A Pilot Study of Momelotinib in Combination With Hypomethylating Agent for Chronic Phase Myelodysplastic Syndromes/Myeloproliferative Overlap Neoplasms and Chronic Neutrophilic Leukemia (M-HArbOr)
Phase: EARLY_PHASE1
Conditions: Chronic Myelomonocytic Leukemia, Myelodysplastic Syndromes, Myeloproliferative Overlap Neoplasms, Chronic Neutrophilic Leukemia
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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A Pilot Study of Momelotinib in combination with Hypomethylating 
Agent for Chronic Phase Myelodysplastic Syndromes/ 
Myeloproliferative Overlap Neoplasms and Chronic Neutrophilic 
Leukemia (M-HArbOr) 
 
 
IND Sponsor/Principal 
Investigator: 
Tania Jain, MBBS  
The Sidney Kimmel Comprehensive Cancer Center 
(SKCCC) at Johns Hopkins  
1650 Orleans St. 
CRB1 Rm 3M88 
Baltimore, MD 21287 
PH: 410-955-7035  
Fax: 410-955-1969  
Email: tjain2@jhmi.edu 
 
 
Statistician: 
 
Ravi Varadhan, PhD 
 
Co-investigators: 
 
IND Number” 
 
Mark Levis, MD, PhD 
 
177627 
Investigational Agent: 
Momelotinib provided by GlaxoSmithKline (GSK) 
 
 
 
Protocol Version: 
26SEP2025 
 
 
 
 
 
 
 
 
 
 
The study will be conducted according to the protocol and in compliance with Good 
Clinical Practice (GCP), with the Declaration of Helsinki, and with other applicable 
regulatory requirements. 
 
 NCT07071155

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Table of Contents 
1.0 PROTOCOL SYNOPSIS .......................................................................................................... 5 
Key eligibility criteria: .................................................................................................................. 6 
2.0 
TREATMENT SCHEMA ..................................................................................................... 7 
3.0 
STUDY OBJECTIVES .......................................................................................................... 8 
3.1 
Primary objectives ...................................................................................................... 8 
3.2 
Secondary objectives .................................................................................................. 8 
3.3 
Tertiary/exploratory objectives .................................................................................. 8 
4.0 
BACKGROUND AND RATIONALE ..................................................................................... 9 
4.1 
Unmet need in MDS/MPN .......................................................................................... 9 
4.2 
Current treatment landscape in MDS/MPN ............................................................. 10 
4.3 
Rationale for momelotinib ........................................................................................ 13 
4.4       Rationale for momelotinib and hypomethylating agents ......................................... 14 
5.0 DRUG INFORMATION .......................................................................................................... 15 
5.1 Pharmacology and clinical safety profile ........................................................................ 15 
5.2 Momelotinib data from clinical trials.............................................................................. 17 
5.3 Known potential risks ..................................................................................................... 19 
6.0 STUDY DESIGN AND ENDPOINTS ........................................................................................ 20 
6.1 Study design description ................................................................................................. 20 
6.2 Study endpoints .............................................................................................................. 21 
7.0 PATIENT SELECTION ............................................................................................................ 23 
7.1 Inclusion criteria .............................................................................................................. 23 
7.2 Exclusion criteria ............................................................................................................. 25 
7.3 Registration procedure ................................................................................................... 27 
7.4 Early withdrawal or termination ..................................................................................... 27 
7.5 Handling withdrawals or termination ............................................................................. 28 
8.0 TREATMENT PLAN AND STUDY SCHEDULE ......................................................................... 29 
8.1 Study procedures and evaluations ................................................................................. 29 

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8.2 Study treatment and dose adjustments ......................................................................... 32 
8.3 Study schema and sample collection .............................................................................. 36 
8.4 Duration of treatment .................................................................................................... 44 
8.5 Duration of follow-up ..................................................................................................... 45 
9.0 DATA MONITORING AND MANAGEMENT .......................................................................... 45 
9.1 Data Reporting and Monitoring plan .............................................................................. 45 
9.2 Adverse Event Reporting ................................................................................................ 46 
9.3 Collecting and recording adverse events ........................................................................ 48 
9.4 Recording method .......................................................................................................... 49 
9.5 Grading and attribution of adverse events ..................................................................... 50 
9.5.2.1 Health Authority ....................................................................................................... 52 
9.5.2.2 General ...................................................................................................................... 52 
9.6 Toxicity monitoring ......................................................................................................... 56 
9.7 Data management .......................................................................................................... 56 
10.0 MEASUREMENT OF EFFECT AND ENDPOINTS .................................................................. 57 
10.1 Analysis population ....................................................................................................... 57 
10.2 Sample size .................................................................................................................... 57 
10.3 Response rate ............................................................................................................... 57 
10.4 Safety and feasibility ..................................................................................................... 58 
10.5 Erythroid response ........................................................................................................ 58 
10.6 Spleen response ............................................................................................................ 58 
10.7 Patient reported outcomes........................................................................................... 58 
10.8 Overall survival .............................................................................................................. 58 
10.9 Transplantation ............................................................................................................. 58 
10.10 Pharmacokinetics ........................................................................................................ 59 
11.0 CORRELATIVE STUDIES ...................................................................................................... 59 
11.1 NGS mutations .............................................................................................................. 59 
11.2 Targeted sequencing using cell free DNA ..................................................................... 60 
11.3 CCRL2 expression on CD34+ cells ................................................................................. 60 

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11.4 RNA sequencing analysis............................................................................................... 61 
12.0 STATISTICAL DESIGN ......................................................................................................... 61 
12.1 Analysis of primary endpoint ........................................................................................ 61 
12.2 Analysis of secondary endpoints .................................................................................. 62 
12.3 Continuous Toxicity monitoring .................................................................................... 63 
13.0 ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD CLINICAL PRACTICE ........... 63 
13.1 Statement of compliance .............................................................................................. 63 
13.2 Informed consent .......................................................................................................... 64 
13.3 On-study date ............................................................................................................... 64 
13.4 Privacy and confidentiality ............................................................................................ 64 
14.0 REFERENCES ...................................................................................................................... 65 
15.0 APPENDICES ...................................................................................................................... 69 
Appendix 1. International consortium response criteria in MDS/MPN ............................... 70 
Appendix 2: International consortium criteria for progression in MDS/MPN ..................... 71 
Appendix 3: MPN-SAF TSS score ........................................................................................... 72 
Appendix 4: Patient Global Impression of Change (PGIC) .................................................... 73 
Appendix 5: ECOG Performance status ................................................................................ 74 
Appendix 6: Specimen collection details .............................................................................. 75 
Appendix 7: Contraceptives guidance on the study ............................................................. 78 
 
 
 
 
 
 
 

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1.0 PROTOCOL SYNOPSIS 
A Pilot Study of Momelotinib in combination with Hypomethylating Agent for 
Chronic Phase Myelodysplastic Syndromes/Myeloproliferative Overlap 
Neoplasms and Chronic Neutrophilic Leukemia (M-HArbOr) 
Principal investigator: Tania Jain 
 
Hypothesis: Momelotinib (MMB) in combination with hypomethylating agent (HMA) will 
be efficacious in clinical and erythroid responses in patients with myelodysplastic 
syndromes/ myeloproliferative overlap neoplasms (MDS/MPN) and chronic neutrophilic 
leukemia (CNL) 
 
Study design: This is an open-label study of MMB-HMA in MDS/MPN and CNL. We 
will enroll a total of 18 evaluable patients using a modified 3+3 dose escalation design 
followed by expansion. 
Dose Escalation Phase: 
• 
The first 3 patients will receive MMB 150 mg daily in combination with azacitidine 
• 
If 0/3 patients experience dose-limiting toxicities (DLTs) during the DLT evaluation 
period, we will escalate to MMB 200 mg daily 
• 
If 1/3 patients experience a DLT at 150 mg, we will enroll 3 additional patients at 
150 mg: 
o If 1/6 total patients experience DLTs, we will escalate to 200 mg 
o If 2/6 patients experience DLTs, 150 mg will be declared the maximum 
tolerated dose (MTD) 
• 
If ≥2/3 (or >2/6) patients experience DLTs at 150 mg, then 150 mg will exceed the 
MTD and the study will be paused for safety analysis 
Expansion Phase: 
Once the MTD is determined (either 150 mg or 200 mg), all remaining patients up to 
the total of 18 evaluable patients will be treated at the MTD. If 200 mg is determined to 
be safe, approximately 12-15 patients will be treated at this dose level. DLTs will be 
assessed during the first 28 days of treatment. The definition of DLT is provided in 
Section 8.2.7. Continuous safety monitoring will occur throughout the study for all 
patients as detailed in Section 12.3. 
 
Primary objective: The primary objective of this study is to obtain estimates of efficacy 
of MMB in combination with HMA (MMB-HMA) in MDS/MPN and CNL.  
 
Key secondary objective: (1) To evaluate feasibility and safety of MMB-HMA in 
MDS/MPN and CNL. (2) To evaluate erythroid response with MMB-HMA (3) To 
evaluate spleen size reduction with MMB-HMA in MDS/MPN and CNL (4) To evaluate 
patient-reported outcomes with MMB-HMA in MDS/MPN and CNL (5) To evaluate the 
trough concentrations of MMB single agent and with HMA in MDS/MPN and CNL. 
 
Accrual objective: The accrual goal is 18 evaluable patients with MDS/MPN or CNL. 
 

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Accrual period: We anticipate an accrual period of two years. 
 
Key eligibility criteria:  
(1) Patients with a WHO diagnosis of chronic myelomonocytic leukemia (CMML), 
MDS/MPN-not otherwise specified (MDS/MPN-NOS), MDS/MPN with 
neutrophilia (MDS/MPN-N), CNL1,2. 
(2) Age >=18 years 
(3) Blood counts with platelets >25,000/microL, ANC >=0.75 x 10^9/L (without 
transfusion or growth factor support) 
(4) Baseline splenomegaly with ≥5 cm below costal margin or ≥450 cm3 on imaging 
(ultrasound, CT or MRI) 
 
Treatment Description: All patients regardless of race or gender who fit the eligibility 
criteria will be considered for this study. MMB will be administered at a dose of 150mg 
daily for the first 3 patients and escalated to 200 mg daily for the remaining patients, 
unless DLT criteria are met3. Azacitidine will be administered at 75 mg/m2 for days 1-5 
in a 28-day cycle subcutaneously or intravenously. 
 
 
 

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2.0 TREATMENT SCHEMA 
 
 
 
 
 
 
 
 
 
 
Figure 1: Treatment schema for MMB-HMA in MDS/MPN and CNL 

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3.0 STUDY OBJECTIVES 
3.1 
Primary objectives 
The primary objective of this study is to obtain estimates of efficacy of MMB in 
combination with hypomethylating agent (MMB-HMA) in MDS/MPN and CNL. 
 
Primary endpoints: Complete response, partial remission or clinical benefit per 
MDS/MPN IWG criteria4 assessed at 24 weeks.  
 
