. Diamond-Blackfan 
anemia: genotype-phenotype correlations in Italian patients with RPL5 and RPL11 
mutations. Haematologica 2010 Feb; 95(2):206-13. Epub 2009 Sep 22. 


 
  
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Rivier J, Spiess J, McClintock R, Vaughan J and Vale W.  Purification and partial 
characterization of inhibin from porcine follicular fluid.  Biochem Biophys Res Commun 
1985; 133: 120-7. 
Ruckle J, Jacobs M, Kramer W, et. al.  A single-dose, randomized, double-blind, placebo-
controlled study of Sotatercept (ActRIIA-IgG1) in postmenopausal women.  J Bone Miner 
Res 2009; 24 (4): 744-52. 
Sherman ML, Borgstein NG, Mook L, Wilson D, Yang Y, Chen N, Kumar R, Kim K, 
Laadem A. Multiple-dose, safety, pharmacokinetic, and pharmacodynamic study of 
Sotatercept (ActRIIA-IgG1), a novel erythropoietic agent, in healthy postmenopausal 
women. J Clin Pharmacol 2013:1121-30. 
Vlachos A, Ball S, Dahl N, et al. Diagnosing and treating Diamond Blackfan anaemia: 
results of an international clinical consensus conference. Br J Haematol 2008;142:859-
876. 
Vlachos A, Federman N, Reyes-Haley C, Abramson J, Lipton JM. Hematopoietic stem cell 
transplantation for Diamond Blackfan anemia: a report from the Diamond Blackfan Anemia 
Registry. Bone Marrow Transplant 2001; 27(4):381-86. 
Vlachos A, Klein GW, Lipton JM. The Diamond Blackfan Anemia Registry: tool for 
investigating the epidemiology and biology of Diamond-Blackfan anemia. J Pediatr 
Hematol Oncol 2001; 23(6):377-82. 
Vlachos A, Muir E.  How I treat Diamond-Blackfan anemia.  Blood 2010;116(19):3715-23. 
Epub 2010 Jul 22. 
 


 
  
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Appendix 2 
Diamond Blackfan Anemia Diagnosis Criteria 
 
 
Diagnostic Criteria 
  
 
Age less than 1 year 
 
Macrocytic anemia with no other significant cytopenias 
 
Reticulocytopenia 
 
Normal marrow cellularity with a paucity of erythroid precursors 
 
Supporting Criteria 
 
Major 
 
Ribosomal protein gene mutation described in “classical” DBA 
 
Positive family history 
 
Minor 
 
Elevated erythrocyte adenosine deaminase activity 
 
Congenital anomalies described in “classical” DBA 
 
Elevated fetal hemoglobin 
 
No evidence of another inherited bone marrow failure syndrome 
 
 
A diagnosis of “classical” DBA is made if all the diagnostic criteria are met.  When there is a 
positive family history, an otherwise normal individual should be considered as having “non-
classical” DBA if a mutation shared by affected family members is present.  Anyone suspected of 
having DBA, but with insufficient diagnostic criteria, should be considered as having non-classical 
DBA if a reported mutation is present.  A patient can be assigned as having a “probable” diagnosis, 
with a decreasing degree of certitude if:  
3 diagnostic criteria are present along with a positive family history;  
2 diagnostic criteria and 3 minor supporting criteria are present; or,  
a positive family history and 3 minor supporting criteria are evident, even in the absence of 
diagnostic criteria.     
 


 
  
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Appendix 3 
Delphi Expert-Consensus Panel Definitions of 
RBC-Transfusion-Dependence and -Independence 
 
Table 5:  Definitions of RBC Transfusion Dependence and Independence 
 
 
RBC transfusions 
Hb (gm/dL) 
Surveillance Interval 
RBC transfusion 
dependence 
 10 cc/kg/month 
< 8 
3 months 
RBC transfusion 
independence 
None 
> 9 
3 months 
Reduced RBC transfusion 
dependence 
50% decrease 
< 9 
3 months 
 


 
  
