Phase II Study of P1101 in Early Myelofibrosis
Phase: PHASE2
Conditions: Primary Myelofibrosis, Secondary Myelofibrosis
Sponsor: Mayo Clinic

 
 
MC138F  
Protocol version: 12 Sept 2018 
Mayo Clinic Cancer Center 
 
MC138F: Phase II Study of P1101 in Myelofibrosis 
 
 
 
Study Chair: 
  
 
 
 
 
 
 
 
 
Study Cochairs: 
  
 
 
 
Statistician: 
 
 
  
 
 
Drug Availability  
Drug Company Supplied:  P1101 - IND# 125,065 
 
√Study contributor(s) not responsible for patient care 
*IND holder has changed as of MCCC Amendment 3 
 
 
Document History 
(Effective Date) 
Addendum 1 
12Aug2015 
Addendum 2 
30Aug2016 
MCCC Amendment 3 
MCCC Amendment 4 
17Aug2017 
12Sept2018 
 
 
 
 
 
 
 
 
 

MC138F 
2 
Amendment 3 
Protocol version: 12 Sept 2018 
Protocol Resources 
Questions: 
Contact Name: 
Patient eligibility*, test schedule, 
treatment delays/ interruptions/ 
adjustments, dose modifications, adverse 
events,forms completion and submission 
 
 
Protocol document, consent form, 
regulatory issues 
 
 
Serious Adverse Events  
 
 
 
 
*No waivers of eligibility per NCI 
 
 
 
 
 

MC138F 
3 
Amendment 3 
Protocol version: 12 Sept 2018 
Table of Contents 
MC138F: Phase II Study of P1101 in Myelofibrosis .................................................................................... 1 
Protocol Resources ........................................................................................................................................ 2 
Table of Contents .......................................................................................................................................... 3 
Schema  .......................................................................................................................................................... 4 
1.0 
Background ......................................................................................................................... 5 
2.0 
Goals.................................................................................................................................... 6 
3.0 
Patient Eligibility ................................................................................................................. 7 
4.0 
Test Schedule .................................................................................................................... 10 
5.0 
Grouping Factor: ............................................................................................................... 12 
6.0 
Registration/Randomization Procedures ........................................................................... 12 
7.0 
Protocol Treatment ............................................................................................................ 13 
8.0 
Dosage Modification Based on Adverse Events ............................................................... 15 
9.0 
Ancillary Treatment/Supportive Care ............................................................................... 17 
10.0 
Adverse Event (AE) Reporting and Monitoring ............................................................... 18 
11.0 
Treatment Evaluation ........................................................................................................ 25 
12.0 
Descriptive Factors ............................................................................................................ 27 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient .................................................. 27 
14.0 
Body Fluid Biospecimens ................................................................................................. 28 
15.0 
Drug Information ............................................................................................................... 28 
16.0 
Statistical Considerations and Methodology ..................................................................... 30 
17.0  
Pathology Considerations/Tissue Biospecimens ............................................................... 35 
18.0 
Records and Data Collection Procedures .......................................................................... 36 
19.0  
Budget ............................................................................................................................... 37 
20.0 
References ......................................................................................................................... 37 
Appendix I: ECOG Performance Status Scale ............................................................................................ 39 
Appendix II: 
MEDICATION DIARY for Myelofibrosis Patients ......................................................... 40 
Appendix III: 
Patient Information Sheet .................................................................................................. 41 
Appendix IV: MPN-SAF .......................................................................................................................... 42 
Appendix V: TRANSFUSION DIARY ...................................................................................................... 46 
Appendix VI: The Dynamic International Prognostic Scoring System (DIPSS) for primary 
myelofibrosis (PMF) ...................................................................................................................... 47 
 

MC138F 
4 
Amendment 3 
Protocol version: 12 Sept 2018 
Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*PD=Progressive Disease 
 
 
1. Cycle length 28 days 
 
If a patient is deemed ineligible or a cancel, please refer to Section 13.0 for follow-up information. 
 
Generic name:    P1101 
Brand name(s): 
Mayo Abbreviation:     P1101 
Availability:   PharmaEssentia 
PD* at any time (despite dose escalations) 
Unacceptable adverse events  
Event 
Patient refusal  
Monitoring  
Treatment: 
P1101 SQ every other week each cycle1 
Registration 
Cohort 1: Early stage MF (low or intermediate 1 stage) without 
currently available treatment options. 
 
Cohort 2: intermediate-2 or high risk MF patients either not 
eligible for ruxolitinib or having failed under ruxolitinib 
Event Monitoring 

MC138F 
5 
Amendment 3 
Protocol version: 12 Sept 2018 
1.0 
Background 
1.1 
Myelofibrosis Unmet Clinical Needs 
Myelofibrosis (MF) is a clonal myeloproliferative neoplasm (along with ET, PV, and 
CML) that can arise de novo, as primary myelofibrosis, or following essential 
thrombocytosis or polycythemia vera.  Median age at diagnosis is 67 years old.  
Myelofibrosis is characterized by clonal stem cell proliferation, inefficient hematopoiesis, 
bone marrow fibrosis, and increased marrow vascularity.  Bone marrow fibrosis and 
cytokine overexpression contribute to the cytopenias, extramedullary hematopoiesis 
(resulting in hepatosplenomegaly), and constitutional symptoms that are hallmarks of the 
disease.  These associated symptoms can have considerable adverse effects on quality of 
life.  Myelofibrosis is a heterogeneous disease that can follow an indolent course lasting 
years or a rapidly progressive course with attenuated survival. The Dynamic International 
Prognostic Scoring System- plus (DIPSS Plus) is a risk stratification system used to 
predict survival in primary MF.  Early primary MF is defined as low or intermediate-1 
risk and can be distinguished from advanced stages of the disease by evidence of residual 
hematopoiesis and grade 1 or 2 fibrosis on bone marrow biopsy. 
 
Myelofibrosis is associated with a high morbidity and mortality resulting from marrow 
failure, massive splenomegaly, and leukemic transformation. Current drug therapies are 
not curative and have minimal impact on the natural history of the disease.  Allogeneic 
stem cell transplant is the only known therapy with curative potential, however, advanced 
age at diagnosis and poor performance status prevent most patients from being transplant 
eligible.   
 
1.2 
Current available treatment 
Current available treatments for primary MF target both the abnormal clonal stem cell 
proliferation and the pathologic bone marrow fibrosis.  Unfortunately, bone marrow 
changes become irreversible in advanced stages of the disease, when patients become 
symptomatic and warrant treatment.  Hydroxyurea has historically been shown to 
decrease hepatosplenomegaly, improve leukocytosis or thrombocytosis, and decrease 
constitutional symptoms in MF, however, it can cause cytopenias, is potentially 
leukemogenic, and effectiveness seems related to JAK2V617F mutation presence.  
 
Recombinant interferon has shown efficacy in other myeloproliferative neoplasms (ET, 
PV) but dosing schedules were inconvenient and side effects limited use.  Interferon α 
has induced cytogenetic and hematologic remissions in CML (another MPN) with 
evidence of reduction of marrow fibroblasts and bone marrow progenitor cells in vivo 
suggesting it may be effective in primary MF. (Gilbert HS. Cancer. 1998). Pegylated 
IFNα-2a has demonstrated efficacy, better tolerability, and a more reasonable dosing 
schedule.  Hematologic responses are durable, and there has been no proven association 
with transformation to leukemia.  A single institution study at Mayo Clinic showed rIFNα 
-2b monotherapy resulted in both hematologic and molecular responses in MF (Gowin 
Haematologica. 2012)  A prospective single institution study of recombinant IFNα in 18 
early MF patients (Silver Blood. 2011) showed an 80% rate of clinical benefit or stability 
with acceptable toxicities.  JAK2 inhibitors have been approved for use in patients with 
intermediate or high risk MF and effectively reduce spleen size, improve constitutional 
symptoms, anemia, and quality of life. These medications appear best suited for patients 
with debilitating constitutional symptoms or severe symptomatic splenomegaly as 
opposed to patients with early stage myelofibrosis. Pegylated IFNα -2b has been studied 
in the treatment of hepatitis.   

MC138F 
6 
Amendment 3 
Protocol version: 12 Sept 2018 
 
1.3 
P1101 
The study drug P1101 is a long acting pegylated interferon alpha-2b that has not yet been 
studied in MF.  Preclinical safety data supports safe use of P1101 in humans.  Clinical 
effects are expected to be similar to those of other approved Peg-IFNα products.  Three 
clinical studies have looked at safety, efficacy, and maximum tolerated dose including 
one study in polycythemia vera patients.  In this study, the MTD was found to be 540 µg 
subcutaneously every two weeks.  Among 34 evaluable patients, overall hematological 
response rate was 90% with complete response rates of 46% after one year of treatment.  
Sixteen serious adverse events have been reported.  The incidence of treatment related 
emergent adverse events with P1101 was no higher than with Pegasys®.  Adverse events 
were mostly mild to moderate in severity and resolved spontaneously.  Injection site 
erythema was the most common adverse event and headache was second.   
 
Other reported adverse events included myalgia, decreased neutrophil count, back pain, 
increased body temperature, decreased white blood cell count, arthralgia, chills, fatigue, 
eye pain, feeling cold, nausea, transaminitis, somnolence, upper respiratory tract 
infection, feeling hot, decreased appetite, and pyrexia.   
 
1.4  
Rational 
Patients with primary MF have a shortened life span and can have a significantly 
compromised quality of life as a result of progressive disease.  Disease treatment earlier 
may delay progression of disease, prolong overall survival, and improve quality of life.   
We propose an open label nonrandomized pilot study of P1101 in patients with MF with 
the hypothesis that P1101 might have an impact in either early MF or in those with MF 
who are not eligible or failed ruxolitinib.  
 
2.0 
Goals 
 
2.1 
Primary  
 
2.11 The primary objective in this study will be to evaluate for clinical response 
(complete remission [CR], partial remission [PR], or clinical improvement [CI])  
as defined by IWG-MRT criteria (Tefferi et al. Blood. 2013) in a cohort 
of intermediate-2/high risk MF patients.  Response in a second cohort of early 
stage MF patients will also be described.   
 
2.2 
Secondary  
 
2.21 To evaluate the adverse event profile of P1101 in patients with myelofibrosis by 
cohort (early vs intermediate-2/high risk) 
 
2.22 To evaluate the tolerability of P1101 in patients with myelofibrosis by cohort (early 
vs intermediate-2/high risk) 
 
2.3 
Exploratory and Correlative Research 
 
2.31  
To evaluate quality of life (QOL) and patient-reported symptoms using the MPN-
SAF with P1101 for patients with myelofibrosis. (Emanuel et al. J Clin Oncol. 
2012) by cohort (early vs intermediate-2/high risk) 
 

MC138F 
7 
Amendment 3 
Protocol version: 12 Sept 2018 
2.32 
To evaluate the impact of P1101 on bone marrow and histological features of 
myelofibrosis including cytogenetics, blast percentage, fibrosis, and JAK2-
V617F allele burden by cohort (early vs intermediate-2/high risk) 
 
3.0 
Patient Eligibility 
 Overall:  The study will enroll patients into two parallel cohorts – cohort 1, corresponding to the 
“early MF” definition, and the cohort 2, representing a “typical” MF patient. Enrollment will 
occur simultaneously for both cohorts , until the planned sample size will be achieved. 
 
