Clinical trial NCT01981850
Conditions: Primary Myelofibrosis Polycythemia Vera Post-Essential Thrombocythemia Myelofibrosis
Keywords: fibrosis
Sponsor: Hoffmann-La Roche
Start date: 2013-10-01; Completion date: 2020-07-10
Enrollment: 125 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
RO7490677 is an investigational drug that is being developed for possible use in the treatment of myelofibrosis (MF), a disease in which the bone marrow, which is the organ in the body that makes blood cells, is replaced by fibrosis, or excess scar tissue.

The purpose of this study is to gather information on whether RO7490677 has an effect on the MF disease, whether it is safe in patients with MF, and how well it is tolerated.

Detailed description:
Stage 1 of this study has completed. Stage 1 was an open-label, Simon two stage, Phase 2 study to determine the efficacy and safety of two different dose schedules of RO7490677 in participants with PMF and post ET/PV MF. There were two treatment cohorts, each assigned to one of two dose schedules receiving either single-agent RO7490677 or RO7490677 in combination with ruxolitinib. Participants were assigned to a weekly or every four week dosing schedule by the investigator.

Stage 2 is a randomized, double-blind Phase 2 study to determine the efficacy and safety of three different doses of RO7490677 in participants with PMF and post ET/PV MF. Participants will be randomized to one of three doses: 0.3 mg/kg, 3.0 mg/kg or 10 mg/kg of RO7490677. This is the second stage of an adaptive design study as defined in FDA Draft Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics, February 2010. Modifications to dose levels, schedule, and regimen have been made in Stage 2 based on data from Stage 1.

Arms: arm 1: Participants who received no treatment for MF in at least two weeks will be assigned to treatment with single agent RO7490677 at a dose of 10 mg/kg IV on Days 1, 3, 5, 8, 15, and 22 of Cycle 1 and Days 1, 8, 15 and 22 of each subsequent 28 day cycle for six cycles. arm 2: Paricipants who received no treatment for MF in at least two weeks will be assigned to treatment with single agent RO7490677 at a dose of 10 mg/kg administered IV on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles. arm 3: Participants on a stable dose of ruxolitinib for at least 12 weeks, with no improvement in spleen during the last four weeks will be assigned to receive RO7490677 in combination with ruxolitinib at a dose of 10 mg/kg administered IV on Days 1, 3, 5, 8, 15, and 22 of Cycle 1 and Days 1, 8, 15 and 22 of each subsequent 28 day cycle for six cycles. arm 4: Participants on a stable dose of ruxolitinib for at least 12 weeks, with no improvement in spleen during the last four weeks will be assigned to receive RO7490677 in combination with ruxolitinib at a dose of 10 mg/kg administered IV on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles. arm 5: Participants will be treated with single agent RO7490677 at a dose of 0.3 mg/kg IV administered as a 60 minute intravenous infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. arm 6: Participants will be treated with single agent RO7490677 at a dose of 3.0 mg/kg IV administered as a 60 minute intravenous infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. arm 7: Participants will be treated with single agent RO7490677 at a dose of 10 mg/kg IV administered as a 60 minute intravenous infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles.
Interventions: intervention 1: RO7490677 intervention 2: Ruxolitinib
Intervention descriptions: intervention 1: IV infusion intervention 2: IV infusion

Protocol documents:
Prot_000.pdf: 
Official Title: A Phase 2, Prospective Study Of PRM-151 In Subjects With 
Primary Myelofibrosis (PMF), Post-Polycythemia Vera MF (post- 
PV MF), OR Post-Essential Thrombocythemia MF (post-ET MF) 
NCT Number: NCT01981850 
Document Date: Protocol Version 6: 15-December-2016 


PRM-151 
Study Protocol PRM-151G-101  
 
 
 
        Protocol Version 6.0 15Dec2016 
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Clinical Trial Protocol: Study PRM-151G-101 
Study Title: 
A Phase 2, Prospective Study Of PRM-151 In Subjects With 
Primary Myelofibrosis (PMF), Post-Polycythemia Vera MF (post-
PV MF), Or Post-Essential Thrombocythemia MF (post-ET MF) 
Study Number: 
PRM-151G-101 
Study Phase: 
2 
Product Name: 
PRM-151 
IND Number: 
116,932 
EudraCT Number: 
2015-001718-80 
Indication: 
Primary Myelofibrosis (PMF), Post-Polycythemia Vera MF (post-
PV MF), Or Post-Essential Thrombocythemia MF (post-ET MF) 
Sponsor: 
Promedior, Inc. 
 
101 Hartwell Ave. 
 
Lexington, MA 02421 
 
Tel: 1-781-538-4200 
 
Fax: 1-781-538-4300 
Sponsor Contact: 
, RN 
Medical Director: 
 , MD, PhD  
 
Date 
Original Protocol: 
 
Version 1.0 17 Jan 2013
Amendment 1: 
 
Version 2.0 22 Feb 2013                                                                      
Amendment 2: 
 
Version 3.0 10 May 2013                                                                        
Amendment 3: 
 
Version 4.0 14 Feb 2014                                                                       
Amendment 4: 
 
Version 5.0 04 May 2015
Amendment 5: 
 
Version 5.1 UK 09 Nov 2015 
 
Amendment 6: 
 
Version 5.1 France 08 Aug 2016
 


PRM-151 
Study Protocol PRM-151G-101  
 
 
 
        Protocol Version 6.0 15Dec2016 
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Amendment 7: 
 
Version 6.0 15 Dec 2016
 
 
SYNOPSIS: STAGE 2 
Sponsor: 
Promedior, Inc. 
Name of Finished Product: 
Recombinant human Pentraxin-2; PRM-151 
Study Title: 
A Phase 2, Prospective Study Of PRM-151 In Subjects With Primary Myelofibrosis (PMF), 
Post-Polycythemia Vera MF (post-PV MF), Or Post-Essential Thrombocythemia MF (post-ET 
MF) 
Study Number: 
PRM-151G-101 
Study Phase: Phase 2 
Investigational Product; Dose; and Mode of Administration: 
PRM-151; 0.3 mg/kg; 3 mg/kg and 10 mg/kg intravenous 
Comparator; Dose; and Mode of Administration: 
Not applicable 
Primary Objectives(s): 
 
• To determine the effect size of three different doses of PRM-151 on reduction in bone 
marrow fibrosis by > 1 grade in intermediate-1, intermediate-2, and high risk subjects 
with PMF, post-PV MF, or post ET-MF who are anemic or thrombocytopenic and who 
are ineligible for, intolerant of, or have had an inadequate response to ruxolitinib. 
 
Secondary Objective(s): 
 
• To determine if there is a difference in efficacy between the three doses of PRM-151 
used in the study 
• To evaluate the safety and tolerability of three different does of PRM-151 
• To assess the duration of effect of three doses of PRM-151 on reduction in bone 
marrow fibrosis 
• To assess the effect and duration of effect of three doses of PRM-151 on disease 
related anemia, thrombocytopenia, and constitutional symptoms 
• To assess IWG-MRT response (Complete Response, Partial Response, Clinical 
Improvement), stable and progressive disease in subjects treated with three doses of 
PRM-151 
Confidentiality Statement 
The information contained herein is confidential and the proprietary property of Promedior, Inc and any 
unauthorized use or disclosure of such information without the prior written authorization of Promedior is 
expressly prohibited. 


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Exploratory Objectives 
 
• To measure changes in bone marrow fibrosis by quantitative image analysis and 
evaluate changes in bone marrow morphology in subjects receiving PRM-151 
 
• To assess the effect of PRM-151 on other disease related parameters, including 
hematologic abnormalities and spleen size 
 
• To assess the effect of PRM-151 on prognostic factors associated with increased 
mortality as measured by the DIPSS (Dynamic International Prognostic Scoring 
System) 
 
• To evaluate the interaction between selected genetic mutations and cytogenetic 
abnormalities and response to PRM-151 
 
• To explore potential biomarkers of PRM-151 activity in bone marrow samples 
 
• To assess the effect of PRM-151 on bone marrow metabolism by PET imaging (at 
selected institutions) 
 
• To evaluate the correlation of baseline PTX-2 levels with outcomes 
 
• To evaluate the relationship between bone marrow fibrosis reduction and hematologic 
improvements in subjects treated with PRM-151 
 
• To measure progression-free and overall survival in subjects receiving PRM-151 
 
Study Endpoints: 
 
Primary: 
 
• Bone marrow response rate, defined as the percent of subjects with a reduction in bone 
marrow fibrosis score by at least one grade according to WHO criteria (APPENDIX D) 
at any time during the study as determined by a central adjudication panel of expert 
hematopathologists, blinded to subject, treatment, and time of biopsy 
 
Secondary: 
 
• Comparison of primary and secondary efficacy parameters between doses 
 
• Incidence of adverse events (AEs), serious adverse events (SAEs), and changes in 
laboratory test results 
 
• Bone marrow improvement: 


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o Bone marrow response rate at weeks 12, 24, and 36 
 
o Duration of bone marrow response 
 
• Hemoglobin improvement 
 
Baseline Status 
Categories of Hemoglobin Improvement 
Subjects who are transfusion dependent (> 2 
units PRBC every 4 weeks for 12 weeks 
prior to or after C1D1), regardless of 
baseline hemoglobin level 
Percent of subjects with Red cell transfusion 
independence (no transfusions for > 12 
consecutive weeks) 
OR 
50% reduction in RBC transfusions for > 12 
consecutive weeks 
Subjects with baseline hemoglobin < 100 g/L  
AND 
Not transfusion dependent 
Percent of subjects with > 10 g/L and > 20 
g/L increase in hemoglobin for > 12 
consecutive weeks without transfusions 
 
• Platelet improvement: 
 
Baseline Status 
Categories of Platelet Improvement 
Subjects who are transfusion dependent (> 2 
platelet transfusions in any 12 weeks prior to 
or after C1D1), regardless of baseline 
platelet level 
 
Platelet transfusion = either 1 unit apheresed 
(single donor) platelets or 4-8 units pooled 
random donor platelets  
Percent of subjects with: 
Platelet transfusion independence (no 
transfusions for > 12 consecutive weeks) 
 
OR 
 
50% reduction in platelets transfusions for > 
12 consecutive weeks 
Subjects with 25 < baseline platelets < 50 x 
109/L 
 
AND 
Not platelet transfusion dependent 
Percent of subjects with: 
Doubling of baseline platelet count for > 12 
consecutive weeks without platelet 
transfusions 
 
OR 
 
Platelet count > 50 x 109/L for > 12 
consecutive weeks without platelet 
transfusions 
Subjects with baseline platelet count < 25 x 
109/L 
AND 
Not platelet transfusion dependent 
Percent of subjects with: 
Doubling of baseline platelet count for > 12 
consecutive weeks without platelet 
transfusions 
 
OR 


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Platelet count > 25 x 109/L for > 12 
consecutive weeks without platelet 
transfusions 
• Hematologic improvement: 
 
Baseline Status 
Categories of Hematologic Improvement 
Subjects with both Hemoglobin < 100 g/L 
and Platelets < 50 x 109/L 
Percent of subjects who have EITHER 
Hemoglobin improvement OR Platelet 
improvement as described above and no 
worsening of hemoglobin or platelets from 
baseline 
Subjects with only Hemoglobin < 100 g/L 
Percent of subjects who have Hemoglobin 
improvement as described above 
AND 
Did not develop platelets < 50 x 109/L  
 
 
 
Subjects with only Platelets < 50 x 109/L 
Percent of subjects who have Platelet 
improvement as described above 
AND 
Did not develop Hemoglobin < 100 g/L or 
new transfusion dependence 
 
 
• Symptom improvement: 
 
o Percent of subjects with 25% and 50% reduction in MPN-SAF Total Symptom 
Score from baseline at Week 36 
 
o Mean change from baseline at EORTC QLQ-C30 at 36 weeks 
 
• Duration of all improvement parameters listed above 
 
• Percent of subjects with complete response, partial response, clinical improvement, 
stable disease, and progressive disease according to IWG-MRT criteria (Tefferi 2013, 
APPENDIX B) 
 
Exploratory: 
 
• Bone marrow 
 
o Percent of subjects with Grade 0-1 bone marrow fibrosis grade at any time 
during the study and at weeks 12, 24, and 36 
 


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o Duration of Grade 0-1 bone marrow fibrosis grade 
 
o Mean change from baseline to 12, 24, and 36 weeks in bone marrow 
fibrosis by quantitative image analysis 
 
o Changes from baseline to weeks 12, 24, and 36 in bone marrow metabolism 
by FDG or FLT PET scan (where feasible) 
 
o Assessment of changes in bone marrow morphology at 12, 24, and 36 
weeks 
 
• Hematologic and other disease related laboratory parameters 
 
o Mean change from baseline to 36 weeks in: hemoglobin, # RBC units 
transfused in previous 12 weeks, platelet count, # platelet transfusions in 
previous 12 weeks, white blood cell count, absolute neutrophil count, 
reticulocyte count, peripheral blood blast count, and lactic dehydrogenase 
(LDH) 
 
o Percent of subjects with increase in Hgb from < 100 g/L to > 100g/L 
without transfusions, increase in platelets from < 50 x 109/L to > 100 x 
109/L, decrease in WBC from > 25 to < 25, increase in ANC from < 1500 to 
> 1500, decrease in peripheral blood blasts from > 1% to < 1%, and 
disappearance of leukoerythroblastosis, at 36 weeks and for > 12 weeks at 
any time during the study  
 
o Duration of increase in Hgb from < 100 g/L to > 100 g/L without 
transfusions, increase in platelets from < 50 x 109/L to > 100 x 109/L, 
decrease in WBC from > 25 to < 25, increase in ANC from < 1500, to > 
1500, decrease in peripheral blood blasts from > 1% to < 1%, and 
disappearance of leukoerythroblastosis 
 
• Spleen improvement: 
 
o Percent of subjects with 10% and 35% reduction in spleen size from 
baseline by CT at 36 weeks 
o Duration of 10% and 35% reduction in spleen size from baseline 
o Mean change from baseline in spleen size by CT or MRI at 36 weeks 
o Change in spleen and liver metabolism by FDG or FLT PET scan at 12, 
24, and 36 weeks 
 
• DIPSS 
o Percent of subjects with a reduction in DIPSS score and category at 
week 36 
 
o Mean change in DIPSS score from baseline to Week 36 


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Stage 2 Study Design: 
This is a randomized, double-blind Phase 2 study to determine the efficacy and safety of three 
different does of PRM-151 in subjects with PMF and post ET/PV MF.  Subjects will be 
randomized to one of three doses: 0.3 mg/kg, 3.0 mg/kg or 10 mg/kg of PRM-151.  This is the 
second stage of an adaptive design study as defined in FDA Draft Guidance for Industry: 
Adaptive Design Clinical Trials for Drugs and Biologics, February 2010.  Modifications to 
dose levels, schedule, and regimen have been made in Stage 2 based on data from Stage 1. 
 
Approximately 84 subjects with intermediate-1, intermediate-2, or high risk MF who meet 
study eligibility requirements will be enrolled and randomized to treatment with single agent 
PRM-151 at doses of 0.3, 3, or 10 mg/kg IV on Days 1, 3, and 5 of Cycle 1 and Day 1 of each 
subsequent 28 day cycle for nine cycles.  The randomization will be stratified according to 
type of subject (subjects with Hgb < 100 g/L and having received > 2 units PRBC in the 12 
weeks prior to study entry OR subjects with platelet count < 50 x 109/L) and will ensure that 
the final study population will include at least 50% of subjects from the second stratum 
(platelet count < 50 x 109/L).  As outlined in APPENDIX J, all subjects completing 9 cycles of 
the originally assigned treatment may switch to an open label extension and receive PRM-151 
10 mg/kg every 4 weeks.  
 
• Mutational Status and Cytogenetics 
 
o Association of baseline mutational status of JAK2V617F, MPLW515, 
Calreticulin, ASXLI, EZH2, SRSF2, IDH1/2 with selected primary and 
secondary endpoints 
 
o Changes in allele burden of JAK2V617F at week 36.  Changes in allele 
burden of MPLW515, Calreticulin, ASXLI, EZH2, SRSF2, IDH1/2 at 
week 36 will be measured as commercially available assays become 
available 
 
o Association of baseline cytogenetic abnormalities and selected primary 
and secondary endpoints 
 
• Association of baseline PTX-2 levels with selected primary and secondary endpoints 
 
• Evaluation of potential biomarkers of PRM-151 activity in bone marrow biopsies taken 
at baseline, weeks 12, 24, and 36 
 
• Measurement of progression-free and overall survival 
 
 


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The first cycle of the open label phase contains a loading dose of 10 mg/kg on days 1, 3, and 5. 
This will allow for subjects from all three dosing cohorts to receive a loading dose of 10 mg/kg 
while maintaining the blind. Additionally, subjects who have entered the open label extension 
study prior to the approval of this amendment may receive a loading dose (10 mg/kg on days 
1, 3, and 5), to be administered on their next scheduled cycle after approval of this protocol 
amendment. This will allow for these subjects to receive any potential pharmacologic benefit 
of the loading dose.  
As of 14-Nov 16, we have blinded safety data, although limited, on 21 subjects receiving a 
similar 10 mg/kg loading dose in the open label of the PRM-151-202 IPF study after 24 weeks 
of exposure to PRM-151 or placebo in 2:1 ratio. No incremental risk has been reported in these 
subjects.  
 
Subjects enrolled in the open-label phase extension protocol of Stage 1 should continue to 
follow the study procedures outlined in APPENDIX L.  
Enrolled subjects will be considered evaluable for response if they are on study drug for at 
least twelve weeks. 
Study Duration: 
Each subject will participate in the study for approximately 44 weeks.  Participation will 
include a screening evaluation within four weeks prior to the first PRM-151 administration, 
nine study cycles of four weeks each, and an end of study visit four weeks after the end of the 
last cycle.  After completion of 9 cycles, subjects may continue with PRM-151 dosing in the 
open label extension in the absence of disease progression or toxicity warranting 
discontinuation of therapy. 
It is estimated that the study will be completed in approximately 18 months. 


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Study Inclusion and Exclusion Criteria: Inclusion Criteria: 
1. Subjects must be > 18 years of age at the time of signing the Informed Consent Form 
(ICF); 
2. Subjects must voluntarily sign an ICF; 
3. Subjects must have a pathologically confirmed diagnosis of PMF as per the WHO 
diagnostic criteria (APPENDIX C) or post ET/PV MF; 
4. At least Grade 2 marrow fibrosis according to the WHO Grading of Bone Marrow 
Fibrosis (APPENDIX D); 
5. Intermediate -1, intermediate -2, or high risk disease according to the IWG-MRT 
Dynamic International Prognostic Scoring System (APPENDIX E); 
6. A bone marrow biopsy must be performed within four weeks prior to Cycle 1 Day 1 
treatment to establish the baseline fibrosis score; 
7. Subjects must not be candidates for ruxolitinib based on EITHER: 
a. Platelet count < 50 x 109/L, OR 
b. Hgb < 100 g/L have received > 2 units PRBC in the 12 weeks prior to study 
entry, and be intolerant of or had inadequate response to ruxolitinib; 
8. Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance 
Status of 0-2 (APPENDIX  F); 
9. Life expectancy of at least twelve months; 
10. At least four weeks must have elapsed between the last dose of any MF-directed drug 
treatments for myelofibrosis (including investigational therapies) and study enrollment; 
11. Recovery to < Grade 1 or baseline of any toxicities due to prior systemic treatments, 
excluding alopecia;  
12. Women of child bearing potential (WCBP), defined as a sexually mature woman not 
surgically sterilized or not post-menopausal for at least 24 consecutive months if < 55 
years or 12 months if > 55 years, must have a negative serum pregnancy test within 
four weeks prior to the first dose of study drug and must agree to use highly effective 
methods of birth control throughout the study. Highly effective methods of 
contraception include combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation by oral, intravaginal, or 
transdermal administration; progestogen-only hormonal contraception associated with 
inhibition of ovulation by oral, injectable, or implantable administration; intrauterine 
device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; 
partner vasectomy, and total abstinence (only if total abstinence is the preferred method 
and usual lifestyle of the subject). Adequate contraceptive use should be continued 
until 28 days after the final dose of the study drug.  
 
13. Ability to adhere to the study visit schedule and all protocol requirements; 
 
14. Must have adequate organ function as demonstrated by the following: 
 
• ALT (SGPT) and/or AST (SGOT) < 3 x upper limit of normal (ULN), or < 4 x 
ULN (if upon judgment of the treating physician, it is believed to be due to 
extramedullary hematopoiesis [EMH] related to MF); 
• Direct bilirubin < 1.5 x ULN; or < 2 x ULN (if upon judgment of the treating 
physician, it is believed to be related to MF); 


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• Serum creatinine ≤ 2.5 x ULN. 
 
Exclusion Criteria: 
1. White blood cell count > 25 x 109/L or >10% peripheral blood blasts; 
2. Other invasive malignancies within the last 3 years, except non-melanoma skin cancer 
and localized cured prostate and cervical cancer; 
3. History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia 
requiring medication or mechanical control within the last 6 months; 
4. Presence of active serious infection; 
5. Any serious, unstable medical or psychiatric condition that would prevent, (as judged 
by the Investigator) the subject from signing the informed consent form or any 
condition, including the presence of laboratory abnormalities, which places the subject 
at unacceptable risk if he/she were to participate in the study or confounds the ability to 
interpret data from the study; 
6. Known history of human immunodeficiency virus (HIV), or known active hepatitis A, 
B, or C infection; 
7. Organ transplant recipients other than bone marrow transplant; 
8. Women who are pregnant or lactating. 


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Efficacy Assessments: 
Efficacy will be assessed by evaluation of WHO bone marrow fibrosis grade, changes in 
hemoglobin, platelets, peripheral blood blasts, disease related symptoms, and spleen size. 
 
Safety Assessments: 
Safety will be evaluated from reported adverse events, scheduled physical examinations, vital 
signs, and clinical laboratory test results. 
 
A blinded DMC will be established to review safety data from this study, thereby better 
ensuring the safety of study participants. Consistent with US Food and Drug Administration 
(FDA) recommendations (FDA Guidance for Industry, Establishment and Operation of 
Clinical Trial Data Monitoring Committees, 2006), the DMC will be constituted of 
independent clinicians expert in the field of MF and clinical research.  A formal charter will be 
established for the conduct of the DMC. 
 
• The committee is planned to review the safety data in a blinded manner, but a 
procedure will be in place to allow the committee an immediate unblinding of either 
specific cases or of the whole study in case of detection of a potential safety signal 
necessitating an unblinded review of some (or all) subjects. 
Statistical Methods: 
 
General considerations: 
Continuous variables will be summarized by dose group with descriptive statistics (e.g., 
number of observations, number of missing observations, mean, standard deviation [SD], 
median, interquartile range, maximum, and minimum).  Categorical variables will be tabulated 
by frequency of subjects per dose group, and percentages will be calculated using the number 
of available observations as the denominator (i.e. excluding missing values). 
 
Determination of Sample Size 
The chosen sample size of 72 subjects (i.e. 24 subjects per dose arm) is deemed sufficient to 
provide adequate precision to the estimation of the response rate in each treatment arm.  The 
trial will enroll 84 subjects to allow for a discontinuation rate of 15%. 
 
Considerations on the precision of estimate and the power for comparisons planned as 
secondary analyses are provided in the body of the protocol. 
 
Randomization and Stratification 
 
This study is randomized with a 1:1:1 randomization ratio.  A central randomization system 
will be used.  The randomization will be stratified according to the subjects’ baseline 
haematologic status: baseline anemia alone or baseline thrombocytopenia or baseline anemia 
associated with baseline thrombocytopenia.  The randomization system will also ensure that at 
least 50% of the subjects in the final study population will have baseline thrombocytopenia. 
 
 
Missing values: 


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All available efficacy and safety data will be included in data listings and tabulations. 
 
For the primary efficacy criterion, subjects with a reduction in bone marrow fibrosis score by 
at least one grade according to WHO criteria (central adjudication) at any post baseline visit 
will be considered as responders.  Subjects without any central assessment of bone marrow 
fibrosis will be considered as non-responders.  In addition, subjects who discontinue due to 
toxicity prior to completion of one cycle of study drug will be also considered non-responders 
for the efficacy analyses. 
 
All other analyses will be based on observed data only; no missing data will be imputed.  
 
Efficacy analysis populations: 
The primary efficacy analysis will be conducted on the Full Analysis Set (FAS; all randomized 
subjects having received at least one administration of the study medication with at least one 
post-baseline assessment of BMRR (primary efficacy criterion) available.  Subjects who 
discontinue due to toxicity prior to completion of one cycle of study drug will also be kept in 
the FAS and considered non-responders for the efficacy analysis).  A per-protocol analysis 
will also be carried out on the Per Protocol (PP) set, a subset of the FAS composed of all 
subjects treated with the investigational medicinal product (IMP), having received at least the 
planned IMP infusions on days 1, 3, 5, and weeks 4 ,8, and 12 and who did not present any 
major protocol deviations. 
 
The per-protocol set will be used for secondary analyses of the primary efficacy criterion and 
for the analysis of some selected secondary efficacy criteria. 
 
Primary analysis of efficacy 
The primary efficacy analysis will consist in computing the bone marrow response rate 
(percent of subjects with a reduction in bone marrow fibrosis score by at least one grade) and 
its 97.5% two-sided confidence interval within each treatment arm.  This analysis will be 
conducted on the FAS analysis set. 
 
Inferential interpretation: for the 3 mg/kg and 10 mg/kg arms, the lower limit of the 97.5% 
two-sided confidence interval will be compared to 10%, a threshold assumed to define the 
minimal clinically relevant effect.  If the lower limit of the confidence interval is above 10%, 
the corresponding dose will be claimed to have demonstrated clinically relevant efficacy. 
 
The confidence intervals computation will use a method consistent with the stratified design. 
 
Comparison of PRR between treatment arms at week 36 
Pairwise comparisons between the three dose groups will be performed using the Cochran-
Mantel-Haenszel (general association) statistic in the SAS Freq procedure, to take into account 
the stratified design. 
 
Two pairwise comparisons (3 mg/kg versus 0.3 mg/day and 10 mg/kg versus 0.3 mg/day) will 
be computed with the aim to demonstrating superiority and, consequently, will use an adjusted 
a two-sided 0.025 level of significance. 


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The third comparison (10 mg/kg versus 3 mg/kg) is not expected to have enough power to 
demonstrate any difference with the planned sample size.  This comparison is considered 
exploratory and will be conducted using an unadjusted 0.05 level of significance. 
 
Other efficacy analyses: Sensitivity efficacy analysis, secondary efficacy analyses and 
exploratory efficacy analyses: see body of the protocol. 
 
Safety analyses: see body of the protocol. 
 
Date of Original Protocol: Version 1.0 – 17 Jan 2013 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
SYNOPSIS: STAGE 2 ................................................................................................................................ 2 
TABLE OF CONTENTS ......................................................................................................................... 14 
LIST OF TABLES .................................................................................................................................... 20 
LIST OF ABBREVIATIONS .................................................................................................................. 21 
1. 
 INTRODUCTION AND STUDY RATIONALE ...................................................................... 24 
1.1. 
Overview ........................................................................................................................................ 24 
1.2.  
Preclinical Experience .................................................................................................................. 25 
1.2.1. 
Pharmacology ............................................................................................................................ 25 
1.2.2 
Nonclinical Metabolism and Pharmacokinetics ..................................................................... 25 
1.2.3. 
Toxicology .................................................................................................................................. 25 
1.3. 
Clinical Experience ....................................................................................................................... 27 
1.3.1 
Single Ascending Dose Study ................................................................................................... 27 
1.3.2 
Multiple Ascending Dose Study ............................................................................................... 27 
1.3.3. 
Phase 2 Glaucoma Study .......................................................................................................... 28 
1.4. 
Study Rationale ............................................................................................................................. 28 
1.5  
Rationale for Stage 2 Changes ..................................................................................................... 30 
2. 
STAGE 2 STUDY OBJECTIVES ............................................................................................... 34 
2.1  
Primary Objective ......................................................................................................................... 34 
2.2 
Secondary Objectives .................................................................................................................... 35 
2.3.  
Exploratory Objectives ................................................................................................................. 35 
3.  
STAGE 2 STUDY ENDPOINTS ................................................................................................. 36 
3.1  
Primary Endpoint ......................................................................................................................... 36 
3.2. 
Secondary Endpoints .................................................................................................................... 36 
3.3       Exploratory Endpoints ................................................................................................................. 38 
4.  
OVERALL STAGE 2 STUDY DESIGN AND PLAN ............................................................... 41 
4.1.1. 
Study Design: ............................................................................................................................. 41 
4.1.2. 
Subject Assignment to Treatment Groups ............................................................................. 41 
4.1.3. 
Study Duration .......................................................................................................................... 42 
5. 
STAGE 2 SELECTION OF STUDY POPULATION ............................................................... 43 
5.1 
Study Population ........................................................................................................................... 43 
5.1.1. 
Inclusion Criteria ...................................................................................................................... 43 


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5.1.2. 
Exclusion Criteria ..................................................................................................................... 44 
6. 
STAGE 2 STUDY TREATMENT(S) .......................................................................................... 44 
6.1.  
Investigational Product................................................................................................................. 44 
6.2. 
Treatment(s) Administered .......................................................................................................... 44 
6.3. 
Dose for Each Subject ................................................................................................................... 45 
6.4. 
Method of Assigning Subjects to Treatment Groups ................................................................. 45 
6.5. 
Blinding .......................................................................................................................................... 45 
6.5.1. 
Breaking the Blind .................................................................................................................... 45 
6.6. 
Concomitant Medications, Therapies and Medical/Surgical Interventions ............................ 46 
6.7. 
Treatment Compliance ................................................................................................................. 46 
6.8. 
Packaging and Labeling ............................................................................................................... 46 
6.9. 
Storage and Accountability .......................................................................................................... 46 
7. 
STUDY PROCEDURES............................................................................................................... 47 
7.1. 
Informed Consent ......................................................................................................................... 47 
7.2. 
Study Entrance Criteria ............................................................................................................... 47 
7.3. 
Confirmation of Study Eligibility ................................................................................................ 48 
7.4. 
Demographics ................................................................................................................................ 48 
7.5. 
Medical History ............................................................................................................................. 48 
7.6. 
Height and Weight ........................................................................................................................ 48 
7.7. 
Eastern Cooperative Oncology Group Performance Status ..................................................... 48 
7.8. 
Investigational Product Administration ..................................................................................... 48 
7.10. 
Exploratory Laboratory Assessments ..................................................................................... 49 
7.11. 
Efficacy Assessments................................................................................................................. 49 
7.11.1 
Bone Marrow Biopsy ................................................................................................................ 49 
7.11.2 
Assessment of transfusions ....................................................................................................... 50 
7.11.3 
Assessment of spleen size .......................................................................................................... 50 
7.11.3.1. Palpation ..................................................................................................................................... 50 
7.11.3.2.  Imaging ...................................................................................................................................... 50 
7.11.4 
Assessment of Symptoms .......................................................................................................... 50 
7.11.4.1 Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) ............................... 50 
7.11.4.2. EORTC QLQ-C30 ..................................................................................................................... 50 
7.11.5. FDG or FLT PET-CT Imaging .................................................................................................... 50 
7.11.6. 
Response Assessments............................................................................................................... 50 


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7.12. 
Safety Assessments .................................................................................................................... 51 
7.12.1. 
Physical Examination ............................................................................................................... 51 
7.12.2  
Vital Signs .................................................................................................................................. 51 
7.12.3. 
Clinical Laboratory Tests ......................................................................................................... 51 
7.12.4. Pregnancy Test .............................................................................................................................. 52 
7.12.5. 
Electrocardiograms (ECG) Assessments ................................................................................ 52 
7.12.6. 
Immune Response Assessments ............................................................................................... 52 
7.12.7. 
Sample Collection, Storage, and Shipping .............................................................................. 52 
7.13. 
Adverse Events Assessments .................................................................................................... 52 
7.13.1 
Definitions of Adverse Events and Serious Adverse Events .................................................. 52 
7.13.1.1 Adverse Event .............................................................................................................................. 53 
7.13.1.2. Serious Adverse Event ............................................................................................................... 54 
7.13.1.3. Classification of Adverse Events and Serious Adverse Events .............................................. 54 
7.13.1.4. Data Monitoring Committee ..................................................................................................... 55 
7.13.1.5. Relatedness of Adverse Events and Serious Adverse Events ................................................. 55 
7.13.2. 
Procedures for Recording and Reporting Adverse Events ................................................... 56 
7.13.2.1. Adverse Event Monitoring and Period of Observation .......................................................... 56 
7.13.2.1.1. 
Reporting of Adverse Events of Special Interest ............................................................ 56 
7.13.2.2.  Reporting Serious Adverse Events .......................................................................................... 57 
7.13.3 
Reporting Pregnancies .............................................................................................................. 57 
7.13.4.     Medication Error ...................................................................................................................... 58 
7.14. 
Removal of Subjects from the Trial or Investigational Product ........................................... 58 
7.15. 
Other Study Procedures ........................................................................................................... 58 
7.16. 
Appropriateness of Measurements .......................................................................................... 58 
8.0 
STAGE 2 STUDY ACTIVITIES ................................................................................................. 59 
8.1. 
Screening Visit (< 28 Days Prior to First Dose) .......................................................................... 59 
8.2. 
Cycle 1, Day 1 (+/- 1 day) .............................................................................................................. 60 
8.3. 
Cycle 1, Days 3 and 5 (+/- 1 day) .................................................................................................. 60 
8.4. 
Cycles 2 through 9, Day 1 (+/- 3 days) ......................................................................................... 61 
8.5  
Cycle 9, Day 29 (Week 36) (+/- 3 days) ........................................................................................ 61 
8.6. 
End of Study Visit (approximately 28 days [+/- 3 days] after Cycle 9 Day 29 or withdrawal 
from study) ................................................................................................................................................ 62 
9. 
QUALITY ASSURANCE AND CONTROL .............................................................................. 63 


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10. 
STAGE 2 PLANNED STATISTICAL METHODS................................................................... 64 
10.1 
Determination of Sample Size ...................................................................................................... 64 
10.2. 
Randomization and Stratification ........................................................................................... 64 
10.3. 
General considerations for statistical analysis ....................................................................... 64 
10.3.1 
Statistical Analysis Plan............................................................................................................ 64 
10.3.2  
Descriptive statistics .................................................................................................................. 65 
10.3.3. 
Inferential statistics ................................................................................................................... 65 
10.3.4. 
Missing, Unused, and Spurious Data ...................................................................................... 65 
10.3.5. 
Interim Analyses ....................................................................................................................... 66 
10.3.6. 
Software used for statistical analyses ...................................................................................... 66 
10.4 
Protocol deviations ........................................................................................................................ 66 
10.5. 
Analysis datasets ....................................................................................................................... 67 
10.5.1. 
Efficacy Analysis Sets: .............................................................................................................. 67 
10.5.2. 
Safety Analysis Sets: ................................................................................................................. 67 
10.6. 
Planned Statistical Analyses and Methods ............................................................................. 67 
10.6.1 
Efficacy Analyses ...................................................................................................................... 67 
10.6.1.1. Primary analysis of efficacy ...................................................................................................... 67 
10.6.1.2. Sensitivity analyses on the primary endpoint:......................................................................... 67 
10.6.1.3. Secondary and exploratory efficacy analyses: ......................................................................... 68 
10.6.1.3.1. Comparison of PRR between treatment arms...................................................................... 68 
10.6.1.3.2. Analyses of categorical secondary and exploratory efficacy endpoints: ............................ 68 
10.6.1.3.3. Analyses of quantitative secondary and exploratory efficacy endpoints: .......................... 68 
10.6.1.3.4. Inferential analyses for secondary and exploratory efficacy endpoints: ........................... 69 
10.6.2. 
Safety Analysis .......................................................................................................................... 69 
10.6.3. 
Other Analyses .......................................................................................................................... 70 
10.6.3.1. Subject Disposition ..................................................................................................................... 70 
10.6.3.2. Demographic and Baseline Characteristics ............................................................................. 70 
10.6.3.3. Subject Adherence and Extent of Exposure ............................................................................ 70 
10.6.3.4. Concomitant Medications .......................................................................................................... 70 
11.  
 ADMINISTRATIVE REQUIREMENTS .................................................................................. 70 
11.1. 
Investigators and Study Administrative Structure ................................................................ 70 
11.2 
Institutional Review Board (IRB), Independent Ethics Committee (IEC) Approval, or 
Research Ethics Board Attestation (REB) .............................................................................................. 71 


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11.3. 
Ethical Conduct of the Study ................................................................................................... 71 
11.4.  Subject Information and Consent ................................................................................................. 71 
11.5.  
 Subject Confidentiality ............................................................................................................ 72 
11.6. 
 Study Monitoring ..................................................................................................................... 72 
11.7. 
 Case Report Forms and Study Records ................................................................................. 72 
11.8. 
 Data Monitoring Committee ................................................................................................... 73 
11.9. 
 Central Bone Marrow Review Committee ............................................................................ 73 
11.10 
 Protocol Violations/Deviations ................................................................................................ 73 
11.11. 
 Premature Closure of the Study ............................................................................................. 73 
11.12. 
 Access to Source Documentation ............................................................................................ 74 
11.13. 
 Data Generation and Analysis ................................................................................................ 74 
11.14. 
 Retention of Data ..................................................................................................................... 74 
11.15. 
 Financial Disclosure ................................................................................................................. 74 
11.16. 
 Liability and Insurance ........................................................................................................... 75 
11.17. 
 Publication Policy ..................................................................................................................... 75 
12. 
  USE OF INFORMATION.......................................................................................................... 76 
13. 
 INVESTIGATOR AGREEMENT ............................................................................................. 77 
14. REFERENCES .................................................................................................................................... 78 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX A: 
Schedule of Events ………………………………………………… 80 
APPENDIX B:            International Working Group (IWG) consensus criteria 
for treatment response in myelofibrosis with 
myeloid metaplasia* ..........................................................................82 
APPENDIX C: 
Proposed Revised World Health Organization Criteria for 
 Primary Myelofibrosis …………………………………………… 84 
APPENDIX D: 
 
WHO Grading of Bone Marrow Fibrosis  
(EU Consensus Criteria) ……………………………………………85 
APPENDIX E: 
International Working Group for Myeloproliferative 
Neoplasms Research and Treatment (IWG-MRT) 
 