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Appendix 4
 
Karnofsky Performance Status Scale 
 
The Karnofsky Performance Scale Index allows patients to be classified as to their 
functional impairment.  This can be used to compare effectiveness of different therapies 
and to assess the prognosis in individual patients.  
Able to carry on normal activity and to work; no 
special care needed. 
  100   Normal no complaints; no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
80 
Normal activity with effort; some signs 
or symptoms of disease.  
Unable to work; able to live at home and care for 
most personal needs; varying amount of 
assistance needed. 
70 
Cares for self; unable to carry on 
normal activity or to do active work. 
60 
Requires occasional assistance, but is 
able to care for most of his personal 
needs. 
50 
Requires considerable assistance and 
frequent medical care.  
Unable to care for self; requires equivalent of 
institutional or hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and 
assistance. 
30 
Severely disabled; hospital admission 
is indicated although death not 
imminent. 
20 
Very sick; hospital admission 
necessary; active supportive treatment 
necessary. 
10 
Moribund; fatal processes progressing 
rapidly. 
0 
Dead 
References: 
Crooks, V, Waller S, et al. The use of the Karnofsky Performance Scale in determining outcomes and risk in 
geriatric outpatients. J Gerontol. 1991; 46: M139-M144. 
de Haan R, Aaronson A, et al. Measuring quality of life in stroke. Stroke. 1993; 24:320- 327. 
Hollen PJ, Gralla RJ, et al. Measurement of quality of life in patients with lung cancer in multicenter trials of 
new therapies. Cancer. 1994; 73: 2087-2098. 
O'Toole DM, Golden AM. Evaluating cancer patients for rehabilitation potential. West J Med. 1991; 155:384-
387. 
Oxford Textbook of Palliative Medicine, Oxford University Press. 1993;109. 
Schag CC, Heinrich RL, Ganz PA. Karnofsky performance status revisited: Reliability, validity, and 
guidelines. J Clin Oncology. 1984; 2:187-193. 
 


 
  
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Appendix 5 
New York Heart Association – Classification of Heart Failure 
 
Table 7:  Classification of Heart Failure 
Class 
Symptoms 
Class 1 
No limitation of activities.  No symptoms from ordinary activities 
Class 2 
Mild limitation of activity.  Comfortable with rest or mild exertion 
Class 3 
Marked limitation of activity and be comfortable only at rest 
Class 4 
Complete rest, confined to bed or chair; any physical activity brings on 
discomfort and symptoms occur at rest 
 
 


 
  
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Appendix 6 
Side Effects Grading and Reporting 
 
 
Side effects will be graded according to the NCI-CTCAE (version 4). 
 
 
 
 
 
Link for NCI-CTCAE version 4  
 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 
 
  
 
Appendix 7 
Cockcroft-Gault estimation of CrCl: 
 
Cockcroft-Gault estimation of creatinine clearance (CrCl):  
(Cockcroft, 1976; Luke 1990) 
 
CrCl (mL/min) =  
    (140 –age) x (weight, kg)__           
   (Males) 
 
72 x (serum creatinine, mg/dL) 
 
CrCl (mL/min) =  
    (140 –age) x (weight, kg)_    x 0.85         
   (Females)  
72 x (serum creatinine, mg/dL) 
 
 


 
  
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Appendix 8 
 
Handling and Administration Guidelines 
with Drug Accountability Log 
 
Description of Investigational Product(s) 
Process III Clinical Drug Product - Lyophilized Powder: 
 
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 stoppered, sealed, 3-mL glass vials. 
 
The recommended storage temperature for Sotatercept lyophilized drug product is 
2°C to 8°C. 
o Prior to administration, the lyophilized drug product is reconstituted with 1 
mL water for injection (WFI).  The reconstituted drug product consists of a 50 
mg/mL solution of Sotatercept.  The reconstituted Sotatercept, in its original 
container closure system, 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 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. 
 
Sotatercept lyophilized product will be shipped to the investigational site with a 
TempTale monitor in an appropriate nomadic shipper. 
Shipping / TempTales 
All shipments include instructions for the TempTale device within the shipper. All 
TempTales are to be stopped immediately upon receipt and unpacking of the shipment. 
Follow the TempTale Instruction Sheet in the shipper for handling of the temperature 
monitoring device.  
 