3.1 
Inclusion Criteria  
 
3.10 
Evaluable myelofibrosis by IWG-MRT criteria including one or more of the 
following: 
 
• 
Spleen ≥5cm below the left costal margin 
• 
MPN-SAF TSS >10 at baseline 
• 
Hemoglobin <10 g/dL 
 
3.11 
Age ≥18 years. 
 
3.12 
Confirmed diagnosis of myelofibrosis (primary myelofibrosis or myelofibrosis 
secondary to essential thrombocythemia or polycythemia vera) by WHO 
diagnostic criteria (3 major and 2 minor criteria: Major criteria: megakaryocyte 
proliferation and atypia with either reticulin and/or collagen fibrosis, not meeting 
criteria for CML, PV, MDS, or other myeloid neoplasm, JAK2V617F or other 
clonal marker or no evidence of reactive marrow fibrosis.  Minor criteria: 
leukoerythroblastosis, increased LDH, anemia, palpable splenomegaly).   
 
3.13 
For cohort 1: Early stage MF (low or intermediate 1 stage as defined by DIPSS, 
see Appendix VI) without currently available treatment options. 
 
For cohort 2: intermediate-2 or high risk MF patients as defined by DIPSS (see 
Appendix VI) either not eligible for ruxolitinib or having failed under ruxolitinib 
 
3.14  
No prior treatment for myelofibrosis (for Cohort 1 only)  
 
3.15 
ECOG Performance Status (PS) 0, 1 or 2 (Appendix I). 
 
3.16 
The following laboratory values obtained ≤_14 days prior to registration. 
• 
Platelet count ≥100,000/mm3 
• 
Absolute Neutrophil Count (ANC) ≥1000/mm3 
• 
Aspartate transaminase (AST) ≤2.5 x ULN 
• 
Alanine aminotransferase (ALT) ≤2.5 x ULN 
• 
Calculated creatinine clearance must be ≥50 ml/min using the Cockcroft-
Gault formula below: 
Cockcroft-Gault Equation: 
Creatinine clearance for males =  
 
(140 - age)(weight in kg) 
  
 
 
 
 
 
 
(72)(serum creatinine in mg/dL) 
Creatinine clearance for females =  
 
(140 - age)(weight in kg)(0.85) 
 
 
 
 
 
 
(72)(serum creatinine in mg/dL) 

MC138F 
8 
Amendment 3 
Protocol version: 12 Sept 2018 
 
3.17 
Negative pregnancy test done ≤7 days prior to registration, for women of 
childbearing potential only. 
 
3.18 
Ability to complete questionnaire(s) by themselves or with assistance. 
 
3.19a 
Provide informed written consent. 
 
3.19b Willing to return to enrolling institution for follow-up per section 4.0  
 
3.19c 
Willing to provide blood samples for correlative research purposes (see Sections 
6.2 and 14.0) 
 
 
3.2 
Exclusion Criteria  
 
3.21 
Patients who have had chemotherapy or radiation ≤2 weeks of registration. 
 
3.22  
For Cohort 1 only: Patients with evidence of Intermediate 2 or High risk disease 
(according to DIPSS, see Appendix VI).   
 
3.23  
For Cohort 1 only: Patients with a bone marrow biopsy with <15% 
cellularity,evidence of collagen fibrosis, osteosclerosis, or blasts > 10% in 
peripheral blood or marrow (demonstrating advanced disease).   
 
3.24 
Patients who have received a prior stem cell transplant  
 
3.25 
Patients who have received radiation to the spleen within 3 months prior to 
registration 
 
3.26 
Patients with intolerance to compounds similar to pegylated interferon alpha-2b. 
  
3.27  
Patients with evidence of ≥grade 2 peripheral sensory neuropathy.  
 
3.28  
Any of the following, because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown: 
• 
Pregnant women 
• 
Nursing women 
• 
Men or women of childbearing potential who are unwilling to employ 
adequate contraception 
 
3.29a 
Co-morbid systemic illnesses or other severe concurrent disease which, in the 
judgment of the investigator, would make the patient inappropriate for entry into 
this study or interfere significantly with the proper assessment of safety and 
toxicity of the prescribed regimens. 
 
3.29b Immunocompromised patients or patients known to be HIV positive and 
currently receiving antiretroviral therapy.  
 
3.29c 
Uncontrolled simultaneous illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 

MC138F 
9 
Amendment 3 
Protocol version: 12 Sept 2018 
arrhythmia, history of depression, or psychiatric illness/social situations that 
would limit compliance with study requirements. 
 
3.29d Receiving any other investigational agent which would be considered as a 
treatment for the primary neoplasm. 
 
3.29e 
History of myocardial infarction ≤6 months prior to registration, or congestive 
heart failure requiring use of ongoing maintenance therapy for life-threatening 
ventricular arrhythmias. 
 
3.29f  History of significant or major fundoscopic findings including, but not limited to, 
retinal exudates, hemorrhage, detachment, neovascularization, papilloedema, 
optic atrophy, micro-aneurysm or macular changes. 
 
3.29g  Other active malignancy at time of registration.  EXCEPTIONS:  Non-melanotic 
skin cancer or carcinoma-in-situ of the cervix.   
 
 
 
 
 

MC138F 
10 
Amendment 3 
Protocol version: 12 Sept 2018 
4.0 
Test Schedule  
Cycle = 28 days 
 
Prior to 
Registration 
Active Monitoring 
Parameter 
≤14 days 
Cycle 1 
Day 1 
Cycle 1 
Days 8, 15, 22 
±2 days 
Cycle 2 and 
Cycle 3  
Day 15 
Prior to 
Treatment 
Cycle 2 Day 1 
and Beyond 
 
Prior to Treatment 
Cycles 2, 3, 6, 9 & 12 
and every 3 cycles 
thereafter 
Day 1 
±3 days 
At 
Treatment 
Discon-
tinuation 
±7 days 
Medical History 
X 
 
 
 
 
 
 
Prior Diagnosis/Prior Treatment 
X 
 
 
 
 
 
 
Height (pre-study only) 
X 
 
 
 
 
 
 
Weight, ECOG PS 
X 
 
 
 
 
X 
X 
Physical Examination 
X 
 
 
 
 
X 
X 
Serum pregnancy test(HCG)3 
X 
 
 
 
 
 
 
Vital Signs  
X 
X7 
 
 
 
X 
X 
CBC with Differential  and 
peripheral blood smear (Can be 
from home lab for interval 
monitoring) 
X 
 
X7 
X7 
X2 
 
X 
Chemistries (Sodium, 
potassium, creatinine, chloride, 
SGOT (AST), SGPT (ALT), 
Alkaline Phosphatase, Total 
bilirubin, glucose) 
X 
 
X7 
X7 
X2 
 
X 
JAK2, BCR-ABL, CALR, & 
MPL 
X6 
 
 
 
 
X6 
 
Treatment Evaluation (see 
Section 11) 
 
 
 
 
 
X 
X 
EKG 
X 
 
 
 
 
 
 
Transfusion Assessment 
X 
 
 
 
X5 
X 
X 
Symptom Assessment Package 
(Patient Questionnaire Booklet) 
X 
 
 
 
 
X1 
X 

MC138F 
11 
Amendment 3 
Protocol version: 12 Sept 2018 
 
Prior to 
Registration 
Active Monitoring 
Parameter 
≤14 days 
Cycle 1 
Day 1 
Cycle 1 
Days 8, 15, 22 
±2 days 
Cycle 2 and 
Cycle 3  
Day 15 
Prior to 
Treatment 
Cycle 2 Day 1 
and Beyond 
 
Prior to Treatment 
Cycles 2, 3, 6, 9 & 12 
and every 3 cycles 
thereafter 
Day 1 
±3 days 
At 
Treatment 
Discon-
tinuation 
±7 days 
Clinical  measurement of 
spleen and liver by physical 
exam 
X 
 
 
 
 
X 
X 
Research Blood Samples 
 
X7 
 
 
X7, 8 
 
 
Adverse Event monitoring 
X 
X7 
X7 
 
X5, 7 
X 
X 
Bone marrow biopsy and 
aspirate including cytogenetics4 
X 
 
 
 
 
X 
 
Footnotes: 
1. To be completed prior to treatment on Day 1.  Patient questionnaire booklet must be used; copies are not acceptable for this submission. 
2. To be completed on Day 1 of Cycles 4, 5, 7, 8, 10 and 11 at local MD office and faxed to study team 
3. Pregnancy test must be completed ≤7 days prior to registration 
4. ≤90 days prior to registration.  Repeat at cycle 6 and 12 only. 
5. Patients can be contacted by telephone for adverse event assessment when not seen in the clinic. 
6. Must be completed at least 90 days prior to registration. Any positive results at baseline will be repeated again every three cycles (Cycle 3, 
6, 9, etc). 
7. Must be completed prior to treatment. 
8. Research blood samples only collected on C1D1, C2D1, and C3D1 prior to treatment. 
 
 

MC138F 
12 
Amendment 3 
Protocol version: 12 Sept 2018 
5.0 
Grouping Factor:  
 
 Cohort:   Cohort 1 (early stage MF) versus Cohort 2 (intermediate-2 or high risk MF) 
 
 
6.0 
Registration/Randomization Procedures 
6.1 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page and enter 
the registration/randomization application.  The registration/randomization application is 
available 24 hours a day, 7 days a week.  Back up and/or system support contact 
information is available on the Web site.  If unable to access the Web site, call the MCCC 
Registration Office at 
 between the hours of 8 a.m. and 4:30 p.m. Central 
Time (Monday through Friday). 
 
The instructions for the registration/randomization application are available on the 
MCCC web page 
and detail the process for 
completing and confirming patient registration.  Prior to initiation of protocol treatment, 
this process must be completed in its entirety and a MCCC subject ID number must be 
available as noted in the instructions.  It is the responsibility of the individual registering 
the patient to confirm the process has been successfully completed prior to release of the 
study agent.  Patient registration via the registration/randomization application can be 
confirmed in any of the following ways: 
• 
Contact the MCCC Registration Office 
  If the patient was fully 
registered, the MCCC Registration Office staff can access the information from the 
centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section “Finding/Displaying 
Information about A Registered Subject.” 
 
6.2 
Correlative Research 
 
A mandatory correlative research component is part of this study, the patient will be 
automatically registered onto this component (see Sections 3.19c and 14.0). 
 