 
Dynamic International Prognostic Scoring System  
 (DIPSS) for primary myelofibrosis* ………………………………86 
APPENDIX F: 
Eastern Cooperative Oncology Group Performance Status ………. 87 
APPENDIX G: 
Myeloproliferative Neoplasm Symptom Assessment Form  
 (MPN-SAF) ………………………………………………………. 88 
APPENDIX H: 
EORTC QLQ-C30 ………………………………………………… 91 
APPENDIX I:  
National Cancer Institute Common Terminology Criteria  
For Adverse Events (NCI CTCAE) ………………………………...93 
APPENDIX J:  
Stage 2 Extension Study ……………………………………………94 
APPENDIX K: 
SYNOPSIS: STAGE 1 ……………………………………………. 98 
APPENDIX L: 
Synopsis Stage 1 OLE Extension study ……………………………105 
APPENDIX M: 
Summary of Protocol Changes from Version 5…………………….109 
 
 
 


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LIST OF TABLES 
 
Table 1: 
Assessments for Physical Examinations …………………………………. 51 
Table 2: 
Clinical Laboratory Tests …………………………………………………. 51 
Table 3: 
Adverse Event Grading …………………………………………………… 55 
Table 4: 
Adverse Event Relatedness ………………………………………………. 56 
 
 


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LIST OF ABBREVIATIONS 
 
Abbreviation  
Term 
 
AE 
 
 
adverse event 
ALT 
 
 
alanine aminotransferase 
ANC  
 
absolute neutrophil count 
AUC (AUC0-∞) 
area under the concentration-time curve from time zero extrapolated to 
infinite time 
AUC (AUC0-24) 
area under the concentration-time curve from time zero extrapolated to 24 
hours 
AST 
 
 
aspartate aminotransferase 
ASXLI 
 
additional sex combs like transcriptional regulator 1 
BUN  
 
blood urea nitrogen 
C 
 
 
Centigrade 
CBC  
 
complete blood count 
CFR 
 
 
Code of Federal Regulations 
CI 
 
 
clinical improvement 
CIOMS 
 
Council for International Organizations of Medical Sciences 
CL 
 
 
Clearance 
Cmax 
 
 
maximum observed concentration 
CPK  
 
creatine phosphokinase 
CR 
 
 
complete remission 
CRA  
 
Clinical Research Associate 
CRF 
 
 
case report form 
CRO  
 
Contract Research Organization 
CRP 
 
 
C reactive protein 
CSA  
 
Clinical Study Agreement 
CTC 
 
 
common toxicity criteria 
CTCAE 
 
Common Terminology Criteria for Adverse Events 
DIPPS  
 
Dynamic International Prognostic Scoring System 
dL 
 
 
Deciliter 
EC 
 
 
ethics committee 
ECG  
 
Electrocardiogram 
ECOG  
 
Eastern Cooperative Oncology Group 
EDC  
 
electronic data capture 
eCRF  
 
electronic case report form 
e.g. 
 
 
exempli gratia (for example) 
EMH  
 
extramedullary hematopoiesis 
ET 
 
 
essential thrombocytopenia 
EZH2  
 
enhancer of zeste 2 polycomb repressive complex 2 subunit 
FDA  
 
Food and Drug Administration 
G-CSF  
 
granulocyte colony stimulating factor 


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GCP  
 
Good Clinical Practice 
GM-CSF 
 
granulocyte microphage colony stimulating factor 
Hct 
 
 
Hematocrit 
Hgb 
 
 
Hemoglobin 
Hr 
 
 
Hour 
HIV 
 
 
human immunodeficiency virus 
ICF 
 
 
informed consent form 
ICH 
 
 
International Council on Harmonisation 
IDH ½  
 
isocitrate dehydrogenase ½ genes 
IEC 
 
 
independent ethics committee 
IND 
 
 
Investigational New Drug 
INR 
 
 
international normalized ratio 
IPF 
 
 
idiopathic primary fibrosis 
IRB 
 
 
institutional review board 
IU 
 
 
international unit 
IV 
 
 
intravenous, intravenously 
IRS 
 
 
interactive response system 
IWG  
 
International Working Group 
JAK 
 
 
Janus kinase 
Kg 
 
 
Kilograms 
LCM  
 
Lower costal margin 
LDH  
 
lactate dehydrogenase 
MAD  
 
multiple ascending dose 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
MF 
 
 
Myelofibrosis 
Mg 
 
 
Milligrams 
mL 
 
 
Milliliter 
MPN-SAF 
 
myeloproliferative neoplasm symptom assessment form 
Mreg  
 
Macrophage in a protective regulatory state 
MSCs  
 
mesenchymal stromal cells 
n 
 
 
Number 
NCI 
 
 
National Cancer Institute 
NOAEL 
 
no observed adverse effect level 
OLE 
 
 
open label extension 
ORR  
 
overall response rate  
 
 
PD 
 
 
progressive disease 
PK 
 
 
pharmacokinetic(s) 
PMF  
 
primary myelofibrosis 
PR 
 
 
partial remission 
PRBC  
 
packed red blood cells 
PT 
 
 
prothrombin time 
PTT 
 
 
partial thromboplastin time 
PTX-2  
 
pentraxin-2 


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PV 
 
 
polycythemia vera 
QOL  
 
quality of life 
QTc 
 
 
corrected QT interval 
RBC  
 
red blood cell 
REB 
 
 
Research Ethics Board 
SAD  
 
single ascending dose 
SAE 
 
 
serious adverse event 
SAP 
 
 
Statistical Analysis Plan; Serum Amyloid Protein 
SD 
 
 
standard deviation 
SGOT  
 
serum glutamic oxaloacetic transaminase 
SGPT  
 
serum glutamic pyruvic transaminase 
SRSF2  
 
Serine/Arginine-Rich Splicing Factor 2 
TGF β1 
 
transforming growth factor beta 1 
TKI 
 
 
tyrosine kinase inhibitor 
tmax 
 
 
time of maximum observed concentration 
ULN  
 
Upper limit of normal 
UUO  
 
unilateral ureteral obstruction 
Vd 
 
 
volume of distribution 
WBC  
 
white blood cell 
WCBP  
 
women of child-bearing potential 
WHO-DD 
 
World Health Organization Drug Dictionary 
w/v 
 
 
weight/volume 
 
 
 
 


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1. 
 
INTRODUCTION AND STUDY RATIONALE 
 
 
1.1. 
Overview 
Pentraxin-2 (PTX-2), also called Serum Amyloid Protein (SAP) is an endogenous protein that 
circulates in the bloodstream.  Recent discoveries about the biology of tissue repair and fibrosis 
have elucidated the important role that PTX-2 plays biologically in regulating processes that 
relate to scar prevention and healing.  PTX-2 is an agonist that binds to Fc gamma receptors on 
monocytes and promotes their differentiation into regulatory macrophages (Mreg), which 
function to promote epithelial healing and resolution of inflammation and scarring. PTX-2 also 
prevents the differentiation of monocytes into M2 pro-fibrotic macrophages and fibrocytes, 
preventing the formation of fibrosis. PRM-151 is a recombinant human PTX-2. Pre-clinical and 
clinical data exist to support the investigation of PRM-151 in the treatment of fibrotic diseases. 
Myelofibrosis [including Primary Myelofibrosis (MF), Post-Polycythemia Vera (PV) MF and 
Post-Essential Thrombocythemia (ET) MF] is a clonal myeloprolilferative neoplasm, 
characterized by progressive bone marrow fibrosis and subsequent ineffective erythropoiesis, 
dysplastic megakaryocyte hyperplasia, and extramedullary hematopoiesis. The typical clinical 
presentation includes marked splenomegaly, progressive anemia, and constitutional symptoms. 
Bone marrow transplant is the only treatment that can cure subjects with MF, but is associated 
with high morbidity and mortality (Stewart, Pearce et al. 2010); (Ballen 2012). Bone marrow 
fibrosis resolves in subjects after successful transplant as early as one month (Przepiorka, Giralt 
et al. 1998). 
Until recently, there was no approved medical therapy for MF and most subjects were managed 
with various combinations of growth factors, immunomodulatory agents, cytotoxic 
chemotherapy, and steroids.  None of these therapies produced significant responses in the 
majority of subjects.  For this reason, no medication has been approved for MF until recently. 
Ruxolitinib is a Janus kinase inhibitor, recently approved in the US and EU for the treatment of 
subjects with intermediate or high-risk myelofibrosis, including primary myelofibrosis (PMF), 
post-polycythemia vera myelofibrosis (post-PV MF) and post-essential thrombocythemia (post-
ET MF) (JAKAFI® Full Prescribing Information 2011). Treatment with ruxolitinib results in 
reduction in spleen volume and improvement in constitutional symptoms, but does not appear to 
have an effect on bone marrow fibrosis, and symptoms return within one week of discontinuing 
the drug. (Verstovsek 2012). Other Janus kinase inhibitors are in clinical development.  There is 
a clear unmet medical need for new therapies that could improve bone marrow fibrosis in 
subjects with myelofibrosis with a resultant improvement in blood counts and other disease-
related factors. 
 
 
 


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1.2.  Preclinical Experience 
 
 
 
 
1.2.1. Pharmacology 
Following the initial in vitro discovery by Gomer and Pilling suggesting that PTX-2 may 
regulate monocyte differentiation into spindle shaped fibrocytes (Pilling, Buckley et al. 2003), 
they, with others, published several studies on the activity of species-specific serum-derived 
PTX-2 in preventing fibrosis in models of bleomycin-induced lung fibrosis in rats and mice and 
also in a model of ischemia reperfusion injury to mouse heart (Pilling, Roife et al. 2007), 
(Haudek, Xia et al. 2006).  Promedior and its collaborators have expanded the animal fibrosis 
model data using human serum-derived PTX-2 and PRM-151 to demonstrate potent anti-fibrotic 
activity in models of lung injury, skin injury, kidney injury, liver injury, radiation-induced injury, 
and a rabbit trabeculectomy model of eye injury. 
 
 
 
 
1.2.2 Nonclinical Metabolism and Pharmacokinetics 
Promedior, Inc. has used species-specific analytical methods to study the pharmacokinetics of 
human serum-derived PTX-2 and PRM-151 in mice, rats, rabbits, and cynomolgus monkeys by 
different routes of administration.  Dose-proportional increases in systemic exposure of human 
PTX-2 have been observed in rats following IV dosing.  Additionally, the pharmacokinetics of 
PTX-2 and PRM-151 in rats were compared and found to be equivalent.  In multiple—dose 
studies, no differences in pharmacokinetic parameters were observed between the first and last 
dose following two doses of PTX-2 in rats and five doses of PRM-151 in rabbits.  Further, the 
pharmacokinetics of IV-dosed PRM-151 in monkeys was shown to be comparable to other 
mammalian species.  
The t1/2 of IV-dosed PTX-2/PRM-151 (2-7 mg/kg) has been calculated for multiple species, with 
the following results: mouse (4-8 hr) < rabbit (7.3 hr) < monkey (6-15 hr) < rat (13-23 hr) < 
human (30 hr, [human t1/2 from Promedior single, ascending dose study, PRM151A-11EU; 10 
mg/kg dose in healthy volunteers]) (Hawkins and Pepys 1990). 
 
 
 
 
1.2.3. Toxicology 
PRM-151 has been tested in an in vitro blood compatibility study and found to be non-hemolytic.  
No dose-limiting toxicity was observed following single – or 5-day repeated-dosing of PRM-151 
in rats or mice up to the limit dose of 200 mg/kg.  Intravenous dosing of PRM-151 to CD-1 mice 
produced a strong immunogenic response following the third weekly dose.  As a result of this 
immunogenicity, rats were used as the rodent species for subsequent repeated-dosing toxicity 
studies.  In a cynomolgus monkey dose range-finding study, renal toxicity was identified in one 
out of four animals at the end of the single, escalating dose portion of the study.  Due to the 
design of the study, a definitive no observed adverse effect level (NOAEL) could not be 
determined. Based on findings from the dose range-finding study, the top dose for the definitive 
repeat-dose study in monkeys was reduced to 120 mg/kg. 
A definitive 14-day intravenous dose study in Sprague Dawley rats demonstrated no adverse 
toxicological effects at doses ranging from 10 to 200 mg/kg/day. Neurobehavioral evaluations 
(functional observational battery) conducted during this study identified no treatment-related 


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findings.  No adverse toxicological effects were identified in a definitive 14-day intravenous 
dose study in cynomolgus monkeys at doses ranging from 12 to 120 mg/kg/day.  Histological 
examination of the kidneys identified no renal toxicity in any of the 28 study animals dosed for 
14 days with PRM-151.  Electrocardiography measurements collected during this study were 
qualitatively and quantitatively normal with no abnormalities in rhythm.   
In chronic toxicology studies in Sprague Dawley rats (1368-010) and cynomolgus monkeys 
(1368-011), PRM-151 was initially dosed at 50, 100, and 200 mg/kg IV bolus on Days 1, 3, 5, 8 
and weekly thereafter for 26 weeks. Findings from the rat study (1368-010) and the monkey 
study (1368-011) included signs and symptoms in both rats and monkeys consistent with acute 
infusion reactions at 50 mg/kg, 100 mg/kg and 200 mg/kg dose levels.  These reactions were 
observed at all time points in the rat, with deaths occurring on days 15 and 22.  Following a 
modification of the protocol to reduce the highest dose to 150 mg/kg and to lengthen the infusion 
time from 5 minutes to 30 minutes, infusion reactions were significantly decreased and no 
further deaths occurred. 
Acute reactions in the monkey chronic toxicology study (1368-011) were first observed at the 
200 mg/kg dose level on day 15, with continued occurrence on Days 15, 22, and 29.  Most 
reactions resolved within ten minutes with therapeutic diphenhydramine, but deaths of two 
monkeys, one at 50 and one at 100 mg/kg, resulted in termination of the study. 
These findings were unexpected because no acute infusion reactions, dose limiting toxicities, or 
deaths occurred in two prior GLP studies of 14 consecutive daily doses of PRM-151 in rats and 
monkeys, and because PRM-151 has already been administered safely to humans (as a single 
dose to 18 healthy volunteers and 3 subjects with idiopathic pulmonary fibrosis (IPF) and for 
multiple doses on days 1, 3, 5, 8 and 15 to 15 subjects with idiopathic pulmonary fibrosis). In 
studies 1368-010 and 1368-011, PRM-151 manufactured at CMC Biologics at the 2500 L scale 
and formulated at the testing site was administered to rats and monkeys on days 1, 3, 5, 8 and 
weekly thereafter.  In prior GLP toxicology studies, PRM-151 DS manufactured at Catalent 
Biosciences at the 200 L scale with no additional formulation was administered to rats and 
monkeys on days 1-14. Both prior clinical studies utilized GMP drug product manufactured at 
Catalent Biosciences at the 200 L scale.  To determine if the unexpected findings in studies 
1368-010 and 1368-011 were due to differences in drug product or to differences in dosing 
schedule, and to explore mitigation of acute reactions by slower infusion rates, study 1368-012 
was conducted. 
Study 1368-012 in rats, assessed the frequency and severity of acute infusion reactions to both 
formulations of PRM-151 on both daily and weekly dosing schedules, and investigated the 
benefit of slower infusion rates in mitigation of acute toxicity.  Animals in all arms received 200 
mg/kg of PRM-151.  Severe acute infusion reactions and deaths identical to the events in study 
1368-010 occurred only on the intermittent bolus schedules and with all forms of PRM-151, 
indicating that the unexpected acute infusion reactions and deaths observed in studies 1368-010 
and 1368-011 were due to intermittent dosing rather than product differences.  Prolonging the 
rate of infusion to 60 minutes significantly reduced the frequency and severity of infusion 


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reactions and no deaths occurred in animals receiving PRM-151 at the 60 minute infusion rate.  
The increased toxicity with intermittent dosing is most likely due to enhanced immunogenicity in 
the context of cross-species reactivity to a foreign protein.  Immunogenicity of human proteins in 
animals is generally not predictive of reactions in humans. 
In the Phase 1 ascending, single IV-dose study in humans (described in 1.3.1), a 10 mg/kg dose 
produced a mean AUC 0-∞ 3,005 µg*/hr/mL. Following the first IV dose in the 14-day 
toxicology studies, AUC 0-24 was 16,237 µg*/hr/mL in rats and 8,081 µg*hr/mL in monkeys, 
establishing safety margins of 5.4-fold and 2.7-fold, respectively.  Due to the design of the 14-
day toxicology studies (daily dosing), AUC 0-∞ could not be calculated, and the AUC 0-24 is an 
underestimation of total systemic exposure.  Therefore, these calculated safety margins are 
expected to be conservative estimates. 
 
1.3. 
Clinical Experience 
PRM-151 has been evaluated in humans by intravenous administration in a Phase 1, single-
ascending dose study in healthy subjects and subjects with idiopathic pulmonary fibrosis (IPF; 
PRM151A-11EU) and in a Phase 1, Multiple Ascending Dose Study in subjects with IPF 
(PRM151F-12GL) and in Stage 1 of PRM-151G-101, PRM-151 has also been evaluated in 
humans as a sub-conjunctival injection in a randomized, double-masked, placebo-controlled 
study of PRM-151 in the Prevention of Postoperative Scarring in Glaucoma Subjects Following 
Primary Trabeculectomy (PRM151B-21GL). The relevance to humans of acute infusion 
reactions observed in ongoing non-clinical toxicology studies is unknown; the reactions occurred 
at doses significantly higher than the dose intended in this study, and in vivo studies of 
recombinant human proteins in conventional animals are not particularly useful to access the 
immunogenicity and risk of hypersensitivity reactions in humans since they are foreign to the 
animals.  In Stage 1 of PRM-151G-101, two subjects each experienced a single, non-serious, 
Grade 2 hypersensitivity event, related to PRM-151.  Both events were managed with 
medication.  One subject developed the infusion reaction on Day 58 and continued to be treated 
with PRM-151.  The other subject developed the infusion reaction on day 225 during the 
extension study.  The hypersensitivity reactions to date have occurred as isolated events and have 
been manageable (refer to Investigator’s Brochure for details). 
 
 
 
 
1.3.1 Single Ascending Dose Study 
The results of the single-ascending dose study indicate that single doses of PRM-151 
administered intravenously at doses of 0.1 mg/kg to 20 mg/kg are safe and well tolerated.  In this 
study, the plasma concentrations of PRM-151 were measurable only above 0.5 mg/kg dose.  The 
exposure to PRM-151 increased with dose and its half-life was 30 hours in healthy subjects.  
PRM-151 showed limited volume of distribution in healthy subjects.  Pharmacokinetics of PRM-
151 were similar in healthy subjects and IPF subjects following the 10 mg/kg dose. 
 
 
 
 
1.3.2 Multiple Ascending Dose Study 
The results of multiple-ascending dose study indicate that doses of PRM-151 administered by 
intravenous infusion over 30 minutes at doses of 1.0 mg/kg, 5 mg/kg, and 10 mg/kg on days 1, 3, 
5, 8 and 15 are safe and well-tolerated.  The most common AEs in the PRM-151 treated subjects 


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were cough (n=7; 47%), productive cough (n=4; 27%) and dizziness (n=4; 27%), followed by 
fatigue (n=3; 20%) and headache (n=3; 20%).  The incidences of these events were similar in the 
placebo group (cough, 33%, productive cough, 33%; dizziness, 17%, fatigue, 17% and headache, 
17%).  Treatment emergent events of cough, dysphonia and hypotension were numerically more 
frequent in test article-treated subjects than in placebo-treated subjects. They occurred in PRM-
151 treated subjects with the following frequencies: cough 40% (n=6), dysphonia 13% (n=2), 
hypotension 13% (n=2).  No placebo treated subjects reported a treatment emergent adverse 
event of dysphonia or hypotension, and the frequency of cough was 17% (n=1).  Frequency of 
treatment emergent productive cough was 33% (n=2) in the placebo treated subjects and 27% 
(n=4) in PRM-151 treated subjects. 
 
 
 
 
1.3.3. Phase 2 Glaucoma Study 
The results of the randomized study of PRM-151 in glaucoma following trabeculectomy indicate 
that PRM-151 administered as a subconjunctival injection post-operatively on Days 1, 2, 3, 5 and 
9 is safe and well-tolerated.  The majority of adverse events that occurred were ocular events that 
were reported at similar rates for placebo and PRM-151 treated subjects. The most common AE 
reported was intraocular pressure increased occurring in 15 subjects (24.2%) in the PRM-151 
group and 13 subjects (21.0%) in the placebo group.  The majority of adverse events were mild 
to moderate in severity, and most were not considered related to study drug.  A total of 20 
serious adverse events have been reported in 14 subjects; none of the SAEs were considered 
related to study drug. 
Complete summaries of the toxicology and safety of PRM-151 are provided in the Investigator’s 
Brochure for PRM-151. 
 
1.4. 
Study Rationale 
PTX-2 and PRM-151 have demonstrated the ability to reduce pre-existing fibrosis in multiple 
pre-clinical models in different fibrotic diseases, including TGF-β1 and bleomycin-induced lung 
fibrosis, unilateral ureteral obstruction (UUO) and ischemia reperfusion injury (IRI) induced 
renal fibrosis, and radiation induced oral mucositis.  The pathogenesis of fibrosis in 
myelofibrosis is not well understood, but preliminary data suggests that, similar to other fibrotic 
diseases, insufficient production of PTX-2 may play a role.  In idiopathic pulmonary fibrosis 
(IPF), for example, studies have shown that subjects with IPF have lower levels of PTX-2 than 
healthy volunteers, and lower levels of PTX-2 are associated with poorer lung function in IPF 
subjects (Murray, Chen et al.2011). 
Until recently, the fibrosis in myelofibrosis was thought to be “reactive;” with overproduction of 
cytokines by malignant cells stimulating fibroblast-like cells derived from non-malignant 
mesenchymal stromal cells.  This hypothesis has been weakened by the fact that ruxolitinib, 
which causes significant reduction of PMF-associated cytokine levels, does not appear to affect 
bone marrow fibrosis (Verstovsek, Kantarjian et al. 2010). Verstovsek et al (Verstovsek 2013, 
manuscript in preparation) have recently reported findings that suggest that bone marrow derived 
fibrocytes from subjects with myelofibrosis come from the malignant clone rather than from 
mesenchymal stromal cells (MSCs).  Clonal neoplastic fibrocytes were identified in bone 


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marrows of subjects with PMF, and Jak2 mutations and chromosomal abnormalities present in 
the malignant clones in several subjects were present in the bone marrow derived fibrocytes but 
not in the MSCs. Furthermore, serum PTX-2 levels were significantly lower in subjects with 
PMF than healthy volunteers, and PTX-2 inhibited differentiation of monocytes from PMF bone 
marrows into fibrocytes in vitro.  Data with PRM-151 in other fibrotic disease models combined 
with these findings in PMF subject bone marrows support investigation of PRM-151 in subjects 
with PMF. 
PRM-151 differs from traditional mAb-based antagonist drugs.  Preclinical pharmacology and in 
vitro cell biology indicate that PTX-2 acts as a partial agonist of FcyR signaling in 
monocytes/macrophages, stimulating their differentiation into a protective regulatory state 
(Mreg); these cells then secrete IL-10 locally in the tissues. For this reason, it is likely that the 
optimal dose scheduling of PRM-151 will not follow a direct PK/PD relationship that is typical 
of mAb-based antagonists.  Instead, our data indicate that a threshold dosing interval must be 
achieved for PRM-151 in order to effectively modulate the monocyte/macrophage populations in 
tissues, but once modulated, the biologic activity is long lasting.  This suggests that intermittent 
dosing of PRM-151 will be effective to produce the desired pharmacologic effect.  In preclinical 
models of lung fibrosis, efficacy was seen at 1.6 mg/kg of mouse PTX-2 in mice, at 1.6 mg/kg of 
rat PTX-2 in rats and at 6-10 mg/kg of human PTX-2 in mice.  Efficacy was also observed 
following abbreviated therapeutic dose schedules of PTX-2 in both the mouse TGF-β1 lung 
fibrosis model and in the mouse bleomycin-induced lung fibrosis model, further supporting the 
hypothesis that intermittent dosing of PRM-151 may be feasible.  Importantly, the beneficial 
effects of PTX-2 appear to last well beyond the period of treatment.  In a study of PRM-151 in 
TGFβ1 continuous lung injury model of pulmonary fibrosis, mice were treated with vehicle or 
PRM-151 10 mg/kg on days 10, 11, and 12 and sacrificed on either Day 21 or Day 42; vehicle 
treated mice had progressive increase in lung collagen from Day 10 through Day 42, whereas 
PRM-151 treated mice had only a modest increase in lung collagen on Day 21, which remained 
stable through Day 42, resulting in a statistically significant difference in lung collagen between 
vehicle and PRM-151 treated mice at Day 42 (Study 11-014, 2012). 
Nonclinical studies have been conducted to gain an understanding of the relationship between a 
minimal effective dose, dose schedule and PRM-151’s pharmacodynamics effects.  Study 06-
002, “Effect of hSAP on TGF-β1 Induced Lung Fibrosis in Mice,” dosed h PTX-2 every 2 days 
from day -1 to day 13.  The TGF-β1 induced increase in total lung collagen was reduced by 
greater than 50% at the 6 mg/kg and 20 mg/kg dose groups.  The 2 mg/kg dose group had no 
effect in this model, suggesting that the minimal efficacious h PTX-2 dose level in this model 
was 2-6 mg/kg. Study 08-042, “Effects of delayed dosing of hSAP on TGF-β1-induced 
pulmonary fibrosis in mice” dosed h PTX-2 at 6 mg/kg every 2 days from day 4 to day 10.  The 
TGF-β1-induced increase in total lung collagen was again reduced by greater than 50%, and the 
durability of effect lasted through the end of study at Day 21, 11 days after dosing was stopped.  
Similarly, PRM-151 was dosed for 3 consecutive days starting on Day 11 in Study 08-034, 
“Local Delivery and Altered PRM-151 Dose Schedules in a Bleomycin Model”.  In this model of 
established lung disease, lung collagen levels were reduced in all dose groups; however, the 
group dosed with PRM-151 daily on days 11-13 showed the most pronounced reduction in 


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collagen deposition.  The durability of the effect of human PTX-2 following dosing in this model 
was also demonstrated to last through end of study at day 21.  These data support PRM-151 
dosing frequencies of every two weeks at a dose level of 2-6 mg/kg. 
Dose ranging studies in the bleomycin lung model in rats and mice have recently been 
completed, and indicate that doses of PRM-151 higher than 10 mg/kg are less effective than 
doses in the 2-10 mg/kg range, and that doses < 0.5 mg/kg are ineffective in these species.  In an 
in vitro assessment of PRM-151 in mouse and human fibrocyte assays, the IC50 of PRM-151 is 
2.0 µg/ml for mouse fibrocytes and 0.2 µg/ml for human fibrocytes, indicating that PRM-151 is 
more potent in humans than in mice.  PRM-151 is also more potent in human fibrocytes than 
endogenous human PTX-2.  Preclinical and clinical data suggest a potentially effective dose 
range of PRM-151 in humans of 0.2 to 10 mg/kg. 
In a recently completed Phase 1, randomized, blinded, placebo-controlled, multiple ascending 
dose study of PRM-151 in subjects with IPF (PRM151F-12GL), PRM-151 was well tolerated at 
all doses tested.  Subjects in all three PRM-151 dose groups demonstrated improvement in 
Percent Predicted Forced Vital Capacity (FVC) at Day 57 after receiving PRM-151 on Days 1, 3, 
5, 8 and 15.  Mean change from baseline in Percent Predicted FVC at Day 57 was + 2.4 (SD 3.8) 
for all PRM-151 treated subjects and -1.5 (SD 3) for placebo treated subjects (p=0.0524) 
(PRM151F-12GL Draft Clinical Study Report, 2012). 
The PRM-151 dose and administration schedule for Stage 1 was chosen based upon the Phase 1 
multiple ascending dose study in IPF, in which subjects received up to 10 mg/kg PRM-151 on 
days 1, 3, 5, 8 and 15.  Preclinical data supports dosing at two week intervals after an initial 
“loading” period.  In the multiple-ascending dose study, PRM-151 was safe and well-tolerated, 
with no increase in toxicity with increasing dose levels and no acute infusion reactions.  
Vertsovsek et al (manuscript in preparation) have demonstrated that bone marrow derived 
fibrocytes from PMF subjects are less sensitive to PTX-2 than fibrocytes from normal bone 
marrow, suggesting that more intense dosing may be required for a disease modifying effect.  
This study will evaluate an every four week dosing schedule, following a loading period. 
Additional information can be found in the Investigator’s Brochure. 
 
1.5  
Rationale for Stage 2 Changes 
All treatment arms in Stage 1 of PRM-151G-101 met the pre-specified efficacy criteria of > 1 
response to be considered for continued evaluation in Stage 2. Key findings from Stage 1 that led 
to the changes for Stage 2 are listed below. 
• Overall response rate was 43% at 24 weeks and 50% at 36 weeks 
o At 36 weeks of treatment 
 10 Bone Marrow responses 
 4 IWG Symptom responses 


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 10/17 subjects with baseline Hgb < 10 g/L and/or PLT < 50 x 109/L 
showed improvement in Hgb and/or PLT 
• There was no apparent difference in efficacy or safety between PRM-151 administered 
once a week or every four weeks 
• Hematologic improvements were more common with PRM-151 alone 
• Most subjects had improvements in symptoms and modest reductions in splenomegaly, 
although not meeting IWG response criteria 
• PRM-151 was very well tolerated both as a single agent and added to ruxolitinib, 
although adverse events were more common in the subjects also receiving ruxolitinib 
Based on these results, the following changes have been made for Stage 2: 
Design element 
Stage 1 
Stage 2 
Rationale 
Primary Objective 
Evaluate the efficacy 
of two different dose 
schedules of PRM-
151 in intermediate-
1, intermediate-2, or 
high risk subjects 
with PMF, post-PV 
MF, or post ET-MF 
who are not receiving 
therapy for MF, and 
in subjects with PMF, 
post-PV MF, or post 
ET-MF on a stable 
dose of ruxolitinib for 
at least three months. 
To determine the 
effect size of three 
different doses of 
PRM-151 on 
reduction in bone 
marrow fibrosis by > 
1 grade in 
intermediate-1, 
intermediate-2, and 
high risk subjects 
with PMF, post-PV 
MF, or post ET-MF 
who are anemic or 
thrombocytopenic 
and who are 
ineligible for, 
intolerant of, or have 
had an inadequate 
response to 
ruxolitinib. 
Single agent efficacy 
at 10 mg/kg every 4 
weeks supports 
continued evaluation 
 
Identification of 
minimal effective 
dose is important for 
further development 
 
Translational data 
suggests equal to 
greater efficacy at 
lower doses 
Primary Endpoint 
Percent of subjects 
with IWG-MRT 
response or reduction 
in bone marrow 
fibrosis by > 1 grade 
Percent of subjects 
with reduction in 
bone marrow fibrosis 
by > 1 grade 
Reduction in bone 
marrow fibrosis is 
most closely linked to 
the mechanism of 
action of PRM-151; 
assessment of clinical 
benefit related to 
decreased fibrosis, 
including IWG-MRT 
responses, will be 
done via secondary 
endpoints 


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Secondary Endpoints 
Safety  
Change in bone 
marrow fibrosis 
Change in symptoms 
Duration of response 
PK 
Safety 
Change in bone 
marrow fibrosis 
Improvement in 
hemoglobin 
Improvement in 
platelets  
Improvement in 
symptoms 
IWG-MRT response 
rate 
Duration of 
improvements 
Individual assessment 
of disease related 
abnormalities will 
help to define the 
clinical benefit of 
PRM-151 and guide 
future clinical trials 
Eligibility 
Intermediate-1, 2, or 
high risk  
 
Myelofibrosis Grade 
2 or 3 
Intermediate-1,  
Intermediate-2 or 
High risk 
 
Myelofibrosis Grade 
2 or 3 
 
Not candidates for 
ruxolitinib based on 
EITHER 
 
Hgb < 100 g/L and 
requiring at least 2 
units PRBC in the 12 
weeks prior to study 
entry and intolerant 
of or had in adequate 
response to 
ruxolitinib OR 
 
PLT <50 x 109/L 
 
Subjects with 
clinically significant 
anemia or 
thrombocytopenia 
had the greatest 
benefit in Stage 1, 
and will provide the 
best opportunity to 
define the clinical 
benefit of PRM-151 
 
Limiting eligibility to 
subjects who are not 
candidates for 
ruxolitinib ensures 
that we are enrolling 
subjects with the 
highest unmet need 
Duration 
24 weeks 
36 weeks 
Improvements in 
bone marrow fibrosis, 
hemoglobin, and 
platelets were all 
greater at 36 weeks 
than at 24 weeks, 
suggesting that PRM-
151 effects improve 
over time and that 
clinical benefit may 
be underestimated at 


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24 weeks. There is 
insufficient data at 
present to indicate 
that a longer study 
duration is required, 
but longer term data 
obtained from study 
extensions will be 
informative for future 
trials 
Single agent or 
combination with 
ruxolitinib 
Single agent AND 
added to a stable dose 
of ruxolitinib 
Single agent 
Hematologic 
improvements were 
more apparent in 
subjects on single 
agent PRM-151; 
dosing ranging can be 
done best with single 
agent. Future studies 
will assess PRM-151 
in combination with 
ruxolitinib 
Dose 
10 mg/kg 
0.3, 3, and 10 mg/kg 
Efficacy has been 
observed in clinical 
studies at 1, 5, and 10 
mg/kg, but recent 
dose ranging studies 
in rats and mice and 
IC50 data from in 
vitro studies suggest 
an effective dose 
range in humans of 
0.2-10 mg/kg. 
Schedule 
Every week AND 
every 4 weeks 
Every 4 weeks 
No apparent 
difference in efficacy 
or safety between 
schedules in Stage 1 
Randomization 
No 
Yes, randomized, 
blinded and stratified 
Eliminating weekly 
dosing makes 
randomization and 
blinding possible, 
reducing bias and 


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increasing the rigor 
of the study. 
 
Stratification allows 
for independent 
assessment of anemic 
and 
thrombocytopenic 
subjects. 
Control Arm 
None 
None 
All three doses will 
be evaluated 
independently. 
Secondary analyses 
will compare doses; 
indication of a dose 
response will provide 
evidence of efficacy. 
The remainder of this protocol amendment applies only to Stage 2. Please refer to APPENDIX K 
for more information on Stage 1and APPENDIX L for Stage 1 Open Label Extension. 
In the stage 2 study, all subjects completing 9 cycles of the originally assigned treatment may 
switch to an open label extension and receive PRM-151 10 mg/kg every 4 weeks. The first cycle 
of the open label phase contains a loading dose of 10 mg/kg on days 1, 3 and 5. This will allow 
for subjects from all three dosing cohorts to receive a loading dose of 10 mg/kg while 
maintaining the blind. Additionally, subjects who have entered the open label extension study 
prior to the approval of this amendment may receive a loading dose (10 mg/kg on days 1, 3, and 
5), to be administered on their next scheduled cycle after approval of this protocol amendment. 
This will allow for these subjects to receive any potential pharmacologic benefit of the loading 
dose. As of 14-Nov 16, we have blinded safety data, although limited, on 21 patients receiving a 
similar 10 mg/kg loading dose in the open label of the PRM-151-202 IPF study after 24 weeks of 
exposure to PRM-151 or placebo in 2:1 ratio. No incremental risk has been reported in these 
subjects. 
 