If the TempTale does not have an alarm bell showing in the screen, the IP was 
shipped and received in the appropriate temperature range.  The temperature 
parameters should be checked and documented on the TempTale instruction sheet 
and the IP would be ready for use. 
 
Please note: if the alarm bell is showing on the TempTale display upon receipt of 
shipment and stopping of the TempTale, please store the material appropriately and 
quarantine it from use.  Notify Celgene of the excursion right away and await 
confirmation that the IP is acceptable for use or is to be returned or destroyed. 
Sotatercept Preparation and Administration 
The clinical staff will fill out the following information on the Sotatercept Drug Accountability 
Log (see Appendix 8) on the dosing day: 
 
Date 


 
  
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 
Visit 
 
Subject Number 
 
Subject Initials 
 
Dose 
 
Number of mLs used 
 
Lot Number 
 
Time Drug Removed from Refrigerator/Freezer (24 hr clock) 
 
Time Subject Dosed (24-hour clock) 
 
The site personnel will confirm the lot # (for Sotatercept), the number of vials used, and the 
total volume of Sotatercept given and record this information in the source documents and in 
the pharmacy records. 
 
Preparation of Sotatercept for Subcutaneous Dosing 
Investigational Product (ACE-011) Preparation  
 
Process III Clinical Drug Product- Lyophilized: On the day of dosing, the 
pharmacist/designee will: 
 
Pull the appropriate vial(s) from the refrigerator and allow the vial to equilibrate to 
room temperature. 
 
Add 1 mL WFI (Sterile Water for Injection) to a Lyophilized ACE-011 vial  
 
Let the vial sit at room temperature ~2 minutes  
 
Gently invert the vial to dissolve powder that may have gotten into the stopper/neck 
 
Gently swirl the vial for ~10 seconds (NOTE: Do not shake and avoid prolonged 
or vigorous agitation)Allow the vial to sit at room temperature for ~ 3 minutes. This 
procedure will produce a clear 50 mg/mL solution for administration 
 
The reconstituted Sotatercept drug product is a clear to slightly yellowish opalescent 
solution.) 
 
Note 1:  The reconstituted ACE-011, in its original container closure system, may be 
held for up to 6 hours at 2°C to 8°C.  
Note 2:  Once the reconstituted drug product is drawn into a syringe, it should be 
administered within one hour from the time it was drawn.   
Note 3:  The total hold time of the reconstituted drug product, including the hold time in 
a syringe, must not exceed 6 hours. 
 
 
1 mL syringes should be utilized for dispensing.  Syringes need to measure up to 
0.01 mL so that dose reductions can be accurately measured. 
 
Subcutaneous injections should be given in the following order as needed;  1) right 
upper arm, 2) left upper arm, 3) right upper thigh, 4) left upper thigh, 5) abdomen.   
 
Sufficient care should be taken so that the injection is not given intramuscularly or 
intravenously.   
 
If a dose volume is required to be split into more than 1 syringe (>1 mL dose 
requirement), then the volumes should be split into similar or equal volumes of 1 mL 


 
  
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or less.  For example, a subject requiring a 1.25 mL injection volume, that volume 
will be split into 2 syringes (one syringe can contain 0.62 mL and one syringe can 
contain 0.63 mL). 
 
 
 


 
  
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Protocol Number - ACE-011-DBA-PI-0001 
Drug Accountability Log for Drug Receipt / Drug Return 
 
Record All Usages of Study Medication 
 
 
 
INVESTIGATOR NAME:  Adrianna Vlachos, MD 
 
    
 
Amount 
 
Date 
Visit  
(Cycle/Day) 
Subject 
No. 
Subject 
Inits. 
Dose 
(mg/
kg) 
No. of 
mLs 
Used 
No. of 
Vials 
Used 
Balance
(No. of 
Vials) 
Lot 
No. 
Time Drug 
Removed from 
Freezer/Refrig 
(24 hr 
 clock) 
Time 
Subject 
Dosed 
(24 hr 
clock) 
RPh 
Inits. 
CRA 
Inits. 
Comments 
 
 
 
 
 
 
 
 
 
 
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