6.3 
Documentation of IRB approval must be on file in the Registration Office before an 
investigator may register any patients. 
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office 
 
If the necessary documentation is not submitted in advance of 
attempting patient registration, the registration will not be accepted and the patient may 
not be enrolled in the protocol until the situation is resolved. 
 
When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Registration Office is no longer necessary. 
 
6.4 
Prior to accepting the registration, registration application will verify the following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 

MC138F 
13 
Amendment 3 
Protocol version: 12 Sept 2018 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
 
6.5 
At the time of registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 
research of Myelofibrosis at Mayo. 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 
research to learn, prevent, or treat other health problems. 
• 
Patient has/has not given permission for MCCC to give his/her sample(s) to 
researchers at other institutions. 
 
6.6 
Treatment cannot begin prior to registration and must begin ≤ 14 days after registration. 
 
6.7 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
 
6.8 
All required baseline symptoms (see Section 10.51) must be documented and graded. 
 
6.9 
Treatment on this protocol must commence at Mayo Clinic Arizona under the supervision 
of a hematologist or healthcare professional. 
 
6.9a 
Study drug is available on site.  
 
6.9b 
Patient questionnaire booklet is available on site; copies are not acceptable for this 
submission.  
 
7.0 
Protocol Treatment 
 
7.1 
Treatment Schedule (Both Cohorts) 
 
Dose level 
Agent 
Dose 
Route 
Day 
-2 
P1101 
50 micrograms 
(mcg) 
SQ 
Day 1   
-1 
P1101 
50 micrograms 
(mcg) 
SQ 
Day 1 and 15  
0* 
P1101 
100 micrograms 
(mcg) 
SQ 
Day 1 and 15  
1 
P1101 
150 micrograms 
(mcg) 
SQ 
Day 1 and 15  
2 
P1101 
200 micrograms 
(mcg) 
SQ 
Day 1 and 15  
3 
P1101 
250 micrograms 
(mcg) 
SQ 
Day 1 and 15  
4 
P1101 
300 micrograms 
(mcg) 
SQ 
Day 1 and 15  
*starting dose level 
 
7.2 
All patients will be started at dose level 0 every other week, and then dose will be 
titrated up by 50mcg increments to a maximum dose of 300mcg every other week as 

MC138F 
14 
Amendment 3 
Protocol version: 12 Sept 2018 
tolerated.   
 
7.3  
Patients can be instructed in administration techniques and granted treatment 
independence with nursing staff approval. Patients should complete the Medication Diary 
(Appendix II) and be instructed to complete the Transfusion Diary (Appendix V). 
 
7.3 
For this protocol, the patient must return to the consenting institution for evaluation at 
least every 4 weeks during treatment through cycle 3 day 1, and then will return every 3 
cycles. 
 
7.5 
Local Medical Doctor (LMD) treatment: 
After cycle 3, day 1 and if the patient is tolerating therapy without excessive toxicity at a 
stable dose level, the patient may be seen by their Local Medical Doctor (LMD).  Patients 
will need to return to Mayo Clinic Arizona at least every 3 cycles for assessment (refer to 
Section 4.0). The registering physician retains responsibility for the patient.   
 
In this case, a written statement outlining drug dosage, method of administration, follow-
up tests required, and telephone number to call to discuss any questions with the 
responsible investigator must be sent with the patient to provide necessary information to 
the LMD.   
 

MC138F 
15 
Amendment 3 
Protocol version: 12 Sept 2018 
8.0 
Dosage Modification Based on Adverse Events  
Treatment modifications are based on adverse events. All adverse events should be graded according to the CTEP Common Terminology 
Criteria for Adverse Events (CTCAE v4.0). Dose modification recommendations listed below are general guidelines, and appropriate dose 
adjustments for patient safety should be done as deemed necessary by the treating physician or his representative. 
 
ALERT: 
ADR reporting may be required for some adverse events (See Section 10) 
 
Dose Modifications for P1101 (Based on Adverse Events in Tables 8.2)  
Starting 
Dose 
Dose level -1 Dose level -2 Dose level -3 Dose level -4 Dose level -5 Dose level -6 
Dose level -7 
100 
micrograms 
(mcg) 
50 
micrograms 
(mcg) Days 1 
and 15 
50 micrograms 
(mcg) Day 1 
only 
Discontinue 
 
 
 
 
150 
micrograms 
(mcg) 
100 
micrograms 
(mcg) 
50 micrograms 
(mcg) Days 1 
and 15 
50 
micrograms 
(mcg) Day 1 
only 
Discontinue 
 
 
 
200 
micrograms 
(mcg) 
150 
micrograms 
(mcg) 
100 
micrograms 
(mcg) 
50 
micrograms 
(mcg) Days 1 
and 15 
50 micrograms 
(mcg) Day 1 
only 
Discontinue 
 
 
250 
micrograms 
(mcg) 
200 
micrograms 
(mcg) 
150 
micrograms 
(mcg) 
100 
micrograms 
(mcg) 
50 micrograms 
(mcg) Days 1 
and 15 
50 
micrograms 
(mcg) Day 1 
only 
Discontinue 
 
300 
micrograms 
(mcg) 
250 
micrograms 
(mcg) 
200 
micrograms 
(mcg) 
150 
micrograms 
(mcg) 
100 
micrograms 
(mcg) 
50 
micrograms 
(mcg) Days 1 
and 15 
50 
micrograms 
(mcg) Day 1 
only 
Discontinue 

MC138F 
16 
Amendment 3 
Protocol version: 12 Sept 2018 
Table 8.2: Dose modification guidelines for P1101 related adverse events (with an attribution of 
possible, probable or definite)  
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
BASED ON INTERVAL ADVERSE EVENTPRIOR TO DAY 15 EACH CYCLE 
Investigations  
Grade 3 Platelet count 
decreased  
P1101 
Omit Day 15 treatment until platelet 
count resolves to grade 2 or less.  
Treatment may be restarted at the next 
lower dose level 
 
Grade 4 Neutrophil 
count decreased   
P1101 
Omit Day 15 treatment until neutrophil 
count resolves to grade 2 or less.  
Treatment may be restarted at the next 
lower dose level 
 
Grade 3 Alanine 
aminotransferase 
(ALT) increased 
P1101 
Omit Day 15 treatment until ALT 
resolves to grade 2 or less.  Treatment 
may be restarted at the next lower dose 
level 
 
Grade 3 Aspartate 
aminotransferase 
(AST) increased 
P1101 
Omit Day 15 treatment until AST 
resolves to grade 2 or less.  Treatment 
may be restarted at the next lower dose 
level 
Non Hematologic 
All other Non-
Hematologic Toxicities 
Grade ≥3 (With the 
exception of nausea, 
vomiting or diarrhea 
controlled with 
appropriate 
medications.) 
P1101 
Omit Day 15 treatment and re-check 
weekly, when returns to ≤ grade 2 
resume treatment at next lower dose 
level.  
AT TIME OF RETREATMENT ON DAY 1 OF EACH CYCLE 
Investigations  
Grade 3 Platelet count 
decreased  
P1101 
Hold treatment until platelet count 
resolves to grade 2 or less, checking 
labs weekly.  Treatment may be 
restarted at the next lower dose level.  
Contact study chair if treatment is held 
beyond 28 days. 
 
Grade 4 Neutrophil 
count decreased   
P1101 
Hold treatment until neutrophil count 
resolves to grade 2 or less, checking 
labs weekly.  Treatment may be 
restarted at the next lower dose level.  
Contact study chair if treatment is held 
beyond 28 days. 

M C 1 3 8 F  
1 7  
A me n d me nt 3  
Pr ot oc ol versi o n:  1 2 Se pt 2 0 1 8  
C T C A E  
S yste m/ Or g a n/ Cl ass 
( S O C) 
A D V E R S E E V E N T  
A G E N T  
A C TI O N * *  
 
Gra de 3 Ala ni ne 
a mi n otra nsferase 
( A L T) i ncrease d 
P 1 1 0 1  
H ol d  treat me nt u ntil A L T res ol ves t o 
gra de 2 or less, c hec ki n g la bs wee kl y.  
Treat me nt ma y be restarte d at t he ne xt 
l o wer d ose le vel.  C o ntact st u d y c hair if 
treat me nt is hel d be y o n d 2 8 da ys. 
 
Gra de 3 As partate  
a mi n otra nsferase 
( A S T) i ncrease d 
P 1 1 0 1  
H ol d  treat me nt u ntil A S T res ol ves t o 
gra de 2 or less, c hec ki n g la bs wee kl y.  
Treat me nt ma y be restarte d at t he ne xt 
l o wer d ose le vel.  C o ntact st u d y c hair if 
treat me nt is hel d be y o n d 2 8 da ys. 
N o n He mat ol o gic  
All ot her N o n -
He mat ol o gic T o xicities  
Gra de > 3 ( Wit h t he  
e xce pti o n of na usea, 
v o miti n g  or diarr hea 
c o ntr olle d wit h 
a p pr o priate 
me dicati o ns.)  
P 1 1 0 1  
H ol d  treat me nt a n d re-c hec k wee kl y, 
w he n ret ur ns t o ≤ gra de 2 res u me  
treat me nt at ne xt l o wer d ose le vel.  
* 
L ocate d at
 
* *  Use t he f oll o w i n g t o descri be acti o ns i n t he Acti o n c ol u m n: 
 
O mit = T he c urre nt d ose(s) f or t he s pecifie d dr u g(s) d uri n g a c y cle is s ki p pe d. T he  patie nt 
d oes n ot ma k e u p t he o mitte d d ose(s) at a later ti me  
 
H ol d/ Dela y = T he  c urre nt d ose(s) of all dr u gs d uri n g a c y cle is dela y e d. T he patie nt  d oes 
ma ke u p t he dela y e d d ose(s) w he n t he patie nt meets t he pr ot oc ol criteria t o restart  dr u gs.  
 
Disc o nti n ue = T he s pecifie d dr u g(s) are t otall y st o p pe d.  
 
N O T E:   If t he patie nt e x perie nces a si g nifica nt a d verse e ve nt re q uiri n g a d ose re d ucti o n at t he start 
of t he ne xt c ycle, t he n t he d ose will re mai n l o were d f or t hat e ntire s u bse q ue nt c y cle.  If t hat c y cle is 
c o m plete d wit h n o f urt her a d verse e ve nts > Gra de 2, t he n t he d ose ma y be i ncrease d, at t he 
i n vesti gat or’s discreti o n, o ne le vel at a ti me, i n t he f oll o wi n g c y cles.  
 
9. 0  
A ncill ar y Tre at me nt/ S u p p orti ve C are  
9. 1  
A ntie metics ma y be use d at t he discreti o n of t he atte n di n g p h ysicia n.  
 