2. 
STAGE 2 STUDY OBJECTIVES 
 
2.1  
Primary Objective 
The primary objective of this study is: 


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• To determine the effect size of three different does of PRM-151 on reduction in bone 
marrow fibrosis by > 1 grade in intermediate-1, intermediate-2, and high risk subjects 
with PMF, post-PV MF, or post ET-MF who are anemic or thrombocytopenic and who 
are ineligible for, intolerant of, or have had an inadequate response to ruxolitinib. 
2.2 
Secondary Objectives  
The secondary objectives of this study are: 
• To determine if there is a difference in efficacy between the three doses of PRM-151 
used in the study 
• To evaluate the safety and tolerability of three different doses of PRM-151 
• To assess the duration of effect of three doses of PRM-151 on reduction in bone marrow 
fibrosis 
• To assess the effect and duration of effect of three doses of PRM-151 on disease related 
anemia, thrombocytopenia, and constitutional symptoms 
• To assess IWG-MRT response (Complete Response, Partial Response, Clinical 
Improvement), stable and progressive disease in subjects treated with three doses of 
PRM-151 
2.3.  Exploratory Objectives 
The exploratory objectives of this study are: 
• To measure changes in bone marrow fibrosis by quantitative image analysis and evaluate 
changes in bone marrow morphology in subjects receiving PRM-151 
• To assess the effect of PRM-151 on other disease related parameters, including 
hematologic abnormalities and spleen size 
• To assess the effect of PRM-151 on prognostic factors associated with increased 
mortality as measured by the DIPSS (Dynamic International Prognostic Scoring System) 
• To evaluate the interaction between selected genetic mutations and cytogenetic 
abnormalities and response to PRM-151 
• To explore potential biomarkers of PRM-151 activity in bone marrow samples 
• To assess the effect of PRM-151 on bone marrow metabolism by PET imaging (at 
selected institutions) 
• To evaluate the correlation of baseline PTX-2 levels with outcomes 
• To evaluate the relationship between bone marrow fibrosis reduction and hematologic 
improvements in subjects treated with PRM-151 
• To measure progression-free and overall survival in subjects receiving PRM-151 


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3.  
STAGE 2 STUDY ENDPOINTS 
 
3.1  
Primary Endpoint 
The Primary endpoint for the study is: 
• Bone marrow response rate, defined as the percent of subjects with a reduction in bone 
marrow fibrosis score by at least one grade according to WHO criteria (APPENDIX D) at 
any time during the study as determined by a central adjudication panel of expert 
hematopathologists, blinded to subject, treatment, and time of biopsy 
3.2. 
Secondary Endpoints 
The secondary endpoints for the study are: 
• Comparison of primary and secondary efficacy parameters between doses 
• Incidence of adverse events (AEs), serious adverse events (SAEs), and changes in 
laboratory test results 
• Bone marrow improvement: 
• Bone marrow response rate at weeks 12, 24, and 36 
• Duration of bone marrow response 
• Hemoglobin improvement 
Baseline Status 
Categories of Hemoglobin 
Improvement 
Subjects who are transfusion dependent (> 2 units 
PRBC every 
4 weeks for 12 weeks prior to or after C1D1), 
regardless of baseline hemoglobin level 
Percent of subjects with Red cell 
transfusion independence (no 
transfusions for > 12 consecutive 
weeks) 
 
OR 
 
50% reduction in RBC transfusions 
for > 12 consecutive weeks 
Subjects with baseline hemoglobin < 100 g/L 
AND 
Not transfusion dependent 
Percent of subjects with > 10 g/L and 
> 20 g/L increase in hemoglobin for ≥ 
12 consecutive weeks without 
transfusions 
 
• Platelet improvement 
Baseline Status 
Categories of Platelet Improvement 
Subjects who are transfusion dependent (> 2 
platelet transfusions in any 12 weeks prior to 
or after C1D1), regardless of baseline platelet 
level 
 
 
Percent of subjects with: 
Platelet transfusion independence (no 
transfusions for > 12 consecutive weeks) 
 
OR 


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Platelet transfusion = either 1 unit apheresed 
(single donor) platelets or 4-8 units pooled 
random donor platelets 
50% reduction in platelets transfusions for > 
12 consecutive weeks 
Subjects with 25 < baseline platelets < 50 X 
109/L 
 
AND 
Not platelet transfusion dependent 
Percent of subjects with: 
Doubling of baseline platelet count for > 12 
consecutive weeks without platelet 
transfusions 
 
OR 
 
Platelet count > 50 X 109/L for > 12 
consecutive weeks without platelet 
transfusions, 
Subjects with baseline platelet count < 25 x 
109/L 
 
AND 
Not platelet transfusion dependent 
Percent of subjects with: 
Doubling of baseline platelet count for > 12 
consecutive weeks without platelet 
transfusions 
 
OR 
 
Platelet count > 25 x 109/L for > 12 
consecutive weeks without platelet 
transfusions 
 
• Hematologic improvement 
Baseline Status 
Categories of Hematologic Improvement 
Subjects with both Hemoglobin < 100 g/L 
and Platelets < 50 x 109/L 
Percent of subjects who have EITHER 
Hemoglobin improvement OR Platelet 
improvement as described above and no 
worsening of hemoglobin or platelets from 
baseline 
Subjects with only Hemoglobin <100 g/L 
Percent of subjects who have Hemoglobin 
improvement as described above 
AND 
Did not develop platelets < 50 x 109/L 
Subjects with only Platelets <50 x 109/L 
Percent of subjects who have Platelet 
improvement as described above 
AND 
Did not develop Hemoglobin <100 g/L or 
new transfusion dependence 
 
 
• Symptom improvement: 


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• Percent of subjects with 25% and 50% reduction in MPN-SAF Total Symptom 
Score from baseline at Week 36 
• Mean change from baseline in EORTC QLQ-C30 at 36 weeks 
• Duration of all improvement parameters listed above 
• Percent of subjects with complete response, partial response, clinical improvement, stable 
disease, and progressive disease according to IWG-MRT criteria (Tefferi 2013, 
APPENDIX B) 
 3.3 Exploratory Endpoints 
The exploratory endpoints for the study include: 
• Bone marrow: 
o Percent of subjects with Grade 0-1 bone marrow fibrosis grade at any time during 
the study and at weeks 12, 24, and 36 
o Duration of Grade 0-1 bone marrow fibrosis grade 
o Mean change from baseline to 12, 24, and 36 weeks in bone marrow fibrosis by 
quantitative image analysis 
o Changes from baseline to weeks 12, 24, and 36 in bone marrow metabolism by 
FDG or FLT PET scan (where feasible) 
o Assessment of changes in bone marrow morphology at 12, 24, and 36 weeks 
• Hematologic and other disease related laboratory parameters: 
o Mean change from baseline to 36 weeks in: hemoglobin, # RBC units transfused 
in previous 12 weeks, platelet count, # platelet transfusions in previous 12 weeks, 
white blood cell count, absolute neutrophil count, reticulocyte count, peripheral 
blood blast count, and -lactic dehydrogenase (LDH) 
o Percent of subjects with increase in Hgb from < 100 g/L to > 100 g/L without 
transfusions, increase in platelets from < 50 x 109/L to > 100 x 109/L, decrease in 
WBC from > 25 to < 25, increase in ANC from < 1500 to > 1500, decrease in 
peripheral blood blasts from > 1% to < 1%, and disappearance of 
leukoerythroblastosis, at 36 weeks and for > 12 weeks at any time during the 
study 


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o Duration of increase in Hgb from < 100g/L to > 100 g/L without transfusions, 
increase in platelets from < 50 x 109/L to > 100 x 109/L, decrease in WBC from > 
25 to < 25, increase in ANC from 
 < 1500 to > 1500, decrease in peripheral blood blasts from > 1% to < 1%, and 
disappearance of leukoerythroblastosis 
• Spleen improvement: 
o Percent of subjects with 10% and 35% reduction in spleen size from baseline by 
CT at 36 weeks 
o Duration of 10% and 35% reduction in spleen size from baseline 
o Mean change from baseline in spleen size by CT or MRI and palpation (in 
subjects with palpable spleen at baseline) at 36 weeks 
o Change in spleen and liver metabolism by FDG or FLT PET scan at 12, 24, and 
36 weeks 
• DIPSS: 
o Percent of subjects with a reduction in DIPSS score and category at week 36 
o Mean change in DIPSS score from baseline to Week 36 
 
• Mutational Status and Cytogenetics: 
 
o Association of baseline mutational status of JAK2V617F, MPLW515, 
Calreticulin, ASXL1, EZH2, SRSF2, IDH1/2 with selected primary and 
secondary endpoints 
 
o Changes in allele burden of JAK2V617F at week 36.  Changes in allele burden of 
MPLW515, Calreticulin, ASXL1, EZH2, SRSF2, IDH1/2 at week 36 will be 
measured as commercially available assays become available. 
 
o Association of baseline cytogenetic abnormalities and selected primary and 
secondary endpoints 
 
 
• Association of baseline PTX-2 levels with selected primary and secondary endpoints 
 
• Evaluation of potential biomarkers of PRM-151 activity in bone marrow biopsies taken at 
baseline, weeks 12, 24, and 36 
 


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• Measurement of progression-free and overall survival 
 
 


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4.  
OVERALL STAGE 2 STUDY DESIGN AND PLAN 
 
 
 
4.1.1. Study Design: 
 
Stage 2: This is a randomized, double-blind Phase 2 study to determine the efficacy and safety of 
three different does of PRM-151 in subjects with PMF and post ET/PV MF.  Subjects will be 
randomized to one of three doses: 0.3 mg/kg, 3.0 mg/kg or 10 mg/kg of PRM-151.  This is the 
second stage of an adaptive design study as defined in FDA Draft Guidance for Industry: 
Adaptive Design Clinical Trials for Drugs and Biologics, February 2010.  Modifications to dose 
levels, schedule, and regimen have been made in Stage 2 based on data from Stage 1. 
Approximately 84 subjects with intermediate-1, and intermediate -2, or high risk MF who meet 
study eligibility requirements will be enrolled and randomized to treatment with single agent 
PRM-151 at doses of 0.3, 3, or 10 mg/kg IV on Days 1, 3, 5 of Cycle 1 and Day 1 of each 
subsequent 28 day cycle for nine cycles. 
All subjects completing 9 cycles of the originally assigned treatment may switch to an open label 
extension and receive PRM-151 10 mg/kg every 4 weeks.  The first cycle of the open label phase 
contains a loading dose of 10 mg/kg on days 1, 3 and 5. This will allow for subjects from all 
three dosing cohorts to receive a loading dose of 10 mg/kg while maintaining the blind. 
Additionally, subjects who have entered the open label extension study prior to the approval of 
this amendment may receive a loading dose (10 mg/kg on days 1, 3, and 5), to be administered 
on their next scheduled cycle after approval of this protocol amendment. This will allow for 
these subjects to receive any potential pharmacologic benefit of the loading dose.    
Enrolled subjects will be considered evaluable for response if they are on study drug for at least 
twelve weeks. 
The Schedule of Events can be found in APPENDIX A. 
 
 
 
4.1.2. Subject Assignment to Treatment Groups 
Subjects will be randomized to one of three doses of PRM-151.  The randomization will be 
stratified according to type of baseline hematologic abnormality (subjects with Hgb < 100g/L 
and having received > 2 units PRBC in the 12 weeks prior to study entry OR subjects with 
platelet count < 50 X 109/L) and will ensure that the final study population will include at least 
50% of subjects from the second stratum (platelet count < 50 X 109/L). 
 


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4.1.3. Study Duration 
 
Each subject will participate in the study for approximately 44 weeks.  Participation will include 
a screening evaluation within four weeks prior to the first PRM-151 administration, nine study 
cycles of four weeks each, and an end of study visit four weeks after the end of the last cycle. 
All subjects may switch to an open label extension utilizing the 10 mg/kg dose after completing 
9 cycles of the originally assigned treatment.  Subjects may continue with PRM-151 dosing in 
the absence of disease progression or toxicity warranting discontinuation of therapy. Please see 
APPENDIX J for details. 
It is estimated that the study will be completed in approximately 18 months. 
 


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5. 
STAGE 2 SELECTION OF STUDY POPULATION 
 
5.1 
Study Population 
 
 
 
5.1.1. Inclusion Criteria 
This Phase 2 study will enroll up to 111 subjects with MF, 27 in Stage 1, and up to an additional 
84 subjects in Stage 2 
Each subject must meet all of the following inclusion criteria to be enrolled in the study: 
1. Subjects must be > 18 years of age at the time of signing the Informed Consent Form 
(ICF); 
2. Subjects must voluntarily sign an ICF; 
3. Subjects must have a pathologically confirmed diagnosis of PMF as per the WHO 
diagnostic criteria (see APPENDIX C) or post ET/PV MF; 
4. At least Grade 2 marrow fibrosis according to the WHO Grading of Bone Marrow 
Fibrosis (APPENDIX D); 
5. Intermediate -1, intermediate -2, or high risk disease according to the IWG-MRT 
Dynamic International Prognostic Scoring System (see APPENDIX E); 
6. A bone marrow biopsy must be performed within four weeks prior to Cycle 1 Day 1 
treatment to establish the baseline fibrosis score; 
7. Subjects must not be candidates for ruxolitinib based on EITHER: 
a. Platelet count < 50 x 109/L, OR 
b. Hgb < 100 g/L have received > 2 units PRBC in the 12 weeks prior to study entry, 
and be intolerant of or had inadequate response to ruxolitinib; 
8. Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance Status 
of 0-2. (APPENDIX F); 
9. Life expectancy of at least twelve months; 
10. At least four weeks must have elapsed between the last dose of any MF-directed drug 
treatments for myelofibrosis (including investigational therapies) and study enrollment; 
11. Recovery to < Grade 1 or baseline of any toxicities due to prior systemic treatments, 
excluding alopecia; 
12. Women of child bearing potential (WCBP), defined as a sexually mature woman not 
surgically sterilized or not post-menopausal for at least 24 consecutive months if < 55 
years or 12 months if > 55 years, must have a negative serum pregnancy test within four 
weeks prior to the first dose of study drug and must agree to use highly effective methods 
of birth control throughout the study.  Highly effective methods of contraception include 
combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation by oral, intravaginal, or transdermal administration; progestogen-
only hormonal contraception associated with inhibition of ovulation by oral, injectable, or 
implantable administration; intrauterine device (IUD); intrauterine hormone-releasing 
system (IUS); bilateral tubal occlusion; partner vasectomy, and total abstinence (only if 


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total abstinence is the preferred method and usual lifestyle of the subject). Adequate 
contraceptive use should be continued until 28 days after the final dose of the study drug.  
13.  Ability to adhere to the study visit schedule and all protocol requirements; 
14.  Must have an adequate organ function as demonstrated by the following: 
o ALT (SGPT) and/or AST (SGOT) < 3 x upper limit of normal (ULN), or < 4 x 
ULN (if upon judgment of the treating physician, it is believed to be due to 
extramedullary hematopoiesis [EMH] related to MF); 
o Direct bilirubin < 1.5 x ULN; or < 2 x ULN (if upon judgment of the treating 
physician, it is believed to be due to EMH related to MF); 
o Serum creatinine < 2.5x ULN. 
 
5.1.2. Exclusion Criteria 
Subjects meeting any of the following exclusion criteria are not to be enrolled in the study: 
1. White blood cell count > 25 x 109/L or > 10% peripheral blood blasts; 
2. Other invasive malignancies within the last 3 years, except non-melanoma skin cancer and 
localized cured prostate and cervical cancer; 
3. History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia 
requiring medication or mechanical control within the last 6 months; 
4. Presence of active serious infection; 
5. Any serious, unstable medical or psychiatric condition that would prevent, (as judged by 
the Investigator) the subject from signing the informed consent form or any condition, 
including the presence of laboratory abnormalities, which places the subject at 
unacceptable risk if he/she were to participate in the study or confounds the ability to 
interpret data from the study; 
6. Known history of human immunodeficiency virus (HIV), or known active hepatitis A, B, 
or C infection; 
7. Organ transplant recipients other than bone marrow transplant; 
8. Women who are pregnant or lactating. 
 
6. 
STAGE 2 STUDY TREATMENT(S) 
 
6.1.  Investigational Product 
PRM-151 will be supplied by Promedior as a solution for Injection. 
 
6.2. 
Treatment(s) Administered 
All subjects will receive intravenous (IV) infusions of 0.3 mg/kg, 3.0 mg/kg or 10 mg/kg PRM-
151, with dose based on the subject’s weight on Day 1 for Days 1, 3 and 5 of Cycle 1, and all 
subsequent doses based on the subjects’ weight on the first day of each cycle. Subjects will be 
observed for one hour after each dose.  Refer to the Pharmacy Manual and the Investigator’s 
Brochure for detailed instructions on special precautions and handling. 


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PRM-151 will be held for any treatment emergent Grade 3 non-hematologic or any Grade 4 
adverse event and resumed when adverse event has resolved to Grade 1 or baseline. 
6.3. 
Dose for Each Subject 
Subjects will be randomized to treatment with single agent PRM-151 at doses 0.3, 3, or 10 mg/kg 
IV administered as a 60 minute intravenous infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of 
each subsequent 28 day cycle for nine cycles. 
For OLE dosing refer to Appendix J.  
 
 
6.4. 
Method of Assigning Subjects to Treatment Groups 
Subjects will be randomized to treatment cohorts in a double-blind fashion.  Randomization will 
be accomplished using an interactive response system (IRS). The IRS will contain the 
randomization schedule.  At the screening visit, the investigative site will contact IRS.  The site 
will enroll the subject into the IRS by indicating minimal information to sufficiently distinguish 
one subject from another and will receive the subject ID number. At the Cycle 1, Day 1 visit, the 
unblinded pharmacist (or designee) will access IRS to randomize the subject.  The system will 
associate that subject with the next available treatment on the randomization schedule.  IRS will 
inform the unblinded pharmacist (or designee) to which PRM-151 dose the subject has been 
assigned. 
The unblinded pharmacist will contact IRS at each dosing visit.  The randomization schedule 
allows for overage, such as enrollment, which will be controlled by IRS and when a sufficient 
number of subjects have been enrolled, the randomization part of the system will be stopped.  The 
portion of the system that manages re-supply will remain active until the last subject completes 
the study. 
 
6.5. 
Blinding 
This study will be Subject, Investigator, Assessor (central adjudication panel of expert 
hematopathologists) and Sponsor-blinded.  The site Pharmacist will be unblinded to the dose 
assignment.  Additional details regarding procedures for maintaining the blind can be found in the 
Pharmacy Manual. 
 
 
 
6.5.1. Breaking the Blind 
Blinding should only be broken in emergency situations for reasons of subject safety.  Whenever 
possible, the Investigator should attempt to contact the Promedior Medical Monitor before 
breaking the blind.  When the blind is broken, the reason must be fully documented in the source 
documents and entered into the eCRF as applicable.  At all other times treatment and 
randomization information will be kept confidential and will not be release to the 
Investigator/blinded study staff until conclusion of the study. 
 


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6.6. 
Concomitant Medications, Therapies and Medical/Surgical 
Interventions 
Concomitant medications, therapies, and medical/surgical interventions must be documented on 
the electronic case report form (eCRF) beginning at the signing of informed consent.  Subjects are 
not permitted to receive any treatment for myelofibrosis. 
 
The following concomitant medications are excluded during the study: 
• Hematopoietic 
growth 
factors, 
including 
erythropoietin, 
G-CSF, 
GM-CSF, 
thrombopoietin.  Exception: G-CSF may be used as part of the management of febrile 
neutropenia, and must be documented in the CRF. 
• Any therapy that is or may be active against myelofibrosis including JAK kinase inhibitors, 
chemotherapy, biologics (including antibodies), androgens, radiation therapy, any tyrosine 
kinase inhibitors (TKIs), any immunomodulatory agents, or investigational agents other 
than the treatment regimen in this protocol. 
• Hydroxyurea is not permitted 
• Anagrelide is not permitted 
• Steroids, with the exception of prednisone < 10 mg po qd at a stable dose for at least three 
months for a condition unrelated to MF, or as intra-articular injection for an acute problem.  
If steroids are required for management of an infusion reaction, it will be documented in 
the CRF. 
6.7. 
Treatment Compliance 
PRM-151 is administered under controlled conditions by the Investigator or designee; therefore, 
full subject compliance with study treatment is anticipated in this study. 
 
6.8. 
Packaging and Labeling 
PRM-151 is supplied in 10 ml single use vials as a clear to opalescent, sterile 20.0 mg/mL solution 
10 mM sodium phosphate, 5% (w/v) sorbitol, and 0.01% (w/v) polysorbate 20 with a pH of 7.5.  
Each vial contains 8 ml PRM-151 (160 mg of PRM-151). 
6.9. 
Storage and Accountability 
PRM-151 will be provided to the clinical site in a temperature controlled, monitored container.  
Investigational product should be stored under refrigerated conditions (2 C-8 C [35.6 ºF-46.4ºF] 
and protected from light.  Vigorous mixing or vortexing should be avoided. 
Investigational product will be dispensed at the study site and stored in a locked storage area.  The 
disposition of all investigational product delivered to a Principal Investigator must be recorded on 
a subject-by-subject basis by completing the Clinical Trial Material Accountability Log.  The date 
and time of administration of the investigational product must be documented on the appropriate 
eCRF. 


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The Principal Investigator, Clinical Research Coordinator, or designee (e.g., Pharmacist) must 
ensure that all documentation regarding investigational product receipt, storage, dispensing, 
loss/damaged and return of used/unused product is complete, accurate, and ready for review at 
each monitoring visit and/or audit.  The sites must ensure that the investigational product is 
available for the monitor to inventory and prepare for return shipment to the Sponsor or designee, 
if required. 
All packing slips and other shipment documentation must be retained as well as any investigational 
product return forms. 
See the Pharmacy Manual for additional details. 
 
7. 
STUDY PROCEDURES 
Detailed descriptions of subject evaluations required for this protocol are described in this section.  
These evaluations will be performed during the indicated days and weeks of the study as described 
in Stage 2 Study Activities and in the Schedule of Events table in APPENDIX A. 
Subjects enrolled in the open-label extension protocol of Stage 1 will continue to follow the study 
procedures outlined in Appendix L.    
Subjects following Stage 2 extension protocol should continue to follow the study procedures 
outlined in Appendix J.    
All data collected are to be recorded on the appropriate eCRF page. 
The Investigator at the clinical trial site is responsible for maintaining a record of all subjects pre-
screened, screened, and enrolled into the study. 
 
7.1. 
Informed Consent 
Prior to conducting any study-related procedures, written informed consent must be obtained from 
the subject or the subject’s legally authorized representative. 
The nature, scope, and possible consequences, including risks and benefits, of the study will be 
explained to the subject by the Investigator or designee in accordance with the guidelines described 
in Section 11.4.  Documentation and filing of informed consent documents should be completed 
according to Section 11.4. 
 
7.2. 
Study Entrance Criteria 
At Screening, each subject will be reviewed for eligibility against the study entrance criteria.  
Subjects who do not meet the study entrance criteria will not be allowed to participate in the 
study.  The reason(s) for the subject’s ineligibility for the study will be documented.  All subjects 
must undergo a bone marrow biopsy for grading of bone marrow fibrosis.  Subjects with a 
myelofibrosis Grade < 2, according to the WHO criteria (APPENDIX D), as determined by the 
local pathologist, will not be allowed to participate in the study. 


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7.3. 
Confirmation of Study Eligibility 
Subject eligibility according to the study inclusion and exclusion criteria will be confirmed at study 
entry on the basis of review of the study entrance criteria. 
 
7.4. 
Demographics 
Subject demographic information including gender, age, date of birth, race, ethnicity and number 
of years since diagnosis of MF will be collected prior to the subject receiving the first dose of 
PRM-151. 
 
7.5. 
Medical History 
Medical history will be recorded in the eCRF. Any relevant and/or significant previous or existing 
medical condition(s) that occurred within 5 years prior to time of informed consent should be 
reported as medical history.  Prior therapies for myelofibrosis will be recorded in the eCRF. 
Transfusion history and complete blood counts for three months prior to screening, and between 
screening and first dose, will be recorded in the eCRF. Results of prior bone marrow biopsies will 
be collected and recorded in the eCRF. 
 
7.6. 
Height and Weight 
Height and weight will be recorded for all subjects. 
 
7.7. 
Eastern Cooperative Oncology Group Performance Status 
Performance status will be assessed following the Eastern Cooperative Oncology Group (ECOG) 
scoring system (APPENDIX F). 
 
7.8. 
Investigational Product Administration 
Medical personnel authorized by the Investigator will be responsible for the administration of 
study drug and for observation of each subject throughout the study. 
Subjects will receive PRM-151 administered as a 60 minute intravenous infusion at a dose of 0.3 
mg/kg, 3.0 mg/kg, or 10 mg/kg on Days 1, 3 and 5 of Cycle 1 and Day 1 of each subsequent 28 
day cycle for nine cycles.  
Subjects responding to treatment with PRM-151 may continue to receive it as long as there is 
benefit. Please see APPENDIX J for details. 
In the case of Grade 2 occurrence of signs and symptoms consistent with infusion related reaction, 
follow institutional protocol and reduce the rate of infusion of PRM-151 to half the initial rate; 
consider discontinuing infusion of PRM-151 if symptoms do not respond to medical intervention. 
If signs and symptoms resolve with intervention including discontinuation of PRM-151, PRM-151 
infusion may be restarted at half the initial rate.  
In the case of Grade 3 or greater occurrence of signs and symptoms consistent with infusion related 
reaction, discontinue infusion of PRM-151. 


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If PRM-151 resulted in signs consistent with Grade 2 or 3 infusion related reaction, during a prior 
administration, infuse PRM-151 over 1 hour and use the following premedication for all 
subsequent PRM-151 administration:  
 
a. Diphenhydramine 50 mg IV or clemastine 2 mg IV or an equivalent dose of an 
antihistaminic drug   
b. Dexamethasone 10 mg IV or equivalent corticosteroid  
 
7.9. 
Pharmacokinetic Assessments 
 
In Stage 2, samples for pharmacokinetic analysis will not be collected.  Pentraxin-2 levels will be 
drawn prior to each dose for pharmacodynamic assessment and correlation with potential anti-
pentraxin 2 antibodies. 
 
 
7.10. Exploratory Laboratory Assessments 
 
At time points throughout the study, as indicated in the Schedule of Events (APPENDIX A), blood 
samples will be collected and DNA will be isolated from peripheral whole blood for the purpose 
of associating baseline mutational status with select primary and secondary endpoints. DNA 
sampling is not mandatory for subjects. Subjects can still enroll in the trial if they opt out of DNA 
sampling.  Samples will be analyzed for cytogentic abnormalities and for mutations JAK2V617F, 
MPLW515, Calreticulin, ASXL1, EZH2, SRSF2, IDH1/2. Samples will also be analyzed to assess 
changes in the allele burden of JAK2V617F at week 36 (Cycle 1 Day 1 to Cycle 9 Day 29).   These 
samples will also be analyzed to assess changes in the allele burden of MPLW515, Calreticulin, 
ASXL1, EZH2, SRSF2, IDH1/2 at week 36 (Cycle 9, Day 29) as quantitative assays become 
commercially available. 
Additional assays may be performed that contribute to the objectives of the trial. Additional bone 
marrow biopsy slides will be collected for immunohistochemical analysis for disease and 
mechanism related proteins and cellular markers. 
Sample handling details will be provided. 
 
7.11. Efficacy Assessments 
 
The following efficacy assessments, in addition to some of the safety assessments described in 
7.12 will be performed. 
 
 
 
7.11.1 Bone Marrow Biopsy  
Bone marrow biopsy will be performed at screening, Cycle 4, Day 1, Cycle 7, Day 1, and Cycle 
9, Day 29. Analysis will include confirmation of diagnosis and assessments of reticulin stain and 
trichrome stain. Slides will be sent to a central committee of hematopathologists who will be 


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blinded to subject, treatment, and collection time for centralized grading of fibrosis.  A charter will 
be established for the central committee. Quantification of marrow fibrosis will be performed in a 
blinded fashion by computer assisted image analysis. Unstained slides will be collected for 
analysis of disease and mechanism related changes.  
 
 
7.11.2 Assessment of transfusions 
Subjects will be required to enter all RBC and platelet transfusion in a transfusion diary, which 
will be reviewed at each visit. Data will be entered in the eCRF. 
 
 
7.11.3 Assessment of spleen size 
7.11.3.1. Palpation 
During the physical examination, the spleen will be measured in centimeters below the left costal 
margin and recorded in the eCRF. 
7.11.3.2.  Imaging 
On Cycle 1 Day 1, Cycle 4 Day 1, Cycle 7 Day 1, and Cycle 9 Day 29, CT or MRI will be used to 
measure spleen volume in all subjects.  For subjects who receive PET-CT imaging as described in 
7.11.5, the PET-CT will be used to assess spleen volume and subjects will not require additional 
imaging. 
 
 
 
7.11.4 Assessment of Symptoms 
7.11.4.1 Myeloproliferative Neoplasm Symptom Assessment Form 
(MPN-SAF) 
The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) will be administered 
to evaluate the effects of PRM-151 treatment on subject quality of life (QOL) (APPENDIX G). 
7.11.4.2. EORTC QLQ-C30 
The EORTC QLQ-C30 will be administered to evaluate the effects of PRM-151 treatment on 
subject quality of life (QOL) (APPENDIX H). 
7.11.5. FDG or FLT PET-CT Imaging  
At sites where it is feasible, FDG or FLT PET-CT scans will be done to assess changes in 
metabolism of bone marrow, spleen, and liver at Cycle 1 Day 1, Cycle 4 Day 1, Cycle 7 Day 1 and 
Cycle 9 Day 29. Subjects receiving PET-CT imaging will not require additional CT or MRI scans 
as described in 7.11.3.2. 
7.11.6. Response Assessments  
Subjects will be assessed for response at Cycle 2 through Cycle 9. Response Assessments are based 
on International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-
MRT) criteria, to measure the overall response rate (ORR), defined as a clinical improvement (CI), 
partial remission (PR), and complete remission (CR) according to the International Working Group 
(IWG) Criteria (APPENDIX B). 
 


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7.12. Safety Assessments 
 
7.12.1. Physical Examination 
Abbreviated physical examinations will be performed by the Investigator and will include a review 
of the subject’s general appearance as well as evaluation of the following body systems (Table 1). 
Any abnormal change in findings after exposure to the study drug will be recorded as an adverse 
event (AE) on the appropriate eCRF. 
Table 1: 
 
Assessments for Physical Examinations 
 
Assessment 
 
 
 
 
Assessment 
 
 
 
General appearance 
 
 
 
Throat 
 
 
Head and neck 
 
 
 
Cardiovascular 
 
 
Eyes 
 
 
 
 
 
Abdomen 
 
 
 
 
 
 
 
 
Chest and lungs 
 
 
 
7.12.2  Vital Signs 
Vital signs, including pulse, temperature (oral, temporal, or tympanic), respiration rate, and 
systolic and diastolic blood pressure will be measured and recorded on the eCRF.  
 
 
 
 
7.12.3. Clinical Laboratory Tests 
Blood samples will be collected for clinical laboratory testing and sent to a central laboratory as 
listed below. In the event the central lab cannot be used to get a reliable result for a laboratory test, 
local laboratory tests may be used after this has been agreed upon by the Medical Monitor. 
 
Table 2: 
 
Clinical Laboratory Tests 
Clinical Chemistry: 
• 
Sodium 
 
• 
Bicarbonate 
• 
Glucose 
• 
Asparate transaminase 
(AST) 
• 
Alkaline phosphatase 
• 
Uric acid 
• 
Potassium 
• 
Calcium 
• 
Albumin 
• 
Alanine aminotransferase 
(ALT) 
• 
Creatine phosphokinase 
(CPK) 
• 
Chloride 
• 
Creatinine 
• 
Phosphorus 
• 
Bilirubin, direct and 
indirect 
• 
Lactate dehydrogenase 
(LDH) 
• 
Blood urea nitrogen 
(BUN) 
• 
Serum pregnancy test 


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• 
Urine pregnancy test 
(local lab) 
Hematology: 
• 
Hemoglobin 
• 
Hematocrit 
• 
Platelets 
• 
White Blood Cell (WBC) 
with differential 
• 
Red Blood Cell (RBC) 
• 
Reticulocyte count 
• 
Blast count 
• 
Absolute Neutrophil 
(ANC) 
• 
Partial thromboplastin 
time (PTT) 
• 
Prothrombin time (PT) 
• 
International normalized 
ratio (INR) 
• 
Nucleated red blood 
cells, immature cells, and 
other leukoerythroblasitc 
changes 
 
For subjects receiving warfarin, the PT, PTT and international normalized ratio (INR) must be 
obtained.  Abnormal INRs will be tested twice weekly until the INR is stable for one month, 
followed by monthly monitoring of the INRs. 
 
 
 
7.12.4. Pregnancy Test 
A serum β-hCG pregnancy test will be performed for women of childbearing potential within 4 
weeks prior to dosing on Cycle 1 Day 1.  The serum pregnancy test will be sent to a central 
laboratory for testing and the results must be available and negative before dosing.  Pregnancy 
testing is not required for postmenopausal or surgically sterilized women. Urine pregnancy test 
will be performed at the local lab thereafter, as indicated in Schedule of Events table in 
APPENDIX A. 
 
 
 
7.12.5. Electrocardiograms (ECG) Assessments 
Electrocardiograms (ECG) Assessments will be performed at screening and in the event of an 
infusion reaction. 
 
 
 
7.12.6. Immune Response Assessments 
Blood samples (4 mL) will be collected prior to each dose of PRM-151 to measure antibodies to 
PTX-2. In addition, if a subject experiences an acute infusion related reaction, a blood sample will 
be collected for cytokines and antibodies against PRM-151. A blood sample for cytokines and 
antibodies against PRM-151 may be obtained in the event of a suspected adverse reaction. All 
samples collected may not be analyzed. 
 
 
 
7.12.7. Sample Collection, Storage, and Shipping 
Detailed instructions for laboratory sample collection, processing, and shipping instructions will 
be provided. All samples for exploratory assessments from the study will be stored at – 80C. 
 
7.13. Adverse Events Assessments 
 
7.13.1 Definitions of Adverse Events and Serious Adverse Events 


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7.13.1.1 Adverse Event 
An AE is any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic 
function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase 
of a clinical study, whether or not considered investigational product-related.  This includes an 
exacerbation of a pre-existing condition. 
 
Adverse events include: 
 
• Worsening (change in nature, severity, or frequency) of conditions present at the 
onset of the study; 
• Intercurrent illnesses; 
• Drug interactions; 
• Events related to or possibly related to concomitant medications; 
• Abnormal laboratory values (this includes significant shifts from baseline within 
the range of normal that the Investigator considers to be clinically important); 
• Clinically significant abnormalities in physical examination, vital signs, and 
weight. 
Throughout the study, the Investigator must record all AEs on the AE eCRF, regardless of the 
severity or relationship to investigational product.  The Investigator should treat subjects with AEs 
appropriately and observe them at suitable intervals until the events stabilize or resolve.  Adverse 
events may be discovered through observation or examination of the subject, questioning of the 
subject, complaint by the subject, or by abnormal clinical laboratory values. 
In addition, AEs may also include laboratory values that become significantly out of range.  In the 
event of an out-of-range value, the laboratory test should be repeated until it returns to normal or 
can be explained and the subject’s safety is not at risk. 
Additional illnesses present at the time when informed consent is obtained are regarded as 
concomitant illnesses and will be documented on the appropriate pages of the eCRF.  Illnesses 
first occurring or detected during the study, and worsening of a concomitant illness during the 
study, are to be regarded as AEs and must be documented as such in the CRF. 
Infusion reactions were reported in two subjects in Stage 1 of this study. In the event of acute 
hypersensitivity or other infusion reaction, institutional protocol should be initiated and a blood 
sample drawn for anti-PTX-2 antibodies and cytokines.  Signs and symptoms of an infusion 
reaction may include the following: headache, fever, facial flushing, pruritus, myalgia, nausea, 
chest tightness, dyspnea, vomiting, erythema, abdominal discomfort, diaphoresis, shivers, 
hypertension, hypotension, lightheadedness, palpitations, urticaria and somnolence. Although 
unlikely, serious allergic reactions (e.g., anaphylaxis) may occur at any time during the infusion. 
In the case of Grade 2 occurrence of signs and symptoms consistent with infusion related reaction, 
follow institutional protocol and reduce the rate of infusion of PRM-151 to half the initial rate; 
consider discontinue infusion of PRM-151 if symptoms do not respond to medical intervention. If 


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signs and symptoms resolve with intervention including discontinuation of PRM-151, PRM-151 
infusion may be restarted at half the initial rate. 
In the case of Grade 3 or greater occurrence of signs and symptoms consistent with infusion related 
reaction, discontinue infusion of PRM-151. 
If PRM-151 resulted in signs and symptoms consistent with Grade 2 or 3 Infusion related reaction, 
infuse PRM-151 over 1 hour and use the following premedication for all subsequent PRM-151 
administration: 
a. Diphenhydramine 50 mg IV or clemastine 2 mg IV or an equivalent dose of an 
antihistaminic drug   
b. Dexamethasone 10 mg IV or an equivalent corticosteroid  
Infusion related reactions must be reported to Promedior as described in section 7.13.2.1.1, 
Reporting of Adverse Events of Special Interest. 
7.13.1.2. Serious Adverse Event 
A serious AE (SAE) is any AE occurring at any dose that results in any of the following outcomes: 
• Death; 
• Is life-threatening; 
• Requires hospitalization; 
• Requires prolongation of existing hospitalization; 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; 
• A congenital anomaly or birth defect; 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered an SAE when, based upon appropriate medical judgment, they may jeopardize 
the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition.  A life-threatening AE is defined as an AE that placed the subject, in the view of 
the initial reporter, at immediate risk of death from the AE as it occurred (i.e., it does not include 
an AE that, had it occurred in a more severe form, might have caused death). 
7.13.1.3. Classification of Adverse Events and Serious 
Adverse Events 
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
Version 4.0 grading scale (APPENDIX I) should be referenced when assessing the intensity of an 
AE.  If an AE is not described in the NCI CTCAE v 4.0, the severity should be recorded based on 
the scale below.  The severity of all AEs/SAEs should be recorded on the appropriate eCRF page 
as Grade 1, 2, 3, or 4 corresponding, respectively, to a severity of mild, moderate, severe, or life 
threatening as outlined in Table 3. 
http://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 


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Table 3: 
Adverse Event Grading
Severity 
 
 
 
 
Definition
 
Grade 1 
Mild; asymptomatic or mild symptoms, clinical or 
diagnostic observations only; intervention not 
indicated. 
Grade 2 
Moderate; 
minimal, 
local 
or 
noninvasive 
intervention indicated; limiting age-appropriate 
instrumental ADL. 
Grade 3 
Severe or medically significant but not immediately 
life-threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self care 
ADL.  
Grade 4 
Life-threatening consequences; urgent intervention 
indicated. 
Grade 5 
Death related to AE. 
 
 
 
 
 
Clarification between Serious and Severe: The term “severe” is often used to describe the 
intensity (severity) of a specific event (as in mild, moderate, or severe myocardial infarction); the 
event itself, however, may be of relatively minor medical significance (such as severe headache).  
This is not the same as “serious,” which is based on the outcome or action criteria usually 
associated with events that pose a threat to life or functioning.  Seriousness (not severity) and 
causality serve as a guide for defining regulatory reporting obligations. 
7.13.1.4. Data Monitoring Committee 
A DMC will be established to review safety data from this study, thereby better ensuring the safety 
of study participants.  Consistent with US Food and Drug Administration (FDA) recommendations 
(FDA Guidance for Industry, Establishment and Operation of Clinical Trial Data Monitoring 
Committees, 2006), the DMC will be constituted of independent clinicians expert in the field of 
MF and clinical research.  A formal charter will be established for the conduct of the DMC. 
The committee is planned to review unblinded safety data at periodic intervals. The DMC may ask 
to schedule ad-hoc meetings as needed. No interim efficacy data are planned to be reviewed by the 
DMC. Details of safety review are provided in the DMC Charter.  
7.13.1.5. Relatedness of Adverse Events and Serious 
Adverse Events 
Relationship of an AE or SAE to investigational product is to be determined by the Investigator 
based on the definitions in Table 4. 


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Table 4: 
 
Adverse Event Relatedness 
Relationship to Product(s) Definition
 
Not Related 
 
 
Unrelated to investigational product. 
 
Possibly Related 
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of investigational product, but which  
could also be explained by concurrent disease or other drugs or 
chemicals. 
Probably Related 
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of investigational product, unlikely to be 
attributable to concurrent disease or other drugs and chemicals and 
which follows a clinically reasonable response on de-challenge.  The 
association of the clinical event or laboratory abnormality must  
also have some biologic plausibility, at least on theoretical grounds. 
 
 
7.13.2. Procedures for Recording and Reporting Adverse 
Events 
 
7.13.2.1. Adverse Event Monitoring and Period of 
Observation 
Adverse events (AEs) will be monitored continuously throughout the study. 
 
For the purposes of this study, the period of observation extends from the time at which the subject 
or the subject’s legally authorized representative gives informed consent until the subject’s final 
evaluation of the study.  If the Investigator considers it necessary to report an AE in a study subject 
after the end of the safety observation period, he or she should contact the Sponsor to determine 
how the AE should be documented and reported. 
 