3.2 
Secondary objectives 
(1) To evaluate feasibility and safety of MMB-HMA in MDS/MPN and CNL  
(2) To evaluate erythroid response with MMB-HMA 
(3) To evaluate spleen size reduction with MMB-HMA in MDS/MPN and CNL  
(4) To evaluate efficacy of MMB-HMA on patient-reported outcomes in MDS/MPN and 
CNL  
(5) To evaluate the trough concentrations MMB with HMA in MDS/MPN and CNL. 
 
Secondary endpoints:  
(1) Feasibility will be defined as the proportion of patients who maintain 60% relative 
dose intensity for 24 weeks. 
(2) Incidence, severity, and duration of adverse events will be assessed on an ongoing 
basis while patients are on treatment, using CTCAE version 5.0 and evaluated by 
predetermined physical exam, laboratory values for blood counts and chemistries. 
(3) Erythroid response will be evaluated at 12 weeks and 24 weeks, and defined by 
hemoglobin increase by ≥2.0 g/Dl in patients with anemia at enrollment or transfusion 
independence for ≥8 weeks for patients requiring at least 4 packed red blood cell 
(PRBC) transfusions in the 8 weeks prior to initiation of treatment4.  
(4) Spleen response will be evaluated at 12 weeks and 24 weeks, as reduction in 
spleen volume of ≥ 35% from baseline and by spleen response by consensus 
response criteria3,4. 
(5) Patient reported outcomes (PRO) will be evaluated by 50% reduction in MPN-SAF 
TSS from baseline at week 12 and week 24 and patient’s global impression of change 
(PGIC) at week 12 and week 245. 
(6) Trough plasma concentration for MMB and metabolite M21 will be measured as a 
trough (approximately 20-26 hours after the previous dose of MMB an prior to the next 
dose on study intervention) at 12 weeks and 24 weeks in 10 patients. 
 
3.3 
Tertiary/exploratory objectives 
Additional exploratory objectives will include estimates of survival, transplantation 
outcomes in those who undergo a blood or marrow transplantation (BMT) especially 

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with mutations in EZH2, RUNX1, or SETBP1, responses in specific somatic mutations 
especially combinations of ASXL1/SRSF2/SETBP1, single cell RNA sequencing, cell 
free DNA analysis for evaluation of clonal signatures, and CCRL2 evaluations to 
determine genomic aberrations and mechanism of resistance or relapse to MMB-HMA. 
 
4.0 BACKGROUND AND RATIONALE  
4.1 
Unmet need in MDS/MPN 
 
Myeloproliferative/ myelodysplastic neoplasms (MDS/MPN) are clonal myeloid 
malignancies including chronic myelomonocytic leukemia (CMML), MDS/MPN with 
neutrophilia (MDS/MPN-N, also known as bcr-abl1 negative atypical chronic myeloid 
leukemia, aCML), MDS/MPN with SF3B1 and thrombocytosis (MDS/MPN-SF3B1-T, 
previously called as MDS/MPN with ringed sideroblasts and thrombocytosis) and 
MDS/MPN-not otherwise specified (MDS/MPN-NOS, also referred to as MDS/MPN-
unclassified)1,2. Chronic neutrophilic leukemia is a rare clonal MPN. While rare and 
heterogenous, these diagnoses have common features of Philadelphia chromosome 
negativity, proliferative or hypercellular along with dysplastic marrow features, 
commonly seen extramedullary hematopoiesis, and blood count aberrations including 
leukocytosis, anemia and thrombocytosis or even thrombocytopenia. 
 
The diagnosis in MDS/MPN is based on features of bone marrow morphology, 
blood counts and molecular findings. The genomic landscape in MDS/MPN is diverse, 
an aid to diagnosis of subtype of MDS/MPN, and bears prognostic value. While 
cytogenetics and copy number analysis are often normal, gene mutations are a 
common feature seen in over 90% patients with MDS/MPN.  In CMML, co-expression of 
TET2 and SRSF2 mutations results in shift towards monocytosis, and subsequent 
acquisition of ASXL1 or growth signaling mutations such as NRAS or CBL result in high-
risk disease6,7. Mutations in SETBP1 and CSF3R occur commonly in MDS/MPN-N and 
CNL8,9. ETNK1 mutations were recently reported in about 9% MDS/MPN-N but also 
seen in a smaller fraction of CMML8,10. MDS/MPN-NOS is the subtype is that is the least 
defined. Common mutations reported here include epigenetic regulators (ASXL1, 
TET2), spliceosome pathways (SRSF2, ZRSR2, U2AF1), signal transduction pathways 
(JAK2, NRAS), and TP53 which invariably has a negative impact on survival7.  
 
Despite the heterogeneity, the diagnostic entities in MDS/MPN overlap have 
shared marrow features, and treatment options for all of these diagnoses remain limited 
while prognosis is dismal. In patients with high risk or advanced disease, survival is 
under 2 years11. Many patients are not candidates for potentially curative allogeneic 

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bone or marrow transplantation (BMT) due to lack of disease control or advanced age 
or comorbidities. Despite BMT, relapse as well as nonrelapse mortality remains a 
challenge12-14. 
 
4.2 
Current treatment landscape in MDS/MPN 
 
Current treatment options for MDS/MPN are limited and often include hypomethylating 
agents and in select eligible patients, BMT. However, responses with either are low. Our 
data and others’ have shown that responses to HMA are minimal, short-lived, and never 
curative15-17. Even if clinical response is noted, there is no reduction in mutational 
burden or elimination of the mutant clone16,17. Prior studies have explored the role of 
other agents in MDS/MPN based on data from MDS or myelofibrosis. Hydroxyurea has 
resulted in responses but at the cost of anemia and pancytopenia18,19. Additionally, 
transformation to acute leukemia was notably higher with hydroxyurea compared to 
decitabine18. Use of interferon resulted in little clinically meaningful improvement20.  
 
While there is no established standard for treatment in chronic phase, HMAs are 
commonly used to control myeloproliferation, decrease splenomegaly, and alleviate 
other disease-related symptoms or cytopenias. The applicability of HMA in MDS/MPN 
overlaps is derived from its use in MDS and CMML. HMA are often used as a bridge to 
transplant, and in those with no targetable mutations in MDS/MPN overlap neoplasms, 
which is most commonly the case. Responses, however, have remained poor, 
highlighting the significant unmet need for MDS/MPN overlap which have a unique 
biology and often do not have targetable mutations (data from prior studies summarized 
below). More recently, JAK inhibitors have been used either as a single agent or in 
combination with HMA in this disease with the demonstration of activation of JAK-STAT 
pathway in CMML or by virtue of CSF3R mutations21,22. Data that exist to date on the 
use of HMA or JAK inhibitors or combination thereof is summarized below: 
 
Reference 
Agent 
Diagnosis 
included 
Response rates 
Duration of 
response 
Survival 
outcomes 
Hypomethylating agent alone (Azacitidine or decitabine) 
Adès et al. 
201323 
Azacitidine 
CMML 
(n=76) 
43% response by 
IWG 2006, 17% 
CR 
Variable; 
patients who 
achieved a 
response had 
better OS 
(median 29.6 
mo vs 19 mo) 
Median 
survival 26 
mo 
Kongtim et 
al. 201624 
Azacitidine or 
decitabine in 
37 (all patients 
CMML 
(n=47 with 
CMML-1/2, 
41% complete 
remission/ 
marrow complete 
 
Post-
transplant 
PFS was 

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included were 
treated with 
HMA as bridge 
to BMT) 
n=36 with 
post-CMML 
AML) 
remission with 
Aza or Dec 
superior 
with HMA 
(43%) vs 
other 
therapies 
(27%) 
Coston et 
al. 201925 
Azacitidine 
(n=56) or 
decitabine 
(n=65) 
CMML 
(n=121) 
41% response by 
IWG MDS/ 56% 
by MDS/MPN 
IWG, CR <20%; 
no difference by 
Aza or Dec 
Median 
duration of 
best response 
4-6mo 
Median 
survival 
HMA treated 
31 mo (vs 
18mo with 
conventional 
care) 
Duchman 
et al. 
201826 
Azacitidine 
(n=68) or 
decitabine 
(n=106) 
CMML 
(n=174) 
52% ORR, 17% 
CR by IWG 
2006; responses 
not different by 
Aza or Dec 
NR 
Median 
survival 23 
mo 
Sun et al. 
202327 
HMA (N=9) 
aCML 
(N=31) 
ORR 33.3% to 
HMA 
NR 
Median 
survival 20 
mo 
Jain et al. 
202328 
Azacitidine or 
decitabine 
aCML 
(N=13) 
8/13 had 
improvement in 
leucocytosis 
Variable 
Variables 
Kong et al. 
201929 
Decitabine  
aCML 
(N=7, 
overall 
cohort 
n=54) 
NR 
NR 
Median 
survival 10 
mo for the 
overall 
cohort  
Triguero et 
al. 202230 
Azacitidine 
CMML 
(n=91) 
58% ORR by 
MDS/MPN IWG  
14 mo 
Median 
survival 24 
mo 
Tong et al. 
201531 
Decitabine 
aCML 
(n=4) 
3/4 CR by MDS 
IWG 
Hematological 
response 1-
2.5mo 
 
Hausman 
et al. 
201632 
Decitabine 
aCML 
(n=1) 
Hematological 
response and 
transfusion 
independence 
NR 
Underwent 
transplant  
Jiang et al. 
2016 
Decitabine 
aCML 
(n=2) 
Marrow response 
and 
hematological 
response in both 
patients 
NR 
NR 
JAK inhibitors alone 
Dao et al. 
201433 
Ruxolitinib 
aCML 
(n=1), 
CSF3R 
T618I 
mutated 
Improvement in 
blood counts, 
reduction of 
spleen/symptoms 
NR 
NR 

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Padron et 
al. 201634 
Ruxolitinib 
CMML 
(n=20) 
Total response 
rate (combining 
IWG MDS2006 
and spleen 
response) 35% 
NR 
 
Padron et 
al. 2022 
(abstract)35 
Ruxolitinib 
CMML 
(n=29) 
MDS/MPN IWG 
ORR 17%, 
Clinical benefit 
66% 
NR 
Median OS 
24 mo 
Kuykendall 
et al. 2024 
(abstract)36 
Fedratinib 
aCML 
(n=6), CNL 
(n=5), 
MDS/MPN-
U (n=7), 
MDS/MPN-
RS-T (n=6) 
53% at week 24 
NR 
Median OS 
19.7mo 
Hypomethylating agent plus JAK inhibitor 
Assi et al. 
201711 
Ruxolitinib 
plus 
azacitidine 
CMML 
(n=17), 
MDS/MPN-
U (n=17), 
aCML 
(n=4) 
57% objective 
response by 
MDS/MPN IWG 
2015. 
75% with 
pretreatment 
splenomegaly 
had >50% 
reduction in 
splenomegaly. 
45% responders 
responded only 
after addition of 
azacitidine 
Median 8 mo 
(range, 2.3-32 
mo) 
CMML: 15.1 
mo, 
MDS/MPN-
U: 26.5 mo, 
aCML: 8 mo 
Montalban-
Bravo et al. 
202137 
HMA alone 
(n=19), HMA 
Rux (n=6), 
Ruxolitinib 
(n=5), HMA 
combination 
(N=4), 
Chemotherapy 
(n=3) 
aCML 
(n=65) 
ORR for HMA 
26%, HMA Rux 
0, Ruxolitinib 9%, 
HMA 
combination 
50%, 
Chemotherapy 
100% 
Median 2.7 
mo 
Median 
survival 25 
mo 
 
aCML, atypical CML; CMML, chronic myelomonocytic leukemia; HMA, hypomethylating agent; IWG, international 
working group; MDS/MPN-U, MDS/MPN overlap unclassified; NR, not reported; ORR, overall response rate. 
 