9. 2  
Bl o o d pr o d ucts a n d gr o wt h fact ors s h o ul d be utilize d as cli nicall y warra nte d a n d 
f oll o wi n g i nstit uti o nal p olicies a n d rec o m me n dati o ns.  T he use of gr o wt h fact ors s h o ul d 
f oll o w p u blis he d g ui deli nes of t he A merica n S ociet y of Cli nical O nc ol o g y ( 4 2) U p date of 
Rec o m me n dati o ns f or t he Use of He mat o p oietic C ol o n y -Sti m ulati n g Fact ors: E vi de nce -
Base d, Cli nical Practice G ui deli nes.  J Cli n O nc ol 1 8( 2 0): 3 5 5 8 -3 5 8 5, 2 0 0 0.  
 
9. 3  
Patie nts s h o ul d recei ve f ull s u p p orti ve care w hile o n t his st u d y.  T his i ncl u des bl o o d 
pr o d uct s u p p ort, a nti bi otic treat me nt, a n d treat me nt of ot her ne wl y dia g n ose d or 
c o nc urre nt me dical c o n diti o ns.  All bl o o d pr o d ucts a n d c o nc o mita nt me dicati o ns s uc h 
as a nti diarr heals, a nal gesics, a n d/ or a ntie metics recei ve d fr o m t he first da y of st u d y 
treat me nt a d mi nistrati o n u ntil 3 0 da ys after t he fi nal d ose will be rec or de d i n t he 
me dical rec or ds.  
 

MC138F 
18 
Amendment 3 
Protocol version: 12 Sept 2018 
9.4 
Diarrhea:  This could be managed conservatively with loperamide.  The recommended 
dose of loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea 
free (maximum 16 mg/day). 
 
In the event of grade 3 or 4 diarrhea, the following supportive measures are allowed:  
hydration, octreotide, and antidiarrheals.   
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed.  
Patients with severe diarrhea or any diarrhea associated with severe nausea or vomiting 
should be hospitalized for intravenous hydration and correction of electrolyte 
imbalances. 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site: 
     
 
Adverse event monitoring and reporting is a routine part of every clinical trial.  First, 
identify and grade the severity of the event using the CTCAE version 4.0.  Next, 
determine whether the event is expected or unexpected (see Section 10.2) and if the 
adverse event is related to the medical treatment or procedure (see Section 10.3).  With 
this information, determine whether the event must be reported as an expedited report 
(see Section 10.4).  Important: Expedited adverse event reporting requires submission of 
an AdEERS Multiple Agent Template found at 
 
 
10.11 Expedited reports are to be completed within the timeframes and via the 
mechanisms specified in Sections 10.4. All AEs reported via expedited 
mechanisms must also be reported via the routine data reporting mechanisms 
defined by the protocol (see Sections 10.52 and 18.0). 
 
10.12 Each CTCAE term in the current version is a unique representation of a specific event 
used for medical documentation and scientific analysis and is a single MedDRA 
Lowest Level Term (LLT).   
 
 
• 
NOTE:  A severe AE, as defined by the above grading scale, is NOT 
the same as serious AE which is defined in the table in Section 10.4. 
 
10.2 
Expected vs. Unexpected 
 
• 
The determination of whether an AE is expected is based on the agent-
specific information provided in Section 15.0 of this protocol. 
 
• 
Unexpected AEs are those not listed in the agent-specific information 
provided in Section 15.0 of this protocol. 
 
NOTE: “Unexpected adverse experiences” means any adverse experience that is 

MC138F 
19 
Amendment 3 
Protocol version: 12 Sept 2018 
neither identified in nature, severity, or frequency of risk in the information 
provided for IRB review nor mentioned in the consent form.  
 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a medical 
treatment suggest there is evidence to indicate a causal relationship between the 
drug and the adverse event.  
 
10.31 Special Situations for Expedited Reporting 
 
Exceptions to Expedited Reporting: EXPECTED Serious Adverse Events 
 
 
An expedited report or notification form may not be required for specific Grade 
1, 2, 3 and 4 Serious Adverse Events where the AE is EXPECTED. Any 
protocol specific reporting procedures MUST BE SPECIFIED BELOW and will 
supersede the standard Expedited Adverse Event Reporting Requirements (Note: 
These adverse events must still be reported through the routine reporting 
mechanism [i.e. Nadir/adverse events form]; see footnote 1): 
  
System Organ Class (SOC) 
Adverse event/Symptoms 
CTCAE Grade at which the 
event will not be 
expeditedly reported. 
General disorders and 
administrations site conditions 
Fatigue  
Grade 3  
Malaise 
Investigations 
White blood cell decreased 
Grade 3 and Grade 4 
Platelet count decreased 
Neutrophil count decreased 
Blood and lymphatic system 
disorders 
Anemia 
Grade 3 and Grade 4 
1. These exceptions only apply if the adverse event does not result in hospitalization. If the 
adverse event results in hospitalization, then the standard expedited adverse events reporting 
requirements must be followed.  
 
Specific protocol exceptions to expedited reporting should be reported expeditiously by 
investigators ONLY if they exceed the expected grade of the event, except in the event of a 
hospitalization (follow reporting instructions for section 10.4). 
 
10.311 Persistent or Significant Disabilities/Incapacities 
 
Any AE that results in persistent or significant incapacity or substantial 

MC138F 
20 
Amendment 3 
Protocol version: 12 Sept 2018 
disruption of the ability to conduct normal life functions (formerly referred to 
as disabilities), congenital abnormities or birth defects, must be reported 
immediately if they occur at any time following treatment with an agent under 
an IND/IDE since they are considered to be a serious AE and must be reported 
to the sponsor as specified in 21 CFR 312.64(b). 
 
10.312 Death 
 
• 
Any death occurring within 30 days of the last dose, 
regardless of attribution to an agent/intervention under an 
IND/IDE requires expedited reporting within 24-hours. 
 
• 
Any death occurring greater than 30 days with an attribution 
of possible, probable, or definite to an agent/intervention 
under an NCI IND/IDE requires expedited reporting within 
24-hours. 
 
• 
Reportable categories of Death  
 
• 
Death attributable to a CTCAE term. 
 
• 
Death Neonatal:  A disorder characterized by 
cessation of life during the first 28 days of life. 
 
• 
Death NOS:  A cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
 
• 
Sudden death NOS:  A sudden (defined as instant or 
within one hour of the onset of symptoms) or an 
unobserved cessation of life that cannot be attributed 
to a CTCAE term associated with Grade 5. 
 
• 
Death due to progressive disease should be reported 
as Grade 5 “Neoplasms benign, malignant and 
unspecified (incl cysts and polyps) – Other 
(Progressive Disease)” under the system organ class 
(SOC) of the same name.  Evidence that the death 
was a manifestation of underlying disease (e.g., 
radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a 
disease process) should be submitted. 
 
10.313 Secondary Malignancy 
 
• 
A secondary malignancy is a cancer caused by treatment for a 
previous malignancy (e.g., treatment with investigational 
agent/intervention, radiation or chemotherapy).  A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 

MC138F 
21 
Amendment 3 
Protocol version: 12 Sept 2018 
• 
All secondary malignancies that occur following treatment with an 
agent under an IND/IDE must be reported via AdEERS.  Three 
options are available to describe the event: 
 
o Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myelocytic Leukemia [AML]) 
 
o Myelodysplastic syndrome (MDS) 
 
o Treatment-related secondary malignancy 
 
• 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
 
10.314 Second Malignancy 
 
• 
A second malignancy is one unrelated to the treatment of a prior 
malignancy (and is NOT a metastasis from the initial malignancy).  
Second malignancies require ONLY routine reporting via CDUS. 
 
 

MC138F 
22 
Amendment 3 
Protocol version: 12 Sept 2018 
10.4  
Expedited Reporting Requirements: 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
sponsor within the timeframes detailed in the table below using the AdEERS Multiple Agent Template 
 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
7 Calendar Days 
24-Hour 3 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
7 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in 
section 10.31 of the protocol. 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported via  paper Adverse Event 
Expedited Report – Single Agent or Multiple Agents within 24 hours of learning of the 
AE, followed by a complete expedited report within 3 calendar days of the initial 24-hour 
report.3 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 
calendar days of learning of the AE.3 
   Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as 
follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
Effective Date:  May 5, 2011 

MC138F 
23 
Amendment 3 
Protocol version: 12 Sept 2018 
10.42 General reporting instructions 
The Mayo IND Coordinator will assist the sponsor-investigator in the processing 
of expedited adverse events and forwarding of suspected unexpected serious 
adverse reactions (SUSARs) to the FDA and IRB. 
Use Mayo Expedited Event Report 
form 
for investigational agents or 
commercial/investigational agents on the same arm.  
 
10.43 Reporting of re-occurring SAEs 
ALL SERIOUS adverse events that meet the criteria outlined in table10.4 MUST 
be immediately reported to the sponsor within the timeframes detailed in the 
corresponding table. This reporting includes, but is not limited to SAEs that re-
occur again after resolution. 
 
10.44.  Reporting of SAEs to PharmaEssentia 
 
SAE reporting forms should be faxed or emailed directly to: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

MC138F 
24 
Amendment 3 
Protocol version: 12 Sept 2018 
10.5 
Other Required Reporting 
 
10.51  Adverse events to be graded at each evaluation and pretreatment symptoms/conditions to 
be evaluated at baseline per the CTCAE v4.0 grading unless otherwise stated in the table 
below: 
 
System/Organ/Class 
(SOC) 
Adverse 
event/Symptoms 
Baseline 
Each 
evaluation 
Investigations 
White blood cell 
decreased 
X 
X 
Neutrophil count 
decreased 
X 
X 
Platelet count 
decreased 
X 
X 
Gastrointestinal 
Disorders 
Diarrhea 
 
X 
# of stools 
X 
 
Nausea 
X 
X 
Vomiting 
X 
X 
 
 
10.52 Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.51 
 
10.521 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
 
10.522 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
 
10.523 Grade 5 AEs (Deaths) 
 
10.5231 
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
 
10.5232 Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
 
10.53 Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion 
of the Active Monitoring Phase (i.e., compliance with Test Schedule in Section 
4.0). 
 