 
 
7.13.2.1.1. Reporting of Adverse Events of Special 
Interest 
The Investigator must report suspected Infusion Related Reaction, regardless of severity, on an 
Adverse Event of Special Interest (AESI) form.  This form must be completed and submitted, 
either by e-mail or fax, immediately but no later than 24 hours of the Investigator’s learning of the 
event to Pivotal’s Safety Unit: 
 
• e-mail: drugsafety@pivotal.es 


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• Fax (US SAEs): +1 877 853 3275 
• Fax (non-US SAEs): +34 91 307 60 47 
7.13.2.2. Reporting Serious Adverse Events 
The Investigator must report all SAEs to the Safety Unit of Pivotal S.L. within 24 hours of 
discovery either by e-mail or fax to: 
• e-mail: drugsafety@pivotal.es 
• Fax (US SAEs): +1 877 853 3275 
• Fax (non-US SAEs): +34 91 307 60 47 
A completed SAE report is to be sent to Pivotal’s Safety Unit within 24 hours of discovering the 
event.  The initial report should include at least the following information: 
• Subject’s Study Number; 
• Description and date of the event; 
• Criterion for serious; and 
• Preliminary assignment of causality to study drug. 
The Safety unit will contact the Investigator either by email or telephone for follow-up information 
regarding the SAE, as appropriate. 
The Investigator must promptly report all required information to the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC)/Research Ethics Boards (REB).  It is the responsibility 
of the Sponsor to ensure that each Investigator receives a copy of any CIOMS I/MedWatch report 
that has been submitted to the appropriate regulatory agencies notifying them of an unexpected 
related SAE.  The Investigator or Sponsor must ensure that the IRB/IEC/REB receives a copy of 
the report and that a copy is also filed within their study files. 
 
 
 
 
7.13.3 Reporting Pregnancies 
Pregnancy itself is not considered an AE. If a subject becomes pregnant or the partner of a subject 
participating in the study becomes pregnant during the study or within 3 months of discontinuing 
any study drug, the Investigator should report the pregnancy on a separate pregnancy report form 
provided to the sites.  Only pregnancies occurring from the time of first study treatment dose 
administered to the subject will be reported and documented. The study treatment will be 
immediately discontinued for any female subject who becomes pregnant during study 
participation, if study treatment is ongoing at that time.  The subject/partner should be followed 
by the Investigator until completion of the pregnancy.  If the pregnancy ends for any reason before 
the anticipated date, the Investigator should notify the Sponsor.  At the completion of the 
pregnancy, the Investigator will document the outcome of the pregnancy. This pregnancy report 
form must be completed and submitted, either by e-mail or fax, immediately but no later than 24 
hours of the Investigator’s learning of the event to Pivotal’s Safety Unit: 
 
• e-mail: drugsafety@pivotal.es 


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• Fax (US SAEs): + 1 877 853 3275 
• Fax (non-US SAEs): +34 91 307 60 47 
Any pregnancy complication, spontaneous or elective abortion, still birth, neonatal death, or 
congenital anomaly will be recorded as an AE or SAE, and reported, as applicable. 
 
 
 
 
7.13.4. Medication Error 
A medication error is defined as a mistake made in prescribing, dispensing, administration and/or 
use of the investigational medicinal product.  All medication errors must be recorded in the eCRF. 
7.14. Removal of Subjects from the Trial or Investigational Product 
A subject’s participation in the study may be discontinued at any time at the discretion of the 
Investigator. The following may be justifiable reasons for the Investigator to remove a subject 
from the study: 
• Non-compliance, including failure to appear at one or more study visits; 
• The subject withdraws consent; 
• The subject was erroneously included in the study; 
• The subject develops an exclusion criterion; 
• The subject suffers an intolerable adverse event; 
• The subject becomes pregnant; 
• The study is terminated by the Sponsor. 
The subject is free to withdraw consent and discontinue participation in the study at any time 
without prejudice to further treatment.  If a subject discontinues participation in the study, or the 
subject is discontinued by the Investigator, the Investigator will notify the Sponsor and, when 
possible, will perform the procedures indicated for the final visit.  Follow-up information will be 
obtained during the final telephone contact, if possible, for subjects who discontinue their 
participation in or are withdrawn from the study. 
Any adverse events (AEs) experienced up to the point of discontinuation must be documented on 
the AE eCRF.  If AE’s are present when the subject withdraws from the study, the subject will be 
re-evaluated within 30 days of withdrawal.  All ongoing SAEs at the time of withdrawal will be 
followed until resolution. 
Subjects withdrawn from the study will be replaced at the discretion of the medical monitor and 
the Investigator.  A replacement subject will be randomized to treatment with single agent PRM-
151 at doses of 0.3, 3, or 10 mg/kg IV. 
7.15. Other Study Procedures 
Not applicable 
7.16. Appropriateness of Measurements 


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Subjects will be assessed for safety at all visits based on history, physical examination, and 
laboratory values.  Subjects will be assessed for efficacy every four weeks by hematologic 
parameters (Hgb, WBC with differential, ANC, and platelet count), measurement of 
splenomegaly, and symptom assessment, and at Weeks 12, 24, and 36 by bone marrow biopsy to 
assess change in fibrosis.  Global assessment of fibrosis will be assessed at Baseline, Weeks 12, 
24, and 36 by FDG or FLT PET-CT. 
 
8.0 STAGE 2 STUDY ACTIVITIES 
The Schedules of Events can be found in APPENDIX A. Quality of Life assessments (MPN-SAF 
and EORTC QLQ-C30) should be done as early in the visit as possible and prior to phlebotomy, 
bone marrow biopsy or any other procedure that may affect subject responses. In the event the 
central lab cannot be used to get a reliable result for a laboratory test, local laboratory tests may be 
used after this has been agreed upon by the Medical Monitor. 
 
8.1.     Screening Visit (< 28 Days Prior to First Dose) 
 
• Provide written informed consent 
• Recording of demographics and medical history 
• Assessment of inclusion/exclusion criteria 
• MPN-SAF 
• EORTC QLQ-C30 
• IWG-MRT DIPPS (risk assessment) 
• Bone marrow biopsy (< 4 weeks prior to first dose) 
• Abbreviated physical examination with spleen measurement (as defined in Table 1). 
• Recording of prior and concomitant medications 
• Assessment of Adverse Events 
• Vital signs 
• Height and weight 
• ECOG Performance Status 
• Serum pregnancy test for women of child-bearing potential (central lab (< 4 weeks prior to 
first dose)  
• Complete blood count (CBC) (central lab)  
• Chemistry evaluations (central lab)   
• Coagulation parameters (central lab)  
• 12 lead Electrocardiogram (ECG) 
• Review of transfusions 
• Review of excluded medications 
• Access IRS to register subject 


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8.2.   
Cycle 1, Day 1 (+/- 1 day) 
 
• FDG or FLT PET-CT (where feasible) or CT or MRI (within 2 weeks prior to C1D1) 
• Update medical history 
• Re-assess inclusion/exclusion criteria 
• MPN-SAF 
• EORTC QLQ-C30 
• IWG-MRT DIPSS (risk assessment) 
• Abbreviated physical exam with spleen measurement 
• Recording of concomitant medications 
• Monitoring of adverse events 
• Vital signs (before, immediately after study drug infusion and 1 hour post infusion) 
• Weight 
• ECOG Performance Status 
• Urine pregnancy test for women of child-bearing potential (local lab)  
• Complete blood count (CBC) (central lab) 
• Chemistry evaluations (central lab)  
• Coagulation parameters (central lab)  
• Blood sample for Infusion Related Reaction Cytokines and anti-pentraxin 2 antibodies 
(pre-dose) 
• Blood samples for genetic analysis  
• Review of transfusions 
• Review of excluded medications 
• Blood sample for pentraxin-2 levels (pre-dose) 
• Blood sample for anti-pentraxin 2 antibodies (pre-dose) 
• Unblinded Pharmacist (or designee) to access IRS to randomize subject to dosing cohort 
• PRM-151 administration 
 
8.3.   
Cycle 1, Days 3 and 5 (+/- 1 day) 
 
• Recording of concomitant medications 
• Monitoring of adverse events 
• Vital signs  
• ECOG Performance Status 
• Unblinded Pharmacist (or designee) to access IRS to confirm dosing 
• PRM-151 administration 
 
 
 


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8.4.   
Cycles 2 through 9, Day 1 (+/- 3 days) 
 
• MPN-SAF 
• EORTC QLQ-C30 
• IWG-MRT Response Assessment (PMF, post-EV MF and post PV MF patients) 
• Bone marrow biopsy (Cycle 4 and Cycle 7, Day 1 +/- 3 days) 
• FDG or FLT PET-CT (where feasible) or CT or MRI (Cycle 4 and Cycle 7, Day 1 +/- 3 
days) 
• Abbreviated physical exam with spleen measurements 
• Response Assessment 
• Recording of concomitant medications 
• Monitoring of adverse events 
• Vital signs  
• Weight 
• ECOG Performance Status 
• Urine pregnancy test for women of child-bearing potential (local lab) 
• Complete blood count (CBC) (central lab) 
• Chemistry evaluations (central lab) 
• Coagulation parameters (central lab) 
• Review of transfusions  
• Review of excluded medications 
• Blood sample for pentraxin -2 levels (pre-dose) 
• Blood sample for anti pentraxin 2 antibodies (pre-dose) 
• Unblinded Pharmacist (or designee) to access IRS to confirm dosing 
• PRM-151 administration 
 
    8.5  Cycle 9, Day 29 (Week 36) (+/- 3 days) 
 
• MPN-SAF 
• EORTC QLQ-C30 
• IWG-MRT DIPSS (risk assessment) 
• IWG-MRT Response Assessment (PMF, post-EV MF and post PV MF patients) 
• PET-CT or CT or MRI (+/- 3 days) 
• Bone marrow biopsy (+/- 3 days) 
• Abbreviated physical exam with spleen measurements 
• Recording of concomitant medications 
• Monitoring of adverse events 
• Vital signs 
• ECOG Performance Status 
• Complete blood count (CBC) (central lab)  


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• Chemistry evaluations (central lab)  
• Coagulation parameters (central lab)  
• Review of transfusions  
• Review of excluded medications 
• Blood sample for pentraxin-2 levels (pre-dose if continuing treatment in extension) 
• Blood sample for anti-pentraxin 2 antibody (pre-dose)  
• Blood samples for genetic analysis  
8.6. End of Study Visit (approximately 28 days [+/- 3 days] after Cycle 
9 Day 29 or withdrawal from study) 
• MPN-SAF 
• EORTC QLQ-C30 
• Abbreviated physical exam and spleen measurement 
• Recording of concomitant medications 
• Monitoring of adverse events 
• Vital signs 
• ECOG Performance Status 
• Complete blood count (CBC) (central lab)  
• Chemistry evaluations (central lab) 
• Review of transfusions  
• Review of excluded medications 
 
 
 
 
 
 
 
 
 
 
 


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9. 
QUALITY ASSURANCE AND CONTROL 
Training will occur at the site initiation visit; instruction manuals will be provided to aid 
consistency in data collection and reporting across sites. 
Clinical sites will be monitored by the Sponsor or its designee to ensure the accuracy of data 
against source documents. 
The required data will be captured in a validated clinical data management system that is compliant 
with the FDA 21 Code of Federal Regulations (CFR) Part 11 Guidance.  The clinical trial database 
will include an audit trail to document any evidence of data processing or activity on each data 
field by each user.  Users will be trained and given restricted access, based on their role(s) in the 
study, through a password-protected environment. 
Data entered in the system will be reviewed manually for validity and completeness against the 
source documents by a clinical monitor from the Sponsor or its designee.  If necessary, the study 
site will be contacted for corrections or clarifications; all missing data will be accounted for. 
 
 
 


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10. STAGE 2 PLANNED STATISTICAL METHODS 
 
10.1 Determination of Sample Size 
The chosen sample size of 72 subjects (i.e. 24 subjects per dose arm) is deemed sufficient to 
provide adequate precision to the estimation of the response rate in each treatment arm. The trial 
will enroll 84 subjects to allow for a discontinuation rate of 15%. 
On the basis of the available data, it is assumed that the response rate on the primary endpoint 
will be 5% in the 0.3 mg/kg arm, 46% in the 10 mg/kg arm and at least 46% in the 3 mg/kg arm.  
A sample size of 24 subjects will ensure an absolute precision of +/- 8% to the evaluation of the 
response rate in the 0.3 mg/kg arm (assuming the response rate is 5%) and an absolute precision 
of +/- 20% of the response rate in the 3 mg/kg and 10 mg/kg arms (assuming the response rate is 
46%). 
In addition, with 24 subjects in each arm, the probability to demonstrate that the observed 
response rate in the 3 mg/kg and 10 mg/kg arms is larger than 10% by comparing the lower limit 
of the exact 97.5% two-sided confidence interval of the observed rate to 10% is larger than 0.999 
(assuming the response rate is 46%) 
In addition, it is planned to perform pairwise comparisons between dose arms as part of the 
secondary efficacy analysis. A sample size of 24 subjects per arm will ensure a power of 82% to 
detect a difference of 39% between two treatment arms (assuming the best response rate is 46%) 
with a two-sided type one error of 0.025. Consequently if the assumption of response rates of 5% 
in the 0.3 mg/kg arm and 46% in the 3 and 10 mg/kg arm is true, the study will be sufficiently 
powered (power = 82%) to demonstrate a significant superiority of any of the higher doses over 
the smallest dose, using an adjusted two-sided 0.025 type-one error rate. 
 
 
10.2. Randomization and Stratification 
This study is randomized with a 1:1:1 randomization ratio.  A central randomization system will 
be used. The randomization will be stratified according to the subject’s baseline hematologic 
status: baseline anemia (Hgb < 100 g/L and having received > 2 units PRBC in 12 weeks prior to 
study entry) alone or baseline thrombocytopenia (platelet count < 50 x 109/L) alone; or baseline 
anemia associated with baseline thrombocytopenia.  The randomization system will also ensure 
that at least 50% of the subjects in the final study population will have baseline 
thrombocytopenia. 
 
10.3. General considerations for statistical analysis 
 
 
 
10.3.1 Statistical Analysis Plan 
The statistical section of the protocol presents the main features of the planned statistical 
analysis.  A detailed statistical analysis plan (SAP) will be prepared by the Venn Life Sciences 


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statistician, validated by the sponsor and signed before the database lock prior to any unblinded 
statistical analysis. 
Any change to the planned statistical methods will be documented in the clinical study report. 
 
 
 
10.3.2  Descriptive statistics 
Quantitative variables will be described by treatment group using the following statistics: 
number of available data, number of missing values, mean, standard deviation, median, Q1, Q3, 
minimum and maximum values.  When relevant, confidence intervals will also be computed. 
Qualitative variables will be described by treatment group using number of available data, 
number of missing values, frequency counts for each category and corresponding percentage. 
Percentages will be calculated using the number of available data as the denominator (i.e. not 
including missing values). When relevant, confidence intervals will also be computed. 
 
 
 
 
10.3.3. Inferential statistics 
The primary efficacy analysis is both descriptive and inferential.  The exact confidence interval 
for the response rate in each arm will be computed and its lower bound will be compared to 10%. 
In addition, one secondary objective of the study is to determine if there is a difference in 
efficacy between the three doses of PRM-151 used in the study. These comparisons will be done 
only if at least one dose arm is demonstrated to have a response rate superior to 10% in the 
primary analysis. The comparison between the 3 mg/kg arm and 10 mg/kg arm is not expected to 
be sufficiently powered to detect any statistically significant difference. The two main 
comparisons (3 mg/kg arm versus 0.3 mg/kg arm and 10 mg/kg arm versus 0.3 mg/kg) will use 
an adjusted type-one error rate of 0.025 to control the overall type-one error rate.  The 3 mg/kg 
versus 10 mg/kg comparison will only be provided with an exploratory purpose and will be done 
without correction of the type-one error. 
For all the other secondary efficacy analyses involving formal statistical comparisons, no 
adjustment of the type-one error rate will be conducted. As a consequence, the results of these 
tests will have to be interpreted bearing in mind the issue of multiplicity and the increased risk of 
erroneously obtaining statistically significant results. 
 
 
 
10.3.4. Missing, Unused, and Spurious Data 
All available efficacy and safety data will be included in data listings and tabulations. For the 
primary efficacy criterion analysis, subjects with a reduction in bone marrow fibrosis score by at 
least one grade according to WHO criteria (central adjudication) at any post baseline visit will be 
considered as responders. Subjects without any central assessment of bone marrow fibrosis will 
be considered as non-responders.  In addition, subjects who discontinue due to toxicity prior to 
completion of one cycle of study drug will also be considered non-responders for the efficacy 
analyses. 


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Except for the imputation of missing values for the analysis of the primary criterion as described 
above, all other analyses will be based on observed data only; no missing data will be imputed. 
 
 
 
10.3.5. Interim Analyses 
 
There is no interim analysis planned. 
 
 
 
10.3.6. Software used for statistical analyses 
 
The < SAS software, version 9.2 or higher >, will be used for the statistical analysis. 
 
10.4 Protocol deviations 
Major protocol deviations are defined as deviations liable to prevent or change the interpretation 
of the results of the primary efficacy analysis of the study. The following deviations will be 
considered as major (this list is not exhaustive and will be reviewed at the time of the blind 
review meeting): 
 
• non compliance with the inclusion or non inclusion criteria 
• non compliance with study treatment 
• no post-baseline data for the primary efficacy endpoint 
• intake of forbidden medication 
 
All other deviations will, a priori, be considered as minor deviations. However, all deviations 
will be reviewed and adjudicated as either major or minor during the blind review meeting 
before database lock and code break. 
 
 


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10.5. Analysis datasets 
The statistical analysis will be conducted on the following subject data sets: 
 
 
 
10.5.1. Efficacy Analysis Sets: 
The Full Analysis Set (FAS) will consist in all randomized subjects having received at least one 
administration of the study medication with at least one post-baseline assessment of BMRR 
(primary efficacy criterion) available.  Subjects who discontinue due to toxicity prior to 
completion of one cycle of study drug will also be kept in the FAS and considered non-
responders for the efficacy analysis. 
The full analysis set will be the primary population for the efficacy analyses in this trial. 
The Per Protocol (PP) set: a subset of the FAS consisting of all subjects who are randomized, 
and who did not present any major protocol deviations, who are evaluable based on having 
received at least 3 cycles of study drug, and who have an ORR measurement. The per-protocol 
set will be used for secondary analyses of the primary efficacy criterion and for the analysis of 
some selected secondary efficacy criteria. 
 
 
 
10.5.2. Safety Analysis Sets: 
The Safety (SAF) dataset: composed of all randomized subjects having received at least one 
dose of study drug and having a post-baseline safety observation. This data set will be used to 
perform the analysis of safety. 
 
10.6. Planned Statistical Analyses and Methods 
 
 
 
10.6.1 Efficacy Analyses 
 
10.6.1.1. Primary analysis of efficacy 
The primary efficacy analysis will consist in computing the bone marrow response rate (percent 
of subjects with a reduction in bone marrow fibrosis score by at least one grade, see Section 3.1) 
and its 95% (unadjusted) and 97.5% (adjusted) two-sided confidence intervals within each 
treatment arm.  This analysis will be conducted on the FAS analysis set.  
Inferential interpretation: for the 3 mg/kg and 10 mg/kg arms, the lower limit of the 97.5% two-
sided confidence interval will be compared to 10%, a threshold assumed to define the minimal 
clinically relevant effect. If the lower limit of the confidence interval is above 10%, the 
corresponding dose will be claimed to have demonstrated clinically relevant efficacy. 
The confidence intervals computation will use a method consistent with the stratified design. 
 
10.6.1.2. Sensitivity analyses on the primary endpoint: 
Sensitivity analyses on the FAS: 


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To further examine a potential stratum effect, the BMRR and its confidence interval will be 
computed for each dose arm within each stratum, at least for the dose by stratum combination 
cells with sufficiently large sample sizes (i.e. greater than 10). 
Sensitivity analyses on the PP set: 
The analysis described above in Section 10.6.1.1. for the primary analysis on the FAS will be 
repeated on the PP analysis. 
10.6.1.3. Secondary and exploratory efficacy analyses: 
 
10.6.1.3.1. Comparison of PRR between 
treatment arms 
Pairwise comparisons between the three dose groups will be performed using the Cochran-
Mantel-Haenszel (general association) statistic in the SAS Freq procedure, to take into account 
the stratified design, using the following statement: 
 
 
 
tables Stratum*Treatment*Response / cmh; 
The Breslow-Day Test for Homogeneity of the Odds Ratios will be examined to detect a 
potential significant stratum difference in the odds ratios.  
Two pairwise comparisons (3 mg/kg versus 0.3 mg/day and 10 mg/kg versus 0.3 mg/day) will be 
computed with the aim to demonstrating superiority and, consequently, will use an adjusted a 
two-sided 0.025 level of significance. 
The third comparison (10 mg/kg versus 3 mg/kg) is not expected to have enough power to 
demonstrate any difference with the planned sample size.  This comparison is considered 
exploratory and will be conducted using an unadjusted 0.05 level of significance. 
These analyses will be computed on both the FAS (primary analysis set) and PP analysis sets. 
10.6.1.3.2. Analyses of categorical secondary and 
exploratory efficacy endpoints: 
Percentages and or rates will be computed, together with their 95% confidence intervals, within 
each treatment arm. 
 
10.6.1.3.3. Analyses of quantitative secondary 
and exploratory efficacy endpoints: 
Descriptive statistics for quantitative variables (see Section 10.3.2) will be computed, together 
with the 95% CI of the mean (or median depending on the variable) 


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10.6.1.3.4. Inferential analyses for secondary and 
exploratory efficacy endpoints: 
For all categorical or quantitative secondary efficacy endpoints, formal pairwise between arms 
comparisons will be computed. These comparisons will use a two-sided 0.05 level of 
significance, hence without any correction for multiplicity (See section 10.3.3). The results of 
these tests will have to be interpreted cautiously bearing in mind the issue of multiplicity and the 
increased risk of erroneously obtaining statistically significant results. 
No between arms comparisons will be computed for the exploratory efficacy endpoints, only 
descriptive analyses will be computed. 
 
 
 
 
10.6.2. Safety Analysis 
 
Safety evaluations will be based on the incidence, intensity, and type of adverse events, and 
clinically significant changes in the subject’s physical examination, vital signs and clinical 
laboratory results.  Safety variables will be tabulated and presented for all subjects who receive 
any amount of study medication.  Exposure to study drug and reasons for discontinuation of 
study treatment will be tabulated.  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
adverse event coding system for purposes of summarization.  All adverse events occurring on 
study will be listed in by-subject data listings.  Treatment-emergent events (TEAEs) will be 
tabulated, where treatment-emergent is defined as any adverse event that occurs after 
administration of any amount of study drug, or any event that is present at baseline but worsens 
in intensity or is subsequently considered drug-related by the Investigator.  By treatment 
tabulations will be performed by MedDRA system organ class (SOC) and preferred term (PT) 
for deaths if any, serious adverse events; all treatment-emergent adverse events; TEAEs leading 
to discontinuation of study therapy due to adverse event or toxicity and TEAEs resulting in study 
discontinuation. Events that are considered related to treatment (possibly or probably drug-
related) will also be tabulated.  Tabulation will also be provided that enumerates adverse events 
by maximum severity. 
Laboratory evaluations will be summarized by time of collection and by treatment group. In 
addition, change from baseline to any post-dose values will be summarized for vital signs and 
clinical laboratory results. 
The frequency of subjects with abnormal safety laboratory results will be tabulated by treatment. 
Shift tables for each cycle will be produced for selected laboratory parameters, to include at least 
hemoglobin, WBC count, neutrophils, lymphocytes, platelets, AST, ALT, bilirubin, LDH, 
creatinine, alkaline phosphatase and electrolytes. These tables will summarize by cycle and dose 
level the number of subjects with each baseline CTC grade and changes to the maximum CTC 
grade in the cycle. 


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Clinically significant laboratory abnormalities will be tabulated or presented in individual data 
listings, depending on their number. 
Vital signs assessments will be summarized over time in a similar fashion to laboratory 
parameters, and any abnormal values will be tabulated.  
 
 
 
10.6.3. Other Analyses 
 
10.6.3.1. Subject Disposition 
A listing and table of proportions of subjects discontinuing the study for each reason will be 
provided by treatment / dose group.  Details will be included in the Statistical Analysis Plan. 
10.6.3.2. Demographic and Baseline Characteristics 
Summary statistics will be provided for the demographic and baseline characteristics; details will 
be in the Statistical Analysis Plan. 
10.6.3.3. Subject Adherence and Extent of Exposure 
Compliance with study drug will be computed for each subject as proportion of prescribed study 
drug actually taken.  Details will be included in the Statistical Analysis Plan. 
Extend of exposure: Summary statistics will be provided for overall duration of study treatment, 
number of injections received and cumulative dose of IP received. 
10.6.3.4. Concomitant Medications 
A listing of table of proportions of subjects taking each concomitant medication will be 
provided. Details will be included in the Statistical Analysis Plan. 
 
11.   
ADMINISTRATIVE REQUIREMENTS 
 
11.1. Investigators and Study Administrative Structure 
Before initiation of the study, the investigators must provide the sponsor with a completed Form 
FDA 1572. Investigational product may be administered only under the supervision of the 
investigators listed on this form. Curriculum vitae must be provided for the investigators and 
sub-investigators listed on Form FDA 1572. 
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, any amendments to the protocol, the study treatments, and their study related 
duties and functions. The Investigator must maintain a list of sub-investigators and other 
appropriately qualified persons to whom he or she has delegated significant study related duties. 
 


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11.2 Institutional Review Board (IRB), Independent Ethics Committee 
(IEC) Approval, or Research Ethics Board Attestation (REB) 
Before initiation of the study, the Investigator must provide the Sponsor with a copy of the 
written IRB/IEC/REB approval of the protocol and the informed consent form.  This approval 
must refer to the informed consent form and to the study title, study number, and version and 
date of issue of the study protocol, as given by the Sponsor on the cover page of the protocol. 
Status reports must be submitted to the IRB/IEC/REB at least once per year. The IRB/IEC/REB 
must be notified of completion of the study.  Within three months of study completion or 
termination, a final report must be provided to the IRB/IEC/REB. A copy of these reports will be 
sent to the study clinical monitor. The Investigators must maintain an accurate and complete 
record of all submissions made to the IRB/IEC/REB, including a list of all reports and 
documents submitted.  AEs which are reported to FDA or other Regulatory agencies (IND Safety 
Reports) must be submitted promptly to the IRB/IEC/REB. 
11.3. Ethical Conduct of the Study 
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigators abide by 
Good Clinical Practice (GCP) as described in the 21 CFR Parts 50, 54, 56, and 312 and the 
International Conference on Harmonisation (ICH) GCP Guidelines. Compliance with these 
regulations and guidelines also constitutes compliance with the ethical principles described in the 
Declaration of Helsinki. 
 
11.4.  Subject Information and Consent 
Before enrolling in the clinical study, the subject must consent to participate after the nature, 
scope, and possible consequences of the clinical study and have been explained in a form 
understandable to him or her. 
An informed consent form (assent form if applicable) that includes information about the study 
will be prepared and given to the subject.  This document will contain all GCP and ICH-required 
elements. The informed consent (or assent) form must be in a language understandable to the 
subject and must specify who informed the subject. 
After reading the informed consent form, the subject must give consent in writing. Consent must 
be confirmed at the time of consent by the personally dated signature of the subject and by the 
personally dated signature of the person conducting the informed consent discussions. 
If the subject is unable to read, oral presentation and explanation of the written informed consent 
form and information to be supplied must take place in the presence of an impartial witness. 
Consent must be confirmed at the time of consent orally and by the personally dated signature of 
the subject or by a local legally recognized alternative (e.g., the subject’s thumbprint or mark). 
The witness and the person conducting the informed consent discussions must also sign and 
personally date the informed consent document. It should also be recorded and dated in the 
source document that consent was given. 


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A copy of the signed and dated consent document(s) must be given to the subject. The original 
signed and dated consent document will be retained by the Investigator. 
The investigator will not undertake any measures specifically required solely for the clinical 
study until valid consent has been obtained. 
A model of the informed consent form to be used in this study will be provided to the sites 
separately from this protocol. 
 
 
11.5.   
Subject Confidentiality 
Subject names will not be supplied to the Sponsor.  Only the subject number and subject initials 
will be recorded in the eCRF, and if the subject name appears on any other document, it must be 
obliterated before a copy of the document is supplied to the Sponsor. Study findings stored on a 
computer will be stored in accordance with local data protection laws. The subjects will be told 
that representatives of the Sponsor, a designated CRO, the IRB/IEC/REB, or regulatory 
authorities may inspect their medical records to verify the information collected, and that all 
personal information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. The Investigator will maintain a personal subject 
identification list (subject numbers with the corresponding subject names) to enable records to be 
identified. 
 
11.6.  
Study Monitoring 
Monitoring procedures that comply with current Good Clinical Practice (GCP) guidelines will be 
followed. Review of the eCRFs for completeness and clarity, cross-checking with source 
documents, and clarification of administrative matters will be performed. 
The study will be monitored by the Sponsor or its designee.  Monitoring will be performed by a 
representative of the Sponsor (Clinical Study Monitor) who will review the eCRFs and source 
documents. The site monitor will ensure that the investigation is conducted according to protocol 
design and GCP guidelines by frequent site visits and communications (e.g., email, letter, 
telephone, and facsimile). 
 
11.7.  
Case Report Forms and Study Records 
Case report forms are provided for each subject in electronic format. Electronic Data Capture 
(EDC) will be used for this study. The study data will be recorded from the source documents 
into the eCRF. The electronic files will be considered as the eCRFs. 
All forms must be filled out by authorized study personnel. All corrections to the original eCRF 
entry must indicate the reason for the change. The Investigator is required to sign the eCRF after 
all data have been captured for each subject/subject. If corrections are made after review and 
signature by the Investigator, he or she must be made aware of the changes, and his or her 
awareness documented by re-signing the eCRF. 


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11.8.  
Data Monitoring Committee 
A Data Monitoring Committee (DMC) will be established for purposes of independent 
assessment of safety during study conduct, as described in Section 7.13.1.4. 
 
11.9.  
Central Bone Marrow Review Committee 
All bone marrow assessments will be performed by a committee of expert hematopathologists, 
who will be blinded to subject, dose, and time of biopsy. The rules for assessment and 
adjudication will be defined in the Central Bone Marrow Review Committee charter. 
 
11.10  
Protocol Violations/Deviations 
The Investigator will conduct the study in compliance with the protocol. The protocol will not be 
initiated until the IRB/IEC/REB and the appropriate regulatory authorities have given 
approval/favorable opinion. Modifications to the protocol will not be made without agreement of 
the Sponsor. Changes to the protocol will require written IRB/IEC/REB approval/favorable 
opinion prior to implementation, except when the modification is needed to eliminate an 
immediate hazard(s) to subjects. The IRB/IEC/REB may provide, if applicable regulatory 
authorities permit, expedited review and approval/favorable opinion for minor change(s) in 
ongoing studies that have the approval/favorable opinion of the IRB/IEC/REB. The sponsor will 
submit all protocol modifications to the regulatory authorities in accordance with the governing 
regulations. 
A record of subjects screened, but not entered into the study, is also to be maintained. For any 
subject who does not meet the inclusion or exclusion criteria, a protocol exception may be 
requested by the Investigator. This exception may be approved by the Sponsor’s Medical 
Monitor prior to enrollment and the protocol exception must be fully documented in the source 
documents and on the appropriate page of the eCRF.  
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
subjects, the Investigator will contact the Sponsor or its designee, if circumstances permit, to 
discuss the planned course of action.  Any departures form the protocol must be fully 
documented as a protocol deviation.  Protocol deviations may be required to be submitted to the 
IRB/IEC/REB in accordance with local requirements. 
Protocol modifications will only be initiated by the Sponsor and must be approved by the 
IRB/IEC/REB and submitted to FDA or other applicable international regulatory authority 
before initiation. 
 
11.11. 
Premature Closure of the Study 
If the Sponsor, Investigator, or regulatory authorities discover conditions arising during the study 
which indicate that the clinical investigation should be halted due to an unacceptable subject risk, 
the study may be terminated after appropriate consultation between the Sponsor and the 
Investigator(s). In addition, a decision on the part of the Sponsor to suspend or discontinue 
development of the investigational product may be made at any time. Conditions that may 
warrant termination of the study or site include, but are not limited to: 


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• The discovery of an unexpected, significant, or unacceptable risk to the subjects enrolled 
in the study; 
• Failure of the Investigator to comply with pertinent global regulations; 
• Submission of knowingly false information from the study site to the Sponsor or other 
pertinent regulatory authorities; 
• Insufficient adherence by the Investigator to protocol requirements; 
• Administrative reasons as determined by the Sponsor. 
 
11.12. 
Access to Source Documentation 
Regulatory authorities, the IRB/IEC/REB, or the Sponsor or its designee may request access to 
all source documents, eCRFs, and other study documentation for on-site audit or inspection.  
Direct access to these documents must be guaranteed by the Investigator, who must provide 
support at all times for these activities. Monitoring and auditing procedures that comply with 
current GCP guidelines will be followed.  On-site review of the eCRFs for completeness and 
clarity, cross-checking with source documents, and clarification of administrative matters may be 
performed. 
 
11.13. 
Data Generation and Analysis 
The clinical database will be developed and maintained by the Sponsor or designee (CRO) or an 
electronic data capture technology provider as designated by the Sponsor. 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
Version 12.0 or later. Concomitant medication will be coded using WHO-Drug Dictionary 
(WHO-DD). Centralized laboratories may be employed as described in the study manual to aid 
in consistent measurement of efficacy and safety parameters. 
 
11.14. 
Retention of Data 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application and until there are no pending or contemplated marketing applications or 
at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. The Sponsor will notify the Investigator if these documents must be 
retained for a longer period of time. It is the responsibility of the Sponsor to inform the 
Investigator or institution as to when these documents no longer need to be retained. 
Records will be maintained by the Sponsor for a period of 25 years and will be accessible for 
onsite inspection by regulatory agency inspectors. 
 
11.15. 
Financial Disclosure 
The Investigator should disclose any financial interests in the Sponsor as described in 21 CFR 
Part 54 prior to beginning this study. The appropriate form will be provided to the Investigator 
by the Sponsor, which will be signed and dated by the Investigator, prior to the start of the study 
and one year after the conclusion of the study. 


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11.16. 
Liability and Insurance 
The Sponsor has subscribed to an insurance policy covering, in its terms and provisions, its legal 
liability for injuries caused to participating subjects and arising out of this research performed 
strictly in accordance with the scientific protocol as well as with applicable law and professional 
standards. 
 
11.17. 
Publication Policy 
Publication of any data from this trial by the investigators must be carried out in accordance with 
the Clinical Study Agreement. 
 
 


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12.  
 
USE OF INFORMATION 
This document contains information that is confidential and/or proprietary to the Sponsor. This 
information is being provided to you solely for the purpose of evaluating and/or conducting a 
clinical study for the Sponsor. You may disclose the contents of this document only to study 
personnel under your supervision, IRBs, ECs, or duly authorized representatives of regulatory 
agencies for this purpose under the condition that they maintain confidentiality. The contents of 
this document may not be used in any other clinical study, disclosed to any other person or 
entity, or published without the prior written permission of the Sponsor. The foregoing shall not 
apply to disclosure required by any applicable governmental regulations or laws; however, you 
will give prompt notice to the Sponsor prior to any such disclosure. All other nonpublic 
information provided by the Sponsor, as well as any information that may be added to this 
document, also is confidential and/or proprietary to the Sponsor and must be kept in confidence 
in the same manner as the contents of this document. 
 
 


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13.  
INVESTIGATOR AGREEMENT 
I have read and approve this protocol.  My signature, in conjunction with the signature of the 
Sponsor, confirms the agreement of both parties that the clinical study will be conducted in 
accordance with the protocol and all applicable laws and regulations including, but not limited 
to, the International Conference on Harmonisation Guideline for Good Clinical Practice (GCP), 
the Code of Federal Regulations (CFR), the ethical principles that have their origins in the 
Declaration of Helsinki, and applicable privacy laws. 
Nothing in this document is intended to limit the authority of a physician to provide emergency 
medical care under applicable regulations. 
 
 
 
Principal Investigator printed name 
 
 
 
 
 
 
Principal Investigator signature 
 
Date 
 
 
 
 
 
 
 
 
Investigational site or name of institution and 
location (printed) 
 
 
 
 
 
 
 
 
 
 
 


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14. REFERENCES 
 
Ballen, K. (2012). “How to manage the transplant question in myelofibrosis” Blood Cancer J 
2(3): e 59. 
Haudek, S. B., Y. Xia, et al. (2006).  “Bone marrow-derived fibroblast precursors mediate 
ischemic cardiomyopathy in mice.” Proc Natl Acad Sci U S A 103(48): 18284-9. 
 
Hawkins, P. N. and M. B. Pepys (1990). “A primed state exists in vivo following histological 
regression of amyloidosis.” Clin Exp Immunol 81(2):325-8. 
 
Murray, L. A., Q. Chen, et al (2011). “TGF-beta driven lung fibrosis is microphage dependent 
and blocked by Serum amyloid P.” Int J Biochem Cell Biol 43(1): 154-162.  
 
Passamonti, F., F. Cervantes, et al. (2010). “A dynamic prognostic model to predict survival in 
primary myelofibrosis: a study by the IWG-MRT (International Working Group for 
Myeloproliferative Neoplasms Research and Treatment).” Blood 115(9): 1703-8. 
 
Pilling, D., C. D. Buckley, et al. (2003). “Inhibition of fibrocyte differentiation by serum amyloid 
P.” J Immunol 171(10): 5537-46. 
 
Pilling, D., D. Roife, et al. (2007). “Reduction of bleomycin-induced pulmonary fibrosis by 
serum amyloid P.”  J Immunol 179(6): 4035-44. 
Przepiorka, D., S. Giralt, et al. (1998). “Allogeneic marrow transplantation for 
myeloproliferative disorders other than chronic myelogenous leukemia: review of forty 
cases.” Am J Hematol 57(1): 24-8. 
Simon, R. (1989). “Optimal two-stage designs for phase II clinical trials.” Control Clin Trials 
10(1): 1-10. 
Stewart, W. A., R. Pearce, et al. (2010). “The role of allogeneic SCT in primary myelofibrosis: a 
British Society for Blood and Marrow Transplantation study.” Bone Marrow Transplant 
45(11): 1587-93. 
Verstovsek, S., H. Kantarjian, et al. (2010). “Safety and efficacy of INCB018424, and JAK1 and 
JAK2 inhibitor, in myelofibrosis.” N Eng J Med 363 (12): 1117-27. 
 
JAKAF1.  JAKAF ® (ruxolitinib) tablets, for oral use; US Full Prescribing Information, 2011. 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
And ResponseCriteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 
1982; 5:649-655. The EasternCooperative Oncology Group, Robert Comis M.D., Group 
Chair. 
Study 11-014. The effects of PRM-151 on a mouse model of established TGF-b1-induced 
pulmonary fibrosis (Study  
# 11-014, draft). 2012 


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Tefferi A, Barosi G, Mesa R, et al. International Working Group (IWG) consensus criteria for 
treatment responsein myelofibrosis with myeloid metaplasia, for the IWG for 
Myelofibrosis Research and Treatment(IWG-MRT). Blood. 2006; 108:1497-1503. 
 