With BMT, potential cures are possible12-14,38. In a single center study from the Mayo 
Clinic, BMT resulted in overall survival was 55%, relapse 29% and nonrelapse mortality 
25% at a median follow up of 21 months14. In our multi-institution study, haploidentical 
donor BMT resulted in overall survival of 56%, progression-free survival 48%, relapse 
27% and NRM 25% at 3 years with graft failure in 6% patients12. These outcomes with 

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BMT are overall inferior to those expected with acute myeloid malignancies. We believe 
that this difference is at least in part due to limited bridging therapies for MDS/MPN and 
lack of disease control or remission prior to BMT in MDS/MPN. Furthermore, many 
patients cannot even get to BMT due to poor disease control. Our study demonstrated 
suboptimal disease control in the form of enlarged spleen or increased blasts at the time 
of BMT specifically increase risk of relapse12. Hence, better approaches for bridging to 
BMT need to be explored in MDS/MPN.  
 
The advances in therapies for MDS/MPN are limited by the lack of understanding of the 
underlying biology, limitations in classification, and implications of molecular profile. 
Clinical trials often exclude these diagnoses aimed at MDS or MPN, due to presumed 
poor prognosis. This in turn limits further understanding of underlying biology and 
pathophysiology of MDS/MPN. In the presence of RUNX1, EZH2, and SETBP1, 
responses to HMA are almost non-existent15. Additionally, specific mutation combination 
of ASXL1, SRSF2, and SETBP1 portends a significantly poor prognosis and is 
commonly accompanied with growth signaling mutations28. Hence, inclusion of 
molecular profiles in diagnosis as well as treatment responses is critical to further the 
field.  
 
4.3 
Rationale for momelotinib 
 
Momelotinib (MMB) is a small molecular inhibitor of JAK1 and JAK2 and activin A 
receptor, type 1/activin-like kinase 2 (ACRV1/ALK2). Preclinical data demonstrate that 
MMB inhibits ACVR1-mediated expression of hepcidin in the liver, thereby increasing 
iron availability for erythropoiesis39. MMB inhibits ACVR1/ALK2, decreases hepcidin 
production, and ameliorates anemia of chronic disease in rodents.40  The compound has 
demonstrated significant activity in vivo in JAK2-dependent nonclinical models. 
Momelotinib shows selectivity over other tyrosine and serine/threoninie kinases and 
potent in vitro inhibitory activity against JAK2 V617F mutant, which is seen in 
myelofibrosis and several MDS/MPN.  
 
MMB has potent inhibitory in vitro activity against JAKV617F mutation, resulting in 
inhibition of JAK1 and JAK2 signaling events. Via inhibition of JAK2 signaling, it inhibits 
the formation of V617F mutant myeloid colonies suggesting a strong overall inhibition of 
JAK-STAT pathway. MMB has demonstrated activity in both in vitro JAK2-dependent 
cellular assays and in in vivo animal models. In addition to JAK-STAT pathway 
inhibition, MMB also has a unique mechanism of inhibition of ACVR1 which offers the 
possibility of anemia improvement. 
 

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The biology of MDS/MPN is complex and remained poorly understood until recently. A 
growing body of data now suggests that GM-CSF hypersensitivity that signals via JAK-
STAT pathway plays a major role in CMML and other MPNs22,34. Not surprisingly, JAK 
inhibitors like ruxolitinib have demonstrated promising activity in CMML and other 
MDS/MPN34,41, demonstrating the therapeutic potential of targeting JAK-STAT signaling 
in MDS/MPN. Anemia is commonly seen at presentation in MDS/MPN. The drivers of 
anemia in these diagnoses can be complex including clonal proliferation, progressive 
fibrosis, sequestration due to splenomegaly, and exacerbation of myelosuppression by 
commonly used JAK inhibitors, ruxolitinib or fedratinib. Furthermore, these patients also 
have anemia resulting from chronic inflammation due to hyperactivation of 
ACVR1/hepcidin axis and chronically elevate inflammatory cytokines as seen in MPNs42. 
High circulating hepcidin levels interfere with iron metabolism and decrease iron 
absorption from the gut, increasing iron retention within cellular stores and decreasing 
iron availability for effective erythropoiesis, despite iron overload from recurrent 
transfusions. Hepcidin production can also be stimulated through interleukin-6 induced 
JAK-STAT signaling, leading to significant elevation of hepcidin in anemia patients with 
MPNs43. Importantly, JAK-STAT-directed hepcidin production is dependent on basal level 
of ACVR1/SMAD1/5/8 signaling, and thus dysregulated hepcidin cannot be corrected by 
JAK-STAT inhibition alone44-46. Taken together, these data suggest that hyperactivation 
of ACVR1 and dysregulated JAK-STAT signaling result in loss of iron hemostasis and 
iron-restricted anemia in MPNs. Ruxolitinib and fedratinib are potent inhibitors of JAK-
STAT signaling but lack activity against ACVR1. In contrast, MMB results in inhibition of 
ACVR1-mediated expression of hepcidin in the liver and consequently the anemia benefit 
that has been reported in myelofibrosis3,39,40,47.  
 
4.4       Rationale for momelotinib and hypomethylating agents 
 
Pre-clinical work from the Karantanos lab at the Johns Hopkins School of Medicine has 
shown high C-C motif atypical chemokine receptor-like 2 (CCRL2) expression in CD34+ 
cells from MDS/MPN patients48. CCRL2 induces JAK2/STAT signaling48 and CCRL2-
expressing cells while refractory to azacitidine, show high sensitivity to the JAK2 
inhibition49. HMAs remain the mainstay of treatment in MDS/MPN and CNL. We 
hypothesize that the combination of HMA and MMB will allow for improved efficacy of 
HMA by improving resistance conferred by high CCRL2 expression in MDS/MPN. 
Furthermore, HMA and JAK inhibitors have independent activity in MDS and MPN, 
respectively50,51. MMB specifically has demonstrated spleen size reduction in 26.5% 
patients as well as ≥50% reduction in total symptom score in 28.4% patients in patients 
who had not been treated with a JAK inhibitor in the past51.  
 

15 
 
Furthermore, toxicity profiles of HMA and MMB are non-overlapping. Previously, the 
safety and efficacy of combination of HMA and JAK inhibitors has been reported with 
ruxolitinib in MPNs and MDS/MPN11,52. We have observed no unexpected side effects 
with combining HMA with momelotinib or fedratinib in the Johns Hopkins Leukemia Clinic 
in MPN patients. We have used MMB at 200 mg daily in at least 2 patients who have 
been on treatment for over 2 months at the time of this writing. Hence, in this study, we 
propose a treatment combination of HMA and MMB with a goal to improve disease 
features as well as to specifically improve anemia.   
 
Given the availability of luspaterecept for MDS/MPN with SF3B1 mutation and overall 
lower risk of this entity, we will only include CMML, MDS/MPN-N, MDS/MPN-NOS, and 
CNL in this study. Additionally, mechanisms of anemia in MDS/MPN with SF3B1 mutation 
are likely not driven by ACVR1 overexpression. Hence the rationale for the role of MMB 
in this entity is unclear.  
 
In summary, we propose a clinical trial of momelotinib in combination with 
hypomethylating agent (MMB-HMA) in patients with chronic (<10% blasts) phase 
MDS/MPN to evaluate efficacy and safety in this patient population. 
 
 
5.0 DRUG INFORMATION  
5.1 Pharmacology and clinical safety profile 
          
MMB is a potent and selective small-molecule inhibitor of JAK1, JAK2, and ACRV1/ALK2. 
MMB shows selectivity over other tyrosine and serine/threonine kinases and potent in 
vitro inhibitory activity against the JAK2V617F mutant signaling. MMB has demonstrated 
significant activity in JAK2-dependent models53. Additionally, MMB inhibition of ACVR1 
results in reduced SMAD1/5/8 signaling, reduction of hepatic hepcidin transcription, and 
consequently increased erythropoiesis in a rodent model of anemia of chronic 
disease39,40.  
 
MMB has been investigated in 22 studies including phase 1, 2 and 3 clinical trials. Of 
these, 21 studies have been completed, which includes 6 in healthy volunteers, 8 in 
patients with MPNs, 4 in solid tumor patients, 1 in patients with renal impairment, 1 in 
patients with hepatic impairment. Overall, 1423 subjects have been dosed with MMB so 
far. Molecular enzyme and receptor binding studies indicate that MMB demonstrated little 
propensity for common receptor- and enzyme-mediated drug-induced adverse events 
(AEs). In addition, in vitro studies with Caco-2 cells indicated that MMB and M21 do not 

16 
 
inhibit thiamine transport54. MMB was metabolized via multiple metabolic pathways and 
was eliminated as a combination of metabolites and unchanged parent drug. MMB 
metabolism involved oxidation and scission of the morpholine ring, amide hydrolysis, N-
dealkylation, nitrile hydrolysis, nitrile oxidation, and taurine conjugation of the 
cyanomethylamide. Metabolite profiling identified 3 major metabolites: an amide 
hydrolysis product M19, a morpholino cleavage metabolite M20, and a morpholino lactam 
metabolite M21. M21 is the major and pharmacologically active circulating plasma 
metabolite in humans, and M19 is the major metabolite in mice, rats, and dogs. 
Cardiovascular safety pharmacology studies indicate that MMB does not significantly 
affect cardiovascular parameters at pharmacologically relevant doses. A dose of 100 
mg/kg MMB decreased arterial blood pressure and concurrently increased heart rate. 
QTc intervals were not notably altered by MMB administration and exposure at this dose 
level was approximately 4-fold above the estimated free drug Cmax in patients with MF. 
MMB was presented for the phase 3 clinical trials as film-coated tablets containing 50 mg, 
100 mg, 150 mg or 200 mg of MMB (free base equivalent) as its dihydrochloride 
monohydrate salt. 
 
The pharmacokinetics of MMB were evaluated in various phase 1,2 and in 3 phase 3 
studies, 
SIMPLIFY-1 
(GS-US-352-0101), 
SIMPLIFY-2 
(GS-US-352-1214), 
and 
MOMENTUM (SRA-MMB-301)3,51,55. In SIMPLIFY-1, and MOMENTUM (SRA-MMB-
301), in addition to trough PK samples in multiple visits, frequent PK samples were 
collected at week 2 in a subgroup of myelofibrosis patients (approx. 20 patients in each 
study). The data from the PK subgroups of subjects with myelofibrosis from studies 
SIMPLIFY-1 and SIMPLIFY-2 were pooled together. The Cmax range was 104 to 1050 
ng/mL (median 437 ng/mL) and the AUC range was 608.4 to 6748 ng h/mL (median 2918 
ng h/mL)56. 
 