 

MC138F 
25 
Amendment 3 
Protocol version: 12 Sept 2018 
11.0 
Treatment Evaluation 
Revised International Working Group for Myeloproliferative Neoplasms Research and Treatment 
(IWG-MRT) as defined by IWG-MRT criteria (Tefferi et al. Blood. 2013) 
Table 11.1 
Response 
categories 
Required criteria 
Complete 
Remission 
(CR) 
Bone marrow:* Age-adjusted normocellularity; <5% blasts; ≤Grade 1 myelofibrosis**, 
AND 
Peripheral blood: Hemoglobin ≥100 g/L and <UNL; Neutrophil count ≥1 x 109/L and 
<UNL; 
Platelet count ≥100 x 109/L and <UNL; <2% immature myeloid cells***, AND 
Clinical: Resolution of disease symptoms; Spleen and liver not palpable; No evidence 
of EMH 
Partial 
Remission 
(PR) 
Peripheral blood: Hemoglobin ≥100 g/L and <UNL; Neutrophil count ≥1 x 109/L and 
<UNL; 
Platelet count ≥100 x 109/L and <UNL; <2% immature myeloid cells***, AND 
Clinical: Resolution of disease symptoms; Spleen and liver not palpable; No evidence 
of EMH 
OR 
Bone marrow:* Age-adjusted normocellularity; <5% blasts; ≤Grade 1 myelofibrosis**, 
AND 
Peripheral blood: Hemoglobin ≥85 but <100 g/L and <UNL; Neutrophil count ≥1 x 
109/L and <UNL; 
Platelet count ≥50 but <100 x 109/L and <UNL; <2% immature myeloid cells***, AND 
Clinical: Resolution of disease symptoms; Spleen and liver not palpable; No evidence 
of EMH 
Clinical 
improvement 
(CI) 
The achievement of anemia, spleen or symptoms response without progressive disease 
or 
increase in severity of anemia, thrombocytopenia or neutropenia‡ 
Anemia 
response 
Transfusion-independent patients: a ≥20 g/L increase in hemoglobin level† 
Transfusion-dependent patients: becoming transfusion-independent†† 
Spleen 
Response § 
A baseline splenomegaly that is palpable at 5-10 cm, below the LCM, becomes not 
palpable§§, OR 
A baseline splenomegaly that is palpable at >10 cm, below the LCM, decreases by 
≥50%§§ 
A baseline splenomegaly that is palpable at <5 cm, below the LCM, is not eligible for 
spleen response 
A spleen response requires confirmation by MRI or CT showing ≥35% spleen volume 
reduction (optional) 
Symptoms 
response 
A ≥50% reduction in the Myeloproliferative Neoplasm Symptom Assessment Form 
total symptom score (MPN-SAF TSS) 
Progressive 
Disease ¥ 
(PD) 
Appearance of a new splenomegaly that is palpable at least 5 cm below the LCM, OR 
A ≥100% increase in palpable distance, below LCM, for baseline splenomegaly of 5 to 
10 cm, OR 
A 50% increase in palpable distance, below LCM, for baseline splenomegaly of >10 cm, 
OR 
Leukemic transformation confirmed by a bone marrow blast count of ≥20%, OR 
A peripheral blood blast content of ≥20% associated with an absolute blast count of ≥1 x 
10(9)/L that lasts for at least two weeks 

MC138F 
26 
Amendment 3 
Protocol version: 12 Sept 2018 
Stable 
Disease 
(SD) 
Belonging to none of the above listed response categories 
Relapse 
(REL) 
No longer meeting criteria for at least CI after achieving CR, PR or CI, OR 
Loss of anemia response persisting for at least one month, OR 
Loss of spleen response persisting for at least one month 
 
Key: UNL, upper normal limit; LCM, left costal margin; MRI, magnetic resonance imaging; CT, 
computed tomography; EMH, extramedullary hematopoiesis (no evidence of EMH implies the absence of 
pathology- or imaging study-proven non-hepatosplenic EMH) ; 
 
*Baseline and post-treatment bone marrow slides are to be stained at the same time and interpreted at one 
sitting by a central review process. Cytogenetic and molecular responses are not required for CR 
assignment. 
 
**Grading of myelofibrosis is according to the European classification (Thiele et al. Haematologica 
2005;90:1128) . It is underscored that the consensus definition of “a complete remission bone marrow” is 
to be used only in those patients where all other criteria, including resolution of leukoerythroblastosis, are 
met. It should also be noted that it was a particularly difficult task for the working group to reach a 
consensus regarding what represents a complete histological remission. 
 
***Immature myeloid cells constitute blasts + promyelocytes + myelocytes + metamyelocytes + 
nucleated red blood cells. In splenectomized patients, <5% immature myeloid cells is allowed. 
 
See table 11.1 for definitions of anemia response, spleen response and progressive disease. Increase in 
severity of anemia constitutes the occurrence of new transfusion dependency or a ≥20 g/L decrease in 
hemoglobin level from pre-treatment baseline that lasts for at least 12 weeks. Increase in severity of 
thrombocytopenia or neutropenia is defined as a 2-grade decline, from pre-treatment baseline, in platelet 
count or absolute neutrophil count, according to Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0. In addition, assignment to clinical improvement (CI) requires a minimum platelet 
count of ≥25,000 x 10(9)/L and absolute neutrophil count of ≥0.5 x 10(9)/L 
 
Applicable only to patients with baseline hemoglobin of <100 g/L. In patients not meeting the strict 
criteria for transfusion-dependency at the time of study enrollment (see below), but have received 
transfusions within the previous month, the pre-transfusion hemoglobin level should be used as the 
baseline 
 
Transfusion dependency before study enrollment is defined as transfusions of at least 6 units of packed 
red blood cells (PRBC), in the 12 weeks prior to study enrollment, for a hemoglobin level of <85 g/L, in 
the absence of bleeding or treatment-induced anemia. In addition, the most recent transfusion episode 
must have occurred in the 28 days prior to study enrollment. Response in transfusion dependent patients 
requires absence of any PRBC transfusions during any consecutive “rolling” 12-week interval during the 
treatment phase, capped by a hemoglobin level of ≥85 g/L. 
 
In splenectomized patients, palpable hepatomegaly is substituted with the same measurement strategy 
 
Optional, Spleen or liver responses can be confirmed by imaging studies where a ≥35% reduction in 
spleen volume, assessed by magnetic resonance imaging (MRI) or computed tomography (CT), is 
required. Furthermore, a≥35% volume reduction in the spleen or liver, by MRI or CT, constitutes a 
response regardless of what is reported with physical examination. 
 

MC138F 
27 
Amendment 3 
Protocol version: 12 Sept 2018 
Symptoms are evaluated by the Myeloproliferative Neoplasm Symptom Assessment Form total symptom 
score (MPN-SAF TSS).17 The MPN-SAF TSS is assessed by the patients themselves and includes 
fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, 
weight loss, and fevers. Scoring is from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as 
it can be) for each item. The MPN-SAF TSS is the summation of all the individual scores (0-to-100 
scale). Symptoms response requires ≥50% reduction in the MPN-SAF TSS. 
 
Optional, Progressive disease assignment for splenomegaly requires confirmation my MRI or CT 
showing a ≥25% increase in spleen volume from baseline. Baseline values for both physical examination 
and imaging studies refer to pre-treatment baseline and not to post-treatment measurements. 
  
12.0 
Descriptive Factors  
12.1 
Prior ET/PV disease specific therapy (including drugs, or splenectomy):  Yes vs no. 
12.2 
Prior bleeding events felt to be related to underlying disease:  Yes vs no. 
12.3 
Prior thrombosis: Yes vs no. 
12.4 
Type of Myelofibrosis at registration: Primary Myelofibrosis (PMF) vs. Post ET 
Myelofibrosis vs. Post PV Myelofibrosis.  
12.5 
MF DIPSS Risk at time of registration (Appendix VI):  Low vs. Int-1 vs. Int-2 vs. high 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient   
13.1 
Patients who are without progression will continue treatment per protocol. 
13.2 
Patients who develop PD while receiving therapy will go to the event-monitoring phase. 
13.3 
Patients who go off protocol treatment for reasons other than PD will go to the event-
monitoring phase per Section 18.0. 
13.4 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry. 
The patient will go directly to the event-monitoring phase of the study (or off study, if 
applicable).  
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted.  Event monitoring will be required per Section 18.0 
of the protocol.  
• 
If the patient never received treatment, on-study material and the end of active 
treatment/cancel notification form must be submitted.  Nor further data submission is 
necessary.  
13.5 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable.  All data up until the point of confirmation of a major violation must be 
submitted.  The patient will go directly to the event-monitoring phase of the study.    
Event monitoring will be required per Section 18.0 of the protocol. 
13.6 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given.  On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted.  No further data submission is necessary. 
 

MC138F 
28 
Amendment 3 
Protocol version: 12 Sept 2018 
14.0 
Body Fluid Biospecimens 
14.1  
Summary Table of Research Blood and Body Fluid Specimens to be Collected for this 
Protocol 
Correlative Study 
(Section for more 
information) 
Mandatory 
or Optional 
Blood or 
Body Fluid 
being 
Collected 
Type of 
Collection 
Tube (color 
of tube top) 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
Prior to 
Treatment 
on C1D1, 
C2D1, 
C3D1 
Process 
at site? 
(Yes or 
No) 
Temperature 
Conditions 
for Storage 
/Shipping 
Banking 
Mandatory 
Serum 
Red 
10 mL 
(1) 
X 
yes 
Freeze 
 
 
14.2  
Blood/Blood Products Handling 
 
14.21  All samples must be collected Monday-Friday ONLY. 
 
14.22  Label specimen tube(s) with protocol number, patient study ID number, and time 
and date blood drawn. 
 
14.23  Collect and processing  
 
14.231  Serum specimens will be collected per schedule as outlined in Section 
14.1.  Collect 10 mLs of No Additive blood and allow the blood to clot at 
room temperature x 30 minutes.  Centrifuge the blood at 3000 rpm x 10 
minutes.  Carefully aliquot the 1.0 mL of serum into three aliquots and 
0.5 mL into the 4th aliquot and freeze at - 80°C freezer until requested. 
 
 
15.0 
Drug Information 
 
15.1 
P1101 (PEG-P-IFNa-2b)  
 
15.11 Background:  
P1101 is a long-acting interferon that has only one major form as opposed to the 
8-14 isomers of other FDA approved pegylated interferon products that are 
indicated for the treatment of hepatitis B and C. With P1101, it is anticipated that 
a reduced dosing frequency will be possible (once every two or more weeks) 
compared to that required with other pegylated interferon products. P1101 was 
shown to have slightly longer half-life but maintain serum 2’5’-oligoadenylate 
synthetase (OAS) activity longer than the other pegylated interferon products. 
 
15.12 Formulation:  P1101 will be supplied in a pre-filled syringe containing 500 
micrograms ropeginterferon alfa-2b, sodium chloride, sodium acetate, acetic 
acid, benzyl alcohol, polysorbate 80 and water for injection  
 
15.13 Storage: Syringes are shipped in cooled containers. Syringes must be 
refrigerated at 2°C-8°C immediately upon receipt to ensure optimal retention of 
physical and biochemical integrity and should remain refrigerated until just prior 
to use. Temperature logs must be maintained (in accordance with local pharmacy 
practice) to ensure proper storage conditions. Do not use medication beyond the 

MC138F 
29 
Amendment 3 
Protocol version: 12 Sept 2018 
expiration date stamped on the vial. If a temperature deviation from the allowed 
2°C-8°C is found either during shipment or storage then please contact the 
Sponsor to determine if the drug is still available for use.  Refrigerated syringes 
at 2°C-8°C must have the following conditions adhered to: Do not freeze. Do not 
shake. Keep syringe in outer carton; protect from light. 
 