Tefferi A, Thiele J, et al. Proposals and rationale for revision of the World Health Organization 
diagnosticcriteria for polycythemia vera, essential thrombocythemia, and primary 
myelofibrosis: recommendations from an ad hoc international expert panel. Blood. 2007; 
110: 1092-1097. 
 
Thiele J, Kvasnicka et al. European consensus on grading bone marrow fibrosis and assessment 
of cellularity. Haematologica. 2005; 90(8): 1128-1132. 
 
Verstovsek S, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N 
Engl J Med.2012;366: 799-807.


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APPENDIX A 
Schedule of Events  
 
Screening 
< 28 days 
Cycle 1 28 Day Cycle Length 
Cycle 2, 3, 4, 5, 6, 7, 8, 9,  
28 Day Cycle Length 
Cycle 9, Day 29 
End of Study(14) 
Day (+/- 1 day) 
Day (+/- 3 days) 
(+/- 3 days) 
(+/- 3 days) 
1 
3 
5 
1 
 
 
Informed Consent 
x 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
Past Medical History 
x 
x 
 
 
 
 
 
Inclusion/Exclusion 
x 
x 
 
 
 
 
 
Bone Marrow Biopsy(1) 
x 
 
 
 
x 
x 
 
Physical Exam (2) 
x 
x 
 
 
x 
x 
x 
IWG-MRT Response Assessment 
 
 
 
 
x 
x 
 
Prior/Concomitant Medications 
x 
x 
x 
x 
x 
x 
x 
Transfusion history (previous 12 
weeks and between screening visit) 
x 
x 
 
 
x 
x 
x 
Review of transfusion diaries 
x 
x 
 
 
x 
x 
x 
AE/SAE Assessment(3) 
x 
x 
x 
x 
x 
x 
x 
Vital Signs (4) 
x 
x 
x 
x 
x 
x 
x 
Height (cm) 
x 
 
 
 
 
 
 
Weight (kg) 
x 
x 
 
 
x 
 
 
ECOG Performance Score 
x 
x 
x 
x 
x 
x 
x 
Pregnancy test (5) 
x 
x 
 
 
x 
 
 
Complete Blood Count (6) 
x 
x 
 
 
x 
x 
x 
Chemistry, BUN/creatinine (7) 
x 
x 
 
 
x 
x 
x 
Coagulation (8) 
x 
x 
 
 
x 
x 
 
12 lead ECG (9) 
x 
 
 
 
 
 
 
PET-CT Scan or CT or MRI(10) 
 
x 
 
 
x 
x 
 
Exploratory laboratory assessments(11) 
 
x 
 
 
 
x 
 
Special list of excluded medications 
x 
x 
 
 
x 
x 
x 
Anti-pentraxin 2 antibodies, pre-dose 
 
x 
 
 
x 
x 
 
Pentraxin-2 , pre-dose 
 
x 
 
 
x 
x 
 
MPN-SAF (12) 
x 
x 
 
 
x 
x 
x 
EORTC-QLQC30 (13) 
x 
x 
 
 
x 
x 
x 
Access IRS (14) 
x 
x 
x 
x 
x 
 
 
IWG-MRT DIPPS (risk assessment) 
x 
x 
 
 
 
x 
 


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PRM-151 Administration (16)  
 
x 
x 
x 
x 
 
 
Infusion Related Reaction Cytokines 
and anti-pentraxin 2 antibodies (15) 
 
x 
 
 
 
 
 
1  
Bone marrow biopsy at Screening must have been performed within 4 weeks prior to first infusion of PRM-151; subsequent bone marrow biopsies on Cycle 4, Day 1, Cycle 7, Day 1 and on Cycle 9, Day 29 performed +/- 3 days of 
scheduled visit    
2  
Abbreviated physical exam including spleen measurement by palpation at all time points  
3  
Pre-treatment adverse events, including serious adverse events will be collected from the time of informed consent and after the medical history has been obtained  
4  
Vital signs (including temperature, blood pressure, pulse rate, and respiratory rate) will be performed before and immediately after PRM-151 infusion ,and at the conclusion of the one hour observation period  
5  
Serum pregnancy test within 4 weeks prior to the first dose of the study drug (central lab)  Urine pregnancy test at all subsequent time points (local lab)  
6  
Complete blood count (CBC) includes red blood cell count (RBC), hemoglobin, hematocrit, white blood cell count with differential, absolute neutrophil count (ANC), reticulocyte count, blast count, platelets, and review for blood 
nucleated red blood cells and immature myeloid cells   
7  
Blood chemistry lab parameters include lactic dehydrogenase (LDH), serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), direct and indirect bilirubin, alkaline phosphatase, creatinine phosphokinase (CPK), 
uric acid, calcium, phosphorus, sodium, potassium, chloride, albumin, bicarbonate, BUN, creatinine, and glucose  
8  
Coagulation testing at screening for all subjects to include prothrombin time (PT), and partial thromboplastin time (PTT)  For subjects receiving warfarin, the PT, PTT and international normalized ratio (INR) must be obtained  Abnormal 
INRs will be tested twice weekly until the INR is stable for one month, followed by monthly monitoring of INRs  
9  
ECGs will be obtained at screening and in the event of an infusion related reaction  
10  
FDG or FLT PET-CT scans (depending on feasibility) or CT or MRI at Cycle 1 Day 1 (or within 2 weeks prior), Cycle 4 Day 1, Cycle 7 Day 1 and Cycle 9 Day 29  
11  
Whole blood samples for cytogentics and mutational status to be obtained on Cycle 1 Day 1 and whole blood samples for changes in allele burden will be obtained on Cycle 9 Day 29   
12  
If possible, the questionnaire should be completed prior to performing laboratory and radiology procedures, particularly bone marrow biopsy   
13  
At the Screening visit IRS can be assessed to register a subject by any member of the site staff  Beginning at Cycle 1 Day 1, only the unblinded Pharmacist (or designee) may access IRS  
14  
End of Study Visit is 28 days after Cycle 9, Day 29 or withdrawal from study  
15  
Infusion Related Reaction Cytokines (TNF-α, IFN-γ, IL-2, IL-4, IL-6, IL-8, IL-10) and anti-pentraxin 2 antibodies will be drawn pre-dose on Cycle 1 Day 1 and repeated only in the event of an infusion related reaction or a suspected 
adverse reaction  
16     Subjects will be observed one hour after each dose  
  


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APPENDIX B: International Working Group (IWG) consensus criteria for treatment 
response in myelofibrosis with myeloid metaplasia* 
 
 
 


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*Tefferi A, Cervantes F, Mesa R, et al.  Revised response criteria for myelofibrosis: International Working 
Group -Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet 
(ELN) consensus report. Blood.  2013; 122:1395-1398.  
 


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APPENDIX C: 
Proposed Revised World Health Organization Criteria for Primary 
Myelofibrosis 
Major criteria 
1.  Presence of megakaryocyte proliferation and atypia1, usually accompanied by either 
reticulin and/or collagen fibrosis, or, in the absence of significant reticulin fibrosis, the 
megakaryocyte changes must be accompanied by an increased bone marrow cellularity 
characterized by granulocytic proliferation and often decreased erythropoiesis (ie, 
prefibrotic cellular-phase disease) 
2. Not meeting WHO criteria for PV2, CML3, MDS4, or other myeloid neoplasm 
3. Demonstration of JAK2617V_F or other clonal marker (eg, MPL515W_L/K), or in the 
absence of a clonal marker, no evidence of bone marrow fibrosis due to underlying 
inflammatory or other neoplastic diseases 
Minor criteria 
1.  Leukoerythroblastosis 
2.  Increase in serum lactate dehydrogenase level5 
3.  Anemia 
4.  Palpable splenomegaly 
Diagnosis requires meeting all 3 major criteria and 2 minor criteria. 
1Small to large megakaryocytes with an aberrant nuclear/cytoplasmic ratio and hyperchromatic, bulbous, or 
irregularly folded nuclei and dense clustering. 
2Requires the failure of iron replacement therapy to increase hemoglobin level to the polycythemia vera range in the 
presence of decreased serum ferritin. Exclusion of  polycythemia vera is based on hemoglobin and hematocrit levels. 
Red cell mass measurement is not required. 
3Requires the absence of BCR-ABL. 
4Requires the absence of dyserythropoiesis and dysgranulopoiesis. 
5Degree of abnormality could be borderline or marked.¶  
 
Secondary to infection, autoimmune disorder or other chronic inflammatory condition, hairy cell leukemia or other 
lymphoid neoplasm, metastatic malignancy, or toxic (chronic) myelopathies. It should be noted that subjects with 
conditions associated with reactive myelofibrosis are not immune to primary myelofibrosis and the diagnosis should 
be considered in such cases if other criteria are met,  
 
 
Tefferi A, Thiele J, et al.  Proposals and rationale for revision of the World Health Organization 
diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: 
recommendations from an ad hoc international expert panel.  Blood. 2007; 110:1092-1097. 


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APPENDIX D: 
WHO Grading of Bone Marrow Fibrosis (EU Consensus Criteria) 
 
Grading 
Description* 
MF - 0 
Scattered linear reticulin with no intersections (cross overs) corresponding to 
normal bone marrow 
MF – 1 
Loose network of reticulin with many intersections, especially in perivascular 
areas 
MF – 2 
Diffuse and dense increase in reticulin with extensive intersections, occasionally 
with only focal bundles of collagen and/or focal osteosclerosis 
MF – 3 
Diffuse and dense increase in reticulin with extensive intersections with course 
bundles of collagen, often associated with significant osteosclerosis 
*Fiber density should be assessed in hematopoietic (cellular) areas. 
 
Thiele J, Kvasnicka HM, Facchetti F, et al.  European consensus on grading bone marrow fibrosis and 
assessment of cellularity.  Haematologica 2005; 90:1128-1132 
 
 
 


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APPENDIX E: 
International Working Group for Myeloproliferative Neoplasms 
Research and Treatment (IWG-MRT) Dynamic International 
Prognostic Scoring System (DIPSS) for primary myelofibrosis*  
 
The IWG-MRT Dynamic Prognostic Scoring System is based on 5 prognostic variables at 
presentation: 
 
 
Value 
Prognostic Variable 
0 
1 
2 
Age, y 
≤ 65 
> 65 
 
White blood cell count, x 109/L 
≤ 25 
> 25 
 
Hemoglobin, g/dL 
≥ 10 
 
< 10 
Peripheral blood blast, % 
< 1 
≥ 1 
 
Constitutional Symptoms, Y?N 
N 
Y 
 
 
The values for the prognostic variables are added together to produce a total score, and subjects 
are assigned to risk groups based on their score. 
 
Risk Group 
Number of Risk Factors 
Low 
0 
Intermediate-1 
1-2 
Intermediate-2 
3-4 
High  
5-6 
 
(Passamonti, Cervantes et al. 2010) A dynamic prognostic model to predict survival in primary 
myelofibrosis:  a study by the IWG-MRT (International Working Group for Myeloproliferative 
Neoplasms Research and Treatment).  Blood. 2010;115:1703-1708. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX F: 
Eastern Cooperative Oncology Group Performance Status 
ECOG Performance 
Status* 
Grade 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light house work, 
office work 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined 
to bed or chair 
5 
Dead 
*As published in Am. J. Clin. Oncol. 
 
 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5:649-655.  The 
Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
 
 
 


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APPENDIX G: 
Myeloproliferative Neoplasm Symptom Assessment Form(MPN-SAF) 
Myeloproliferative Neoplasm Symptom 
Assessment Form (MPN-SAF) 
and 
Myelolproliferative Neoplasms Symptom 
Assessment Form Total Symptom Score (MPN-SAF TSS) 
 
Symptoms among the Myeloroliferative Neoplasms (MPNs) are severe and are correlated with 
poor prognosis. The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and 
Myelolproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF 
TSS) are currently the only two validated measures symptom burden specific to the 
Myeloproliferative Neoplasms. The MPN-SAF is a 27-item measure that utilizes the 10-item 
Brief Fatigue Inventory in conjunction with a 17-item assessment of disease symptoms specific 
to the Myeloproliferative Neoplasms. 
 
In order to ease survey administration, the 10- MPN-SAF total symptom score (MPN-SAF TSS), 
was created which includes a one-item assessment of worst fatigue from the BFI and 9 items 
from the original MPN-SAF. This abbreviated measure only includes the most pertinent and 
representative of the MPN symptoms and is intended to be used either as a one-time assessment 
or as a 7-day diary. Both surveys have been validated in clinical setting to be administered 
during a routine office visit (see references and articles below). 
 
References: 
Scherber R, Dueck AC, Johansson P, Barbui T, Barosi G, Vannucchi AM, et. al. The 
Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF): international 
prospective validation and reliability trial in 402 patients. Blood. 2011 Jul 14;118(2):401-8. 
 
Mesa RA, Kantarjian H, Tefferi A, Dueck A, Levy R, Vaddi K, et. al. Evaluating the serial use 
of the Myelofibrosis Symptom Assessment Form for measuring symptomatic improvement:  
performance in 87 myelofibrosis patients on a JAK1 and JAK2 inhibitor (INCB018424) clinical 
trial. Cancer. 2011 Nov 1;117(21):4869-77. 
 
Mendoza TR, al e. The rapid assessment of fatigue severity in cancer patients: use of the Brief 
Fatigue Inventory. Cancer. 1999;85(5):1186-1196.  
 
Johansson P, Mesa R, Scherber R, Abelsson J, Samuelsson J, Birgegård G, et. al. Association 
between quality of life and clinical parameters in patients with myeloproliferative neoplasms.  
Leuk Lymphoma. 2012 Mar;53(3):441-4. 
 
Emanuel R, Dueck, A, Geyer, H, Kiladjian JJ, Slot S, Zweegman Z, et. al. The 
Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF 
TSS): Prospective International Assessment of an Abbreviated Symptom Burden Scoring System 
among 1408 MPN Patients. Journal of Clinical Oncology, in press. 
 


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SUBJECT #___________ 
 
Myeloproliferative Neoplasm Symptom Assessment Form 
(MPN-SAF)    
Instructions: Please circle the number corresponding with how each symptom as affected you. 
 
Symptom 
1 to 10 (0 if absent) ranking* 
1 is most favorable and 10 least favorable 
Please rate your fatigue 
(weariness, tiredness) by circling 
the one number that best 
describes your fatigue right 
NOW 
(No Fatigue) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Please rate your fatigue 
(weariness, tiredness) by circling 
the one number that best 
describes your USUAL level of 
fatigue during past 24 hours 
(No Fatigue) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Please rate your fatigue 
(weariness, tiredness) by circling 
the one number that best 
describes your WORST level of 
fatigue during past 24 hours 
(No Fatigue) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Circle the one number that describes how, during the past 24 hours, 
fatigue has interfered with your 
• General activity 
(Does not Interfere) 0 1 2 3 4 5 6 7 8 9 10 (Completely 
Interferes) 
• Mood 
(Does not Interfere) 0 1 2 3 4 5 6 7 8 9 10 (Completely 
Interferes) 
• Walking ability 
(Does not Interfere) 0 1 2 3 4 5 6 7 8 9 10 (Completely 
Interferes) 
• Normal work (includes 
• work both outside the 
• home and daily chores) 
(Does not Interfere) 0 1 2 3 4 5 6 7 8 9 10 (Completely 
Interferes) 
• Relations with other 
• people 
(Does not Interfere) 0 1 2 3 4 5 6 7 8 9 10 (Completely 
Interferes) 
• Enjoyment of life 
(Does not Interfere) 0 1 2 3 4 5 6 7 8 9 10 (Completely 
Interferes) 
Circle the one number that describes how, during the past Week how 
much difficulty you have had with each of the following symptoms 


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Filling up quickly when you eat 
(Early satiety) 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Abdominal pain 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Abdominal discomfort 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Inactivity 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Problems with headaches 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Problems with concentration - 
Compared to prior to my MPD 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Dizziness/ Vertigo/ 
Lightheadedness 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Numbness/ Tingling (in my 
hands and feet) 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Difficulty sleeping 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Depression or sad mood 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Problems with sexual desire or 
Function 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Cough 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Night sweats 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Itching (pruritus) 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Bone pain (diffuse not joint pain 
or arthritis) 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Fever (>100 F) 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Unintentional weight loss last 6 
months 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
What is your overall quality of 
life? 
(As good as it can be) 0 1 2 3 4 5 6 7 8 9 10 (As bad as it can 
be) 
 


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APPENDIX H:  
 
 
EORTC QLQ-C30 
 


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APPENDIX I: 
National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) 
The United States of America (USA) National Cancer Institute Common Terminology Criteria 
for Adverse Events, version 4.0 (NCI CTCAE, v.4.0) can be found on the following website. 
 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40  
[Accessed: 13 February 2013] 
 
This version of CTCAE is compatible at the AE (Adverse Event) term level where each CTCAE 
term is a Medical Dictionary for Regulatory Activities Terminology (MedDRA) LLT (Lowest 
Level Term).  CTCAE v4.0 includes 764 AE terms and 26 'Other, specify' options for reporting 
text terms not listed in CTCAE.  Each AE term is associated with a 5-point severity scale.  
MedDRA v12.0. 
 
 
 


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APPENDIX J:     
STAGE 2 EXTENSION STUDY 
 
Sponsor: 
Promedior, Inc. 
Name of Finished Product: 
Recombinant human Pentraxin-2; PRM-151 
Study Title: 
A Phase 2, - Prospective Study of PRM-151 In Subjects With Primary Myelofibrosis (PMF), 
Post-Polycythemia Vera MF (post-PV MF), or Post-Essential Thrombocythemia MF (post-ET 
MF) 
Study Number: 
PRM-151G-101 
Study Phase: Phase 2 
Investigational Product; Dose; and Mode of Administration: 
PRM-151 10 mg/kg intravenous 
Comparator; Dose; and Mode of Administration: 
Not applicable 
Primary Objective(s): 
To provide subjects in the parent study an opportunity to remain on treatment and to allow all 
subjects to switch to an open label extension utilizing the 10 mg/kg dose after completing 9 
cycles of the originally assigned treatment. 
Secondary Objective(s): 
• To collect long term safety data of subjects receiving PRM-151 
 
• To collect additional efficacy data on duration of response beyond 36 weeks of 
treatment 
 
• To collect efficacy data on the change of PRM-151 dose level in subjects not achieving 
a response 
Study Design: 
 
This is an open-label extension of study PRM-151G-101 to provide continued access to 
subjects in the parent study. All subjects completing 9 cycles of the originally assigned 


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treatment may switch to an open label extension and receive PRM-151 10mg/kg every 4 
weeks.  The first cycle of the open label phase contains a loading dose of 10mg/kg on days 1,3 
and 5. This will allow for subjects from all three dosing cohorts to receive a loading dose of 
10mg/kg while maintaining the blind. Additionally, subjects who have entered the open label 
extension study prior to the approval of this amendment may receive a loading dose (10 mg/kg 
on days 1, 3, and 5), to be administered on their next scheduled cycle after approval of this 
protocol amendment. This will allow for these subjects to receive any potential pharmacologic 
benefit of the loading dose.  
Study Duration: 
 
Subjects may continue with PRM-151 dosing in the absence of disease progression or toxicity 
warranting discontinuation of therapy until drug is made available in another way. Cycle 
numbers will continue from the parent protocol, with cycle 9 Day 29 of the parent protocol 
becoming Cycle 10 Day 1 of the extension study. 
Response Assessments: 
In addition to the schedule of assessments listed below, response assessments will be done on 
Day 1 of every third cycle (every 12 weeks) beginning on Day 1 of Cycle 13 and may include 
the following, as described below: 
Bone Marrow Biopsies: 
An optional bone marrow biopsy will be performed every 12 weeks. 
MPN SAF and EORTC QLQ-C30: 
Symptoms will be assessed using the MPN SAF and EORTC QLQ-C30 on Day 1 on every 
cycle.  
Physical Exam and Spleen Measurement: 
An abbreviated physical exam and spleen measurement by palpation will be done on Day 1 of 
every cycle. 
PET-CT or CT or MRI: 
These will be performed every 24 weeks. 
Stage 2 Extension 
Study 
SCHEDULE OF 
ASSESSMENTS 
Cycle 1011 
(Cycle 9, Day 29) 
Extension Cycles 
28 Day Cycle Length 
Day 1 (+/-3 days)      
Day (+/- 3 days) 
1 
3 
5 
1 


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Informed Consent 
x 
 
 
 
AE/SAE assessment 
(1) 
x 
x 
x 
x 
Physical Exam (2) 
x 
 
 
x 
Prior/Con Meds 
x 
x 
x 
x 
Special list of 
excluded medications 
x 
x 
x 
x 
Vital Signs (3) 
x 
x 
x 
x 
Weight (kg) 
x 
 
 
x 
ECOG Performance 
Score 
x 
 
 
x 
Urine Pregnancy Test 
x 
 
 
x 
Complete Blood 
Count (4) 
x 
 
 
x 
Chemistry, 
BUN/creatinine (5) 
x 
 
 
x 
Coagulation (6) 
x 
 
 
x 
Review transfusion 
diaries 
x 
 
 
x 
Bone Marrow (7) 
x 
 
 
x 
MPN-SAF score (7) 
x 
 
 
x 
EORTC-QLQC30 (7) 
x 
 
 
x 
PET-CT Scan of CT 
or MRI (8) 
x 
 
 
x 
Anti-pentraxin 2 
antibodies, pre-dose 
(9) 
x 
 
 
x 
Pentraxin-2 levels, 
pre-dose (9) 
x 
 
 
x 
Access IRS (10) 
x 
x 
x 
x 


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PRM-151 
Administration(11))(12)  
x 
x 
x 
x 
1. Pre-treatment adverse events, including serious adverse events will be collected from the time of informed consent and after 
the medical history has been obtained.  
2. Abbreviated physical exam and spleen measurement by palpation will be done day 1 of every cycle.  
3. Vital signs (including temperature, blood pressure, pulse rate, and respiratory rate) will be performed before and immediately 
after PRM-151 infusion, and at the conclusion of the one hour observation period. 
4. CBC includes red blood cell count (RBC), hemoglobin, hematocrit, white blood cell count with differential, absolute 
neutrophil count (ANC), reticulocyte count, last count, and platelets.  
5. Blood chemistry lab parameters include lactic dehydrogenase (LDH), serum alanine aminotransferase (ALT), serum aspartate 
aminotransferase (AST), direct and indirect bilirubin, alkaline phosphatase, creatinine phosphokinase (CPK), uric acid, 
calcium, phosphorus, sodium, potassium, chloride, albumin, bicarbonate, BUN, creatinine, and glucose.  
6. Coagulation testing at screening for all subjects to include prothrombin time (PT), and partial thromboplastin time (PTT). For 
subjects receiving warfarin, the PT, PTT and international normalized ratio (INR) must be obtained. Abnormal INRs will be 
tested twice weekly until the INR is stable for one month, followed by monthly monitoring of INRs  
7. MPN-SAF EORTC QLQ-C30, will be performed on Day 1 of every cycle. Bone marrow biopsy window +/- 6 weeks. 
8. PET-CT Scan or CT or MRI will be performed every 24 weeks.  
9. Blood sample for pentraxin-2 and anti-pentraxin 2 antibodies should be drawn pre-dose every 12 weeks. If the subject 
experiences an infusion related reaction, a blood sample for anti-pentraxin 2 antibodies should be drawn prior to any 
subsequent PRM-151 infusions. A blood sample for cytokines and anti-pentraxin 2 antibodies may be obtained in the event of 
a suspected adverse reaction as well. 
10. For consistency, the unblinded pharmacist will continue to access IRS to confirm occurrence of dosing on Day 1 of each 
Cycle.                         
11. Subjects will be observed one hour after each dose. 
12. Loading dose of 10 mg/kg on Days 1, 3 and 5. Alternative loading dose schedule is Days 1, 3 and 6 when days 1, 3 and 5 are 
not possible. Additionally, subjects who have entered the open label extension study prior to the approval of this amendment 
may receive a loading dose (10 mg/kg on days 1, 3, and 5), to be administered on their next scheduled cycle after approval of 
this protocol amendment.  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX K: 
 
SYNOPSIS: STAGE 1 
Sponsor: 
Promedior, Inc. 
Name of Finished Product: 
Recombinant human Pentraxin -2; PRM-151 
Study Title: 
A Phase 2, Open-Label, Prospective Study Of PRM-151 In Subjects With Primary 
Myelofibrosis (PMF), Post-Polycythemia Vera MF (post-PV MF), Or Post-Essential 
Thrombocythemia MF (post-ET MF) 
Study Number: 
PRM-151G-101 
Study Phase: Phase 2 
Investigational Product; Dose; and Mode of Administration: 
PRM-151 10 mg/kg intravenous 
Comparator; Dose; and mode of Administration: 
Not applicable 
Primary Objective(s): 
 
• To evaluate the efficacy of two different dose schedules of PRM-151 in 
intermediate -1, intermediate -2, or high risk subjects with PMF, post-PV MF, 
or post ET-MF who are not receiving therapy for MF, and in subjects with 
PMF, post-PV MF, or post ET-MF on a stable dose of ruxolitinib for at least 
three months. 
Secondary Objective(s): 
 
• To evaluate the safety and tolerability of two different dose schedules of PRM-
151 in intermediate-1, intermediate -2, or high risk subjects with PMF, post-PV 
MF, or post ET-MF who are not receiving therapy other than transfusions, and 
the safety and tolerability of two different dose schedules of PRM-151 in 
subjects with PMF, post-PV MF, or post ET-MF on a stable dose of ruxolitinib 
 
• To assess the effect of PRM-151 on bone marrow fibrosis 
 
• To measure the duration of response 
 
• PK of PRM-151 in subjects receiving single agent PRM-151 and in subjects 
receiving ruxolitinib. 
 
Exploratory Objectives 
 
• To evaluate the effect of PRM-151 on plasma cytokine levels comparing 
baseline on Cycle 1, Day 1 to Day 1 of Cycles 2, 3, 4 and Day 29 of Cycle 6 
 


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• To evaluate the effect of PRM-151 on PBMC mRNA and miRNA expression 
levels comparing baseline on Cycle 1, Day 1 to Day1 of Cycles 2, 3, 4 and Day 
29 of Cycle 6 
 
• To evaluate the correlation of baseline PTX-2 levels with outcomes. 
 
Study Endpoints: 
 
Primary: 
• The overall response rate (ORR), defined as a clinical improvement (CI), partial 
remission (PR), and complete remission (CR) according to the International 
Working Group (IWG) Criteria (Appendix B) 
 
• Stable disease with improvement in bone marrow fibrosis score by at least one 
grade according to the European Consensus on Grading of Bone Marrow 
Fibrosis (Appendix D) will also be considered a response (bone marrow 
response). 
 
Secondary: 
• Incidence of adverse events (AEs), serious adverse events (SAEs), and changes 
in laboratory test results 
 
• Change in bone marrow fibrosis 
 
• Change in the modified Myeloproliferative Neoplasms Symptom Assessment 
Form (MPN-SAF) Score (Appendix G) 
 
• Duration of response 
 
• PK parameters including Cmax (maximum drug concentration), tmax (time to 
maximum concentration, AUC, clearance, and volume of distribution. 
 
Exploratory: 
 
• Changes in levels of circulating plasma cytokine levels including but not 
limited to CRP, IL-1ra, MIP-1β, TNFα, IL-6 and VEGF comparing baseline on 
Cycle 1, Day 1 to Day 1 of Cycles 2, 3, 4 and Day 29 of Cycle 6 
 
• Changes in levels of PBMC mRNA and miRNA expression levels comparing 
baseline on Cycle 1, Day 1 to Day 1 of Cycles 2, 3, 4 and Day 29 of Cycle 6. 
 
• Correlation of baseline PTX-2 levels with outcomes. 
Study Design: 
 


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This is an open-label, Simon two stage, Phase 2 study to determine the efficacy and 
safety of two different dose schedules of PRM-151 in subjects with PMF and post 
ET/PV MF. There are two treatment cohorts, each assigned to one of two dose 
schedules of PRM-151. Subjects will be assigned to a weekly or every four week 
dosing schedule by the investigator based on their ability to visit the study site on a 
weekly basis. This is an adaptive design as defined in FDA Draft guidance for 
Industry: Adaptive Design Clinical Trials for Drugs and Biologics, February 2010. 
Modifications to dose levels, schedule, or regimen may be made in Stage 2 based on 
data from Stage 1. 
 
Stage 1:  
 
Cohort 1: Approximately 12 subjects with intermediate -1, intermediate -2, or high risk 
MF who have received no treatment for MF in at least two weeks will be enrolled and 
assigned to treatment with single agent PRM-151 at a dose of 10 mg/kg IV on Days 1, 
3, 5, 8, 15, and 22 of Cycle 1 and Days 1, 8, 15 and 22 of each subsequent 28 day cycle 
for six cycles, OR single agent PRM-151 at a dose of 10 mg/kg administered IV on 
Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles. 
Subjects responding to therapy may continue receiving it as long as there is a benefit. 
 
Cohort 2: Approximately 12 subjects with intermediate -1, intermediate -2, or high risk 
MF on a stable dose of ruxolitinib for at least 12 weeks, with no improvement in spleen 
during the last four weeks will be enrolled. Subjects will be assigned to receive PRM-
151 in combination with ruxolitinib either at a dose of 10 mg/kg administered IV on 
Days 1, 3, 5, 8, 15, and 22 of Cycle 1 and Days 1, 8, 15 and 22 of each subsequent 28 
day cycle for six cycles, OR in combination with ruxolitinib at a dose of 10 mg/kg 
administered IV on Days 1, 3, 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle 
for six cycles. Subjects responding to therapy may continue receiving it as long as there 
is a benefit. 
 
Stage 2: 
 
If at least one response is seen in any arm of either cohort in Stage 1, an additional 20 
subjects may be enrolled and treated on that dosing schedule.  All non-responding arms 
will be closed. Subjects responding to therapy may continue receiving it as long as 
there is a benefit. 
 
Enrolled subjects will be considered evaluable for response if they are on study drug 
for at least four weeks. 
Study Duration: 
 
Each subject will participate in the study for approximately 32 weeks. Participation 
will include a screening evaluation within four weeks before the first PRM-151 
administration, six study cycles of four weeks each, and an end of study visit four 
weeks after the end of the last cycle. Subjects may continue with PRM-151 dosing in 


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the absence of disease progression or toxicity warranting discontinuation of therapy, as 
long as there is evidence of clinical benefit, as judged by the Investigator. 
 
Subjects who have no benefit in the parent study may switch to a schedule in which 
responses occur after completing 6 cycles of the originally assigned treatment. 
 
It is estimated that the study will be completed in approximately 18 months. 
Study Inclusion and Exclusion Criteria: 
 
Inclusion Criteria: 
 
1. Subjects must be > 18 years of age at the time of signing the Informed Consent 
Form (ICF); 
 
2. Subjects must voluntarily sign an ICF; 
 
3. Subjects must have a pathologically confirmed diagnosis of PMF as per the 
WHO diagnostic criteria (see Appendix C) or post ET/PV MF (note that all 
diagnoses must include the presence of at least Grade 2 marrow fibrosis 
according to the European Consensus on Grading of Bone Marrow Fibrosis 
(Appendix D) with intermediate -1, intermediate -2, or high risk disease 
according to the IWG-MRT Dynamic International Prognostic Scoring System 
(Appendix E); 
 
4. A biopsy must be performed within four weeks prior to Cycle 1 Day 1 
treatment to establish the baseline fibrosis score; 
 
5. Subjects must have an Eastern Cooperative Oncology Group (ECOG) 
performance Status of 0-2. (Appendix F); 
 
6. Life expectancy of at least six months; 
 
7. At least two weeks must have elapsed between the last dose of any MF-directed 
drug treatments for myelofibrosis (including investigational therapies) and 
study enrollment, except for ruxolitinib for Cohort 2 (see Inclusion Criteria); 
8. Recovery to < Grade 1 or baseline of any toxicities due to prior systemic 
treatments, excluding alopecia; 
9. Women of child bearing potential (WCBP), defined as a sexually mature 
woman not surgically sterilized or not post-menopausal for at least 24 
consecutive months if < 55 years or 12 months if > 55 years, must have a 
negative serum pregnancy test within four weeks prior to the first dose of study 
drug and must agree to use adequate methods of birth control throughout the 
study. Adequate methods of contraception include use or oral contraceptives or 
Depo-Provera, with an additional barrier method (diaphragm with spermicidal 
gel or condoms with spermicide), double-barrier methods (diaphragm with 


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spermicidal gel and condoms with spermicide), partner vasectomy, and total 
abstinence. 
 
10. Ability to adhere to the study visit schedule and all protocol requirements; 
 
11. For Cohort 2 (PRM-151 added to ruxolitinib) Subjects only; 
 
12. Must have been on a stable dose of ruxolitinib treatment for at least 12 weeks 
with no further improvement in splenomegaly for at least four weeks; 
 
13. Must have adequate organ function as demonstrated by the following: 
 
• ALT (SGPT) and or AST/ (SGOT) < 3 x upper limit of normal (ULN), 
or < 4 x ULN (if upon judgement of the treating physician, it is believed 
to be due to extramedullary hematopoiesis [EMH] related to MF); 
 
• Direct bilirubin < 1.5 x ULN; or < 2 x ULN (if upon judgement of the 
treating physician, it is believed to be due to EMH related to MF);  
 
• Serum creatinine ≤ 2.5 mg/dL OR serum creatinine < 2.5 x ULN. 
 
Exclusion Criteria: 
 
1. Other invasive malignancies within the last 3 years, except non-melanoma skin 
cancer and localized cured prostate and cervical cancer; 
 
2. History of strike, unstable angina, myocardial infarction, or ventricular 
arrhythmia requiring medication or mechanical control within the last 6 
months; 
 
3. Presence of active serious infection; 
 
4. Any serious, unstable medical or psychiatric condition that would prevent, (as 
judged by the Investigator) the subject from signing the informed consent form 
or any condition, including the presence of laboratory abnormalities, which 
places the subject at unacceptable risk if he/she were to participate in the study 
or confounds the ability to interpret data from the study; 
 
5. Known history of human immunodeficiency virus (HIV), or known active 
hepatitis A, B, or C infection; 
 
6. Organ transplant recipients other than bone marrow transplant; 
 
7. Women who are pregnant or lactating. 
Efficacy Assessments: 
 


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Safety Assessments: 
 
Safety will be evaluated from reported adverse events, scheduled physical 
examinations, vital signs, and clinical laboratory test results. 
 
This Phase 2 clinical trial will have an independent Data Monitoring Committee 
(DMC) to conduct interim reviews of safety data, and provide an independent 
evaluation on a predetermined and ad-hoc basis of accumulating safety data.  All 
adverse events reported to Promedior will be considered by Promedior and the DMC 
regardless of the reported causality by the study site. In assessing adverse events, 
Promedior and the DMC will consider only treatment emergent adverse events, defined 
as adverse events that occur after at least one exposure to study drug. The DMC will 
review all safety data at the following pre-determined times: 
 
• when the first 12 subjects reach Cycle 4, Day 1 
 
• when the first 24 subjects have completed the study 
 
The DMC will review the following events immediately on an ad-hoc basis and will 
make a recommendation about whether the study may proceed: 
 
• any death 
 
• any event of anaphylaxis 
 
• any SAEs 
 
• any treatment emergent Grade 3 non-hematologic toxicity 
 
• any treatment emergent grade 4 hematological adverse event or a treatment 
emergent grade 3 hematologic adverse event that represents a change of 2 
grades from grade 1, or a doubling of transfusion frequency. 
 
Statistical Methods: 
 
The objective is to demonstrate superiority within each cohort and dose schedule, 
comparing observed ORR in each arm to a fixed uninteresting level ORR of 0.1. Let π 
denote population expected value of the primary parameter ORR. The objective of the trial 
is to reject the null-hypothesis 
 
Ho: π < 0.1 
Efficacy will be assessed by evaluation of the overall response rate (ORR) categorized 
according to the International Working Group (IWG) Criteria (APPENDIX B) 
modified to include stable disease with improvement in bone marrow fibrosis by at 
least one grade. 


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in favor of the alternative hypothesis 
 
HA: π > 0.4 
 
The design will be two-staged within each arm based on Simon (Simon 1989) as shown in 
the figure below: 
 
 
 
 
The design maintains the type I error probability at 3.4 % which is less than 5 %.  
Furthermore, for π > 0.4, there is a high probability of at least 94 % to demonstrate 
superiority. The probability under H_0 to stop after stage 1 is 53 %, which implicit 
consequence that the expected number of subjects is 15, compared to a maximum number 
of subjects of 26. 
 
 
 
Date of Original Protocol: Version 1.0 17 Jan 2013 


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APPENDIX L: SYNOPSIS: STAGE 1 OPEN LABEL EXTENSION STUDY 
Sponsor: 
Promedior, Inc. 
Name of Finished Product: 
Recombinant human Pentraxin -2; PRM-151 
Study Title: 
A Phase 2, Open-Label, Prospective Study Of PRM-151 In Subjects With Primary 
Myelofibrosis (PMF), Post-Polycythemia Vera MF (post-PV MF), Or Post-Essential 
Thrombocythemia MF (post-ET MF) 
Study Number: 
PRM-151G-101 
Study Phase: Phase 2 
Investigational Product; Dose; and Mode of Administration: 
PRM-151 10 mg/kg intravenous 
Comparator; Dose: and Mode of Administration: 
Not applicable 
Primary Objective(s): 
 
To provide subjects achieving clinical benefit as determined by the investigator in the parent 
study an opportunity to remain on treatment and to allow subjects not achieving a benefit to 
switch to a potentially more effective schedule of PRM-151 
 
Secondary Objective(s): 
 
To collect long term safety data of subjects receiving PRM-151 
 
To collect additional efficacy data on duration of response beyond 6 months of treatment 
 
To collect efficacy data on the change of PRM-151 schedule in subjects not achieving a 
response 
Study Design: 
This is an open-label, extension of study PRM-151G-101 to provide access to subjects in the 
parent study who have achieved benefit in the parent study. Additionally, subjects who have 
no benefit in the parent study may switch to a schedule of PRM-151 in which responses have 
occurred after completing 6 cycles of the originally assigned treatment. Subjects may switch 
schedules of PRM-151 and/or drop ruxolitinib in the extension but subjects are not allowed to 
add ruxolitinib if they were in Cohort 1. After study completion and data analysis, all subjects 
remaining on PRM-151 in this extension will switch to the dose selected for future clinical 
development. 
Study Duration: 
Subjects may continue with PRM-151 dosing in the absence of disease progression or toxicity 
warranting discontinuation of therapy, as long as there is evidence of clinical benefit or until 


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drug is made available in another way.  Cycle numbers will continue from the parent protocol, 
with Cycle 6 Day 29 of the parent protocol becoming Cycle 7 Day 1 of the extension study. 
Response Assessments: 
In addition to the schedule of assessments listed below, response assessments will be done on 
Day 1 of every third cycle (every 3 months) beginning on Day 1 of Cycle 10 and may include 
the following, as described below: 
 
Bone Marrow Biopsies: 
A bone marrow biopsy will be performed only to determine or confirm a change in response 
category. This will be done at the following time points depending on the subjects’ response 
category at the time of the most recent bone marrow biopsy: 
 
• CR: Bone marrow biopsy will be done only if there is a change in status indicating 
potential disease progression. 
 