The effect of renal impairment on the PK and safety of MMB was evaluated in Study GS-
US-352-1152 following a single dose of MMB 200 mg. No differences in exposure of MMB 
or its metabolites M21 (Cmax and AUC) were observed between subjects with moderate 
or severe renal impairment and matched healthy control subjects. Therefore, dose 
adjustments of MMB are not necessary in subjects with mild to severe renal impairment. 
 
The effect of hepatic impairment on the PK and safety of MMB was evaluated in Study 
GS-US-352-1153 following a single dose of MMB 200 mg. The observed differences in 
plasma exposures of MMB and its M21 metabolite between subjects with moderate 
hepatic impairment and healthy control subjects were not considered to be clinically 
relevant.57 Therefore, dose adjustments of MMB are not considered necessary in subjects 
with mild or moderate hepatic impairment. In patients with severe hepatic impairment, 
however, MMB AUC∞ was increased (GMR, 197%; 90%CI, 129%–301%), and M21 AUC∞ 

17 
 
was decreased (GMR, 52%; 90%CI, 34%–79%). Therefore, patients with severe hepatic 
impairment (Child-Pugh Class C), if enrolled, will be started at 150 mg momelotinib once 
daily. 
 
5.2 Momelotinib data from clinical trials 
 
        5.2.1 SIMPLIFY-1 Study 
 
SIMPLIFY-1 was an international, randomized, double-blind, active-controlled phase 3 
study evaluating MMB versus ruxolitinib in 432 subjects with myelofibrosis, previously 
untreated with a JAK inhibitor51. MMB was non-inferior to ruxolitinib for spleen response 
rate at week 24 with 26.5% (57 subjects) in the MMB group and 29.5% (64 subjects) in 
the ruxolitinib group achieved this endpoint. A lower percentage of subjects in the MMB 
group (28.4%) achieved a TSS response compared with the ruxolitinib group (42.2%) at 
week 24 (statistically did not meet non-inferiority). 
 
A greater proportion of subjects in the MMB group were TI at week 24 (66.5%) compared 
with the ruxolitinib group (49.3%, Figure 2), i.e., had no RBC transfusion and no 
hemoglobin level below 8 g/dL in the prior 12 weeks, excluding cases associated with 
clinically overt bleeding. This difference was nominally significant (p < 0.001). A smaller 
proportion of the MMB group was transfusion dependence at week 24 (30.2%) compared 
with the ruxolitinib group (40.1%), i.e., had ≥ 4 units of RBC transfusion or a hemoglobin 
level below 8 g/dL in the prior 8 weeks, excluding cases associated with clinically overt 
bleeding. This difference was nominally significant (p = 0.001). 
 

18 
 
 
       
 
      5.2.2 SIMPLIFY-2 Study 
 
SIMPLIFY-2 was an international, randomized, open-label, phase 3 study evaluating 
MMB versus best available therapy (BAT) in 156 subjects with MF who were previously 
treated with ruxolitinib55. A similar proportion of subjects had a splenic response at week 
24 in the MMB group (7 subjects, 6.7%) compared with the BAT group (3 subjects, 5.8%), 
which was treated with ruxolitinib in 89% of patients. A substantially higher, and nominally 
statistically superior TSS response rate at week 24 was observed in MMB-treated 
subjects compared to those in the BAT control group (26.2%) and (5.9%) respectively 
MMB (nominal p < 0.001), a 4-fold improvement. A greater proportion of subjects in the 
MMB group were transfusion independent at week 24 (43.3%) compared with the BAT 
group (21.2%), i.e, had no RBC transfusion and no hemoglobin level below 8 g/dL in the 
prior 12 weeks. The median rate of RBC transfusion (excluding cases associated with 
clinically overt bleeding) was lower in the MMB group (0.5 units/month) compared with 
the BAT group (1.2 units/month) at week 24. This was despite the imbalance in the 
baseline inclusion where all patients had required either an RBC transfusion or a dose 
reduction while on ruxolitinib (prior to MMB treatment on SIMPLIFY-2) and had grade 3 
thrombocytopenia, anemia or bleeding. Additionally, 58% of patients in the MMB arm 
required a dose reduction of ruxolitinib and had these grade 3 adverse events, compared 
with 39% of patients in the BAT arm. Furthermore, 40% of patients in the MMB group did 
not need transfusions over the treatment period compared with 27% of patients in the 
Figure 2: Kaplan Meier Estimates of proportion of Patients Not Requiring RBC 
Transfusion During 24 Weeks of Ruxolitinib or MMB Treatment (SIMPLIFY-1) 

19 
 
BAT group. Throughout the study, mean hemoglobin and mean platelet counts were 
higher in the MMB arm compared to the BAT arm.  
 
        5.2.3 MOMENTUM Study 
 
MOMENTUM is an international, randomized, double-blind, active-controlled, phase 3 
study intended to confirm the differentiated clinical benefit of MMB versus danazol in 
symptomatic, anemic subjects with myelofibrosis who have previously received approved 
JAK inhibitor therapy3. The study met its primary efficacy endpoint of statistically 
significant superiority of MMB [24.6% (95% CI: 17.49, 32.94)] over danazol [9.2% (95% 
CI: 3.5, 19.0)] in the proportion of subjects with ≥ 50% reduction in symptoms from 
baseline at week 24 in MFSAF TSS. Transfusion independence at week 24 was 30.8% 
(95% CI: 23.0, 39.5) for the MMB group and 20.0% (95% CI: 11.1, 31.8) for the danazol 
group. Lastly, spleen response rate was 40.0% (95% CI: 31.5, 49.0) for the MMB group 
and 6.2% (95% CI: 1.7, 15.0) for the danazol group (Figure 3). All patients on this study 
had received prior ruxolitinib and 5% had also been treated with fedratinib prior to 
enrollment on this trial.  
 
 
 
 
5.3 Known potential risks 
 
In prior studies, cytopenias and gastrointestinal side effects have been reported with 
MMB. In SIMPLIFY-1, most common adverse events included thrombocytopenia 
Figure 3: Percent Change from Baseline in Spleen Volume at Week 24 for Each 
Subject in MOMENTUM study 

20 
 
(18.7%), diarrhea (18.2%), and headache (17.8%). In the group of patients exposed to 
MMB, the most commonly reported Grade 3 or 4 adverse events were thrombocytopenia 
(13.4%), anemia (11.7%), pneumonia (7.3%) and hypertension (4.9%). In SIMPLIFY-2, 
the most commonly reported adverse events in the MMB group were diarrhea (32.7%), 
asthenia and nausea (19.2%), and cough and thrombocytopenia (17.3%); and the most 
common Grade 3 or 4 adverse events were anemia (22.9%), thrombocytopenia (15.3%), 
asthenia (7.6%) and neutropenia and pneumonia (6.3%). The 2 most commonly reported 
adverse events in MOMENTUM study were thrombocytopenia and diarrhea (22.3% 
each). Safety data from the above phase 3 randomized studies in the momelotinib clinical 
development program were pooled and analyzed. The most commonly reported adverse 
events include infections (39.7%), diarrhea (22.8%), thrombocytopenia (21.0%), nausea 
(16.7%), anemia (13.8%) and headache (13.4%). The most common Grade 3 or 4 events, 
occurring in at least 5% of subjects during randomized treatment with momelotinib, were 
thrombocytopenia (10.7%) and anemia (8.3%). As of March 14, 2025, based on a review 
of the GSK global safety database – including ongoing interventional and completed 
studies across all phases (n=1424) and post-marketing reports (1600 patient-years)--- 
using the broad SMQ definition of severe cutaneous adverse reactions (SCARs), there 
were 3 cases of cutaneous adverse reactions that were severe and considered related to 
momelotinib (data available with GSK). There is no data on effects of MMB on human 
male or female fertility; however, in animal studies, MMB impaired fertility in rats. There 
are no data on the presence of MMB in human milk. MMB was present in rat pups 
following nursing from treated dams, with adverse effects in the offspring. A risk to the 
breastfed child cannot be excluded. Hence, patients must not breastfeed during treatment 
with MMB and for at least 1week after completing therapy.  
 
 
6.0 STUDY DESIGN AND ENDPOINTS 
 
6.1 Study design description 
 
This is an open-label, phase 1 study of MMB-HMA in MDS/MPN and CNL. 
Approximately 18 evaluable patients will be included in this study using a modified 3+3 
dose escalation design followed by expansion. 
 
Dose Escalation Phase: 
• 
The first 3 patients will receive MMB 150 mg daily in combination with azacitidine 
• 
If 0/3 patients experience dose-limiting toxicities (DLTs) during the DLT evaluation 
period, we will escalate to MMB 200 mg daily 
• 
If 1/3 patients experience a DLT at 150 mg, we will enroll 3 additional patients at 

21 
 
150 mg: 
o If 1/6 total patients experience DLTs, we will escalate to 200 mg 
o If 2/6 patients experience DLTs, 150 mg will be declared the maximum 
tolerated dose (MTD) 
• 
If ≥2/3 (or >2/6) patients experience DLTs at 150 mg, then 150 mg will exceed the 
MTD and the study will be paused for safety assessment 
 
Expansion Phase: 
Once the MTD is determined (either 150 mg or 200 mg), all remaining patients up to 
the total of 18 evaluable patients will be treated at the MTD. If 200 mg is determined to 
be safe, approximately 12-15 patients will be treated at this dose level. DLTs will be 
assessed during the first 28 days of treatment. The definition of DLT is provided in 
Section 8.2.7. Continuous safety monitoring will occur for the entirety of the study for all 
patients as detailed in Section 12.3. 
 
6.2 Study endpoints 
 
             6.2.1 Primary endpoints 
 
To evaluate efficacy with MMB-HMA in MDS/MPN and CNL, we will measure the 
proportion of patients who achieve a clinical response at week 24 (compared to baseline) 
defined as complete response, partial remission or clinical benefit by international 
consortium response criteria for MDS/MPN in adults4.  
 