Study medication labels will contain the following information: site number, 
subject number, visit number, product description, dosage strength, dosing 
instruction, expiry date, lot number, storage conditions, and caution statements. 
 
15.14 Administration:  P1101should be given by subcutaneous injections in the 
abdomen around but not within two inches of the navel. If the abdomen appears 
inappropriate according to the investigator’s judgment, then study drug can be 
injected subcutaneously to the thigh. 
 
15.15 Pharmacokinetic information:  Mean P1101 serum concentration time 
curves were comparable across treatment groups and reached a peak at 
approximately 3 to 5 days after dosing and then declined gradually, with 
elimination half-lives of 60 to 118 hours. Single dose pharmacokinetic 
parameters (Cmax, AUC and AUC0-t) for P1101 increased with dose. The 
results of the power model analysis of dose proportionality for P1101 
suggested more than proportional kinetics with increasing dose, as the 
slopes of the power model ranged from 1.19 to 1.36. The lack of dose 
proportionality for P1101 in this study may be attributed partly due to the 
high intersubject pharmacokinetic variability, and the small number of 
subjects. 
 
 
 
 
 
15.16 Potential Drug Interactions:  No information available. 
 
15.17 Known potential toxicities:  Adverse events reported most frequently (>10% of 
subjects) in either treatment in the single dose study include injection site 
erythema, headache, myalgia, decreased neutrophil count, back pain, increased 
body temperature, decreased white blood cell count, arthralgia, chills, fatigue, 
eye pain, feeling cold, nausea, increased alanine aminotransferase, somnolence, 
upper respiratory tract infection, feeling hot, decreased appetite, and pyrexia.  
 
Adverse events reported in the repeated dose study have so far been mild to 
moderate. These include anemia, dizziness, dry mouth, dry skin, dyspnea, ear 
pain, epigastralgia, epistaxis, fatigue, fidget, flank pain, headache, myalgia, 
pruritus, respiratory distress, skin allergy, skin erythema, somnolence, sore 
throat, UTI, WBC decrease.  
 
Investigators should also be informed of published data on marketed pegylated 
interferon.  Subjects receiving repeated doses of interferon α-2b, have reported 
adverse events that include influenza-like symptoms, fever, headache, fatigue, 
rigors, musculoskeletal pain, arthralgia, back pain, injection site disorders 
(bruising, itching, and irritation), dry mouth, nausea/vomiting, diarrhea, 
abdominal pain, anorexia, weight, dizziness, impaired concentration, impaired 
memory, depression, anxiety/emotional lability/irritability, insomnia, alopecia, 
pruritus, dermatitis, rash, increased sweating, dyspnea, cough, and 
hypothyroidism. Common laboratory adverse events include neutropenia, 

MC138F 
30 
Amendment 3 
Protocol version: 12 Sept 2018 
thrombocytopenia, increases in triglycerides and total cholesterol, abnormalities 
indicative of altered thyroid and liver function. Ten to fifteen percent of patients 
develop antibodies to interferon. 
 
Serious adverse events that have been reported with this class of drugs include 
suicide attempt, suicidal ideation, severe depression, relapse of drug 
addiction/overdose, nerve palsy (facial, oculomotor), cardiomyopathy, 
myocardial infarction, retinal ischemia, retinal vein thrombosis, transient 
ischemic attack, supraventricular arrhythmias, loss of consciousness, 
neutropenia, infection (pneumonia, abscess), autoimmune thrombocytopenia, 
hyperthyroidism, rheumatoid arthritis, interstitial nephritis, lupus-like syndrome, 
aggravated psoriasis and urticaria. 
 
15.18  Drug procurement:   Drug is supplied by PharmaEssentia and provided free of 
charge to study subjects. 
 
 
15.19 Nursing Guidelines:  
 
15.191 Patients may experience injection site reactions including pain, erythema. 
 
15.192 Monitor LFT’s, report increases to the study team. 
 
15.193 Monitor CBC w/diff. Leukopenia and neutropenia have been seen with 
agent. 
 
15.194 Patients may experience fever. Treat symptomatically and monitor for 
effectiveness. 
 
15.195 Arthralgias, and back pain were common. Treat symptomatically and 
monitor for effectiveness.   
 
15.196 Given the similarity between this agent and pegylated IFN, patients may 
experience similar reactions and side effects. Carefully review those with 
patients based on the published data for pegylated IFN.  Additionally this 
information is found in section 15.17 of the protocol.  
 
16.0 
Statistical Considerations and Methodology  
 
16.1  
Overview: This protocol will assess the efficacy of P1101in patients with myelofibrosis 
using a two-stage phase II study design. Cohort 2 will be formally analyzed for safety and 
efficacy as described by the decision rules below.  Cohort 1 analysis will be descriptive 
only; no formal efficacy decision rules will be applied.  Recruitment occurs separately for 
cohort 1 and cohort 2.  We currently plan to enroll and complete Stage 1.  The 
protocol will be amended to expand to Stage 2. 
 
16.11 Primary Endpoint (Cohort 1 &  2):  The primary endpoint of this trial is best 
overall response.  An evaluable patient will be classified as a treatment success for the 
primary endpoint if the patient’s best overall response is CR, PR or CI (Clinical 
Improvement) as determined by International Working Group Criteria [detailed in 
Section 11.0] over all cycles of study treatment.  All patients meeting the eligibility 

MC138F 
31 
Amendment 3 
Protocol version: 12 Sept 2018 
criteria who have signed a consent form, have begun treatment, and have not experienced 
a major treatment violation within the first cycle of treatment will be evaluable for 
response. Any evaluable patient not meeting the definition for treatment success will be 
deemed as having a treatment failure.  The primary endpoint will be formally tested 
based on the decision rules below for cohort 2.  For cohort 1, the primary endpoint will 
be summarized for descriptive purposes only.   
 
16.2  
Statistical Design: 
 
16.21  Decision Rule(Cohort 2 only) : The largest success proportion where the 
proposed treatment regimen would be considered ineffective in this population is 
10%, and the smallest success proportion that would warrant subsequent studies 
with the proposed regimen in this patient population is 30%. The following two-
stage Fleming design (1982) uses 12 or 35 patients to test the null hypothesis that 
the true success proportion in a given patient population is at most 10%.  
 
16.211  STAGE 1(Cohort 2 only): Enter 12 patients into the study. If 0 successes 
are observed in the first 12 evaluable patients, we will consider this 
regimen ineffective in this patient population and terminate this study. If 
4 or more successes are observed in the first 12 evaluable patients, we 
may recommend further testing of this regimen in subsequent studies in 
this population (a decision to complete the planned accrual specified by 
the design will be based on availability of budget, assuming no safety 
concerns). Otherwise, if the number of successes is 1, 2, or 3, we will 
consider a protocol amendment to expand to Stage 2. In cohort 2, after 
the first 3 patients are enrolled a recruitment pause will occur  as asafety 
precaution measure.  Safety/toxicity data will be analyzed in these 3 
patients and a decision to continue the study will be made by the 
Principal Investigator, statistician and study team. . 
 
 
16.212  STAGE 2(Cohort 2 only): Enter an additional 23 patients into the study. 
If 6 or fewer successes are observed in the first 35 evaluable patients, we 
will consider this regimen ineffective in this patient population. If 7 or 
more successes are observed in the first 35 evaluable patients, we may 
recommend further testing of this regimen in subsequent studies in this 
population. 
 
16.213  Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used 
in any decision making process. Analyses involving over accrued 
patients is discussed in Section 16.34. 
 
16.22  Sample Size: The two-stage study design to be utilized is fully described in 
Section 16.21. A minimum of 12 and a maximum of 35 evaluable patients will be 
accrued onto this phase II (Cohort 2 only) study unless undue toxicity is 
encountered. We are currently planning to enroll to Stage 1 only.  We 
anticipate accruing an additional 1 patient to Stage 1 to account for ineligibility, 
cancellation, major treatment violation, or other reasons. Maximum projected 
accrual to Stage 1 is therefore 13 patients for cohort 2.  Anticipated enrollment 
in cohort 1 is expected to be low, therefore a maximum of 6 patients will be 

MC138F 
32 
Amendment 3 
Protocol version: 12 Sept 2018 
enrolled in cohort 1.   Cohort 1 will be analyzed for descriptive purposes only,  
Total sample size is a maximum of 19 patients in both cohorts for Stage 1. 
 
16.23   Accrual Time and Study Duration:  The anticipated accrual rate is approximately 
1 patient per month. Therefore, the accrual period for Stage 1 of this phase II 
study is expected to be 19 months.  The Stage 1 analysis can begin approximately 
25 months after the trial begins, i.e., as soon as the last patient has been followed 
for 6 months.  
 
16.24  Power and Significance Level (Cohort 2 only): Assuming that the number of 
successes is binomially distributed, the significance level is >/=10% and the 
probability of declaring that this regimen warrants further studies (i.e., statistical 
power) under various success proportions and the probability of stopping accrual 
after the first stage can be tabulated as a function of the true success proportion 
as shown in the following table.  These computations assume that the study is 
carried out in its entirety (i.e., accrual continues to Stage 2 if indicated by the 
responses observed in Stage 1). 
 
If the true success proportion is . . .  
0.10 
0.15 
0.20 
0.25 
0.30 
0.35 
then the probability of declaring that 
the regimen warrants further studies 
is . . .  
0.07 
0.28 
0.58 
0.81 
0.93 
0.98 
and the probability of stopping (and 
rejecting Ha) at stage 1 is . . .  
0.28 
0.14 
0.07 
0.03 
0.01 
<0.01 
and the probability of stopping at 
stage 1 is . . .  
0.31 
0.23 
0.27 
0.38 
0.52 
0.66 
 
16.25  Other Considerations: Adverse events, quality/duration of response, and patterns 
of treatment failure observed in this study, as well as scientific discoveries or 
changes in standard care will be taken into account in any decision to terminate 
the study. 
 
16.3  
Analysis Plan: The analysis for this trial will commence at planned time points (see 
Section 16.2) and at the time the patients have become evaluable for the primary 
endpoint. Such a decision will be made by the Statistician and Study Chair, in accord 
with CCS Standard Operating Procedures, availability of data for secondary endpoints 
(e.g., laboratory correlates), and the level of data maturity. It is anticipated that the 
earliest date in which the results will be made available via manuscript, abstract, or 
presentation format is approximately 19 months after the trial begins, i.e., as soon as the 
last patient has been followed for 6 months. 
 