• PR: For subjects with bone marrow histological remission, bone marrow biopsy 
(BMB) will be done only if there is a change in status indicating disease progression. 
For subjects without bone marrow histological remission BMB will be done every 6 
months until CR is documented or until indication of potential disease progression. 
 
• CI: BMB will be done if the clinical status changes from CI to PR or PD 
 
• Stable disease with improvement in bone marrow fibrosis: BMB will be done if the 
clinical status changes from SD to CI, PR, or PD. 
 
MPN SAF Score: 
The subjects MPN symptoms will be assessed using the MPN SAF every 3 months. 
 
Physical Exam and Spleen Measurement: 
An abbreviated physical exam and spleen measurement by palpation will be done every 3 
months. 
 
STAGE 1 OPEN LABEL EXTENSION STUDY 
 
 
SCHEDULE OF 
ASSESSMENTS 
 
Weekly Dosing  
Extension Cycles  
 
Q4 Weekly Dosing 
 Extension Cycles  


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1. Pre-treatment adverse events, including serious adverse events will be collected from the 
time of informed consent and after the medical history has been obtained 
2. Vital signs (including temperature, blood pressure, pulse rate, and respiratory rate) will 
be performed before infusions. 
3. CBC includes red blood cell count (RBC), hemoglobin, hematocrit, white blood cell 
count with differential, absolute neutrophil count (ANC), and platelets. Results should be 
reviewed prior to PRM-151 infusion. CBC can be drawn up to 7 days prior to PRM-151 
infusion. 
4. Blood chemistry lab parameters include lactic dehydrogenase (LDH), serum alanine 
aminotransferase (ALT), serum aspartamine aminotransferase (AST), direct and indirect 
bilirubin, alkaline phosphatase, creatinine phosphokinase (CPK), uric acid, calcium, 
phosphorus, sodium, potassium, chloride, bicarbonate, BUN, creatinine, and glucose. 
 
 
 
28 Day Cycle Length 
28 Day Cycle Length 
Day (+/- 3 days) 
Day (+/- 3 days) 
1 
8 
15 
22 
Day 1 
Informed Consent 
x 
 
 
 
x 
Prior/Con Meds 
x 
x 
x 
x 
x 
AE/SAE assessment (1) 
x 
x 
x 
x 
x 
Vital Signs (2) 
x 
x 
x 
x 
x 
Weight (kg) 
x 
 
 
 
x 
ECOG Performance Score 
x 
 
 
 
x 
Urine Pregnancy Test 
x 
 
 
 
x 
Complete Blood Count (3) 
x 
 
 
 
x 
Chemistry, BUN/creatinine (4) 
x 
 
 
 
x 
Transfusion History over past 3 
months or since last visit 
x 
 
 
 
x 
Special list of excluded 
medications 
x 
 
 
 
x 
Anti-pentraxin 2 antibodies, pre 
dose (5) 
x 
 
 
 
x 
PRM-151 Administration 
x 
x 
x 
x 
x 
Response Assessments (6) 
x 
 
 
 
x 


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5. Blood sample for anti-pentraxin 2 antibodies should be drawn pre-dose every 12 weeks. 
If the subject experiences an infusion related reaction, a blood sample for anti-pentraxin 2 
antibodies should be drawn prior to any additional PRM-151 infusions. 
6. The following components of response assessment will begin on Cycle 10, Day 1 and 
continue on Day 1 of every third cycle thereafter: Abbreviated physical exam and spleen 
measurements, MPN-SAF, and Investigator Response Assessment based on IWG-MRT 
criteria.  Bone marrow biopsies will be performed only to determine or confirm a change 
in response category as described above. 
 
 


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APPENDIX M: 
 
Summary of Protocol Changes from Version 5 
Section(s) 
Change 
Rationale  
Cover Page 
Added the following: 
• 
Added Country Specific Amendments  
• 
Amendment 5 Version 6 information. 
• 
EudraCT Number 
• 
New Medical Director 
 
 MD, PhD 
• 
The last protocol version was erroneously 
referred to as Amendment 5, Version 5 
but has been corrected to Amendment 4, 
Version 5, 
• 
Administrative 
Clarifications  
Synopsis:  Stage 2 
Study Design,  
• 
Added a loading dose for in subjects in 
Stage 2 open label extension study 
• 
Provided additional safety information 
from the IPF trial.  
• 
Referred to Appendix J for Stage 2 OLE 
• 
Referred to Appendix L for Stage 1 OLE.  
 
• 
This will allow for 
subjects from all three 
dosing cohorts to 
receive a loading dose 
of 10 mg/kg while 
maintaining the blind. 
Additionally, subjects 
who have entered the 
open label extension 
study prior to the 
approval of this 
amendment may receive 
a loading dose (10 
mg/kg on days 1, 3, and 
5), to be administered 
on their next scheduled 
cycle. This will allow 
for these subjects to 
receive any potential 
pharmacologic benefit 
of the loading dose.  
 
• 
Added clarification that, 
based on available data 
through NOV 14, in 
patients with IPF 
receiving a loading dose 
in an open label study, 
no incremental risk has 
been reported. 
 
• 
Clarification on the 
Stage 2 OLE loading 
dose schedule and Stage 
1 OLE study 


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Synopsis: 4 Inclusion 
Criteria # 12; 5.1.1. 
• 
Added clarification for contraception and 
adding highly effective methods to align 
with IB v10 and country amendment 5.1. 
• 
To align with IB v10 
and the country specific 
amendments.  
Synopsis: Inclusion 
Criteria # 14; 5.1.1. 
• 
Modified units of measurement of serum 
creatinine to: “≤ 2.5 x ULN”  
• 
Updated the unit of 
measurement for 
clarification.  
Synopsis: Endpoints, 
3.3 
• 
Clarified that spleen size is measured by 
CT or MRI and removed “(in subjects 
with palpable spleen at baseline)”  
• 
Clarification that the 
use of MRI to measure 
spleen size, for patients 
not receiving PET-CT, 
was intended to be 
allowed as an 
alternative to CT. 
1.1 Overview 
• 
Added “PRM-151 is a recombinant 
human PTX-2”. 
• 
Per IRB request.  
1.5 Rationale for Stage 
2 Changes, 7. Study 
Procedures 
• 
Added a loading dose for subjects in 
Stage 2 open label extension study. 
• 
Referred to Appendix K and L for Stage 1 
and Stage 1 OLE information.  
• 
This will allow for 
subjects from all three 
dosing cohorts to 
receive a loading dose 
of 10 mg/kg while 
maintaining the blind. 
Additionally, subjects 
who have entered the 
open label extension 
study prior to the 
approval of this 
amendment may receive 
a loading dose (10 
mg/kg on days 1, 3, and 
5), to be administered 
on their next scheduled 
cycle. This will allow 
for these subjects to 
receive any potential 
pharmacologic benefit 
of the loading dose.  
• 
Added reference for 
additional information 
on Stage 1 and Stage 1 
OLE.  
4.1.1 Study Design 
• 
Added a loading dose for in subjects in 
Stage 2 open label extension study. 
 
• 
This will allow for 
subjects from all three 
dosing cohorts to 
receive a loading dose 
of 10 mg/kg while 
maintaining the blind. 
Additionally, subjects 
who have entered the 
open label extension 
study prior to the 
approval of this 
amendment may receive 
a loading dose (10 


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mg/kg on days 1, 3, and 
5), to be administered 
on their next scheduled 
cycle. This will allow 
for these subjects to 
receive any potential 
pharmacologic benefit 
of the loading dose.  
 
6.2 Treatment(s) 
Administered 
• 
Clarified that PRM-151 can be resumed 
when adverse event has resolved to Grade 
1 or baseline. 
• 
To account for adverse 
events that may return 
to baseline but not 
Grade 1 (eg 
hemoglobin; platelets). 
6.3 Dose for Each 
Subject  
• 
Removed dosing for Stage 2 OLE and 
referred to Appendix J for dosing 
information.  
• 
To provide clarification 
and consistency 
throughout the 
document. 
7.8 Investigation 
Product 
Administration; 
7.13.1.1 
Provided clarification on premedication for IRR: 
a. 
Diphenhydramine 50 mg IV “or 
clemastine 2 mg IV or an equivalent 
antihistaminic” 
b. Dexamethasone 10 mg IV “or an 
equivalent corticosteroid” 
• 
To provide additional 
options for 
premedication for IRR.  
7.10. Exploratory 
Laboratory 
Assessments 
• 
Added clarification that DNA sampling is 
not mandatory for subjects and they can 
still enroll in the trial if they opt out of the 
sampling. 
• 
Revised for clarification “week 36” to 
“Cycle 9 Day 29” 
• 
Added clarification that the baseline 
blood sample for DNA sampling will also 
be used for the cytogenetic analysis. 
• 
Updates added for 
clarification on 
exploratory 
assessments. 
7.11.1 Bone Marrow 
Biopsy 
• 
Revised the title by removing “and 
Aspirate”.  
 
• 
Removed cytogenetic analysis on marrow 
biopsy/aspirate  
 
• 
Obtaining an aspirate 
was never intended, and 
not implemented.  
 
• 
It was never intended or 
implemented to obtain a 
bone marrow aspirate 
for cytogenetic testing. 
The exploratory 
endpoint of cytogenetic 
testing is performed on 
peripheral blood. 
7.11.3.2. Imaging 
• 
Added “MRI” 
• 
Updated title to “Imaging” 
• 
Clarification that the 
use of MRI to measure 
spleen size, for patients 
not receiving PET-CT, 
was intended to be 


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allowed as an 
alternative to CT. 
• 
Clarification to title as 
other imaging 
procedures can be 
performed.  
7.11.6 Response 
Assessments 
• 
Added this section to help clarify the 
IWG-MRT response assessment. 
• 
To provide clarification 
on the IWG-MRT 
response assessment.  
7.12.3 Clinical 
Laboratory Tests 
• 
Added clarification on which labs are 
central laboratory or local. 
• 
To provide clarification 
on the laboratory 
assessments.  
7.12.4 Pregnancy Test 
• 
Added information regarding pregnancy 
testing requirements for clarification. 
• 
To provide clarification 
on pregnancy testing.  
7.12.6 Immune 
Response Assessment  
• 
Added anti-pentraxin 2 antibodies 
collection for IRR and anti-pentraxin 2 
antibodies and cytokines in the event of 
an suspected adverse reaction. 
• 
To provide additional 
options to monitor 
IRR/suspected adverse 
reactions 
7.13.1.4 Data 
Monitoring Committee 
• 
Added clarification on the data to be 
reviewed by the DMC.  
• 
To provide clarification 
that unblinded safety 
data will be reviewed by 
the DMC, to align with 
the DMC charter 
7.13.2.2 Reporting 
Serious AEs 
• 
Removed “Only serious Treatment 
Emergent AEs (TEAEs), defined as 
adverse events occurring after at least one 
dose of study drug, will be recorded.” All 
AEs will be recorded.  
• 
To provide clarification 
that all AEs are 
collected.  
7.13.3 Reporting 
Pregnancies 
• 
Added reporting clarification for 
reporting pregnancies. 
• 
To provide clarification 
on pregnancy reporting.  
8.0 Stage 2 Study 
Procedures  
• 
Clarifications on the process for local labs 
use when a central lab result is not 
reliable.  
• 
To provide clarification 
for sites on the process 
for when a test result 
cannot be determined in 
the central lab. 
8.1 Screening, 8.2 
Cycle 1, Day 1, 8.5 
Cycle 9, Day 29 
Clarification was added on: 
• 
When IWG-MRT DIPPS (risk 
assessment) is assessed 
• 
Which assessment are done at central labs 
• 
That bone marrow biopsy at screening is 
obtained <4 weeks prior to first dose 
• 
To provide clarification 
on risk assessment, 
laboratory assessments 
and bone marrow 
biopsy.  
8.2 Cycle 1, Day 1 
Clarification was added for: 
• 
option for MRI 
• 
To provide clarification 
on laboratory 
assessments and 
imaging assessment.  


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• 
Added when blood sample for infusion 
related cytokines (pre-dose) occurs for 
clarification 
• 
Added anti-pentraxin 2 antibodies 
collection for infusion related reactions 
• 
Removed “Blood samples for exploratory 
laboratory assessments” to specify 
collection is for “genetic analysis”. 
• 
Specified which labs are to be done at 
central lab 
8.3 Cycle 1, Days 3 
and 5 
• 
Specified which labs are to be done at 
central laboratory. 
• 
To provide clarification 
on laboratory 
assessments.  
8.4 Cycle 2 through 9, 
Day 1 
Clarification was added for: 
• 
Modified +/- 1days to +/- 3 days window  
• 
Specified which labs are to be done at 
central laboratory. 
• 
Added IWG-MRT Response Assessment 
for clarification 
• 
Clarified pentraxin levels  
• 
Clarified anti-pentraxin-2 sample should 
be taken “pre-dose”  
• 
Updated language of recording of 
transfusion diary to reviewing 
• 
To allow for a wider 
visit window. 
• 
To provide clarification 
on window for visit, 
laboratory assessments, 
transfusion diary and 
response assessments.  
8.5 Cycle 9, Day 29 
(week 36) 
Clarification was added for: 
• 
Modified +/- 1-3 days to +/- 3 days 
window  
• 
Added MRI as an option. 
• 
Removed “Blood samples for exploratory 
laboratory assessments” to specify 
collection is for “genetic analysis”. 
• 
Clarified pentraxin levels  
• 
Clarified anti-pentrxin-2 sample should 
be taken “pre-dose” 
 
• 
To allow for a wider 
visit window 
• 
To provide clarification 
on window for visit, 
imaging procedures and 
laboratory assessments.  
8.6 End of Study 
Clarification was added for: 
• 
To allow for a winder 
visit window. 
• 
To provide clarification 
on the window allowed 


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• 
Modified +/- 1-3 days to +/- 3 days 
window  
• 
Specified which labs are to be done at 
central laboratory. 
• 
Updated language on recording of 
transfusion diary to reviewing 
for visit, lab collection 
and transfusion diary 
recording.  
Appendix A Schedule 
of Events 
Modified Schedule of Events Table to align with 
protocol: 
• 
Revised “Completion of” to “Review” 
transfusion diaries 
• 
Modified +/- 1days to +/- 3 days 
• 
Added MRI as an option 
• 
Removed language “On Cycle 1 Day 1, in 
addition to the blood sample for central 
lab, blood sample for local lab must be 
done for hemoglobin and/or platelet to 
confirm eligibility by the Investigator 
prior to dosing.” 
• 
Added clarification to footnote # 10; MRI 
(within 2 weeks prior to C1D1)  
• 
Added clarification to footnote 
#11“cytogenetics” and removed list of 
“exploratory laboratory assessments”  
• 
Added footnote # 15 “Subjects will be 
observed one hour after each dose.” for 
clarification. 
• 
Added IWG-MRT DIPSS (risk 
assessment) and IWG-MRT Response 
• 
Added anti-pentraxin 2 antibodies to 
collection for IRR.  
• 
To align with the 
updates in the body of 
the protocol and add 
clarification in the 
schedule of events.  
Appendix J Stage 2 
Extension Study 
Clarifications were added: 
Study Design: 
• 
Added clarification on dosing schedule.  
Response Assessments: 
• 
Added MRI as an option 
• 
Removed language for every 12 weeks 
and added Day 1 of every cycle for 
clarification.  
• 
To align with updates in 
the body of the protocol 
amendment.  


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Modified Schedule of Events Table: 
• 
Modified +/- 1 day to +/- 3 days for Cycle 
1 Day 1 
• 
Added Days 1, 3, and 5 for Cycle 10 
• 
Removed from footnote # 4 “Results 
should be reviewed prior to PRM-151 
infusion CBC can be drawn up to 7 days 
prior to PRM-151 infusion.” 
• 
Added to footnote # 7 the bone marrow 
biopsy window and clarification that 
assessment of MPN-SAF and EORTC 
QLQ-C30 is performed at Day 1 of every 
cycle.  
• 
Added to footnote # 8 “MRI”  
• 
Added to footnoate # 9 “A blood sample 
for cytokines and anti-pentraxin 2 
antibodies may be obtained in the event 
of a suspected adverse reaction as well.” 
• 
Added footnote # 11 “Subjects will be 
observed one hour after each dose.” 
• 
Added footnote # 12 “ Loading dose of 
10 mg/kg on Days 1, 3 and 5. Alternative 
loading dose schedule is Days 1, 3 and 6 
when days 1, 3 and 5 are not possible. 
Additionally, subjects who have entered 
the open label extension study prior to the 
approval of this amendment may receive 
a loading dose (10 mg/kg on days 1, 3, 
and 5), to be administered on their next 
scheduled cycle after approval of this 
protocol amendment.” 
Appendix L 
Added Synopsis: Stage 1 Open Label Extension 
Study and added Schedule of Events Stage 1 Open 
Label Extension Study to provide clarification for 
subjects still in the Stage 1 OLE. 
• 
To provide clarification 
for subjects in the Stage 
1 OLE.  
Appendix M 
Updated Summary of Protocol Changes from 
Amendment 4, Version 5 
• 
To easily refer to 
updates made from the 
previous protocol 
amendment.  
Throughout 
Formatting updates and minor 
corrections/clarifications to text. 
• 
Grammatical updates.  
 

SAP_001.pdf: 
Official Title: A Phase 2, Prospective Study Of PRM-151 In Subjects With 
Primary Myelofibrosis (PMF), Post-Polycythemia Vera MF (post- 
PV MF), OR Post-Essential Thrombocythemia MF (post-ET MF) 
NCT Number: NCT01981850 
Document Date: SAP Version 1: 22-July-2020 


STATISTICAL ANALYSIS PLAN APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
Pentraxin—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan BO42355
STATISTICAL ANALYSIS PLAN
TITLE:
A PHASE 2, PROSPECTIVE STUDY OF PRM-151 IN 
SUBJECTS WITH PRIMARY MYELOFIBROSIS (PMF), 
POST-POLYCYTHEMIA VERA MF (POST-PV MF), OR 
POST-ESSENTIAL THROMBOCYTHEMIA MF (POST-ET MF).
PROTOCOL NUMBER:
BO42355 (PRM-151G-101)
STUDY DRUG:
RO7490677 (PRM-151; Recombinant human 
Pentraxin-2)
VERSION NUMBER:
1
IND NUMBER:
116,932
EUDRACT NUMBER:
2015-001718-80
SPONSOR:
F. Hoffmann-La Roche Ltd
PLAN PREPARED BY:
, M.Sc.
DATE FINAL:
See electronic date stamp below.
Date and Time(UTC)        Reason for Signing                              Name
22-Jul-2020 08:49:08
Company Signatory






Pentraxin—F. Hoffmann-La Roche Ltd
4/Statistical Analysis Plan BO42355
1.
BACKGROUND
Myelofibrosis (MF) (including primary MF, post-polycythemia vera [PV] MF and 
post-essential thrombocythemia [ET] MF) is a clonal myeloproliferative neoplasm, 
characterized by progressive bone marrow fibrosis and subsequent ineffective 
erythropoiesis, dysplastic megakaryocyte hyperplasia, and extramedullary 
hematopoiesis. The typical clinical presentation includes marked splenomegaly, 
progressive anemia, and constitutional symptoms. Bone marrow transplant is the only 
curative treatment for MF, but the procedure is associated with high morbidity and 
mortality (Stewart et al. 2010; Ballen 2012). Bone marrow fibrosis resolves in subjects 
after successful transplant as early as one month (Przepiorka et al. 1998).
Before 2011, there was no approved medical therapy for MF and most symptomatic 
subjects were managed with various combinations of growth factors, immunomodulatory 
agents, cytotoxic chemotherapy, and steroids. For many subjects, these therapies were 
not effective at all or were associated with transient alleviation of certain symptoms of 
the disease. Ruxolitinib is a Janus kinase inhibitor, approved in the United States (US)
and European Union (EU) for the treatment of subjects with intermediate or high-risk 
myelofibrosis, including primary myelofibrosis (PMF), post-polycythemia vera 
myelofibrosis (post-PV MF) and post-essential thrombocythemia (post-ET MF) (JAKAFI®
Full Prescribing Information 2011). Treatment with ruxolitinib results in reduction in 
spleen volume and improvement in constitutional symptoms. However, ruxolitinib is not 
believed to be disease modifying and does not have convincing effects on bone marrow 
fibrosis (Verstovsek et al. 2012). Futhermore, 20% of subjects discontinue ruxolitinib 
due to intolerance or lack of efficacy within the first year of therapy (Palandri et al. 2020). 
Other Janus kinase inhibitors are in clinical development and fedratinib was approved by 
US Food and Drug Administration (USFDA) in 2019 (Blair 2019). There is a clear unmet 
medical need for new therapies for MF, in particular therapies that are potentially 
disease modifying and improve bone marrow function. 
Pentraxin-2 (PTX-2), also known as serum amyloid protein is an endogenous protein 
that circulates in the bloodstream. Recent discoveries about the biology of tissue repair 
and fibrosis have elucidated the important role that PTX-2 plays biologically in regulating 
processes that relate to scar prevention and healing. PTX-2 is an agonist that binds to 
Fc gamma receptors on monocytes and promotes their differentiation into regulatory 
macrophages (Mreg), which function to promote epithelial healing and resolution of 
inflammation and scarring. PTX-2 also prevents the differentiation of monocytes into M2 
pro-fibrotic macrophages and fibrocytes, preventing the formation of fibrosis. rhPTX-2
(recombinant human pentraxin-2, RO7490677) is a recombinant version of human 
pentraxin-2 (rhPTX-2). Similar to endogenous PTX-2, rhPTX-2 circulates as a 
non-covalent, homo-pentameric glycoprotein. Pre-clinical and clinical data support the 
investigation of rhPTX-2 in the treatment of fibrotic diseases (Murray et al. 2010; Pilling 
et al. 2007; Raghu et al. 2018; Verstovsek et al. 2016; Duffield et al. 2010).


Pentraxin—F. Hoffmann-La Roche Ltd
5/Statistical Analysis Plan BO42355
Study BO42355 was developed to examine the efficacy and safety of rhPTX-2 in 
intermediate-1, intermediate-2, and high risk subjects with PMF, post-PV MF, or 
post-ET MF subjects. More details regarding the study are provided in the Appendix 1,
Appendix 2, Appendix 3, and Appendix 4 (Protocol Synopses for the various study 
stages).
Of note, rhPTX-2 was developed by Promedior and acquired by Roche in 2020. 
Detailed Statistical Analysis Plans (SAPs) (Stage 1 Version 2.0: 11 April 2019; Stage 2 
Version 2.0: 5 March 2018) were prepared by Promedior and signed prior to the 
respective Stage 1 and Stage 2 primary database lock (DBL) and analyses. This
present SAP was prepared by Roche and signed before the final DBL of the Stage 1 and 
Stage 2 open label extensions (OLEs) of the study. The aim of this SAP is to highlight 
the analyses that will be performed for the final analysis and reported in a Clinical Study 
Report (CSR) for both main Stage 1 and Stage 2, and inclusive of their respective OLEs.
2.
STUDY DESIGN
Study BO42355 is a Phase II study, divided into 2 stages: Stage 1 and Stage 2, each
with a respective OLE.
The objective of Stage 1 was to evaluate the efficacy of two different dose schedules of 
rhPTX-2 in subjects with DIPSS defined intermediate-1, intermediate-2, or high risk PMF, 
post-PV MF, or post ET-MF. The two dosing schedules were tested as monotherapy 
and as an add-on therapy to subjects on a stable dose of ruxolitinib for at least three 
months.
The objective of the Stage 2 was to determine the effect size of three different doses of 
monotherapy of rhPTX-2 on reduction in bone marrow fibrosis by 1 grade at any time 
during the study in DIPSS intermediate-1, intermediate-2, and high risk subjects with 
PMF, post-PV MF, or post ET-MF who are anemic and/or thrombocytopenic and who 
are ineligible for, intolerant of, or have had an inadequate response to ruxolitinib.
Please see study design in
Figure 1 and more details in Appendix 1, Appendix 2, Appendix 3 and Appendix 4
(protocol synopses for the various study stages).


Pentraxin—F. Hoffmann-La Roche Ltd
6/Statistical Analysis Plan BO42355
Figure 1
Study Design
PMF=Primary myelofibrosis; Post-ET=Post-Essential Thrombocythemia; PV MF=Polycythemia 
vera Myelofibrosis; RUX= Ruxolitinib.
Note: For Stage 1 and Stage 2 Open-Label Extension, subjects received rhPTX-2 10mg/kg.
In this document, reference to Stage 1 and Stage 2 will correspond to the main stage; 
otherwise, it will specify (i.e. OLE).
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis for each stage and OLE are in Appendix 1, Appendix 2, 
Appendix 3 and Appendix 4.  For the Schedule of Assessments see Appendix 5 and
Appendix 6.
2.2
EFFICACY ENDPOINTS
2.2.1
Primary Efficacy Endpoint
Stage 1:
The primary endpoint for Stage 1 is the Overall Response Rate (ORR). Response rate 
is defined as the percent of subjects with a response as per International Working 
Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria
(assessed by the investigator), is defined as either:

achieving clinical improvement (CI), partial remission (PR), or complete 
remission (CR) at a post-baseline assessment of treatment response 
OR

having at least stable disease (SD) for three consecutive end-of-cycle response 
assessments (e.g. Day 1 of the subsequent cycle) in conjunction with 
improvement in the bone marrow fibrosis score (as determined by adjudicated 
Stage 2
Stage 1


Pentraxin—F. Hoffmann-La Roche Ltd
7/Statistical Analysis Plan BO42355
review) relative to baseline by at least one grade at any time point during the 
period of stable disease. 
Stage 2:
The primary endpoint for Stage 2 is the bone marrow response rate (BMRR). Response
rate is defined as the percent of subjects with a reduction in bone marrow fibrosis by at 
least one grade according to World Health Organization (WHO) criteria (see Appendix D 
of the protocol) from baseline to any time during the study as determined by a central 
adjudication panel of expert hematopathologists, blinded to subject, treatment, and time 
of biopsy. 
2.2.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are as follows for:
Stage 1: 

Bone Marrow MF grade shifts relative to baseline over time

Modified Myeloproliferative Neoplasm-Symptom Assessment Form Total Symptom 
Score (MPN-SAF TSS) changes from baseline over time
Stage 2:

Bone Marrow improvement:
–
Bone marrow (BM) response rate (MF Grade) at each visit (reduction of 1 grade 
versus baseline)
–
Duration of BM response defined for responding subjects as time from first 
decrease from baseline of one grade to time of return to baseline levels. If no 
return to baseline levels or worse than baseline then duration will be censored 
at the last BM assessment.

Hemoglobin improvement (number and percentage of subjects):
–
For red blood cell transfusion dependent subjects at baseline (at least 2 units 
every 4 weeks for 12 weeks prior to Cycle [C]1Day [D]1), improvement is 
defined as either:
1)
absence of any packed red blood cells (PRBC) transfusion during any 
consecutive 12 weeks interval with hemoglobin level of 80g/L
OR
2)
at least a 50% reduction in PRBC transfusions for 12 consecutive weeks with 
hemoglobin level of 80g/L
–
For red blood cell transfusion independent subjects improvement is defined 
as:
10 g/L increase in hemoglobin level for 12 consecutive weeks without 
transfusions

Platelet improvement (number and percentage of subjects)


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–
For transfusion dependent subjects at baseline, improvement is defined as
either:
1)
becoming transfusion independent for 12 consecutive weeks
OR
2)
reduction in transfusions need ≥50% from baseline for 12 consecutive weeks
–
For transfusion independent subjects with baseline platelet count below
100^9/L,, improvement is defined as:
50% increase in the number of platelet for 12 consecutive weeks or
normalization of platelet count (above lower limit normal)

Symptom improvement:
Percent of subjects with 50% reduction in MPN-SAF TSS from baseline 
over time(Tefferi 2013)

Percent of subjects with complete response, partial response, clinical improvement,
stable disease and progressive disease according to IWG-MRT criteria.
2.2.3
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints are as follows for:
Stage 1:

Bone marrow biopsy results for:
–
Myeloblasts (%), at each time point and change from baseline
–
Cellularity (%), at each time point and change from baseline
–
Collagen and reticulin grade shifts relative to baseline over time

Modified MPN-SAF TSS

Spleen size over time
Stage 2:

Proportion of subjects with bone-marrow MF Grade 0 or 1 at 12, 24, and 36 weeks

Proportion of subjects with 30% decrease, 30% increase, and stable (< 30% change)
cellularity at 12, 24, and 36 weeks compared to baseline

Change from baseline to Week 36 in hemoglobin for subjects with baseline 100 g/L

Number of units transfused in prior 12 weeks at baseline and Week 36 for
transfusion dependent subjects

Change from baseline to Week 36 in number of units transfused in prior 12 weeks for
transfusion dependent subjects

Proportion of subjects with increase from baseline to week 36 in hemoglobin (Hgb)
from 100 g/L to 100 g/L without transfusions

Proportion of subjects with increase in Hgb from 100 g/L at baseline to 100 g/L
without transfusions for 12 consecutive weeks


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
Number of units transfused in prior 12 weeks at baseline and Week 36 for platelet 
transfusion dependent subjects

Proportion of subjects with increase from baseline to Week 36 in platelet from 50 to 
100 without transfusions

Proportion of subjects with decrease from baseline to Week 36 in peripheral blood 
blasts from 1% to 1%

Percent of subjects with 10% reduction in spleen volume from baseline by computed 
tomography (CT) or magnetic resonance imaging (MRI) at each visit

Percent of subjects with 35% reduction in spleen size volume from baseline by CT or 
MRI at each visit

Change from baseline in spleen size volume by CT or MRI at each visit

Percent of subjects with 10% reduction in liver volume from baseline by CT or MRI at 
each visit

Percent of subjects with 35% reduction in liver size volume from baseline by CT or 
MRI at each visit

Change from baseline in liver size volume by CT or MRI at each visit

MPN-SAF total symptom score and change from baseline over time

Mean change from baseline in European Organization for Research and Treatment 
of Cancer Quality of Life-Core 30 questionnaire (EORTC QLQ-C30) at 36 weeks

Time to treatment failure (TTF) defined as either: 
–
Any discontinuation from the study
–
Progressive disease
–
Study drug permanently stopped
–
Death
2.3
PHARMACOKINETIC ENDPOINTS
In Stage 1, the individual plasma concentration-time data following intravenous infusion 
of rhPTX-2 will be analyzed to obtain the following pharmacokinetic (PK) parameters, 
where applicable:

Cmax (maximum observed plasma concentration)

tmax (time at which the maximum plasma concentration was observed)

AUC0-last (area under the plasma concentration-time curve from time 0 to time of last 
measurable plasma concentration)

AUC0-(area under the plasma concentration-time curve from 0-time extrapolated to 
infinity)

t1/2 (apparent terminal elimination half-life)

CL (clearance)

Vd (volume of distribution)


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The PK endpoint for Stage 2 subjects is the total PTX-2 level prior to drug administration 
at the pre-defined timepoints (see Appendix 5 and Appendix 6 Schedule of Assessment).  
Samples for rhPTX-2 PK analysis were not collected in Stage 2.
2.4
SAFETY OUTCOME MEASURES
Safety parameters to be measured include exposure, adverse events (AE) (including 
serious adverse events [SAEs], adverse events of special interest [AESI], AE leading to 
drug discontinuation, and deaths), clinical laboratory results (hematology, chemistry, and 
anti-drug antibodies), vital signs, electrocardiogram (ECG), and concomitant medication 
use.
2.5
DETERMINATION OF SAMPLE SIZE
Details regarding the sample size for Stage 1 and Stage 2 are described in the
Appendix 1 and Appendix 3 (Protocol Synopsis). 
For the OLE, no target sample size was delineated. The sample size was determined by 
the number of subjects who rollover from the main study. The study was intended to 
provide access to rhPTX-2 for any subjects in the main study for whom the investigator 
felt clinical benefit could be realized or extended.
2.6
ANALYSIS TIMING
The full study analysis will be conducted at the completion of the study as defined in the 
protocol (completion of each stage and OLE).  This being an open-label non-inferential 
study, occasional exploratory analyses may be conducted throughout the study to inform 
the clinical development plan.
3.
STUDY CONDUCT
3.1
RANDOMIZATION
Subjects in Stage 1 were not randomized.
Subjects in Stage 2 were randomized to treatment group with a 1:1:1 randomization ratio. 
A central randomization system was used. The randomization was stratified according 
to the subjects’ baseline hematologic status: baseline anemia alone (subjects with 
Hgb100 g/L and having received2 units PRBC in the 12 weeks prior to study entry)
or baseline thrombocytopenia (platelet count 50 x 10
9/L) or baseline anemia 
associated with baseline thrombocytopenia. The randomization system ensured that at 
least 50% of the subjects in the final study population have baseline thrombocytopenia
from the second stratum (platelet count 50 x 109/L).
3.2
INDEPENDENT REVIEW FACILITY
For Stage 1 and Stage 2, all bone marrow assessments were performed by a committee 
of expert hematopathologists, who were blinded to subject, dose, and time of biopsy. 


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The rules for assessment and adjudication are defined in the Central Bone Marrow 
Review Committee charter. 
3.3
DATA MONITORING COMMITTEE
Stage 1 had no Data Monitoring Committee (DMC) in place.
In Stage 2, a DMC was established for purposes of independent assessment of safety 
during study conduct.
4.
STATISTICAL METHODS
Except where specified, all continuous variables will be summarized by treatment group 
with descriptive statistics (the number of non-missing values, mean, standard deviation, 
median, minimum, and maximum). All categorical variables will be summarized with 
frequency counts and percentages, by treatment group.
4.1
ANALYSIS POPULATIONS
4.1.1
All treated Population
Stage 1:
All subjects who have received at least one dose of rhPTX--2. The primary assessment 
of all efficacy analyses will be performed on this population.
Stage 2:
The all treated population will consist of subjects:

randomized and, who have received at least one administration of the drug
In the event of subjects, having received treatments that differed from those assigned 
according to the randomization schedule, then the efficacy analyses will be conducted 
according to the randomized treatment (As randomized analysis).
This population will be the primary population for the efficacy analyses.
4.1.2
Pharmacokinetic Population
Stage 1:
The PK population includes all subjects who have received at least one dose of rhPTX-2
and have at least one measurable post-dose total PTX-2 concentration result.
The PK evaluable population includes all subjects who completed at least 1 cycle and 
had sufficient total PTX-2 concentration data to accurately estimate at least one PK 
parameter in at least 1 cycle.
Stage 2:
The PK population includes all subjects who have received at least one dose of rhPTX-2
and have at least one post-dose total PTX-2 concentration result.


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4.1.3
Safety Population
For both stages, the safety population consists of subjects who have received at least 
one dose of study drug. 
For Stage 2, in the event of subjects having received treatments that differed from those 
assigned according to the randomization schedule, then the safety analyses will be 
conducted according to the treatment actually received (As Treated Analysis).
4.1.4
Open Label Extension Population
For both stages, the OLE population consists of all subjects who received at least one 
dose of rhPTX-2 during the OLE phase. 
4.1.5
Open Label Extension Subjects with Bone Marrow Biopsy
Population
For both stages, the OLE patient populations with BM biopsy consist of all subjects who 
received at least one dose of rhPTX-2 during the OLE phase and have at least one BM 
biopsy result available during the OLE.
4.2
ANALYSIS OF STUDY CONDUCT
All analyses will be performed by study stage separately. The number of subjects who 
are enrolled and/or randomized (Stage 2 only) will be tabulated by treatment group, 
center and country.  Major eligibility exceptions, major protocol deviations and reasons 
for study discontinuation will be summarized by treatment group for all subjects.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
Descriptive summaries will be provided for all baseline characteristics. The summaries 
will be provided for both stages separately. Demographic and baseline variables that 
will be summarized by treatment group include at least:

Stratification factors (Stage 2 only):
–
Baseline anemia (Hgb < 100 g/L and having received > 2 units PRBC in 
12 weeks prior to study entry) alone 
–
Baseline thrombocytopenia (platelet count 50 x 109 /L) alone
–
Baseline anemia associated with baseline thrombocytopenia

Demographics for both Stages:
–
Gender
–
Age at consent (continuous and categorical)
–
Race
–
Ethnicity (if available)
–
Weight at baseline


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Should country policy prohibit the collection of race and/or age information, subjects will 
appear in the missing category of summary tables.

MF history for Stage 1:
–
Number of years since diagnosis
–
Bone marrow fibrosis grade at baseline
–
Spleen size below left costal margin at baseline
–
Type of MF (PMF, post-PV MF or post-ET MF)
–
Risk group with PMF (low, intermediate-1, intermediate-2, or high)
–
Red blood cell transfusion history 3 months prior to first dose
–
Number of subjects transfused (PRBC, Platelets, Fresh frozen plasma)
–
Number of subjects with baseline hemoglobin 100 g/L at baseline
–
Number of subjects with platelets < 50 g/L and <25 g/L at baseline
–
Number of units of platelet and RBC transfusions
–
Number of subjects previously treated with ruxolitinib

MF history for Stage 2:
–
Number of years since diagnosis
–
Bone marrow fibrosis grade at baseline
–
Spleen size measured by CT, positron emission tomography-CT (PET-CT) or 
MRI at baseline
–
Type of MF (PMF, post-PV MF or post-ET MF)
–
Risk group with MF (DIPSS low, intermediate-1, intermediate-2, or high)
–
Number of subjects with at least one transfusion in 12 weeks prior to baseline
(RBC and platelet)
–
Number of subjects with baseline hemoglobin 100 g/L at baseline
–
Number of subjects with platelets < 50 g/L and <25 g/L at baseline
–
Number of units of platelet and RBC transfusions
–
Number of subjects previously treated with ruxolitinib
In addition, for both stages, ruxolitnib history will be presented.
4.4
EFFICACY ANALYSIS
All analyses will be performed separately for each stage.
4.4.1
Primary Efficacy Endpoint
Stage 1:
The ORR will be compared against a fixed level of 10% using one-proportion Z-test. 