             6.2.2 Secondary endpoints 
 
(1) To evaluate feasibility and safety of MMB-HMA in MDS/MPN and CNL, we will: 
      (i) Determine the proportion of patients who maintain 60% relative dose intensity for 
24 weeks. 
     (ii) Measure the incidence, duration, and severity of adverse events per CTCAE v.5.0 
as reported from physical exams, changes in vital signs, laboratory data including 
hematology parameters and serum chemistry. 
      (iii) Determine the proportion of patients experiencing grade ≥ 3 adverse events or 
severe adverse events as defined by CTCAE v.5.0 
 
(2) To evaluate erythroid response with MMB-HMA in MDS/MPN and CNL (in patients 
with anemia at enrollment), we will: 
      (i) Determine the proportion of patients who achieve erythroid response at week 12 
per international consortium criteria 

22 
 
      (ii) Determine the proportion of patients who achieve erythroid response at week 24 
per international consortium criteria 
 
(3) To evaluate spleen size reduction with MMB-HMA in MDS/MPN and CNL, we will:  
      (i) Determine the proportion of patients who achieve a spleen response at week 12 
per international consortium criteria 
      (ii) Determine the proportion of patients who achieve a spleen response at week 24 
per international consortium criteria 
      (iii) Determine the proportion of patients who achieve a spleen volume reduction of ≥ 
35% from baseline at week 12 
      (iv) Determine the proportion of patients who achieve a spleen volume reduction of ≥ 
35% from baseline at week 24 
 
(4) To evaluate efficacy of MMB-HMA on patient-reported outcomes in MDS/MPN 
and CNL, we will: 
       (i) Evaluate the proportion of patients who have a 50% reduction in MPN-SAF TSS 
from baseline to week 12 in patients with baseline TSS ≥ 10 
       (ii) Evaluate the proportion of patients who have a 50% reduction in MPN-SAF TSS 
from baseline to week 24 in patients with baseline TSS ≥ 10 
       (iii) Evaluate the overall change in MPN-SAF TSS compared to baseline at week 12 
       (iv) Evaluate the overall change in MPN-SAF TSS compared to baseline at week 24 
       (v) Evaluate the patient’s global impression of change (PGIC) at week 12 (Appendix 4) 
       (vi) Evaluate the PGIC at week 24 
 
(5) To evaluate the trough concentrations of MMB single agent and with HMA in 
MDS/MPN and CNL: 
        (i) Evaluate trough concentrations of MMB at week 12 and at week 24 in 10 
patients  
        (ii) Evaluate trough concentrations of metabolite M21 at week 12 and 24 in 10 
patients  
 
6.2.3 Exploratory endpoints 
 
(1) To evaluate survival, we will estimate overall survival defined as time from first 
treatment to death from any cause. For reference, the median overall survival in the 
diagnoses included in around 2 years. 
 
(2) To estimate outcomes of BMT in the subset of patients undergoing BMT following 
treatment with MMB-HMA, especially in patients with EZH2, SETBP1 or RUNX1 
mutations.  

23 
 
 
(3) To estimate responses in specific mutation combinations, we will correlate responses 
with somatic mutations specifically a combination of ASXL1, SRSF2, and SETBP1.  
 
(4) To evaluate reduction in somatic mutation burden, we will use highly sensitive cell-
free DNA from peripheral blood 
 
(5)  To evaluate the role of CCRL2 expression in MDS/MPN patient samples and MMB-
HMA response, we will correlate response with CCRL2 expression in patient CD34+ 
cells.   
 
(6) To evaluate additional mechanisms of resistance to MMB-HMA, we will obtain single 
cell analysis at week 12. To identify resistant clones and mechanism of resistance, we 
will evaluate single cell RNA sequencing in 3 responders and 2 non-responders. 
 
7.0 PATIENT SELECTION 
7.1 Inclusion criteria 
 
1. 
 Patients of age 18 or older with a diagnosis of MDS/MPN or CNL as specified 
below 
 
2.          Eligible diagnoses by WHO or ICC diagnostic criteria: 
 
• a. Chronic myelomonocytic leukemia 
• b. MDS/MPN with neutrophilia, previously known as atypical chronic 
myeloid leukemia 
• c. Chronic neutrophilic leukemia 
• d. MDS/MPN-not otherwise specified 
 
3. 
Chronic phase disease with <10% blasts in peripheral blood and marrow within 1 
month from planned start of treatment 
 
4.          Eastern Cooperative Oncology Group (ECOG) Performance Score58 of 0-2 
(Appendix 5) 
 
5. 
Patients can be treatment naïve or could have undergone prior treatments for 
MDS/MPN as below: 
    

24 
 
 
a.       Prior treatment with non-JAK inhibitors or hypomethylating agents are 
allowed (e.g., hydroxyurea, immunomodulatory agents, steroids). 
Hydroxyurea can be continued until or even beyond initiation of treatment 
for 2 months if needed for cytoreduction 
b.       If non-MMB JAK inhibitors were used for treatment and stopped due to 
side effects (e.g., anemia from ruxolitinib, gastrointestinal toxicity from 
fedratinib, etcetera), these patients will be allowed to enroll on this study 
as long as JAK inhibitor was stopped at least 2 weeks prior to anticipated 
start date of treatment 
c.       If prior hypomethylating agent was used and stopped longer than 3 months 
prior to anticipated start date of treatment due to side effects, these 
patients will be eligible. However, if hypomethylating agents were stopped 
due to lack of clinical benefit, these patients will not be deemed eligible 
d.       Prior treatment with erythropoietic stimulating agents is allowed if last 
treatment was more than 4 weeks prior to anticipated start date of 
treatment 
e.      Splenic radiation should have been performed more than 2 months before 
anticipated start date of treatment 
f.       Any prior or ongoing investigation therapy or agents should be stopped 
longer than 4 weeks of anticipated start date of treatment 
 
6. 
Blood counts with platelets >=25,000/microL, ANC >=0.75 x 10^9/L (without 
transfusion or growth factor support) 
 
7.         Baseline splenomegaly with ≥5 cm below costal margin or ≥450 cm3 on imaging 
(ultrasound, CT or MRI) 
 
8.         Adequate organ function with creatinine clearance measured by Cockcroft-Gault 
calculation ≥30 mL/min, total bilirubin ≤1.5×ULN (isolated bilirubin >1.5 x ULN is 
acceptable if bilirubin is fractionated and direct bilirubin <35%), INR ≤1.5 × ULN 
unless participant is receiving anticoagulant therapy as long as PT or aPTT is 
within the therapeutic range of intended use of anticoagulants, albumin ≥2.5 g/dL. 
 
9.        Patients who have previously undergone an allogeneic stem cell transplantation 
will be allowed to enroll as long as: BMT was > 6 months ago from screening, and 
there is no evidence of grade >1 acute GVHD, and there is no acute/chronic GVHD 
requiring systemic immunosuppression. 
 
10.      Willing and able to sign the informed consent form 
 
11.      Life expectancy > 24 weeks 
 
12.      Willing and able to complete patient-reported outcome assessments using an 
ePRO device according to protocol 
 

25 
 
13.      Patients of child-bearing potential, or those with partners of child-bearing potential 
or pregnant or lactating partners, who are willing to follow highly effective 
contraceptive requirements. List of contraceptives allowed during the study is 
provided in Appendix 7. Females of reproductive potential should use effective 
contraception during study treatment and for 6 months following the last dose for 
HMA-MMB and 1 week following the last dose for MMB. Males with female 
partners of reproductive potential should use effective contraception during study 
treatment and for 3 months following the last dose for HMA-MMB and 1 week 
following the last dose for MMB. Patients should not breastfeed during treatment 
and for 1 week after the last dose.  
 
14.      Patients of child-bearing potential with a negative highly sensitive serum pregnancy 
test within 24 hours before the first dose of momelotinib. 
 
7.2 Exclusion criteria 
1. 
Diagnosis of MDS/MPN with SF3B1 mutation and thrombocytosis (excluded due 
to unclear role of ACRV1 in the pathogenesis of anemia) 
 
2. 
Peripheral blood or marrow (by immunohistochemistry) blast percentage ≥10%  
 
3. 
Prior lack of response to MMB or hypomethylating agents. 
 
4. 
Known history of allergic reaction to momelotinib 
 
5. 
AST or ALT above 2.5 x ULN (above 5 X ULN if liver is involved by extramedullary 
hematopoiesis as judged by the investigator or if related to iron chelator therapy 
that was started within the prior 60 days) 
 
6. 
The following treatments within the time periods as specified: 
 
a.     Momelotinib at any time prior to screening 
b.     Erythropoietic stimulating agents within 4 weeks of treatment 
c.     Investigational agent within 4 weeks of the first dose of study treatment 
d.     Immunosuppressive agents within 28 days (low dose steroids ≤10 mg daily 
prednisone or equivalent is allowed) 
e.    Potent cytochrome P450 3A4 (CYP3A4) inducers, except for rifampin and 
rifampicin, within 14 days prior to the first dose of momelotinib. Strong 
CYP3A4 inducers can lead to decreased MMB exposure and risk a lack of 
efficacy. Therefore, alternative medicinal product to strong CYP3A4 inducer 
should be considered.  
 
*Momelotinib is a BCRP inhibitor. Coadministration of momelotinib has the 
potential to increase the plasma concentration of BCRP substrates, such as 
rosuvastatin and sulfasalazine. While this is not an exclusion, participants should 
be monitored for adverse reactions with coadministration. 

26 
 
 
*Momelotinib is an organic anion transporting polypeptide (OATP) 1B1/1B3 
substrate. Concomitant use with an OATP1B1/1B3 inhibitor may increase 
momelotinib exposure. While this is not an exclusion patients should be 
monitored for adverse reactions with coadministration with OATP1B1/1B3 
inhibitors, including ciclosporin. 
 
7. 
Unsuitable for spleen volume measurements due to prior splenectomy or unwilling 
or unable to undergo any imaging (ultrasound, CT without contrast or MRI without 
contrast) for spleen volume measurement per requirements 
 
8.         Patients with an active invasive concurrent malignancy, whose natural history or 
treatment has a significant potential to interfere with the safety or efficacy 
assessment of the investigational regimen. Localized prostate cancer that has 
been treated surgically or by radiotherapy with curative intent and presumed cured 
is allowed. History of non-melanoma skin cancers such as basal cell carcinoma or 
squamous cell carcinoma are also allowed. Completely resected intraepithelial 
carcinoma of cervix or papillary thyroid or follicular thyroid cancers are also allowed 
at the investigator’s discretion.  
 
9.        Untreated or active infections are excluded as below: 
 
a. Chronic active or acute viral hepatitis A, B, or C infection. Participants with 
positive hepatitis C antibody due to prior resolved disease can be enrolled, 
only if a confirmatory negative hepatitis C RNA test is obtained. If HBsAg 
and/or anti-HBc antibody is positive, we recommend consultation with a 
hepatologist regarding monitoring for reactivation versus prophylactic 
hepatitis B therapy. 
b. HIV with CD4+ cell count under 400 cells/ μL or on treatment with anti-
retroviral therapy that is specifically excluded per the criteria above. HIV 
patients on established anti-retroviral therapy allowed per protocol for at 
least 4 weeks and CD4+ count above or equal to 400 cells/ μL 
c. Infections requiring intravenous antibiotics 
 
10.      Nonhematologic toxicities from prior therapies that are unresolved and are of grade 
>1 
 
11.      Documented myocardial infarction or unstable/uncontrolled cardiac disease (e.g, 
unstable angina, congestive heart failure [New York Heart Association > Class III]) 
within 6 months of start of treatment. 
 