16.31  Primary Endpoint (Both Cohorts) 
 
16.311  Definition:  The primary endpoint of this trial is the best overall response 
rate where a response is defined in Section 16.11. 
 
16.312  Estimation: The proportion of successes will be estimated by the number 
of successes divided by the total number of evaluable patients. 
Confidence intervals for the true success proportion will be calculated 
according to the approach of Duffy and Santner (1987). 
 

MC138F 
33 
Amendment 3 
Protocol version: 12 Sept 2018 
16.313  Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used 
in any decision making processes; however, they will be included in final 
point estimates and confidence intervals as though they were accrued in 
the final stage. 
 
16.32  Definitions and Analyses of Secondary Endpoints (Both Cohorts) 
 
16.321  Survival time is defined as the time from registration to death due to any 
cause. The distribution of survival time will be estimated using the 
method of Kaplan-Meier (1958).  
 
16.322  Adverse events: All eligible patients that have initiated treatment will be 
considered evaluable for assessing adverse event rate(s). The maximum 
grade for each type of adverse event will be recorded for each patient, 
and frequency tables will be reviewed to determine patterns. 
Additionally, the relationship of the adverse event(s) to the study 
treatment will be taken into consideration. 
 
16.33  Exploratory & Correlative Endpoints (Both Cohorts) 
 
16.331  Patient-reported outcomes:  Patient-reported outcomes will be an 
exploratory component of this trial.  Patient-reported symptoms and 
quality of life (QOL) will be described at each time point using the mean, 
confidence interval, median, and range.  The MPN-SAF will be analyzed 
using published scoring algorithms. For the MPN-SAF, we will 
investigate changes in individual symptoms, changes in a symptom scale 
composed of symptoms specific to MF patients (night sweats, itching, 
abdominal discomfort, abdominal pain, early satiety, and bone pain) 
similar to the subset of symptoms used in the COMFORT clinical trials, 
and changes in the MPN Total Symptom Score (MPN-TSS, Emanuel et 
al, J Clin Oncol 2012 [in press]).  Interpretation will take into 
consideration that the MPN-TSS includes symptoms potentially 
irrelevant to this MF population.  Graphical procedures will include 
stream plots of individual patient scores and plots of average values over 
time.  Correlational analyses will be done to determine the relationships 
among patients-reported symptoms and QOL, as well as with clinical 
outcomes (best overall response and overall survival) and clinician-
assessed symptoms (NCI CTCAE v4).  Such correlations will be done at 
single data time points. 
 
16.4  
Data & Safety Monitoring: 
 
16.41  The study chair(s) and the study statistician will review the study at least twice a 
year to identify accrual, adverse event, and any endpoint problems that might be 
developing. The Mayo Clinic Cancer Center (MCCC) Data Safety Monitoring 
Board (DSMB) is responsible for reviewing accrual and safety data for this trial 
at least twice a year, based on reports provided by the MCCC Statistical Office. 
 
16.42  Adverse Event Stopping Rules: The stopping rules specified below are based on 
the knowledge available at study development. The stopping rule applies to the 

MC138F 
34 
Amendment 3 
Protocol version: 12 Sept 2018 
overall study, irregardless of cohort.  We note that the Adverse Event Stopping 
Rule may be adjusted in the event of either (1) the study re-opening to accrual or 
(2) at any time during the conduct of the trial and in consideration of newly 
acquired information regarding the adverse event profile of the treatment(s) 
under investigation. The study team may choose to suspend accrual because of 
unexpected adverse event profiles that have not crossed the specified rule below. 
 
Accrual will be temporarily suspended to this study if at any time we observe 
events considered at least possibly related to study treatment (i.e. an adverse 
event with attribute specified as “possible”, “probable”, or “definite”) that satisfy 
the following: 
 
• 
if 2 or more patients in the first 6 treated patients in either cohort (or 30% 
after the first 6 treated patients have been accrued) experience a grade 4 or 
higher non-hematologic adverse event. 
 
We note that we will review grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to verify their attribution and to monitor the emergence 
of a previously unrecognized treatment-related adverse event. 
 
16.5 
Results Reporting on ClinicalTrials.gov: At study activation, this study will have been 
registered within the “ClincialTrails.gov” website. The Primary and Secondary Endpoints 
(i.e., “Outcome Measures”) along with other required information for this study will be 
reported on ClinicalTrials.gov. For purposes of timing of the Results Reporting, the 
initial estimated completion date for the Primary Endpoint of this study is 19 months after 
the study opens to accrual. The definition of “Primary Endpoint Completion Date” 
(PECD) for this study is at the time the last patient registered has completed treatment. 
 
16.6  
Inclusion of Women and Minorities 
 
16.61  This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
 
16.62  There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, and there is no reason to 
expect such differences to exist. Therefore, although the planned analysis will, as 
always, look for differences in treatment effect based on racial and gender 
groupings, the sample size is not increased in order to provide additional power 
for subset analyses. 
 
16.63  The geographical region served by this study, has a population which includes 
approximately 7% minorities. Based on prior MMC studies involving similar 
disease sites, we expect about 7% of patients will be classified as minorities by 
race and about 33% of patients will be women. Expected sizes of racial by 
gender subsets for patients registered to this study are shown in the following 
table: 
 
 
 

MC138F 
35 
Amendment 3 
Protocol version: 12 Sept 2018 
Accrual Estimates by Gender/Ethnicity/Race 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
0 
1 
 
1 
Not Hispanic or Latino 
6 
12 
 
18 
Ethnic Category: Total of all subjects* 
6 
13 
 
19 
Racial Category 
 
American Indian or Alaska Native 
0 
0 
 
0 
Asian 
0 
0 
 
0 
Black or African American 
0 
1 
 
1 
Native Hawaiian or other Pacific Islander 
0 
0 
 
0 
White 
6 
12 
 
18 
Racial Category: Total of all subjects* 
6 
13 
 
19 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, South or Central American, 
or other Spanish culture or origin, regardless of race.  The term “Spanish origin” can also be 
used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
 
 
Racial 
Categories: 
American Indian or Alaska Native – a person having origins in any of the original peoples 
of North, Central, or South America, and who maintains tribal affiliations or community 
attachment. 
Asian – a person having origins in any of the original peoples of the Far East, Southeast Asia, 
or the Indian subcontinent including, for example, Cambodia, China, India, Japan, Korea, 
Malaysia, Pakistan, the Philippine Islands, Thailand, and Vietnam.  (Note: Individuals from 
the Philippine Islands have been recorded as Pacific Islanders in previous data collection 
strategies.)  
Black or African American – a person having origins in any of the black racial groups of 
Africa.  Terms such as “Haitian” or “Negro” can be used in addition to “Black or African 
American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the original 
peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle East, or 
North Africa. 
 
17.0  
Pathology Considerations/Tissue Biospecimens   
 
None 
 
 
 

MC138F 
36 
Amendment 3 
Protocol version: 12 Sept 2018 
18.0 
Records and Data Collection Procedures   
18.1 
Submission Timetables 
 
Initial Material(s) -  
Case Report Form (CRF) 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
On-Study  
≤2 weeks after registration 
Adverse Event - Baseline 
Measurement - Baseline 
Bone Marrow and Cytogenetics 
Bone Marrow Biopsy Report including 
Cytogenetics 
JAK2V617F, BCR/ABL, CALR AND MPL 
Research Blood Submission 
End of Active Treatment/Cancel Notification  
Submit ≤2 weeks after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
Patient Questionnaire  
≤2 weeks after registration – Patient questionnaire booklet 
must be used; copies are not acceptable for this submission. 
Booklet Compliance  
≤2 weeks after registration – This form must be completed 
only if the [name of booklet(s) – or whatever verbiage you 
want to use to describe the booklet(s)] contains absolutely NO 
patient provided assessment information. 
 
Test Schedule Material(s)  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation 
during treatment 
At end of treatment 
Evaluation/Treatment  
X 
X 
Concurrent Transfusion 
X 
X 
Interval Laboratory 
X 
X 
Bone Marrow and Cytogenetics 
X3 
 
Bone Marrow Biopsy Report including 
Cytogenetics 
X3 
 
JAK2V617F, BCR/ABL, CALR AND MPL 
X 
 
Nadir/Adverse Event  
X 
X 
Measurement  
X 
X 
Research Blood Submission 
X (see Section 14.0) 
 
Patient Questionnaire  
X1 
 
Booklet Compliance  
X2 
 
End of Active Treatment/Cancel Notification  
 
X 
ADR/AER 
At each occurrence 
(see Section 10.0) 
 
1. Patient questionnaire booklet must be used; copies are not acceptable for this submission. 
2. This form must be completed only if the booklet contains absolutely NO patient provided 
assessment information. 
3. Only required when bone marrow biopsy is performed. 

MC138F 
37 
Amendment 3 
Protocol version: 12 Sept 2018 
 
 
Follow-up Material(s)  
CRF 
Event Monitoring Phase1 
q. 3 months until 
PD and/or 
subsequent 
treatment2 
At PD2 
After PD and/or 
subsequent 
treatment q. 6 mos. 
Death 
New Primary 
Event Monitoring  
X 
X 
X 
X 
At each occurrence 
1. If a patient is still alive __3___ years after registration, no further follow-up is required. 
2. Submit copy of documentation of response or progression to the MCCC Operations Office, Attention: 
QAS  
 
19.0  
Budget 
 
 
19.1 
Costs charged to patient:  routine clinical care 
 
19.2 
Tests to be research funded: P1101 study drug is supplied by PharmaEssentia and 
provided free of charge to study subjects. 
 
 
19.3 
Other budget concerns: none 
 
20.0 
References 
 
1. Recombinant interferon-α may retard progression of early primary myelofibrosis: a preliminary report.  
Blood. 2011 Jun 16;117(24):6669-72. doi: 10.1182/blood-2010-11-320069. Epub 2011 Apr 25. 
2. Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative 
Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus 
report.Tefferi A, Cervantes F, Mesa R, Passamonti F, Verstovsek S, Vannucchi AM, Gotlib J, Dupriez B, 
Pardanani A, Harrison C, Hoffman R, Gisslinger H, Kröger N, Thiele J, Barbui T, Barosi G. 
3. The renaissance of interferon therapy for the treatment of myeloid malignancies.  Kiladjian JJ, Mesa 
RA, Hoffman R. 2011 May 5;117(18):4706-15. doi: 10.1182/blood-2010-08-258772. Epub 2011 Mar 9. 
4. PEG-IFN-alpha-2a therapy in patients with myelofibrosis: a study of the French Groupe d'Etudes des 
Myelofibroses (GEM) and France Intergroupe des syndromes Myéloprolifératifs (FIM). Ianotto 
JC, Kiladjian JJ, Demory JL, Roy L, Boyer F, Rey J, Dupriez B, Berthou C, Abgrall JF. Br J Haematol. 
2009 Jul;146(2):223-5. doi: 10.1111/j.1365-2141.2009.07745.x. Epub 2009 May 26.5.  Experience 
with pegylated interferon α-2a in advanced myeloproliferative neoplasms in an international cohort of 118 
patients. Gowin K, Thapaliya P, Samuelson J, Harrison C, Radia D, Andreasson B, Mascarenhas J, 
Rambaldi A, Barbui T, Rea CJ, Camoriano J, Gentry A, Kiladjian JJ, O'Connell C, Mesa R. 
Haematologica. 2012 Oct;97(10):1570-3. doi: 10.3324/haematol.2011.061390. Epub 2012 Mar 14. 
6. Primary myelofibrosis: 2013 update on diagnosis, risk-stratification, and management. Tefferi A. Am J 
Hematol. 2013 Feb;88(2):141-50. doi: 10.1002/ajh.23384. 
7. Long term treatment of myeloproliferative disease with interferon-alpha-2b: feasibility 
and efficacy. Gilbert HS. Cancer. 1998 Sep 15;83(6):1205-13 
8. Dynamic International Prognostic Scoring System (DIPSS) predicts progression to acute myeloid 
leukemia in primary myelofibrosis. Passamonti F, Cervantes F, Vannucchi AM, Morra E, Rumi E, 
Cazzola M, Tefferi A. Blood. 2010 Oct 14;116(15):2857-8.  
 