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The hypothesis test will be performed separately in each of the 4 treatment groups and 
overall, each at the 5% significance level (one-sided; statistical significance will be 
concluded if the lower bound of the 2-sided 90% CI is above 10%).
Subjects with no post-baseline IWG response assessments will be considered 
non-responders.  
Stage 2:
The BMRR will be described as the percent of subjects with a reduction in bone marrow 
fibrosis score by at least one grade from baseline to any time of the study.
The BMRR will be presented within each treatment group with the corresponding 95% CI.
The BMRR will be analyzed using a logistic regression with bone marrow response at 
any time during the study (yes/no) as response variable and treatment group as 
explanatory variable. The analysis will be adjusted on randomized stratum. Pairwise 
comparisons between the 3 treatment groups will be performed.
Two pairwise comparisons (3 mg/kg versus 0.3 mg/day and 10 mg/kg versus 0.3 mg/day) 
will be computed with the aim to demonstrate superiority and therefore, will use an 
adjusted two-sided level of significance of 0.025.  The third comparison (10 mg/kg 
versus 3 mg/kg) is not expected to have enough power to demonstrate any difference 
with the planned sample size.  This comparison is considered exploratory and will be 
conducted using an unadjusted two-sided 0.05 level of significance. 
The protocol proposed a threshold of 10% as the lower limit for clinically relevant 
response. For the 3 mg/kg and 10 mg/kg groups, the lower limit of the 97.5% two-sided 
confidence interval will be compared to this threshold of 10%. If the lower limit of the 
confidence interval is above 10%, the corresponding dose will be claimed to have 
demonstrated clinically relevant efficacy.
For subjects with no readable post-baseline BM biopsy results available, the 
conservative rule to consider them as non-responders will be used.
4.4.2
Secondary Efficacy Endpoints
Stage 1:
For Stage 1, no formal hypothesis testing will be performed for the secondary efficacy 
endpoints. All summaries will be presented by treatment group and overall.
The bone marrow biopsy results will be analyzed as:

Myelofibrosis grade shifts relative to baseline at Weeks 12 and 24.

Myeloblasts and cellularity will be presented at baseline, Weeks 12 and 24 as well as 
change from baseline 

Collagen grade shifts relative to baseline at Weeks 12 and 24.


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The modified MPN-SAF TSS will be presented descriptively at baseline and at the 
beginning of each cycle (Cycle 2 onward). In addition, the number of subjects with25% 
and50% reduction relative to baseline at the beginning of each cycle (Cycle 2 onward) 
will be presented.
Stage 2:
Duration of effect of the three doses on reduction in bone marrow fibrosis:

To assess the duration of effect of the three doses on bone marrow improvement a 
Kaplan-Meier plot will be provided. Duration of BM improvement will be defined for 
responding subjects as time from first decrease from baseline of one grade to time of 
return to baseline levels. If no return to baseline levels then duration will be 
censored at the last BM assessment

Effect and duration of effect of the three doses on disease related anemia, 
thrombocytopenia, and constitutional symptoms:  For patients with improvement, the 
duration of improvement is defined as the number of weeks of improvement from the 
first12 weeks of improvement period.
IWG-MRT response will be summarized by treatment group at each visit by percent of 
subjects with complete response, partial response, clinical improvement, stable disease 
and progressive disease according to IWG-MRT criteria.
4.4.3
Exploratory Efficacy Endpoints
The exploratory endpoints will be summarized using tables, listings and graphs as 
appropriate.
4.4.4
Sensitivity Analyses
For Stage 2, a non-stratified analysis of BMRR will be computing as a sensitivity analysis.
4.4.5
Subgroup Analyses
Stage 1:

Primary endpoint results will be presented by risks groups (intermediate-1, 
intermediate-2, or high risk subjects).
Stage 2:

Primary endpoint results will be presented:
–
by risks groups (intermediate-1, intermediate-2, or high risk subjects)
–
for each strata separately (baseline anemia alone, baseline thrombocytopenia 
alone, baseline anemia and thrombocytopenia)
–
by transfusion status at baseline with transfusion dependency defined as: 2 
units PRBC every 4 weeks for 12 weeks prior to or after C1D1 
–
by PTX-2 level at baseline classify by High/Low category (median as the cutoff)


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The platelet improvement analyses will be presented by platelet levels (subjects with 
platelet <50 x10^9/L at baseline and subjects with platelet <25 x10^9/L at baseline)
4.5
PHARMACOKINETIC ANALYSES
The Stage 1 PK analysis will be reported in a dedicated report.
For all Stage 2 subjects, pre-dose plasma concentrations of total PTX-2 will be 
presented descriptively at each time point by treatment group, including arithmetic and 
geometric means, median, range, standard deviations, and coefficients of variation. 
4.6
BIOMARKER ANALYSES
All biomarker data will be presented in a dedicated report.
4.7
SAFETY ANALYSES
The safety analysis population will be used for all safety analyses. Analyses will be 
performed for both stages separately, as well as for the OLE phases.
4.7.1
Exposure to Study Medication
Information on study drug administration will be summarized by duration, starting dose, 
and cumulative dose. In addition, treatment exposure will be summarized, including the 
percentage of the planned dose given at each cycle.
Withdrawals of subjects from study treatment will be reported as listings and summary 
tables.
4.7.2
Adverse Events
Coding of all adverse events will be done using the latest version of the Medical 
Dictionary for Regulatory Activities (MedDRA). As part of the safety data transfer to 
Roche, the adverse events will be re-coded in legacy coding domain after database lock. 
Consequently, no queries are planned to be raised for any discrepancies in MedDRA 
Preferred Terms (PTs). This might result in some event terms that are vague (for 
example - 'heart problems') to be coded to less accurate, more high level concepts (eg 
Cardiac disorder for the example given). All AEs and routine laboratory parameters will 
be assessed according to the National Cancer Institute Common Terminology Criteria 
for Adverse Event (NCI CTCAE) version 4.0 grading system.
For AEs, the most extreme intensity will be used for reporting. All AEs occurring during 
or after the first treatment will be described by summary tables divided by body system, 
NCI CTCAE grade, and relation to study treatment. In tables showing the overall 
incidence of AEs, subjects who experienced the same event on more than one occasion 
are counted only once in the calculation of the event frequency and the AE with the most 
extreme severity will be included.


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For selected events of particular interest (Infusion Related Reaction[IRR]) more detailed 
analyses will be conducted. The analyses will depend on the specific question of 
interest for that particular AE. IRR will be presented by anti-drug antibody status. In 
addition, the IRR event frequency and severity will be included in the analysis. 
Treatment discontinuations due to IRR will be listed.
AE leading to treatment discontinuations and early study withdrawals will be summarized
by treatment group and by reason. In addition, all serious AE will be summarized.
Deaths reported during the study treatment period and those reported during follow-up 
(i.e. follow-up is 4 week after the last visit cycle) after treatment completion or 
discontinuation will be summarized by treatment group.
4.7.3
Laboratory Data
Laboratory values will be listed for subjects individually, with flagging of values outside 
the normal range. Shift tables will be used to present the number and percentage of 
subjects with changes in grade based on the NCI CTCAE version 4.0 grading system.
The frequency and percentage of positive, negative and untested serological laboratory 
parameters will be reported by cycle and treatment group.
4.7.4
Vital Signs
Vital signs (absolute and change from baseline) will be summarized according to 
treatment group over time without any replacement for missing data. 
Electrocardiogram and physical exam abnormalities will be listed.
4.8
OLE STUDY ANALYSES
The OLE analyses will be performed separately for the OLE Stage 1 and Stage 2. 
The listings will include the treatment regimen the patient received during the main stage 
and during the OLE. 
For Stage 1, OLE begins with the first infusion of Cycle 7.  As with the main study, cycles 
are 28 days in length. The “OLE Baseline” consists of assessments at the end of 
Cycle 6 / beginning of Cycle 7 (pre-dose).
For Stage 2, OLE begins with the first infusion of Cycle 10. As with the main study, 
cycles are 28 days in length. The “OLE Baseline” consists of assessments at the end of 
Cycle 9 / beginning of Cycle 10 (pre-dose).
The synopses for the OLE are in Appendix 2 and Appendix 4. 
The primary and secondary endpoints for both stages, will be also produced on the OLE 
population when applicable. The OLE tables will be classified as per the original dose 


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received on the main stage and overall. For subjects who change doses, improvement 
will be analyzed.
4.9
MISSING DATA
All available efficacy and safety data will be included in data listings and tabulations.  No 
imputation of values for missing data will be performed. Subjects with missing post 
baseline response data, for any reason, will be counted as non responders.
4.10
INTERIM ANALYSES
No efficacy interim analyses are planned. This SAP aims to define the analyses to be 
produced for the final analysis.


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5.
REFERENCES
Blair HA. Fedratinib: first approval. Drugs. 2019;79(15):1719-1725.
Ballen K. How to manage the transplant question in myelofibrosis. Blood Cancer J 
2012;2(3):e59.
Duffield JS, Lupher Jr ML. PRM-151 (recombinant human serum amyloid P/pentraxin 2) 
for the treatment of fibrosis. Drug news & perspectives 2010;23(5):305-15.
JAKAFI. JAKAFI ® (ruxolitinib) tablets, for oral use; US Full Prescribing Information. 
2011.
Murray LA, Rosada R, Moreira AP, et al. Serum Amyloid P Therapeutically Attenuates 
Murine Bleomycin-Induced Pulmonary Fibrosis via Its Effects on Macrophages. 
PLoS One 2010;5(3): e9683. https://doi.org/10.1371/journal.pone.0009683
Palandri F, Breccia M, Bonifacio M, et al. Life after ruxolitinib: Reasons for 
discontinuation, impact of disease phase, and outcomes in 218 patients with 
myelofibrosis. Cancer 2020;126(6):1243-52.
Pilling D, Roife D, Wang M, et al. Reduction of bleomycin-induced pulmonary fibrosis by 
serum amyloid P. J Immunol. 2007;179(6):4035-44. doi: 
10.4049/jimmunol.179.6.4035.
Przepiorka D, Giralt S, Khouri I, et al. Allogeneic marrow transplantation for 
myeloproliferative disorders other than chronic myelogenous leukemia: review of 
forty cases. Am J Hematol 1998;57(1):24-8..
Raghu G, Van Den Blink B, Hamblin MJ, et al. Effect of recombinant human pentraxin 2 
vs placebo on change in forced vital capacity in patients with idiopathic pulmonary 
fibrosis: a randomized clinical trial. JAMA 2018;319(22):2299-307.
Stewart W A, Pearce R, Kirkland KER Pearce, et al. The role of allogeneic SCT in 
primary myelofibrosis: a British Society for Blood and Marrow Transplantation 
study. Bone Marrow Transplant 2010;45(11):1587-93.
Tefferi A, Cervantes F, Mesa R, et al. Revised response criteria for myelofibrosis: 
international Working Group-Myeloproliferative Neoplasms Research and 
Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report. Blood. 
2013;122(8):1395-8.
Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of 
ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807.
Verstovsek S, Vannucchi AM, Griesshammer M, et al. Ruxolitinib versus best available 
therapy in patients with polycythemia vera: 80-week follow-up from the 
RESPONSE trial. Haematologica. 2016;101(7):821-9.


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Appendix 1
Protocol Synopsis – Stage 1


PRM-151 
 
Study Protocol PRM-151G-101 
                                                                 FINAL Version 6.1 
 
Page 95 
APPENDIX K:   
SYNOPSIS: STAGE I   
Sponsor: 
Promedior, Inc 
Name of Finished Product: 
Recombinant human Pentraxin-2; PRM-151 
Study Title: 
A Phase 2, Open-Label, Prospective Study Of PRM-151 In Subjects With Primary 
Myelofibrosis (PMF), Post-Polycythemia Vera MF (post-PV MF), Or Post-Essential 
Thrombocythemia MF (post-ET MF) 
Study Number: 
PRM-151G-101 
Study Phase:  Phase 2 
Investigational Product; Dose; and Mode of Administration:  
PRM-151 10 mg/kg intravenous 
Comparator; Dose; and Mode of Administration: 
Not applicable 
Primary Objective(s):  
• To evaluate the efficacy of two different dose schedules of PRM-151 in intermediate-1, 
intermediate-2, or high risk subjects with PMF, post-PV MF, or post ET-MF who are 
not receiving therapy for MF, and in subjects with PMF, post-PV MF, or post ET-MF 
on a stable dose of ruxolitinib for at least three months. 
Secondary Objective(s): 
• To evaluate the safety and tolerability of two different dose schedules of PRM-151 in 
intermediate-1, intermediate-2, or high risk subjects with PMF, post-PV MF, or post 
ET-MF who are not receiving therapy other than transfusions, and the safety and 
tolerability of two different dose schedules of PRM-151 in subjects with PMF, post-PV 
MF, or post ET-MF on a stable dose of ruxolitinib 
• To assess the effect of PRM-151 on bone marrow fibrosis  
• To measure the duration of response 
• PK of PRM-151 in subjects receiving single agent PRM-151 and in subjects receiving 
ruxolitinib. 
Exploratory Objectives 
• To evaluate the effect of PRM-151 on plasma cytokine levels comparing baseline on 
Cycle 1, Day 1 to Day 1 of Cycles 2, 3, 4 and Day 29 of Cycle 6 
• To evaluate the effect of PRM-151 on PBMC mRNA and miRNA expression levels 
comparing baseline on Cycle 1, Day 1 to Day 1 of Cycles 2, 3, 4 and Day 29 of Cycle 6 
• To evaluate the correlation of baseline PTX-2 levels with outcomes. 
Study Endpoints:  
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PRM-151 
 
Study Protocol PRM-151G-101 
                                                                 FINAL Version 6.1 
 
Page 96 
Primary:   
• The overall response rate (ORR), defined as a clinical improvement (CI), partial 
remission (PR), and complete remission (CR) according to the International Working 
Group (IWG) Criteria (Appendix B)   
• Stable disease with improvement in bone marrow fibrosis score by at least one grade 
according to the European Consensus on Grading of Bone Marrow Fibrosis 
(Appendix D) will also be considered a response (bone marrow response). 
Secondary:   
• Incidence of adverse events (AEs), serious adverse events (SAEs), and changes in 
laboratory test results   
• Change in bone marrow fibrosis 
• Change in the modified Myeloproliferative Neoplasms Symptom Assessment Form 
(MPN-SAF) Score (Appendix G)   
• Duration of response 
• PK parameters including Cmax (maximum drug concentration), tmax (time to maximum 
concentration, AUC, clearance, and volume of distribution.  
Exploratory: 
• Changes in levels of circulating plasma cytokine levels including but not limited to 
CRP, IL-1ra, MIP-1β, TNFα, IL-6 and VEGF comparing baseline on Cycle 1, Day 1 to 
Day 1 of Cycles 2, 3, 4 and Day 29 of Cycle 6 
• Changes in levels of PBMC mRNA and miRNA expression levels comparing baseline 
on Cycle 1, Day 1 to Day 1 of Cycles 2, 3, 4 and Day 29 of Cycle 6. 
• Correlation of baseline PTX-2 levels with outcomes. 
Study Design: 
This is an open-label, Simon two stage, Phase 2 study to determine the efficacy and safety of 
two different dose schedules of PRM-151 in subjects with PMF and post ET/PV MF. There are 
two treatment cohorts, each assigned to one of two dose schedules of PRM-151. Subjects will 
be assigned to a weekly or every four week dosing schedule by the investigator based on their 
ability to visit the study site on a weekly basis.  This is an adaptive design as defined in FDA 
Draft Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics, February 
2010.  Modifications to dose levels, schedule, or regimen may be made in Stage 2 based on data 
from Stage 1. 
Stage 1:  
Cohort 1:  Approximately 12 subjects with intermediate-1, intermediate-2, or high risk MF who 
have received no treatment for MF in at least two weeks will be enrolled and assigned to 
treatment with single agent PRM-151 at a dose of 10 mg/kg IV on Days 1, 3, 5, 8, 15, and 22 of 
Cycle 1 and Days 1, 8, 15 and 22 of each subsequent 28 day cycle for six cycles, OR single 
agent PRM-151 at a dose of 10 mg/kg administered IV on Days 1, 3, and 5 of Cycle 1 and Day 
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1 of each subsequent 28 day cycle for six cycles  Subjects responding to therapy may continue 
receiving it as long as there is a benefit.   
Cohort 2:  Approximately 12 subjects with intermediate-1, intermediate-2, or high risk MF on a 
stable dose of ruxolitinib for at least 12 weeks, with no improvement in spleen during the last 
four weeks will be enrolled.  Subjects will be  assigned to receive PRM-151 in combination 
with ruxolitinib either at a dose of 10 mg/kg administered IV on Days 1, 3, 5, 8, 15, and 22 of 
Cycle 1 and Days 1, 8, 15 and 22 of each subsequent 28 day cycle for six cycles, OR in 
combination with ruxolitinib at a dose of 10 mg/kg administered IV on Days 1, 3, and 5 of 
Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles.  Subjects responding to 
therapy may continue receiving it as long as there is a benefit.   
Stage 2:  
If at least one response is seen in any arm of either cohort in Stage 1, an additional 20 subjects 
may be enrolled and treated on that dosing schedule.  All non-responding arms will be closed.  
Subjects responding to therapy may continue receiving it as long as there is a benefit.   
Enrolled subjects will be considered evaluable for response if they are on study drug for at least 
four weeks.   
Study Duration: 
Each subject will participate in the study for approximately 32 weeks.  Participation will 
include a screening evaluation within four weeks before the first PRM-151 administration, six 
study cycles of four weeks each, and an end of study visit four weeks after the end of the last 
cycle.  Subjects may continue with PRM-151 dosing in the absence of disease progression or 
toxicity warranting discontinuation of therapy, as long as there is evidence of clinical benefit, as 
judged by the Investigator. 
Subjects who have no benefit in the parent study may switch to a schedule in which responses 
occur after completing 6 cycles of the originally assigned treatment.  
It is estimated that the study will be completed in approximately 18 months. 
Study Inclusion and Exclusion Criteria: 
Inclusion Criteria: 
1. Subjects must be ≥18 years of age at the time of signing the Informed Consent Form 
(ICF); 
2. Subjects must voluntarily sign an ICF; 
3. Subjects must have a pathologically confirmed diagnosis of PMF as per the WHO 
diagnostic criteria (see Appendix C) or post ET/PV MF (note that all diagnoses must 
include the presence of at least Grade 2 marrow fibrosis according to the European 
Consensus on Grading of Bone Marrow Fibrosis (Appendix D) with intermediate -1, 
intermediate -2, or high risk disease according to the IWG-MRT Dynamic International 
Prognostic Scoring System (see Appendix E);   
4. A biopsy must be performed within four weeks prior to Cycle 1 Day 1 treatment to 
establish the baseline fibrosis score; 
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5. Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance 
Status of 0-2.  (Appendix F); 
6. Life expectancy of at least six months; 
7. At least two weeks must have elapsed between the last dose of any MF-directed drug 
treatments for myelofibrosis (including investigational therapies) and study enrollment, 
except for ruxolitinib for Cohort 2 (see Inclusion Criteria);   
8. Recovery to ≤ Grade 1 or baseline of any toxicities due to prior systemic treatments, 
excluding alopecia; 
9. Women of child bearing potential (WCBP), defined as a sexually mature woman not 
surgically sterilized or not post-menopausal for at least 24 consecutive months if ≤55 
years or 12 months if >55 years, must have a negative serum pregnancy test within four 
weeks prior to the first dose of study drug and must agree to use adequate methods of 
birth control throughout the study.  Adequate methods of contraception include use of 
oral contraceptives or Depo-Provera, with an additional barrier method (diaphragm with 
spermicidal gel or condoms with spermicide), double-barrier methods (diaphragm with 
spermicidal gel and condoms with spermicide), partner vasectomy, and total abstinence. 
10. Ability to adhere to the study visit schedule and all protocol requirements; 
11. For Cohort 2 (PRM-151 added to ruxolitinib) Subjects only:   
12. Must have been on a stable dose of ruxolitinib treatment for at least 12 weeks with no 
further improvement in splenomegaly for at least four weeks; 
13. Must have adequate organ function as demonstrated by the following:  
• 
ALT (SGPT) and/or AST (SGOT) ≤ 3x upper limit of normal (ULN), or ≤ 4 x 
ULN (if upon judgment of the treating physician, it is believed to be due to 
extramedullary hematopoiesis [EMH] related to MF);  
• 
Direct bilirubin ≤ 1.5 x ULN; or ≤ 2x ULN (if upon judgment of the treating 
physician, it is believed to be due to EMH related to MF);  
• 
Serum creatinine ≤ 2.5 mg/dL x ULN. 
Exclusion Criteria: 
1. Other invasive malignancies within the last 3 years, except non-melanoma skin cancer 
and localized cured prostate and cervical cancer; 
2. History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia 
requiring medication or mechanical control within the last 6 months; 
3. Presence of active serious infection; 
4. Any serious, unstable medical or psychiatric condition that would prevent, (as judged by 
the Investigator) the subject from signing the informed consent form or any condition, 
including the presence of laboratory abnormalities, which places the subject at 
unacceptable risk if he/she were to participate in the study or confounds the ability to 
interpret data from the study; 
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5. Known history of human immunodeficiency virus (HIV), or known active hepatitis A, 
B, or C infection; 
6. Organ transplant recipients other than bone marrow transplant; 
7. Women who are pregnant or lactating. 
Efficacy Assessments: 
Efficacy will be assessed by evaluation of the overall response rate (ORR) categorized 
according to the International Working Group (IWG) Criteria (Appendix B) modified to include 
stable disease with improvement in bone marrow fibrosis by at least one grade.   
Safety Assessments: 
Safety will be evaluated from reported adverse events, scheduled physical examinations, vital 
signs, and clinical laboratory test results.   
This Phase 2 clinical trial will have an independent Data Monitoring Committee (DMC) to 
conduct interim reviews of safety data, and provide an independent evaluation on a 
predetermined and ad-hoc basis of accumulating safety data. All adverse events reported to 
Promedior will be considered by Promedior and the DMC regardless of the reported causality 
by the study site.  In assessing adverse events, Promedior and the DMC will consider only 
treatment emergent adverse events, defined as adverse events that occur after at least one 
exposure to study drug. The DMC will review all safety data at the following pre-determined 
times:  
• when the first 12 subjects reach Cycle 4, Day 1 
• when the first 24 subjects have completed the study 
The DMC will review the following events immediately on an ad-hoc basis and will make a 
recommendation about whether the study may proceed: 
• any death 
• any event of anaphylaxis 
• any SAEs  
• any treatment emergent Grade 3 non-hematologic toxicity 
• any treatment emergent grade 4 hematological adverse event or a treatment emergent 
grade 3 hematologic adverse event that represents a change of 2 grades from grade 1, or 
a doubling of transfusion frequency 
 
 
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Statistical Methods:  
The objective is to demonstrate superiority within each cohort and dose schedule, comparing 
observed ORR in each arm to a fixed uninteresting level ORR of 0.1. Let π denote population 
expected value of the primary parameter ORR. The objective of the trial is to reject the null-
hypothesis  
 
 
 
in favor of the alternative hypothesis 
 
: π > 0.4 
 
The design will be two-staged within each arm based on Simon (Simon 1989) as shown in the 
figure below:  
 
 
 
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The design maintains the type I error probability at 3.4% which is less than 5%. Furthermore, 
for π>0.4, there is a high probability of at least 94% to demonstrate superiority. The 
probability under H_0 to stop after stage 1 is 53%, with implicit consequence that the expected 
number of subjects is 15, compared to a maximum number of subjects of 26. 
 
Date of Original Protocol:  Version 1.0 17 Jan 2013 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 2 OLE Synopsis – Stage 1


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APPENDIX L: SYNOPSIS: STAGE 1 OPEN LABEL EXTENSION STUDY 
 
Sponsor: 
Promedior, Inc. 
Name of Finished Product: 
Recombinant human Pentraxin -2; PRM-151 
Study Title: 
A Phase 2, Open-Label, Prospective Study Of PRM-151 In Subjects With Primary 
Myelofibrosis (PMF), Post-Polycythemia Vera MF (post-PV MF), Or Post-Essential 
Thrombocythemia MF (post-ET MF) 
Study Number: 
PRM-151G-101 
Study Phase: Phase 2 
Investigational Product; Dose; and Mode of Administration: 
PRM-151 10 mg/kg intravenous 
Comparator; Dose: and Mode of Administration: 
Not applicable 
Primary Objective(s): 
 
To provide subjects achieving clinical benefit as determined by the investigator in the parent 
study an opportunity to remain on treatment and to allow subjects not achieving a benefit to 
switch to a potentially more effective schedule of PRM-151 
 
Secondary Objective(s): 
 
To collect long term safety data of subjects receiving PRM-151 
 
To collect additional efficacy data on duration of response beyond 6 months of treatment 
 
To collect efficacy data on the change of PRM-151 schedule in subjects not achieving a 
response 
Study Design: 
This is an open-label, extension of study PRM-151G-101 to provide access to subjects in the 
parent study who have achieved benefit in the parent study. Additionally, subjects who have 
no benefit in the parent study may switch to a schedule of PRM-151 in which responses have 
occurred after completing 6 cycles of the originally assigned treatment. Subjects may switch 
schedules of PRM-151 and/or drop ruxolitinib in the extension but subjects are not allowed to 
add ruxolitinib if they were in Cohort 1. After study completion and data analysis, all subjects 
remaining on PRM-151 in this extension will switch to the dose selected for future clinical 
development. 
Study Duration: 
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Subjects may continue with PRM-151 dosing in the absence of disease progression or toxicity 
warranting discontinuation of therapy, as long as there is evidence of clinical benefit or until 
drug is made available in another way.  Cycle numbers will continue from the parent protocol, 
with Cycle 6 Day 29 of the parent protocol becoming Cycle 7 Day 1 of the extension study. 
Response Assessments: 
In addition to the schedule of assessments listed below, response assessments will be done on 
Day 1 of every third cycle (every 3 months) beginning on Day 1 of Cycle 10 and may include 
the following, as described below: 
 
Bone Marrow Biopsies: 
A bone marrow biopsy will be performed only to determine or confirm a change in response 
category. This will be done at the following time points depending on the subjects’ response 
category at the time of the most recent bone marrow biopsy: 
 
• CR: Bone marrow biopsy will be done only if there is a change in status indicating 
potential disease progression. 
 
• PR: For subjects with bone marrow histological remission, bone marrow biopsy 
(BMB) will be done only if there is a change in status indicating disease progression. 
For subjects without bone marrow histological remission BMB will be done every 6 
months until CR is documented or until indication of potential disease progression. 
 
• CI: BMB will be done if the clinical status changes from CI to PR or PD 
 
• Stable disease with improvement in bone marrow fibrosis: BMB will be done if the 
clinical status changes from SD to CI, PR, or PD. 
 
MPN SAF Score: 
The subjects MPN symptoms will be assessed using the MPN SAF every 3 months. 
 
Physical Exam and Spleen Measurement: 
An abbreviated physical exam and spleen measurement by palpation will be done every 3 
months. 
 
STAGE 1 OPEN LABEL EXTENSION STUDY 
 
 
 
Weekly Dosing  
 
Q4 Weekly Dosing 
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1. 
Pre-treatment adverse events, including serious adverse events will be collected from the time of informed consent and after the 
medical history has been obtained 
 
2. 
Vital signs (including temperature, blood pressure, pulse rate, and respiratory rate) will be performed before infusions. 
3. 
CBC includes red blood cell count (RBC), hemoglobin, hematocrit, white blood cell count with differential, absolute neutrophil count 
(ANC), and platelets. Results should be reviewed prior to PRM-151 infusion. CBC can be drawn up to 7 days prior to PRM-151 
infusion. 
4. 
Blood chemistry lab parameters include lactic dehydrogenase (LDH), serum alanine aminotransferase (ALT), serum aspartamine 
aminotransferase (AST), direct and indirect bilirubin, alkaline phosphatase, creatinine phosphokinase (CPK), uric acid, calcium, 
phosphorus, sodium, potassium, chloride, bicarbonate, BUN, creatinine, and glucose. 
5. 
Blood sample for anti-pentraxin 2 antibodies should be drawn pre-dose every 12 weeks. If the subject experiences an infusion related 
reaction, a blood sample for anti-pentraxin 2 antibodies should be drawn prior to any additional PRM-151 infusions. 
6. 
The following components of response assessment will begin on Cycle 10, Day 1 and continue on Day 1 of every third cycle 
thereafter  Abbreviated physical exam and spleen measurements, MPN-SAF, and Investigator Response Assessment based on IWG-
SCHEDULE OF 
ASSESSMENTS 
 
 
 
Extension Cycles  
28 Day Cycle Length 
 Extension Cycles  
28 Day Cycle Length 
Day (+/- 3 days) 
Day (+/- 3 days) 
1 
8 
15 
22 
Day 1 
Informed Consent 
x 
 
 
 
x 
Prior/Con Meds 
x 
x 
x 
x 
x 
AE/SAE assessment (1) 
x 
x 
x 
x 
x 
Vital Signs (2) 
x 
x 
x 
x 
x 
Weight (kg) 
x 
 
 
 
x 
ECOG Performance Score 
x 
 
 
 
x 
Urine Pregnancy Test 
x 
 
 
 
x 
Complete Blood Count (3) 
x 
 
 
 
x 
Chemistry, BUN/creatinine (4) 
x 
 
 
 
x 
Transfusion History over past 3 
months or since last visit 
x 
 
 
 
x 
Special list of excluded 
medications 
x 
 
 
 
x 
Anti-pentraxin 2 antibodies, pre 
dose (5) 
x 
 
 
 
x 
PRM-151 Administration 
x 
x 
x 
x 
x 
Response Assessments (6) 
x 
 
 
 
x 
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MRT criteria.  Bone marrow biopsies will be performed only to determine or confirm a change in response category as described 
above. 
 
 
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Appendix 3- Protocol Synopsis – Stage 2


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SYNOPSIS: STAGE 2  
Sponsor: 
Promedior, Inc 
Name of Finished Product: 
Recombinant human Pentraxin-2; PRM-151 
Study Title: 
A Phase 2, Prospective Study Of PRM-151 In Subjects With Primary Myelofibrosis (PMF), 
Post-Polycythemia Vera MF (post-PV MF), Or Post-Essential Thrombocythemia MF (post-ET 
MF) 
Study Number: 
PRM-151G-101 
Study Phase:  Phase 2 
Investigational Product; Dose; and Mode of Administration:  
PRM-151; 0.3 mg/kg; 3mg/kg and 10 mg/kg intravenous 
Comparator; Dose; and Mode of Administration: 
Not applicable 
Primary Objective(s):  
• 
To determine the effect size of three different doses of PRM-151 on reduction in bone 
marrow fibrosis by ≥ 1 grade in intermediate-1, intermediate-2, and high risk subjects 
with PMF, post-PV MF, or post ET-MF who are anemic or thrombocytopenic and who 
are ineligible for, intolerant of, or have had an inadequate response to ruxolitinib. 
Secondary Objective(s): 
• 
To determine if there is a difference in efficacy between the three doses of PRM-151 
used in the study 
• 
To evaluate the safety and tolerability of three different doses of PRM-151  
• 
To assess the duration of effect of three doses of PRM-151 on reduction in bone 
marrow fibrosis  
• 
To assess the effect and duration of effect of three doses of PRM-151 on disease 
related anemia, thrombocytopenia, and constitutional symptoms  
• 
To assess IWG-MRT response (Complete Response, Partial Response, Clinical 
Improvement), stable and progressive disease in subjects treated with three doses of 
PRM-151 
Exploratory Objectives 
• 
To measure changes in bone marrow fibrosis by quantitative image analysis and 
evaluate changes in bone marrow morphology in subjects receiving PRM-151 
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• 
To assess the effect of PRM-151 on other disease related parameters, including 
hematologic abnormalities and spleen size 
• 
To assess the effect of PRM-151 on prognostic factors associated with increased 
mortality as measured by the DIPSS (Dynamic International Prognostic Scoring 
System) 
• 
To evaluate the interaction between selected genetic mutations and cytogenetic 
abnormalities and response to PRM-151  
• 
To explore potential biomarkers of PRM-151 activity in bone marrow samples 
• 
To assess the effect of PRM-151 on bone marrow metabolism by PET imaging (at 
selected institutions) 
• 
To evaluate the correlation of baseline PTX-2 levels with outcomes 
• 
To evaluate the relationship between bone marrow fibrosis reduction and hematologic 
improvements in subjects treated with PRM-151 
• 
To measure progression-free and overall survival in subjects receiving PRM-151 
Study Endpoints:  
Primary:   
• 
Bone marrow response rate, defined as the percent of subjects with a reduction in bone 
marrow fibrosis score by at least one grade according to WHO criteria (Appendix D) at 
any time during the study as determined by a central adjudication panel of expert 
hematopathologists, blinded to subject, treatment, and time of biopsy 
Secondary:   
• 
Comparison of primary and secondary efficacy parameters between doses 
• 
Incidence of adverse events (AEs), serious adverse events (SAEs), and changes in 
laboratory test results   
• 
Bone marrow improvement: 
o Bone marrow response rate at weeks 12, 24, and 36 
o Duration of bone marrow response  
• 
Hemoglobin improvement  
Baseline Status 
Categories of Hemoglobin Improvement 
Subjects who are transfusion dependent (≥ 2 
units PRBC every 4 weeks for 12 weeks 
prior to or after C1D1), regardless of baseline 
hemoglobin level 
 
Percent of subjects with  
Red cell transfusion independence (no 
transfusions for ≥ 12 consecutive weeks) 
 
OR 
 
50% reduction in RBC transfusions for ≥ 12 
consecutive weeks 
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Subjects with baseline hemoglobin < 100 g/L 
AND 
Not transfusion dependent 
Percent of subjects with ≥ 10 g/L and ≥ 20 
g/L increase in hemoglobin for ≥ 12 
consecutive weeks without transfusions 
• 
Platelet improvement: 
Baseline Status 
Categories of Platelet Improvement 
Subjects who are transfusion dependent (≥ 2 
platelet transfusions in any 12 weeks prior to 
or after C1D1), regardless of baseline platelet 
level 
 
Platelet transfusion = either 1 unit apheresed 
(single donor) platelets or 4-8 units pooled 
random donor platelets 
Percent of subjects with: 
Platelet transfusion independence (no 
transfusions for ≥ 12 consecutive weeks)  
 
OR 
 
50% reduction in platelets transfusions for 
≥ 12 consecutive weeks 
Subjects with 25 < baseline platelets < 50 x 
109/L 
AND 
Not platelet transfusion dependent 
Percent of subjects with: 
Doubling of baseline platelet count for ≥ 12 
consecutive weeks without platelet 
transfusions 
 
OR 
 
Platelet count > 50 x 109/L for ≥ 12 
consecutive weeks without platelet 
transfusions 
Subjects with baseline platelet count < 25 x 
109/L 
AND 
Not platelet transfusion dependent 
Percent of subjects with: 
Doubling of baseline platelet count for ≥ 12 
consecutive weeks without platelet 
transfusions 
 
OR 
 
Platelet count > 25 x 109/L for ≥ 12 
consecutive weeks without platelet 
transfusions 
• 
Hematologic improvement: 
Baseline Status 
Categories of Hematologic Improvement 
Subjects with both Hemoglobin < 100 g/L 
and Platelets < 50 x 109/L 
Percent of subjects who have EITHER 
Hemoglobin improvement OR Platelet 
improvement as described above and no 
worsening of hemoglobin or platelets from 
baseline 
Subjects with only Hemoglobin < 100 g/L 
Percent of subjects who have Hemoglobin 
improvement as described above 
AND 
Did not develop platelets < 50 x 109/L 
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Subjects with only Platelets < 50 x 109/L 
Percent of subjects who have Platelet 
improvement as described above 
AND 
Did not develop Hemoglobin < 100 g/L or 
new transfusion dependence 
• 
Symptom  improvement: 
o Percent of subjects with 25% and 50% reduction in MPN-SAF Total Symptom 
Score from baseline at Week 36  
o Mean change from baseline in EORTC QLQ-C30 at 36 weeks 
• 
Duration of all improvement parameters listed above 
• 
Percent of subjects with complete response, partial response, clinical improvement, 
stable disease, and progressive disease according to IWG-MRT criteria (Tefferi 2013, 
Appendix B) 
Exploratory: 
• 
Bone marrow 
o Percent of subjects with Grade 0-1 bone marrow fibrosis grade at any time 
during the study and at weeks 12, 24, and 36 
o Duration of Grade 0-1 bone marrow fibrosis grade 
o Mean change from baseline to 12, 24, and 36 weeks in bone marrow fibrosis by 
quantitative image analysis 
o Changes from baseline to weeks 12, 24, and 36 in bone marrow metabolism by 
FDG or FLT PET scan (where feasible) 
o Assessment of changes in bone marrow morphology at 12, 24, and 36 weeks 
• 
Hematologic and other disease related laboratory parameters 
o Mean change from baseline to 36 weeks in: hemoglobin, # RBC units 
transfused in previous 12 weeks, platelet count, # platelet transfusions in 
previous 12 weeks, white blood cell count, absolute neutrophil count, 
reticulocyte count, peripheral blood blast count, and  lactic dehydrogenase 
(LDH) 
o Percent of subjects with increase in Hgb from < 100 g/L to > 100 g/L without 
transfusions, increase in platelets from < 50 x 109/L to  > 100 x 109/L, decrease 
in WBC from > 25 to < 25, increase in ANC from < 1500 to ≥ 1500, decrease 
in peripheral blood blasts from > 1% to < 1%, and disappearance of 
leukoerythroblastosis, at 36 weeks and for ≥ 12 weeks at any time during the 
study 
o Duration of increase in Hgb from < 100 g/L to > 100 g/L without transfusions, 
increase in platelets from < 50 x 109/L to  > 100 x 109/L, decrease in WBC 
from > 25 to < 25, increase in ANC from < 1500 to ≥ 1500, decrease in 
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peripheral blood blasts from > 1% to < 1%, and disappearance of 
leukoerythroblastosis  
• 
Spleen improvement: 
o Percent of subjects with 10% and 35% reduction in spleen size from baseline 
by CT at 36 weeks  
o Duration of 10% and 35% reduction in spleen size from baseline 
o Mean change from baseline in spleen size by CT at 36 weeks 
o Change in spleen and liver metabolism by FDG or FLT PET scan at 12, 24, and 
36 weeks 
• 
DIPSS 
o Percent of subjects with a reduction in DIPSS score and category at week 36 
o Mean change in DIPSS score from baseline to Week 36 
• 
Mutational Status and Cytogenetics 
o Association of baseline mutational status of JAK2V617F, MPLW515, 
Calreticulin, ASXL1, EZH2, SRSF2, IDH1/2 with selected primary and 
secondary endpoints 
o Changes in allele burden of JAK2V617F at week 36.  Changes in allele burden 
of MPLW515, Calreticulin, ASXL1, EZH2, SRSF2, IDH1/2 at week 36 will be 
measured as commercially available assays become available 
o Association of baseline cytogenetic abnormalities and selected primary and 
secondary endpoints 
• 
Association of baseline PTX-2 levels with selected primary and secondary endpoints 
• 
Evaluation of potential biomarkers of PRM-151 activity in bone marrow biopsies taken 
at baseline, weeks 12, 24, and 36 
• 
Measurement of progression-free and overall survival 
Stage 2 Study Design: 
This is a randomized, double-blind Phase 2 study to determine the efficacy and safety of three 
different doses of PRM-151 in subjects with PMF and post ET/PV MF. Subjects will be 
randomized to one of three doses:  0.3 mg/kg, 3.0 mg/kg or 10 mg/kg of PRM-151. This is the 
second stage of an adaptive design study as defined in FDA Draft Guidance for Industry: 
Adaptive Design Clinical Trials for Drugs and Biologics, February 2010.  Modifications to 
dose levels, schedule, and regimen have been made in Stage 2 based on data from Stage 1. 
Approximately 84 subjects with intermediate-1, intermediate-2, or high risk MF who meet 
study eligibility requirements will be enrolled and randomized to treatment with single agent 
PRM-151 at doses of 0.3, 3, or 10 mg/kg IV on Days 1, 3, and 5 of Cycle 1 and Day 1 of each 
subsequent 28 day cycle for nine cycles. The randomization will be stratified according to type 
of subject (subjects with Hgb < 100 g/L and having received ≥ 2 units PRBC in the 12 weeks 
prior to study entry OR subjects with platelet count < 50 x 109/L) and will ensure that the final 
study population will include at least 50% of subjects from the second stratum (platelet count 
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< 50 x 109/L). As outlined in Appendix J, all subjects completing 9 cycles of the originally 
assigned treatment may switch to an open label extension and receive PRM-151 10mg/kg 
every 4 weeks. The first cycle of the open label phase contains a loading dose of 10 mg/kg on 
days 1, 3, and 5. This will allow for subjects from all three dosing cohorts to receive a loading 
dose of 10 mg/kg while maintaining the blind. Additionally, subjects who have entered the 
open label extension study prior to the approval of this amendment may receive a loading dose 
(10 mg/kg on days 1, 3, and 5), to be administered on their next scheduled cycle after approval 
of this protocol amendment. This will allow for these subjects to receive any potential 
pharmacologic benefit of the loading dose.  
As of 14-Nov 16, we have blinded safety data, although limited, on 21 subjects receiving a 
similar 10 mg/kg loading dose in the open label of the PRM-151-202 IPF study after 24 weeks 
of exposure to PRM-151 or placebo in 2:1 ratio. No incremental risk has been reported in 
these subjects.  
 