12.      Presence of peripheral neuropathy of grade ≥2 
 
13. 
Pregnant women are excluded from this study because the effects of momelotinib 
on embryotoxicity, survival, and teratogenicity remain unclear. In animal models, 
reduced pup survival was reported in reproductive and developmental toxicity 
studies 

27 
 
 
14.      Patients unable to swallow medications 
 
15.      Patient has any medical condition that puts the patient at an acceptable high risk 
with participation in the study per physician assessment or has any condition that 
confounds the ability to interpret data from the study. 
16.      Any major surgery or radiation or intervention that interferes with safety or feasibility 
of enrollment per investigator assessment  
 
7.3 Registration procedure 
 
The research nurse or data manager should be contacted to confirm a treatment slot is 
available before approaching a subject. All subjects must be registered with the Clinical 
Research Office at Johns Hopkins SKCCC before enrollment to study. 
To register a patient, the following documents should be completed by the research nurse 
or Study Coordinator: 
• Signed patient consent form 
• Registration form 
• Source documents 
 
Subjects will be assigned a screening number (ID) at screening. The screening ID will be 
used on all correlative samples. Treatment may not begin until eligibility has been 
confirmed. The screening ID number will become the study ID. Instructions concerning 
correlative/special studies will be conveyed. 
 
7.4 Early withdrawal or termination 
 
The duration of each cycle is 28 days, and treatment is be planned until disease 
progression or unacceptable side effects. However, treatment on the clinical trial may be 
discontinued for any of the following reasons: 
1. As mentioned above, disease progression by international consensus criteria4 or 
lack of response (response to be considered as clinical benefit, partial response or 
complete response by international consensus criteria for MDS/MPN).  
2. Any unacceptable adverse events 
3. The patient (or legal guardian) may withdraw consent at any time for any reason. 
Consent withdrawn means that the participant has explicitly indicated that they 

28 
 
do not want to be followed any longer; in this case no further data, except data in 
the public domain, may be solicited from or collected on the participant. Consent 
may also be partial; participants may choose to discontinue study treatment and 
remain in the study to be followed for safety/disease assessments.  
4. Further participation would be injurious to participant’s health in investigator’s 
medical assessment 
5. Dosing delays lasting >12 consecutive weeks (discontinuation due to adverse 
events will be managed per Section 8.2.8) 
6. Patient has a documented positive serum pregnancy test 
7. Patient is lost to follow-up 
8. Study termination by sponsor or by local authority or IRB 
9. If during the course of the study, a participant is found not meeting eligibility criteria, 
study PI in collaboration with local investigator will determine whether the patient 
should be withdrawn from study treatment 
10. If a patient is not able to comply with study treatment or study procedures in 
investigator’s opinion, study PI in collaboration with local investigator will determine 
whether the patient should be withdrawn from study treatment 
 
For these patients, end of treatment and follow-up procedures will be conducted as listed 
in Section 8.3.1. Every patient will be followed for 30 days following end of treatment for 
adverse events monitoring. If the participant discontinues study treatment and actively 
withdraws consent for collection of follow-up data (safety follow-up and/or disease 
assessment), then no additional data collection should occur; however, participants will 
have the option of withdrawing consent for study treatment but continuing in the follow-
up period of the study for safety/efficacy assessments. Patients who discontinue for 
reasons other than progressive disease will have post-treatment follow-up for disease 
status and toxicity up to 30 days. After documented disease progression, each patient will 
be followed for overall survival until death, withdrawal of consent, or the end of the study, 
whichever occurs first. 
 
7.5 Handling withdrawals or termination 
 
Reasonable efforts should be made to maintain contact with a patient who withdraws 
early. If the patient remains at participant institution for further care, clinic visits may be 
tracked, and the condition of the patient followed. If the patient is not continuing care at 
SKCCC or another treating site, contact information will be updated at the end of 
treatment visit, including accurate phone numbers, and email address. The importance 
of the follow-up period for adverse events and serious adverse events will be stressed to 
the patient. 

29 
 
 
8.0 TREATMENT PLAN AND STUDY SCHEDULE 
 
8.1 Study procedures and evaluations 
 
        8.1.1 Standard of care study procedures 
 
Several procedures, laboratory and diagnostics will be conducted per standard of care 
for MDS/MPN and CNL. These will include physical examination, vital signs, complete 
blood count with differential, comprehensive metabolic profile, amylase, lipase, serum 
pregnancy test, bone marrow biopsy and aspirate including cytogenetics, FISH, heme 
malignancy fusion panel, and NGS from blood or marrow. During follow up, monitoring of 
physical examination, vital signs, complete blood count with differential, and 
comprehensive metabolic profile will occur following stand of care monitoring for any 
patient with MDS/MPN or CNL.  
 
        8.1.2 Study-specific procedures 
 
Section 8.3.1 summarizes study events and evaluations to be performed at each visit 
and schedule of these visits. Individual procedures are described below. Additional 
procedures or evaluations may be deemed necessary at unscheduled times if deemed 
clinically necessary by treating investigator. Additional evaluations may be deemed 
necessary by study team for reasons of patient safety.  In some cases, such 
evaluation/testing may be potentially sensitive in nature (e.g., HIV, Hepatitis B/C, etc.), 
and thus local regulations may require that additional consent be obtained from the 
patient. In these cases, such evaluations/testing will be performed in accordance with 
those regulations. 
 
        8.1.3 Pre-treatment evaluation and study procedures/evaluation 
 
                  8.1.3.1 Informed consent 
 
Prior to any study procedure or study-related evaluation, informed consent must be 
obtained and documented by the patient’s dated signature or by the patient’s legally 
acceptable representative’s dated signature on a consent form. The dated signature of 
the person conducting the consent discussion must also appear on the consent form. 
 

30 
 
 
                  8.1.3.2 Assessment of inclusion/ exclusion criteria 
 
All inclusion and exclusion criteria will be reviewed by the study team prior to initiation of 
treatment per the study. PI (or site PI at collaborating institutions) or sub-investigator will 
sign the inclusion/exclusion criteria and ensure that the patient qualifies for the clinical 
trial.  
 
                  8.1.3.3 Demographics  
 
Demographical information will be collected at clinic visit and will include birth date, age, 
sex, race, and ethnicity.  
 
                  8.1.3.4 Medical history and concurrent medications 
 
A detailed medical history will be obtained by the investigator or qualified designee. All 
active and prior medical conditions and any condition diagnosed that is considered to be 
clinically significant by the investigator, will be recorded. Details regarding the disease for 
which the patient has enrolled in this study will be recorded separately and not listed as 
medical history. 
 
The investigator or qualified designee from study team will review patient 
medications at the start of screening visit and throughout the study period until the last 
dose of study treatment. Any medications that may be associated with SAEs should be 
recorded as defined in the SAE section of the protocol. 
 
                  8.1.3.5 History and physical examination  
 
Complete medical history should include particular attention to the following details: 
a) 
Presentation for the current diagnosis 
b)         Previous treatment and response 
c) 
Previous transfusions and transfusion reactions 
d) 
Previous serious infections 
e) 
Allergies 
f) 
Current medications 
g) 
Assessment of performance status 
 
Patient’s baseline symptoms that are present at the closest time before the start of the 
study drug will be evaluated and recorded. This will also include MPN-SAF TSS score 
(see Appendix 3). Detailed physical exam including spleen size by palpation 

31 
 
(craniocaudal dimension of spleen as palpable below costal margin) will be recorded by 
investigator. Clinically significant abnormal findings at baseline will be recorded.  
 
                  8.1.3.6 Vital signs 
 
The investigator or qualified designee from study team will record vital signs at screening 
visit and at each visit prior to administration of drug. Vital signs will include blood pressure, 
pulse rate, respiratory rate, temperature, height and weight.  
 
                  8.1.3.7 Performance status 
 
The investigator or qualified designee from study team will record performance status by 
Eastern Cooperative Oncology Group (ECOG) performance status scale (see Appendix 
5). 
 
                  8.1.3.8 Laboratory procedures and data 
 
Laboratory data at baseline will include CBC with differential, comprehensive metabolic 
panel including potassium and creatinine and liver enzymes, LDH, beta-HCG for women 
of child-bearing age, magnesium, phosphorus, uric acid, C-reactive protein, amylase, 
lipase, and coagulation profile. At follow up visits as shown in Section 8.3.1.14, CBC with 
differential, comprehensive metabolic panel, LDH, tumor lysis labs (phosphorus, 
magnesium and uric acid in addition to potassium and creatinine in CMP), and beta-HCG 
for women of child-bearing age, will be performed.  
 
Patients of child-bearing potential must have a negative highly sensitive serum 
pregnancy test within 24 hours before the first dose of momelotinib. In addition, regular 
pregnancy testing will be conducted as noted below while on treatment and up to at least 
1 month after the last dose of MMB. Additional serum or urine pregnancy tests may be 
performed, as determined necessary by the treating physician or required by local 
regulation to establish the absence of pregnancy at any time during the patient’s 
participation in the program. In the event of a positive pregnancy test, the participant must 
stop momelotinib treatment immediately.   
 
                  8.1.3.9 Bone marrow biopsy 
 
Bone marrow biopsy and aspirate will be conducted at baseline within 4 weeks of 
anticipated start day of treatment. Flow cytometry, cytogenetics, hematological 
malignancy fusion panel, next generation sequencing will be sent from the bone marrow. 

32 
 
Additional bone marrow biopsy will be performed after cycle 6 completion (day 168) +/- 
14 days.  
 
                  8.1.3.10 Spleen size assessment 
 
Spleen imaging will be performed at baseline (within 28 days of cycle 1 day 1), on the day 
of week 12 assessment (+/- 5 days), at the day of week 24 assessment (+/- 10 days), and 
every 12 weeks thereafter (+/- 15 days), and at end of treatment or relapse/progression. 
Ultrasound will be the preferred modality of spleen imaging and spleen size dimensions 
(length, height, width) as well as spleen volume will be reported. In situations where 
ultrasound is not feasible, CT or MRI without contrast is allowed. It is strongly encouraged 
to keep the modality of spleen imaging consistent throughout the study.  
 
                  8.1.3.11 Correlative studies 
 
Correlatives studies will include evaluation for NGS, targeted-deep sequencing using cell 
free DNA, single cell analysis and CCRL2 expression on CD34+ cells. NGS will be 
performed on the marrow aspirate (or PB if dry tap) at baseline using standard myeloid 
panel with a sensitivity of at least 5%. Mutations panel should include at least the following 
genes of known relevance in these diagnoses:  JAK2, MPL, CALR, ASXL1, SRSF2, 
SETBP1, EZH2, RUNX1, TET2, DNMT3A, U2AF1, ZRSR2, SF3B1, CSF3R, KRAS, 
NRAS, CBL, PTPN11, TP53, PHF6, IDH1, IDH2, ETV6. NGS performed within 6 months 
from start of treatment can be used as baseline if approved by study PI. PB sample for 
cell free DNA will be obtained at baseline, week 12 and week 24 assessment.  Samples 
for single cell analysis and CCRL2 expression (CD34+ cells from the bone marrow) will 
be collected at baseline and with the bone marrow at week 24 assessment. Additional 
sample will be collected from PB at week 12 for the first 10 patients. These samples will 
be shipped to Hopkins as described in Appendix 6.  
 