MC138F 
38 
Amendment 3 
Protocol version: 12 Sept 2018 
 
 
 
 
 

MC138F 
39 
Amendment 3 
Protocol version: 12 Sept 2018 
Appendix I: ECOG Performance Status Scale 
 
SCORE 
DESCRIPTION  
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 housework, 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.  
 
 
 

MC138F 
40 
Amendment 3 
Protocol version: 12 Sept 2018 
Appendix II: MEDICATION DIARY for Myelofibrosis Patients 
Name _________________________ 
Patient Medical Record #. ________________  Cycle No. _______ 
 
 
Please complete this diary on the days you take the study drugs. Please place the time in the appropriate 
box indicating that you took the medication.  Please also indicate the site, location, where you gave 
yourself your injection of study drug. 
 
If you forget to take your daily dose, please write in “0”, but remember to take your prescribed dose at the 
next regularly scheduled time. 
 
Study Drug: P1101 
 
 
Date 
Dose Time 
Site of injection 
Day 1 
___ / ___ / ___ 
 
 
Day 15 
___ / ___ / ___ 
 
 
 
 
 
My next scheduled visit is : _____________________________________________ 
If you have any questions, please call: ____________________________________ 
Patient Signature: ______________________________  Date:_________________ 
 
 
 
 
 
 
 
 
Area Below Only To Be Completed only by Coordinator 
 
Number of syringes returned_____     
 
Study Coordinator Initials________ 
 
Date______________________ 
 
Discrepancy Yes____ No_____ 

MC138F 
41 
Amendment 3 
Protocol version: 12 Sept 2018 
Appendix III: Patient Information Sheet 
 
 
PATIENT INFORMATION SHEET 
Patient Completed Quality of Life Booklet 
________________________________________________________________________ 
 
You have been given a booklet to complete for this study.  The booklet contains some questions 
about your ‘quality of life’ as a patient receiving treatment for cancer.  Your answers will help us to 
better understand how the treatment you are receiving is affecting the way you feel. 
 
1. This booklet contains MPN-SAF (27 questions) 
 
2. Directions on how to complete each set of questions are written on the top of each set. 
 
3. Please complete the booklet during your scheduled clinical visit and return it to your nurse, 
physician, or research coordinator. 
 
Thank you for taking the time to help us. 
 
 

MC138F 
42 
Amendment 3 
Protocol version: 12 Sept 2018 
Appendix IV: MPN-SAF 
________________________________________________________________________ 
Instructions: Please fill out all questions, as best able, reflecting how these symptoms affected you over 
the LAST WEEK unless directed otherwise. Use a scale of 0 to 10, circling “0” of the symptom is 
absent, “1” being most favorable, and “10” being least favorable. 
1.  Please rate your fatigue (weariness, tiredness) by circling the one number that best describes 
your fatigue right NOW. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
 
 
 
 
 
 
 
 
 
Worst 
fatigue 
 
 
 
 
 
 
 
 
 
imaginable 
2.  Please rate your fatigue (weariness, tiredness) by circling the one number that best describes 
your USUAL level of fatigue during the past 24 hours. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
 
 
 
 
 
 
 
 
 
Worst 
fatigue 
 
 
 
 
 
 
 
 
 
imaginable 
3.  Please rate your fatigue (weariness, tiredness) by circling the one number that best describes 
your WORST level of fatigue during the past 24 hours. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
 
 
 
 
 
 
 
 
 
Worst 
fatigue 
 
 
 
 
 
 
 
 
 
imaginable 
4.  Circle the one number that describes how, during the past 24 hours, fatigue has interfered with 
your: 
General activity 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Does not 
 
 
 
 
 
 
 
 
 
Completely 
interfere 
 
 
 
 
 
 
 
 
 
interferes 
Mood 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Does not 
 
 
 
 
 
 
 
 
 
Completely 
interfere 
 
 
 
 
 
 
 
 
 
interferes 
Walking ability 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Does not 
 
 
 
 
 
 
 
 
 
Completely 
interfere 
 
 
 
 
 
 
 
 
 
interferes 

MC138F 
43 
Amendment 3 
Protocol version: 12 Sept 2018 
Normal work (includes work both outside the home and daily chores) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Does not 
 
 
 
 
 
 
 
 
 
Completely 
interfere 
 
 
 
 
 
 
 
 
 
interferes 
Relations with other people 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Does not 
 
 
 
 
 
 
 
 
 
Completely 
interfere 
 
 
 
 
 
 
 
 
 
interferes 
Enjoyment of life 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Does not 
 
 
 
 
 
 
 
 
 
Completely 
interfere 
 
 
 
 
 
 
 
 
 
interferes 
5.  Circle the one number that describes how, over the last week, the following symptoms have 
affected you. 
Filling up quickly when you eat (early satiety) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Absent 
 
 
 
 
 
 
 
 
 
Worst 
 
 
 
 
 
 
 
 
 
 
imaginable 
Abdominal pain 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Absent 
 
 
 
 
 
 
 
 
 
Worst 
 
 
 
 
 
 
 
 
 
 
imaginable 
Abdominal discomfort 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Absent 
 
 
 
 
 
 
 
 
 
Worst 
 
 
 
 
 
 
 
 
 
 
imaginable 
Inactivity 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Absent 
 
 
 
 
 
 
 
 
 
Worst 
 
 
 
 
 
 
 
 
 
 
imaginable 
Problems with headaches 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Absent 
 
 
 
 
 
 
 
 
 
Worst 
 
 
 
 
 
 
 
 
 
 
imaginable 
Problems with concentration – compared to prior to my MPN 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Absent 
 
 
 
 
 
 
 
 
 
Worst 
 
 
 
 
 
 
 
 
 
 
imaginable 
 
 
 

MC138F 
44 
Amendment 3 
Protocol version: 12 Sept 2018 
Dizziness / vertigo / lightheadedness 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Absent 
 
 
 
 
 
 
 
 
 
Worst 
 
 
 
 
 
 
 
 
 
 
imaginable 
Numbness / tingling (in your hands and feet) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Absent 
 
 
 
 
 
 
 
 
 
Worst 
 
 
 
 
 
 
 
 
 
 
imaginable 
Difficulty sleeping 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Absent 
 
 
 
 
 
 
 
 
 
Worst 
 
 
 
 
 
 
 
 
 
 
imaginable 
Depression or sad mood 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Absent 
 
 
 
 
 
 
 
 
 
Worst 
 
 
 
 
 
 
 
 
 
 
imaginable 
Problems with sexual desire or function 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Absent 
 
 
 
 
 
 
 
 
 
Worst 
 
 
 
 
 
 
 
 
 
 
imaginable 
Cough 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Absent 
 
 
 
 
 
 
 
 
 
Worst 
 
 
 
 
 
 
 
 
 
 
imaginable 
Night sweats 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Absent 
 
 
 
 
 
 
 
 
 
Worst 
 
 
 
 
 
 
 
 
 
 
imaginable 
Itching (pruritus) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Absent 
 
 
 
 
 
 
 
 
 
Worst 
 
 
 
 
 
 
 
 
 
 
imaginable 
Bone pain (diffuse not joint pain or arthritis) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Absent 
 
 
 
 
 
 
 
 
 
Worst 
 
 
 
 
 
 
 
 
 
 
imaginable 

MC138F 
45 
Amendment 3 
Protocol version: 12 Sept 2018 
Fever (greater than 100ºF / 37.8ºC) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Absent 
 
 
 
 
 
 
 
 
 
Worst 
 
 
 
 
 
 
 
 
 
 
imaginable 
Unintentional weight loss last 6 months 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Absent 
 
 
 
 
 
 
 
 
 
Worst 
 
 
 
 
 
 
 
 
 
 
imaginable 
6.  What is your overall quality of life? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As good as 
 
 
 
 
 
 
 
 
 
As bad as 
it can be 
 
 
 
 
 
 
 
 
 
it can be 
 
 
 
 

MC138F 
46 
Amendment 3 
Protocol version: 12 Sept 2018 
Appendix V: TRANSFUSION DIARY 
Name ______________________ 
Patient Medical Record No. ______________ 
 
 
Please complete this diary and bring it with you to your next study visit. Write in the date that you 
received a transfusion, the type of transfusion you received (platelets, red cells, or any other 
product), and the number of units.    
 
 
Date of Transfusion 
 
*Type of Product 
Received (platelets, red 
cells, other) 
 
Number of Units 
Received 
 
 
Pre-Transfusion HGB or 
Platelet count 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*If other, list the type of product 
 
 
 
My next scheduled visit is: _______________________________ 
 
If you have any questions, please call:  ______________________ 
 
 
 
__________________ 
____________________________________ 
(Date) 
(Participant’s Signature) 
 
 
 

MC138F 
47 
Amendment 3 
Protocol version: 12 Sept 2018 
Appendix VI: The Dynamic International Prognostic Scoring System (DIPSS) for primary 
myelofibrosis (PMF) 
 
Each one of these risk factors is assigned 1 adverse point (2 adverse points for hemoglobin lower than 10 
g/dL) 
 
 
• 
age older than 65 years 
• 
hemoglobin lower than 10 g/dL 
• 
leukocyte count higher than 25 x 109/L 
• 
circulating blasts ≥ 1% 
• 
constitutional symptoms 
 
 
Risk Group: 
 
Low (0 adverse points) 
Intermediate-1 (1 or 2 points) 
Intermediate-2 (3 or 4 points) 
High (5 or 6 points) 
 
J Clin Oncol 29:392-397. © 2010 by American Society of Clinical Oncology