Subjects enrolled in the open-label phase extension protocol of Stage 1 should continue to 
follow the study procedures outlined in Appendix L.  
Enrolled subjects will be considered evaluable for response if they are on study drug for at 
least twelve weeks.   
Study Duration: 
Each subject will participate in the study for approximately 44 weeks.  Participation will 
include a screening evaluation within four weeks prior to the first PRM-151 administration, 
nine study cycles of four weeks each, and an end of study visit four weeks after the end of the 
last cycle.  After completion of 9 cycles, subjects may continue with PRM-151 dosing in the 
open label extension in the absence of disease progression or toxicity warranting 
discontinuation of therapy. 
It is estimated that the study will be completed in approximately 18 months. 
Study Inclusion and Exclusion Criteria: 
Inclusion Criteria: 
1. Subjects must be ≥18 years of age at the time of signing the Informed Consent Form 
(ICF); 
2. Subjects must voluntarily sign an ICF; 
3. Subjects must have a pathologically confirmed diagnosis of PMF as per the WHO 
diagnostic criteria (Appendix C) or post ET/PV MF;  
4. At least Grade 2 marrow fibrosis according to the WHO Grading of Bone Marrow 
Fibrosis (Appendix D);  
5. Intermediate-1, intermediate -2, or high risk disease according to the IWG-MRT 
Dynamic International Prognostic Scoring System (Appendix E);   
6. A bone marrow biopsy must be performed within four weeks prior to Cycle 1 Day 1 
treatment to establish the baseline fibrosis score; 
7. Subjects must not be candidates for ruxolitinib based on EITHER: 
a. Platelet count < 50 x 109/L, OR  
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b. Hgb < 100 g/L, have received ≥ 2 units PRBC in the 12 weeks prior to study 
entry, and be intolerant of or had inadequate response to ruxolitinib; 
8. Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance 
Status of 0-2.  (Appendix F); 
9. Life expectancy of at least twelve months; 
10. At least four weeks must have elapsed between the last dose of any MF-directed drug 
treatments for myelofibrosis (including investigational therapies) and study enrollment;  
11. Recovery to ≤ Grade 1 or baseline of any toxicities due to prior systemic treatments, 
excluding alopecia; 
12. Women of child bearing potential (WCBP), defined as a sexually mature woman not 
surgically sterilized or not post-menopausal for at least 24 consecutive months if ≤55 
years or 12 months if >55 years, must have a negative serum pregnancy test within 
four weeks prior to the first dose of study drug and must agree to use highly effective 
methods of birth control throughout the study. Highly effective methods of 
contraception include combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation by oral, intravaginal, or 
transdermal administration; progestogen-only hormonal contraception associated with 
inhibition of ovulation by oral, injectable, or implantable administration; intrauterine 
device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; 
partner vasectomy, and total abstinence (only if total abstinence is the preferred 
method and usual lifestyle of the subject). Adequate contraceptive use should be 
continued until 28 days after the final dose of the study drug.  
13. Ability to adhere to the study visit schedule and all protocol requirements; 
14. Must have adequate organ function as demonstrated by the following:  
• ALT (SGPT) and/or AST (SGOT) ≤ 3x upper limit of normal (ULN), or ≤ 4 x 
ULN (if upon judgment of the treating physician, it is believed to be due to 
extramedullary hematopoiesis [EMH] related to MF);  
• Direct bilirubin ≤ 1.5 x ULN; or ≤ 2x ULN (if upon judgment of the treating 
physician, it is believed to be due to EMH related to MF);  
• Serum creatinine ≤ 2.5 x ULN. 
Exclusion Criteria: 
1. White blood cell count > 25 x 109/L or > 10% peripheral blood blasts; 
2. Other invasive malignancies within the last 3 years, except non-melanoma skin cancer 
and localized cured prostate and cervical cancer; 
3. History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia 
requiring medication or mechanical control within the last 6 months; 
4. Presence of active serious infection; 
5. Any serious, unstable medical or psychiatric condition that would prevent, (as judged 
by the Investigator) the subject from signing the informed consent form or any 
condition, including the presence of laboratory abnormalities, which places the subject 
at unacceptable risk if he/she were to participate in the study or confounds the ability 
to interpret data from the study;  
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6. Known history of human immunodeficiency virus (HIV), or known active hepatitis A, 
B, or C infection;  
7. Organ transplant recipients other than bone marrow transplant;  
8. Women who are pregnant or lactating. 
Efficacy Assessments: 
Efficacy will be assessed by evaluation of WHO bone marrow fibrosis grade, changes in 
hemoglobin, platelets, peripheral blood blasts, disease related symptoms, and spleen size.  
Safety Assessments: 
Safety will be evaluated from reported adverse events, scheduled physical examinations, vital 
signs, and clinical laboratory test results.   
A blinded DMC will be established to review safety data from this study, thereby better 
ensuring the safety of study participants. Consistent with US Food and Drug Administration 
(FDA) recommendations (FDA Guidance for Industry, Establishment and Operation of 
Clinical Trial Data Monitoring Committees, 2006), the DMC will be constituted of 
independent clinicians expert in the field of MF and clinical research.  A formal charter will be 
established for the conduct of the DMC. 
• 
The committee is planned to review the safety data in a blinded manner, but a 
procedure will be in place to allow the committee an immediate unblinding of either 
specific cases or of the whole study in case of detection of a potential safety signal 
necessitating an unblinded review of some (or all) subjects. 
Statistical Methods:  
General considerations: 
Continuous variables will be summarized by dose group with descriptive statistics (e.g., 
number of observations, number of missing observations, mean, standard deviation [SD], 
median, interquartile range, maximum, and minimum). Categorical variables will be tabulated 
by frequency of subjects per dose group, and percentages will be calculated using the number 
of available observations as the denominator (i.e. excluding missing values).   
Determination of Sample Size 
The chosen sample size of 72 subjects (i.e. 24 subjects per dose arm) is deemed sufficient to 
provide adequate precision to the estimation of the response rate in each treatment arm. The 
trial will enroll 84 subjects to allow for a discontinuation rate of 15%. 
Considerations on the precision of estimate and the power for comparisons planned as 
secondary analyses are provided in the body of the protocol. 
Randomization and Stratification 
This study is randomized with a 1:1:1 randomization ratio. A central randomization system 
will be used. The randomization will be stratified according to the subjects’ baseline 
haematologic status: baseline anemia alone or baseline thrombocytopenia or baseline anemia 
associated with baseline thrombocytopenia. The randomization system will also ensure that at 
least 50% of the subjects in the final study population will have baseline thrombocytopenia. 
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Missing values: 
All available efficacy and safety data will be included in data listings and tabulations.   
For the primary efficacy criterion, subjects with a reduction in bone marrow fibrosis score by 
at least one grade according to WHO criteria (central adjudication) at any post baseline visit 
will be considered as responders. Subjects without any central assessment of bone marrow 
fibrosis will be considered as non-responders. In addition, subjects who discontinue due to 
toxicity prior to completion of one cycle of study drug will be also considered non-responders 
for the efficacy analyses. 
All other analyses will be based on observed data only; no missing data will be imputed. 
Efficacy analysis populations: 
The primary efficacy analysis will be conducted on the Full Analysis Set (FAS; all randomized 
subjects having received at least one administration of the study medication with at least one 
post-baseline assessment of BMRR (primary efficacy criterion) available. Subjects who 
discontinue due to toxicity prior to completion of one cycle of study drug will also be kept in 
the FAS and considered non-responders for the efficacy analysis).  A per-protocol analysis 
will also be carried out on the Per Protocol (PP) set, a subset of the FAS composed of all 
subjects treated with the investigational medicinal product (IMP), having received at least the 
planned IMP infusions on days 1, 3, 5, and weeks 4, 8 and 12 and who did not present any 
major protocol deviations.  
The per-protocol set will be used for secondary analyses of the primary efficacy criterion and 
for the analysis of some selected secondary efficacy criteria. 
Primary analysis of efficacy 
The primary efficacy analysis will consist in computing the bone marrow response rate 
(percent of subjects with a reduction in bone marrow fibrosis score by at least one grade) and 
its 97.5% two-sided confidence interval within each treatment arm. This analysis will be 
conducted on the FAS analysis set. 
Inferential interpretation: for the 3 mg/kg and 10 mg/kg arms, the lower limit of the 97.5% 
two-sided confidence interval will be compared to 10%, a threshold assumed to define the 
minimal clinically relevant effect. If the lower limit of the confidence interval is above 10%, 
the corresponding dose will be claimed to have demonstrated clinically relevant efficacy. 
The confidence intervals computation will use a method consistent with the stratified design. 
Comparison of PRR between treatment arms at week 36 
Pairwise comparisons between the three dose groups will be performed using the Cochran-
Mantel-Haenszel (general association) statistic in the SAS Freq procedure, to take into account 
the stratified design. 
Two pairwise comparisons (3 mg/kg versus 0.3 mg/day and 10 mg/kg versus 0.3 mg/day) will 
be computed with the aim to demonstrating superiority and, consequently, will use an adjusted 
a two-sided 0.025 level of significance. 
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The third comparison (10 mg/kg versus 3 mg/kg) is not expected to have enough power to 
demonstrate any difference with the planned sample size. This comparison is considered 
exploratory and will be conducted using an unadjusted 0.05 level of significance. 
Other efficacy analyses: Sensitivity efficacy analysis, secondary efficacy analyses and 
exploratory efficacy analyses: see body of the protocol. 
Safety analyses: see body of the protocol. 
 
Date of Original Protocol:  Version 1.0  17 Jan 2013 
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Appendix 4 OLE Synopsis – Stage 2


PRM-151 
 
Study Protocol PRM-151G-101 
                                                                 FINAL Version 6.1 
 
Page 91 
APPENDIX J: 
 
Stage 2 Extension Study 
Sponsor: 
Promedior, Inc 
Name of Finished Product: 
Recombinant human Pentraxin-2; PRM-151 
Study Title: 
A Phase 2, Prospective Study Of PRM-151 In Subjects With Primary Myelofibrosis (PMF), 
Post-Polycythemia Vera MF (post-PV MF), Or Post-Essential Thrombocythemia MF (post-ET 
MF) 
Study Number: 
PRM-151G-101 
Study Phase:  Phase 2 
Investigational Product; Dose; and Mode of Administration:  
PRM-151 10 mg/kg intravenous 
Comparator; Dose; and Mode of Administration: 
Not applicable 
Primary Objective(s):  
To provide subjects in the parent study an opportunity to remain on treatment and to allow all 
subjects to switch to an open label extension utilizing the 10mg/kg dose after completing 9 
cycles of the originally assigned treatment.  
Secondary Objective(s): 
• 
To collect long term safety data of subjects receiving PRM-151 
• 
To collect additional efficacy data on duration of response beyond 36 weeks of 
treatment 
• 
To collect efficacy data on the change of PRM-151 dose level in subjects not achieving 
a response 
Study Design: 
This is an open-label extension of study PRM151G-101 to provide continued access to 
subjects in the parent study. All subjects completing 9 cycles of the originally assigned 
treatment may switch to an open label extension and receive PRM-151 10mg/kg every 4 
weeks.  The first cycle of the open label phase contains a loading dose of 10mg/kg on days 1,3 
and 5. This will allow for subjects from all three dosing cohorts to receive a loading dose of 
10mg/kg while maintaining the blind. Additionally, subjects who have entered the open label 
extension study prior to the approval of this amendment may receive a loading dose (10 mg/kg 
on days 1, 3, and 5), to be administered on their next scheduled cycle after approval of this 
protocol amendment. This will allow for these subjects to receive any potential pharmacologic 
benefit of the loading dose.  
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Study Duration: 
Subjects may continue with PRM-151 dosing in the absence of disease progression or toxicity 
warranting discontinuation of therapy until drug is made available in another way.  Cycle 
numbers will continue from the parent protocol, with Cycle 9 Day 29 of the parent protocol 
becoming Cycle 10 Day 1 of the extension study. 
Response Assessments: 
In addition to the schedule of assessments listed below, response assessments will be done on 
Day 1 of every third cycle (every 12 weeks) beginning on Day 1 of Cycle 13 and may include 
the following, as described below: 
Bone Marrow Biopsies: 
An optional bone marrow biopsy will be performed every 12 weeks.  
MPN SAF and EORTC QLQ-C30: 
Symptoms will be assessed using the MPN SAF and EORTC QLQ-C30 on Day 1 on every 
cycle. 
Physical Exam and Spleen Measurement: 
An abbreviated physical exam and spleen measurement by palpation will be done on Day 1 on 
every cycle. 
PET-CT or CT or MRI: 
These will be performed every 24 weeks. 
 
 
 
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Page 93 
Stage 2 Extension Study 
SCHEDULE OF ASSESSMENTS 
 
Cycle 10, Day 1 
(Cycle 9, Day 29) 
Extension Cycles 
28 Day Cycle Length 
Day 1 (+/- 3 days) 
Day 1 (+/- 3 days) 
1 
3 
5 
1 
Informed Consent 
x 
 
 
 
AE/SAE assessment (1) 
x 
x 
x 
x 
Physical Exam(2) 
x 
 
 
x 
Prior/Con Meds 
x 
x 
x 
x 
Special list of excluded medications 
x 
x 
x 
x 
Vital Signs (3) 
x 
x 
x 
x 
Weight (kg) 
x 
 
 
x 
ECOG Performance Score  
x 
 
 
x 
Urine Pregnancy Test 
x 
 
 
x 
Complete Blood Count (4) 
x 
 
 
x 
Chemistry, BUN/creatinine (5) 
x 
 
 
x 
Coagulation(6) 
x 
 
 
x 
Completion of transfusion diaries 
x 
 
 
x 
Bone Marrow(7) 
x 
 
 
x 
MPN-SAF score(7) 
x 
 
 
x 
EORTC-QLQC30(7) 
x 
 
 
x 
PET-CT Scan or CT or MRI(8) 
x 
 
 
x 
Anti-pentraxin 2 antibodies, pre-dose(9) 
x 
 
 
x 
Pentraxin-2 levels,  pre-dose(9) 
x 
 
 
x 
Access IRS (10) 
x 
x 
x 
x 
PRM-151 Administration(11)(12) 
x 
x 
x 
x 
1. Pre-treatment adverse events, including serious adverse events will be collected from the time of informed consent and after the 
medical history has been obtained  
2. Abbreviated physical exam and spleen measurement by palpation will be done day 1 of every cycle. 
3. Vital signs (including temperature, blood pressure, pulse rate, and respiratory rate) will be performed before and immediately 
after PRM-151 infusion, and at the conclusion of the one hour observation period..   
4. CBC includes red blood cell count (RBC), hemoglobin, hematocrit, white blood cell count with differential, absolute neutrophil 
count (ANC), reticulocyte count,  last count, and platelets.  
5. Blood chemistry lab parameters include lactic dehydrogenase (LDH), serum alanine aminotransferase (ALT), serum aspartate 
aminotransferase (AST), direct and indirect bilirubin, alkaline phosphatase, creatinine phosphokinase (CPK), uric acid, calcium, 
phosphorus, sodium, potassium, chloride, albumin, bicarbonate, BUN, creatinine, and glucose. 
6. Coagulation testing at screening for all subjects to include prothrombin time (PT), and partial thromboplastin time (PTT). For 
subjects receiving warfarin, the PT, PTT and international normalized ratio (INR) must be obtained. Abnormal INRs will be 
tested twice weekly until the INR is stable for one month, followed by monthly monitoring of INRs 
7. MPN-SAFEORTC QLQ-C30, will be performed on Day 1 of every cycle. Bone marrow biopsy window +/- 6 weeks.  
8. PET-CT Scan or CT or MRI will be performed every 24 weeks. 
9. Blood sample for pentraxin-2 and anti-pentraxin 2 antibodies should be drawn pre-dose every 12 weeks.  If the subject 
experiences an infusion related reaction, a blood sample for anti-pentraxin 2 antibodies should be drawn prior to any subsequent 
PRM-151 infusions. A blood sample for cytokines and anti-pentraxin 2 antibodies may be obtained in the event of a suspected 
adverse reaction as well. 
10. For consistency, the unblinded pharmacist will continue to access IRS to confirm occurrence of dosing on Day 1 of each Cycle.  
11. Subjects will be observed one hour after each dose. 
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12. Loading dose of 10 mg/kg on Days 1, 3 and 5. Alternative loading dose schedule is Days 1, 3 and 6 when days 1, 3 and 5 are not 
possible. Additionally, subjects who have entered the open label extension study prior to the approval of this amendment may 
receive a loading dose (10 mg/kg on days 1, 3, and 5), to be administered on their next scheduled cycle after approval of this 
protocol amendment. 
 
 
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Appendix 5 Schedule of Assessments-Stage 1


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APPENDIX A 
Schedules of Events 
Table 6: 
Schedule of Events: Cohorts 1 and 2, Weekly Dosing 
  
Screening   
≤ 28 days 
Cycle 1 
28 Day Cycle Length 
Cycle 2, 3, 4, 5, 6 
28 Day Cycle Length 
Cycle 6, 
Day 29 
(+/- 1 
day) 
~28 days 
after Cycle 
6, Day 29 or 
withdrawal 
from study  
Day (+/- 1 day) 
Day (+/- 1 day) 
1 
3 
5 
8 
15 
22 
1 
8 
15 
22 
Informed Consent 
x 
  
  
  
  
  
  
  
  
  
  
  
  
Demographics 
x 
  
  
  
  
  
  
  
  
  
  
  
  
Past Medical History  
x 
  
  
  
  
  
  
  
  
  
  
  
Inclusion/Exclusion 
x 
x 
  
  
  
  
  
  
  
  
  
  
  
Bone Marrow Biopsy (1) 
x 
  
  
  
  
  
  
x(11) 
  
  
  
x(11) 
  
Physical Exam (2) 
x 
x 
  
  
x 
  
x 
  
  
x 
x  
Response Assessment 
 
 
 
 
 
 
 
x 
 
 
 
 
 
Prior/Concomitant 
Medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
AE/SAE Assessment (3) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital Signs (4) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Height (cm) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Weight (kg) 
x 
x 
 
 
 
 
 
x 
 
 
 
 
 
ECOG Performance Score  
x 
x 
x 
x 
x 
x 
x 
x 
  
x 
  
x 
x 
Pregnancy Test (5) 
x 
x 
  
  
  
  
  
x 
  
  
  
  
  
Complete Blood Count (6) 
x 
x 
  
  
x 
x 
x  
x 
 x 
x 
x  
x 
x 
Chemistry, 
BUN/creatinine (7) 
x 
x 
  
  
x 
x 
x 
x 
  
x 
  
x 
x 
Coagulation (8) 
x 
x 
  
  
x 
x 
  
  
x 
  
12 lead ECG (13) 
x 
x 
 
 
 
 
 
x 
 
x 
 
 
 
ExploratoryLaboratory 
x 
  
  
  
  
x 
  
  
  
x 
  
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Screening   
≤ 28 days 
Cycle 1 
28 Day Cycle Length 
Cycle 2, 3, 4, 5, 6 
28 Day Cycle Length 
Cycle 6, 
Day 29 
(+/- 1 
day) 
~28 days 
after Cycle 
6, Day 29 or 
withdrawal 
from study  
Day (+/- 1 day) 
Day (+/- 1 day) 
1 
3 
5 
8 
15 
22 
1 
8 
15 
22 
Assessments (9) 
Transfusion History over 
past 3 months or since last 
visit  
x 
x 
  
  
x 
x 
 x 
x 
  
  
x 
x 
Ruxolitinib dose over last 
3 months  
x 
x 
  
  
  
  
  
  
  
Special list of excluded 
medications 
x 
x 
  
  
x 
x 
 x 
x 
  
x 
  
x 
x 
Pharmacokinetic samples 
(10) 
  
x 
x 
x 
x 
x 
x 
x 
 x 
x 
 x 
 x 
  
Anti-pentraxin 2 
antibodies, pre-dose 
x 
 
 
 
x 
x 
x 
 
 
  
x 
  
MPN-SAF score 
x 
x 
  
  
  
  
  
x 
  
  
  
x 
x 
PRM-151 Administration 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
  
Review ruxolitinib self-
administration log – 
Cohort 2 ONLY (12) 
 
x 
 
 
 
 
 
x 
 
 
 
x 
x 
1. 
Bone marrow biopsy must have been performed within 4 weeks prior to first infusion of PRM-151; subsequent bone marrow 
biopsies performed +/- 3 days of scheduled visit 
2  
Abbreviated physical exam including spleen measurement by palpation at all timepoints 
3. 
Pre-treatment adverse events, including serious adverse events will be collected from the time of informed consent and after 
the medical history has been obtained for all subjects receiving at least one dose of PRM-151 
4. 
Vital signs (including temperature, blood pressure, pulse rate, and respiratory rate) will be performed before, immediately 
after, and every hour during the four hour observation periods, and before, immediately after, and at the conclusion of all one hour 
observation periods. Four hour observation periods are required through Cycle 2 Day 1 and subsequent observation periods are 1 
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hour.5. Serum pregnancy test within 4 weeks prior to the first dose of study drug; urine pregnancy tests for all subsequent tests; see 
8.2. 
6. 
CBC includes red blood cell count (RBC), hemoglobin, hematocrit, white blood cell count with differential, absolute 
neutrophil count (ANC), and platelets. Results should be reviewed prior to PRM-151 infusion.  
7. 
Blood chemistry lab parameters include lactic dehydrogenase (LDH), serum alanine aminotransferase (ALT), serum 
aspartamine aminotransferase (AST), direct and indirect bilirubin, alkaline phosphatase, creatinine phosphokinase (CPK), uric acid, 
calcium, phosphorus, sodium, potassium, chloride, bicarbonate, BUN, creatinine, and glucose 
8. 
Coagulation testing at screening for all patients and include prothrombin time (PT), and partial thromboplastin time (PTT). For 
patients receiving warfarin, the PT, PTT and international normalized ratio (INR) must be obtained. Abnormal INRs will be tested 
twice weekly until the INR is stable for one month, followed by monthly monitoring of INRs. 
9. 
Plasma samples will be analyzed for changes in the levels of cytokines including but not limited to CRP, IL-1ra, MIP-1β, 
TNFα, IL-6 and VEGF. PBMC will also be isolated and analyzed for changes in levels of mRNA and miRNA to determine a PRM-
151 response signature.  Blood samples for exploratory laboratory assessments to be obtained on Day 1 of Cycles 1, 2, 3 and 4, and 
Day 29 of Cycle 6. 
10. 
Blood samples for PK analysis (4 mL) will be obtained on Cycles 1, 2 and 6, Day 1 at predose and at  end of infusion, 1, 2, 4, 
and 8 hours post infusion; on Cycle 1, Day 15 at predose, 0.5, 0.75, 1.5, 3 and 6 hours post infusion; at pre-dose on Cycle 1, days 3, 5, 
8 and 22; at pre-dose on Cycle 2, Days, 8, 15 and 22; at pre-dose Cycle 6, Day 15; and anytime on Cycle 6, Day 29.  
11.   
Bone marrow biopsy will be done at screening, on Day 1 of Cycle 4, and on Day 29 of Cycle 6.  
12.  
 Patient Self-administration form for ruxolitinib  
13. 
ECGs will be obtained pre-treatment and an additional ECG at end of infusion for Cycle 6 only, Days 1 and 15 
 
 
 
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Page 70 
Table 7: 
Schedule of Events: Cohorts 1 and 2, Every Four Week Dosing 
 
Screening   
≤ 28 days 
Cycle 1                  
28 Day Cycle Length 
Cycle 2, 3, 4, 5, 6 
 28 Day Cycle Length 
Cycle 6, 
Day 29  
(+/- 1 day) 
28 days after 
Cycle 6, Day 
29 or 
withdrawal 
from study 
(+/- 1 day) 
Day (+/- 1 day) 
Day (+/- 1 day) 
1 
3 
5 
15 
1 
15 
 
 
Informed Consent 
x 
  
  
  
 
  
  
  
  
Demographics 
x 
  
  
  
 
  
  
  
  
Past Medical History  
x 
  
  
 
  
  
  
  
Inclusion/Exclusion 
x 
x 
  
  
 
  
  
  
  
Bone Marrow Biopsy (1) 
x 
  
  
  
 
x(11) 
  
x(11) 
  
Physical Exam (2) 
x 
x 
  
  
x 
x 
 x 
 x 
Response Assessment 
 
 
 
 
 
x 
 
 
 
Prior/Concomitant 
Medications 
x 
x 
x 
x 
x 
x 
x 
x 
AE/SAE Assessment (3) 
x 
x 
x 
x 
x 
x 
x 
x 
Vital Signs (4) 
x 
x 
x 
x 
x 
x 
x 
x 
Height (cm) 
x 
  
  
  
 
  
  
  
  
Weight (kg) 
x 
x 
 
 
 
x 
 
 
 
ECOG Performance Score  
x 
x 
x 
x 
x 
x 
x 
x 
Pregnancy test (5) 
x 
x 
  
  
 
x 
  
  
Complete Blood Count (6) 
x 
x 
  
  
x 
x 
x 
x 
x 
Chemistry, BUN/creatinine 
(7) 
x 
x 
  
  
x 
x 
x 
x 
x 
Coagulation (8) 
x 
x 
  
  
x 
x 
x 
  
12 lead ECG (12) 
x 
x 
 
 
 
x 
 
 
 
Exploratory laboratory 
assessments (9) 
x 
  
  
 
x 
x 
  
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Screening   
≤ 28 days 
Cycle 1                  
28 Day Cycle Length 
Cycle 2, 3, 4, 5, 6 
 28 Day Cycle Length 
Cycle 6, 
Day 29  
(+/- 1 day) 
28 days after 
Cycle 6, Day 
29 or 
withdrawal 
from study 
(+/- 1 day) 
Day (+/- 1 day) 
Day (+/- 1 day) 
1 
3 
5 
15 
1 
15 
 
 
Transfusion history over past 
3 months or since last visit  
x 
x 
  
  
x 
x 
x 
x 
Ruxolitinib dose over last 3 
months  
x 
x 
  
  
  
 
 
 
 
Special list of excluded 
medications 
x 
x 
  
  
 x 
x 
x 
x 
Pharmacokinetic samples 
(10) 
  
x 
x 
x 
x 
x 
x  
  
Anti-pentraxin 2 antibodies, 
pre-dose 
 
x 
 
 
x 
x 
 
x 
 
MPN-SAF score 
x 
x 
  
  
 
x 
x 
x 
PRM-151 Administration 
  
x 
x 
x 
 
x 
  
  
Review ruxolitinib self-
administration log – Cohort 2 
ONLY (12) 
 
x 
 
 
 
x 
 
x 
X 
1. Biopsy must have been performed within 4 weeks prior to first infusion of PRM-151; subsequent bone marrow biopsies 
performed +/- 3 days of scheduled visit 
2. Abbreviated physical exam including spleen measurement by palpation at all timepoints 
3. Pre-treatment adverse events, including serious adverse events will be collected from the time of informed consent and after 
the medical history has been obtained. 
4. Vital signs (including temperature, blood pressure, pulse rate, and respiratory rate) will be performed before, immediately 
after, and every hour during the four hour observation periods, and before, immediately after, and at the conclusion of all one 
hour observation periods. Four hour observation periods are required through Cycle 2 Day 1 and subsequent observation 
periods are 1 hour. . 
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PRM-151 
Study Protocol PRM-151G-101  
 
FINAL Version 4.0 
Page 72 
5. Serum pregnancy test within 4 weeks prior to the first dose of study drug. Urine pregnancy test at all subsequent time points.  
See protocol Section 8.1 
6. Complete blood count ( CBC) includes red blood cell count (RBC), hemoglobin, hematocrit, white blood cell count with 
differential, absolute neutrophil count (ANC), and platelets. Results should be reviewed prior to PRM-151 infusion.  
7. Blood chemistry lab parameters include lactic dehydrogenase (LDH), serum alanine aminotransferase (ALT), serum 
aspartamine aminotransferase (AST), direct and indirect bilirubin, alkaline phosphatase, creatinine phosphokinase (CPK), uric 
acid, calcium, phosphorus, sodium, potassium, chloride, bicarbonate, BUN, creatinine, and glucose. 
8. Coagulation testing at screening for all patients and include prothrombin time (PT), and partial thromboplastin time (PTT). For 
patients receiving warfarin, the PT, PTT and international normalized ratio (INR) must be obtained. Abnormal INRs will be 
tested twice weekly until the INR is stable for one month, followed by monthly monitoring of INRs. 
9. Plasma samples will be analyzed for changes in the levels of cytokines, including but not limited to CRP, IL-1ra, MIP-1, 
TNF, IL-6 and VEGF.  PBMC will also be isolated and analyzed for changes in levels of mRNA and miRNA to determine a 
PRM-151 response signature.  Blood samples for exploratory laboratory assessments to be obtained on Day 1 of Cycles 1, 2, 3 
and 4, and Day 29 of Cycle 6. 
10. Blood samples for PK analysis (4 mL) will be obtained on Cycles 1, 2 and 6, Day 1 at predose and at  end of infusion, 1, 2, 4, 
and 8 hours post infusion; at pre-dose on Cycle 1, Days 3 and 5; on Cycle 1, Day 15 at any time, and any time on Cycle 6, Day 
29. 
11. Bone marrow biopsy will be done at screening, on Day 1 of Cycle 4, and on Day 29 of Cycle 6. 
12. Patient Self-administration form for ruxolitinib 
13. ECGs will be obtained pre-treatment and an additional ECG at end of infusion for Cycle 6 Day 1 only. 
 
 
 
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Appendix 6 Schedule of Assessments-Stage 2


PRM-151 
Study Protocol PRM-151G-101  
 
FINAL Version 6.1 
Page 76 
APPENDIX A 
Schedule of Events
 
Screening  
≤ 28 days 
Cycle 1              
28 Day Cycle Length 
Cycle 2, 3, 4, 5, 6, 7, 8, 9 
28 Day Cycle Length 
Cycle 9, 
Day 29 
End of 
Study(14) 
Day (+/- 1 day) 
Day (+/- 3 day) 
(+/- 3 day) 
(+/- 3 day) 
1 
3 
5 
1 
 
 
Informed Consent 
x 
 
 
 
  
  
  
Demographics 
x 
 
 
 
  
  
  
Past Medical History  
x 
x 
 
 
  
  
  
Inclusion/Exclusion 
x 
x 
 
 
  
  
  
Bone Marrow Biopsy (1) 
x 
 
 
 
x 
x 
  
Physical Exam (2) 
x 
x 
 
 
x 
 x 
 x 
IWG-MRT Response Assessment 
 
 
 
 
x 
x 
 
Prior/Concomitant Medications 
x 
x 
x 
x 
x 
x 
x 
Transfusion history (previous 12 weeks 
and between screening visit) 
x 
x 
 
 
x 
x 
x 
Review of transfusion diaries 
x 
x 
 
 
x 
x 
x 
AE/SAE Assessment (3) 
x 
x 
x 
x 
x 
x 
x 
Vital Signs (4) 
x 
x 
x 
x 
x 
x 
x 
Height (cm) 
x 
 
 
 
  
  
  
Weight (kg) 
x 
x 
 
 
x 
 
 
ECOG Performance Score  
x 
x 
x 
x 
x 
x 
x 
Pregnancy test (5) 
x 
x 
 
 
x 
  
  
Complete Blood Count (6) 
x 
x 
 
 
x 
x 
x 
Chemistry, BUN/creatinine (7) 
x 
x 
 
 
x 
x 
x 
Coagulation (8) 
x 
x 
 
 
x 
x 
  
12 lead ECG (9) 
x 
 
 
 
 
 
 
PET-CT Scan or CT or MRI (10) 
 
x 
 
 
x 
x 
 
Exploratory laboratory assessments(11) 
x 
 
 
x 
  
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PRM-151 
 
Study Protocol PRM-151G-101 
                                                                 FINAL Version 6.1 
 
Page 77 
 
Screening  
≤ 28 days 
Cycle 1              
28 Day Cycle Length 
Cycle 2, 3, 4, 5, 6, 7, 8, 9 
28 Day Cycle Length 
Cycle 9, 
Day 29 
End of 
Study(14) 
Day (+/- 1 day) 
Day (+/- 3 day) 
(+/- 3 day) 
(+/- 3 day) 
1 
3 
5 
1 
 
 
Special list of excluded medications 
x 
x 
 
 
x 
x 
x 
Anti-pentraxin 2 antibodies, pre-dose 
 
x 
 
 
x 
x 
 
Pentraxin-2, pre-dose 
 
x 
 
 
x 
x 
 
MPN-SAF(12) 
x 
x 
 
 
x 
x 
x 
EORTC-QLQC30(12) 
x 
x 
 
 
x 
x 
x 
Access IRS (13) 
x 
x 
x 
x 
x 
 
 
IWG-MRT DIPPS (risk assessment)  
x 
x 
 
 
 
x 
 
PRM-151 Administration(16) 
 
x 
x 
x 
x 
 
 
Infusion Related Reaction Cytokines And 
anti-pentraxin 2 antibodies(15) 
 
x 
 
 
 
 
 
1  
Bone marrow biopsy at Screening must have been performed within 4 weeks prior to first infusion of PRM-151; subsequent bone marrow biopsies on Cycle 4, Day 1, 
Cycle 7, Day 1 and on Cycle 9, Day 29 performed +/- 3 days of scheduled visit  
2  
Abbreviated physical exam including spleen measurement by palpation at all timepoints 
3  
Pre-treatment adverse events, including serious adverse events will be collected from the time of informed consent and after the medical history has been obtained  
4  
Vital signs (including temperature, blood pressure, pulse rate, and respiratory rate) will be performed before and immediately after PRM-151 infusion  and at the 
conclusion of the one hour observation period  
5  
Serum pregnancy test within 4 weeks prior to the first dose of study drug (central lab)  Urine pregnancy test at all subsequent time points (local lab)    
6  
Complete blood count ( CBC) includes red blood cell count (RBC), hemoglobin, hematocrit, white blood cell count with differential, absolute neutrophil count (ANC), 
reticulocyte count, blast count,  platelets, and review of blood smear for nucleated red blood cells and immature myeloid cells   
7  
Blood chemistry lab parameters include lactic dehydrogenase (LDH), serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), direct and indirect 
bilirubin, alkaline phosphatase, creatinine phosphokinase (CPK), uric acid, calcium, phosphorus, sodium, potassium, chloride, albumin, bicarbonate, BUN, creatinine, and 
glucose  
8  
Coagulation testing at screening for all subjects to include prothrombin time (PT), and partial thromboplastin time (PTT)  For subjects receiving warfarin, the PT, PTT and 
international normalized ratio (INR) must be obtained  Abnormal INRs will be tested twice weekly until the INR is stable for one month, followed by monthly monitoring 
of INRs  
9  
ECGs will be obtained at screening and in the event of an infusion related reaction  
10  FDG or FLT PET-CT scans (depending on feasibility) or CT or MRI at Cycle 1 Day 1 (or within 2 weeks prior), Cycle 4 Day 1, Cycle 7 Day 1 and Cycle 9 Day 29    
11  Whole blood samples for cytogentics and mutational status to be obtained on Cycle 1 Day 1 and whole blood samples for changes in allele burden will be obtained on 
Cycle 9 Day 29   
12  If possible, the questionnaire should be completed prior to performing laboratory and radiology procedures, particularly bone marrow biopsy   
13  At the Screening visit IRS can be accessed to register a subject by any member of the site staff   Beginning at Cycle 1 Day 1, only the unblinded Pharmacist (or designee) 
may access IRS 
14  End of Study Visit is 28 days after Cycle 9, Day 29 or withdrawal from study  
15  Infusion Related Reaction Cytokines (TNF-α, IFN-γ, IL-2, IL-4, IL-6, IL-8, IL-10) and anti-pentraxin 2 antibodies will be drawn pre-dose on Cycle 1 Day 1 and repeated 
only in the event of an infusion related reaction or a suspected adverse event   
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PRM-151 
 
Study Protocol PRM-151G-101 
                                                                 FINAL Version 6.1 
 
Page 78 
16  Subjects will be observed one hour after each dose 
 
 
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