8.2 Study treatment and dose adjustments 
 
        8.2.1 Momelotinib 
 
MMB will be administered using modified 3+3 dose escalation design followed by 
expansion. The first three patients will be treated at 150mg daily and if DLT criteria are 
not met, the remaining patients will be treated at 200mg daily to a total of 18 evaluable 
patients3 (all in combination with azacitidine). If DLTs are met with in the dose escalation 
phase (first three patients), then the patients will be treated at 150mg or 200mg daily (in 
combination with azacitidine) as elaborated in Section 6.1. MMB can be administered at 

33 
 
any time of the day but is encouraged to be taken around the same time every day. A 
dose is considered “missed” if not given within 10 hours or the typical time of 
administration. If a dose is missed, the next scheduled dose should be taken the following 
day. No additional doses are to be taken to make up for the missed dose.  
Dose interruptions, reductions, or modifications for toxicity are described in Section 8.2.8. 
The lowest dose of MMB allowed will be 100 mg daily. 
 
        8.2.2 Hypomethylating agent 
 
5-Azacytidine will be used as HMA In the study. Azacitidine will be added at standard 
dose of 75 mg/m2 intravenously or subcutaneously on days day 1-5 of each 28-day cycle. 
Azacitidine can be started at a lower dose of 50 mg/m2 or 25 mg/m2 if deemed 
appropriate due to pre-existing cytopenias (absolute neutrophil count < 1000/mm3 or 
platelet count < 50000/mm3).  
 
        8.2.3 Infection prophylaxis and therapy 
 
All patients are expected to pursue prophylactic antiviral therapy for shingles prevention 
using acyclovir or valacyclovir during treatment. Standard interventions as appropriate for 
any infections occurring during study period should be adopted.  
 
        8.2.4 Prophylaxis and management of expected toxicity 
 
Prophylactic anti-emetics (e.g., ondansetron) will be available to patients for use as 
needed for management of nausea. Similar anti-diarrheas such as loperamide will be 
available for diarrhea as needed. If diarrhea is considered to be related to an infection, 
appropriate investigations and management will be followed.  
 
        8.2.5 Transfusions and growth factor support 
 
Standard parameters for transfusions for hemoglobin (at least for hemoglobin < 7g/dL) 
and platelets (at least for platelets < 10,000 per microliter). Higher thresholds for 
transfusions can be applied in cases of clinical need including but not limited to bleeding, 
cardiac disease, symptomatic anemia etcetera. Growth factors will be avoided during the 
course of the study with exceptions such as sepsis in a setting of neutropenia if deemed 
appropriate by treating team.  
 

34 
 
        8.2.6 Hydroxyurea for leukocytosis 
 
For patients with leukocytosis > 50,000/microliter or worsening leukocytosis during 
screening and baseline, hydroxyurea can be used up to a dose of 2000 mg daily per 
discretion of treatment physician and discussion with study PI. Hydroxyurea can be 
continued for up to 2 months following study initiation. If hydroxyurea is being considered 
for use outside of above parameters, it will need to be discussed with study PI.  
 
        8.2.7 Dose-limiting toxicities 
 
Dose limiting toxicity (DLT) will be defined as the occurrence of any toxicities as listed in 
the table below, except those with a clear alternative explanation occurring during the 
course of the study. All DLTs will be assessed for severity by the investigator with CTCAE 
version 5.0. DLT observation period is defined as the first treatment cycle (cycle 1) which 
will be 4 weeks (28 days) in duration from the start of treatment for all patients.   
 
• Toxicity 
• Definition 
• Non-hematologic 
Any Grade ≥ 3 non-hematologic toxicity EXCEPT: 
• Grade 3 fatigue, asthenia, fever, anorexia, or 
constipation 
• Grade 3 nausea, vomiting, or diarrhea not requiring 
tube feeding, total parenteral nutrition, or 
hospitalization and resolves to grade < 2 within 72 
hours 
• Grade 3 AST or ALT elevation that resolves to 
Grade ≤1 within 72 hours) 
• Grade 3 or 4 isolated electrolyte abnormalities that 
resolve, with or without intervention, to < Grade 2 
levels in < 72 hours 
• Hematologic 
Any of the following: 
• Grade 3 thrombocytopenia with bleeding 
• Any grade 4 thrombocytopenia*  
• Grade 4 decrease in neutrophil count lasting > 14 
days 
• Grade 3 or 4 febrile neutropenia of any duration 
 
*Grade 4 thrombocytopenia in patients enrolled with 
platelets <50,000/microL will be confirmed with a second 
read which can be done the same day. 
 

35 
 
        8.2.8 Dosing delays and modification for toxicity 
 
Adverse events of cytopenias, especially thrombocytopenia or neutropenia can result in 
dose interruptions or modifications, or both as described in the table below. Dose 
reductions will occur in 50 mg daily decrements and the lowest dose allowed for MMB is 
100 mg daily.  
 
Dose adjustments for MMB for adverse events 
 
• Adverse event 
• Action 
Thrombocytopenia 
• Baseline platelet count: ≥100,000/mm3 
• Platelet count: 20,000 to 
<50,000/mm3 
• Reduce the daily dose by 50 mg 
from the last administered dosea 
• Platelet count: <20,000/mm3 
• Interrupt treatment until platelets 
≥50,000/mm3; restart momelotinib 
at a daily dose reduced by 50 mg 
below the last administered dosea 
• Baseline platelet count: ≥50,000 to <100,000/mm3 
• Platelet count: <20,000/mm3 
• Interrupt treatment; Resume when/ 
if platelet count recovers to ≥50% 
of baseline value in the absence of 
platelet transfusion for ≥5 days, at 
a reduced daily dose of MMB 
reduced by 50 mg below the last 
administered dosea 
• Baseline platelet count: <50,000/mm3 
• Platelet counts: <20,000/mm3 
• Interrupt treatment; Resume when/ 
if platelet count recover to 
>25,000/mm3, at a reduced daily 
dose of MMB reduced by 50 mg 
below the last administered dosea 
 
Neutropenia 
• ANC <500/mm3 
• Interrupt treatment as appropriate 
• Resume treatment when ANC 
>750/mm3, at a reduced daily 
dose of MMB reduced by 50 mg 
below the last administered dosea 
• Re-escalation can be allowed upon 
resolution of toxicity and return of 
ANC to baseline level 
 

36 
 
Non-hematological or other toxicities 
• Grade 3 or 4 non-hematologic 
toxicity 
• Interrupt treatment for grade 3 or 4 
non-hematologic toxicity that the 
investigator considers related to 
the study treatment 
• Resume treatment at dose 
reduced by 50 mg daily upon 
resolution of toxicity to grade ≤1 or 
baseline gradea 
• Grade 3 or 4 Severe Cutaneous 
Adverse Reactions (SCARs) 
• Permanently discontinue and do 
not reintroduce 
• Grade ≥2 bleeding event 
• Interrupt treatment for grade ≥2 
bleeding event that the investigator 
considers related to the study 
treatment 
• Resume treatment at dose 
reduced by 50 mg daily upon 
resolution of toxicity to grade ≤1 or 
baseline gradea 
a. 
In situations where grade 4 neutropenia or thrombocytopenia occurs on 100mg daily of MMB, 
rechallenge with 100mg MMB will be allowed upon resolution of the toxicity to grade 2 or better or 
once at pre-treatment levels. This reintroduction will be done upon discussion with IND sponsor,   
b. 
If the previous dose was 100mg daily, then reinitiate treatment at same dose of 100 mg 
 
Dose adjustments for azacitidine for adverse events 
 
Standard dose for azacitidine is 75 mg/m2 intravenously or subcutaneously on days day 
1-5 of each 28-day cycle, and is the recommended dose for this study. Azacitidine can 
be started at a lower dose of 50 mg/m2 or 25 mg/m2 if deemed appropriate due to pre-
existing cytopenias in the form of neutrophil count < 1000/mm3 or platelets <50000/mm3.  
 
While on treatment, for cytopenias that do not improve despite lowering the dose of MMB 
to 100mg daily, we then recommend decreasing the dose of azacitidine from 75mg/m2 to 
50mg/m2 or from 50mg/m2 to 25mg/m2.  
 
8.3 Study schema and sample collection 
 
        8.3.1 Scheduled study visits 
 
Study visits and associated evaluations are described and tabulated below.  

37 
 
 
              8.3.1.1 Screening visit will be conducted when considering the patient for this 
study and can be used for consent. Demographics, medical history, concurrent 
medications will be collected at this visit. Laboratory data will be collected as outlined in 
the table. These assessments and investigations will be conducted within 28 days of start 
of study treatment on cycle 1 day 1. These will include: 
a) 
Evaluation of history and physical examination including spleen size on 
palpation 
b) 
Review of prior and current medications 
c) 
Vital signs 
d) 
ECOG performance status 
e) 
Recording of patient height and weight 
f) 
CBC with differential  
g) 
Comprehensive metabolic panel (sodium, potassium, chloride, bicarbonate, 
BUN, creatinine, total protein, albumin, AST, ALT, alkaline phosphatase total 
bilirubin, calcium), direct bilirubin, magnesium, phosphorus, uric acid, LDH, 
amylase, lipase, C-RP, coagulation profile, HIV, Hepatitis B/C testing 
h) 
Serum pregnancy test 
i) 
Peripheral blood smear evaluation for blasts 
j) 
Bone marrow biopsy and aspirate if not dry tap, including flow cytometry, 
cytogenetics, hematological malignancy fusion panel, next generation 
sequencing (NGS), single cell sequencing, and CCRL2 correlatives 
k) 
Spleen size assessment preferably by ultrasound (CT or MRI without contrast 
are alternatives)  
l) 
pH, glucose, protein, blood, ketones [bilirubin, urobilinogen, nitrite, leukocyte 
esterase] by dipstick. Urine protein: creatinine ratio (uPCR) if urine dipstick 
shows > 2+ protein. 
 
              8.3.1.2 Cycle 1 day 1 (cycle length = 28 days) 
 
a) Confirmation of patient eligibility prior to initiation of study treatment 
b) Record baseline MPN SAF TSS score 
c) Evaluation of history and physical examination including spleen size on palpation 
d) Review of current medications 
e) Vital signs 
f) ECOG performance status 
g) Record patient height and weight 
h) CBC with differential  
i) Comprehensive metabolic panel as above, direct bilirubin, magnesium, 
phosphorus, uric acid, LDH, amylase, lipase, C-RP, serum pregnancy test 

38 
 
j) Administer study treatment and provide medication supply sufficient to last until 
the next study-defined next visit  
k) Provide the patient with adverse event diary 
 
              8.3.1.3 Cycle 1 days 8, 15, 22 (+/- 5 days) 
 
a) History and physical examination 
b) Review of medications 
c) Vital signs 
d) ECOG performance status 
e) CBC with differential  
f) Comprehensive metabolic panel as above, direct bilirubin, magnesium, 
phosphorus, uric acid 
 
              8.3.1.4 Cycle 2 day 1 (+/- 5 days) 
  
a) History and physical examination including spleen size on palpation 
b) Review of medications 
c) Vital signs 
d) ECOG performance status 
e) Record patient height and weight 
f) CBC with differential  
g) Comprehensive metabolic panel, direct bilirubin, magnesium, phosphorus, uric 
acid, LDH, amylase, lipase, C-RP, serum pregnancy test 
h) Record MPN SAF TSS score 
i) Record PGIC 
j) Administer study treatment and provide medication supply sufficient to last until 
next cycle 
k) Ensure the patient has adverse event diary 
 
              8.3.1.5 Cycle 2 day 15 (+/- 5 days) 
 
a) History and physical examination 
b) Review of medications 
c) Vital signs 
d) ECOG performance status 
e) CBC with differential  
f) Comprehensive metabolic panel, direct bilirubin, magnesium, phosphorus, uric 
acid 
 

39 
 
              8.3.1.6 Cycle 3 day 1 (+/- 5 days) 
 
a) History and physical examination including spleen size on palpation 
b) Review of medications 
c) Vital signs 
d) ECOG performance status 
e) Record patient height and weight 
f) CBC with differential  
g) Comprehensive metabolic panel, direct bilirubin, magnesium, phosphorus, uric 
acid, LDH, amylase, lipase, C-RP, serum pregnancy test 
h) Record MPN SAF TSS score 
i) Record PGIC 
j) Administer study treatment and provide medication supply sufficient to last until 
next cycle 
k) Ensure the patient has adverse event diary 
 
              8.3.1.7 Cycle 4 day 1 (+/- 5 days) [Assessment here will be counted towards 
week 12 assessment] 
 
a) History and physical examination including spleen size on palpation 
b) Review of medications 
c) Vital signs 
d) ECOG performance status 
e) Record patient height and weight 
f) CBC with differential  
g) Comprehensive metabolic panel, direct bilirubin, magnesium, phosphorus, uric 
acid, LDH, amylase, lipase, C-RP, serum pregnancy test 
h) Record MPN SAF TSS score 
i) Record PGIC 
j) Administer study treatment and provide medication supply sufficient to last until 
next cycle 
k) Ensure the patient has adverse event diary 
l) Peripheral blood samples for cytogenetics, NGS, and cell free DNA correlatives. 
Blood samples for MMB/M21 trough concentrations (for the first 10 patients) 
m) Spleen size assessment preferably by ultrasound (CT or MRI without contrast are 
alternatives)  
n) MDS/MPN response assessment by international consensus criteria (will 
contribute to interim futility analysis for first 6 patients) 
 
              8.3.1.8 Cycle 5 day 1 and Cycle 6 day 1 (+/- 5 days) 

40 
 
 
a) History and physical examination including spleen size on palpation 
b) Review of medications 
c) Vital signs 
d) ECOG performance status 
e) Record patient height and weight 
f) CBC with differential  
g) Comprehensive metabolic panel, direct bilirubin, magnesium, phosphorus, uric 
acid, LDH, amylase, lipase, C-RP, serum pregnancy test 
h) Record MPN SAF TSS score 
i) Record PGIC 
j) Administer study treatment and provide medication supply sufficient to last until 
next cycle 
k) Ensure the patient has adverse event diary 
 
              8.3.1.9 Cycle 7 day 1 (+/- 10 days) [Assessment here will be counted 
towards week 24 assessment] 
 
a) History and physical examination including spleen size on palpation 
b) Review of medications 
c) Vital signs 
d) ECOG performance status 
e) Record patient height and weight 
f) CBC with differential  
g) Comprehensive metabolic panel, direct bilirubin, magnesium, phosphorus, uric 
acid, LDH, amylase, lipase, C-RP, serum pregnancy test 
h) Blood samples for MMB/M21 trough concentrations (for the first 10 patients) 
i) Record MPN SAF TSS score 
j) Record PGIC 
k) Administer study treatment and provide medication supply sufficient to last until 
next cycle 
l) Ensure patient has adverse event diary 
m) Bone marrow biopsy and aspirate if not dry tap, including flow cytometry, 
cytogenetics, NGS and CD34+cells for single cell analysis and CCRL2 studies 
n) Spleen size assessment preferably by ultrasound (CT or MRI without contrast are 
alternatives)  
o) MDS/MPN response assessment by international consensus criteria 
 
 
              8.3.1.10 Cycle 8 onwards day 1 (+/- 15 days) 

41 
 
 
a) History and physical examination including spleen size on palpation 
b) Review of medications 
c) Vital signs 
d) ECOG performance status 
e) Record patient height and weight 
f) CBC with differential  
g) Comprehensive metabolic panel, direct bilirubin, magnesium, phosphorus, uric 
acid, LDH, amylase, lipase, C-RP, serum pregnancy test 
h) Record MPN SAF TSS score 
i) Record PGIC 
j) Administer study treatment and provide medication supply sufficient to last until 
next cycle 
k) Ensure the patient has adverse event diary 
l) Spleen size assessment preferably by ultrasound (CT or MRI without contrast are 
alternatives) every 3 months 
m) MDS/MPN response assessment by international consensus criteria every 3 
months 
 
              8.3.1.11 At progression or relapse 
 
a) History and physical examination including spleen size on palpation 
b) Review of medications 
c) Vital signs 
d) ECOG performance status 
e) Record patient height and weight 
f) CBC with differential  
g) Comprehensive metabolic panel, direct bilirubin, magnesium, phosphorus, uric 
acid, LDH, amylase, lipase, C-RP 
h) Spleen size assessment preferably by ultrasound (CT or MRI without contrast are 
alternatives) 
i) Bone marrow biopsy and aspirate if not dry tap, including flow cytometry, 
cytogenetics, NGS and CD34+cells for single cell analysis and CCRL2 studies 
 
              8.3.1.12 End of treatment visit 
 
a) History and physical examination  
b) Review of medications 
c) Vital signs 
d) ECOG performance status 

42 
 
e) CBC with differential  
f) Comprehensive metabolic panel, direct bilirubin, magnesium, phosphorus, uric 
acid, LDH, amylase, lipase, C-RP, serum pregnancy test 
g) Record MPN SAF TSS score 
h) Record PGIC 
 
8.3.1.13 End of study visit 
a) History and physical examination  
b) AE assessment 
 
              8.3.1.15 Study Schedule table 
 
 
Screening 4 weeks prior to cycle 1 day 
1 
Cycle 1 day1  
Cycle 1 days 8,15,22 (+/-5 days) 
Cycle 2 day 1 (+/-5 days) 
Cycle 2 day 15 (+/-5 days) 
Cycle 3 day 1 (+/-5 days) 
Cycle 4 day 1 (+/-5 days) [Day of week 
12 assessment] 
Cycle 5 day 1 (+/-5 days) 
Cycle 6 day 1(+/-5 days) 
Cycle 7 day 1) (+/-10 days) [Day of 
week 124 assessment 
Cycle x day 1 (+/-15 days)   
At relapse/ progression 
End of treatment visit 
End of Study Visit* 
Momelotinib 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Azacitidine  
 
D1-
5 
D1-
5 
D1-
5 
D1-
5 
D1-
5 
D1-5 
D1-5 
D1-5 
D1-5 
D1-5 
 
 
 
Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Concurrent meds 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
History/ Physical 
exam 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
MPN-SAF TSS 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Vitals signs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
x 
 
Height  
x 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
 
 
Weight 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
 
 
Performance 
status 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
 
 
CBC with 
differential 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Comprehensive 
metabolic panel  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Coagulation 
profile 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 

43 
 
Direct bilirubin 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
HIV, Hepatitis 
B/C serologies 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
LDH 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
 
 
Amylase/Lipase 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
 
 
C-reactive protein 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
Tumor lysis labs 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Beta-HCG 
(women)* 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
Peripheral blood 
sample for PKs 
 
 
 
 
 
 
X 
(n=1
0) 
 
 
X 
(n=1
0) 
 
 
 
 
Bone marrow 
biopsy 
x 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Cytogenetics/ 
FISH BM 
x 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Heme 
malignancy 
fusion panel BM 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cytogenetics 
from PB 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
Flow cytometry 
BM 
x 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Next generation 
sequencing  
BM 
 
 
 
 
 
 
 
 
BM 
 
BM 
 
 
Ultrasound for 
spleen size 
assessment 
x 
 
 
 
 
 
x 
 
 
x 
q3 
mont
hs 
x 
 
 
MDS/MPN 
response 
assessment 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
Peripheral blood 
smear 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event 
evaluation 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Samples for 
correlative 
studies from PB 
x 
 
 
 
 
 
x 
 
 
x 
 
 
 
 
Samples for 
correlative 
studies from BM 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
 
 
 

44 
 
 
Screening 
Cycle 1 day1  
Cycle 1 days 8,15,22 (+/-5 days) 
Cycle 2 day 1 (+/-5 days) 
Cycle 2 day 15 (+/-5 days) 
Cycle 3 day 1 (+/-5 days) 
Cycle 4 day 1 (+/-5 days) [Day of week 
12 assessment] 
Cycle 5 day 1 (+/-5 days) 
Cycle 6 day 1(+/-5 days) 
Cycle 7 day 1) (+/-10 days)  [Day of 
week 124 assessment 
Cycle x day 1 (+/-15 days)   
At relapse/ progression 
End of treatment visit 
End of Study Visit 
 
*A repeat pregnancy test will also be performed at 1 month following the last dose of MMB or at end of 
study visit. 
            
        8.3.2 Early termination visit 
 
If a patient withdraws participation for any reason prior to completion of study treatment 
plan, any subsequent procedures or evaluations will be per investigator discretion in 
accordance with standard of care management. Evaluations of adverse events and 
serious adverse events will continue as described in Section 7.4. 
 
        8.3.3 Unscheduled study visits 
 
Unscheduled visits are those that occur outside of the Scheduled study visits table 
including but not limited to history/physical examination, inpatient hospitalization or 
unexpected extended hospitalization or management of adverse events. These will be 
documented in the patient’s medical record by investigator or appropriate study designee 
and included on the adverse event log. Adverse event or serious adverse event data will 
be logged appropriately.  
 
8.4 Duration of treatment 
 
Study treatment is planned to continue until clinical benefit is observed or until criteria for 
withdrawal or termination are met as outlined in Section 7.4.  
 

45 
 
8.5 Duration of follow-up 
 
Patients will be followed for at least 30 days from end of study for toxicity monitoring. 
Overall survival data will be continued to be collected as allowed by participant.  
 
 
9.0 DATA MONITORING AND MANAGEMENT 
The SMC Subcommittee will review the study based on DSMP (version 6.0; 2/21/19). In 
addition to Compliance Reviews, all trial monitoring and reporting will be reviewed 
annually by the SKCCC Safety Monitoring Committee. The PI is responsible for internally 
monitoring the study. Data must be reviewed to assure the validity of data, as well as the 
safety of the subjects. The PI will also monitor the progress of the trial, review safety 
reports, and clinical trial efficacy endpoints and to confirm that the safety outcomes favor 
continuation of the study. 
 
 
The SKCCC Compliance Monitoring Program will provide external monitoring for JHU-
affiliated sites in accordance with SKCCC DSMP (Version 6.0, 02/21/2019). The SMC 
Subcommittee provides thorough and ongoing review of patient risks, study progress, 
safety, data accuracy and integrity, and overall protocol compliance, and a full SMC study 
review will occur at least annually. 
 
9.1 Data Reporting and Monitoring plan 
 
Data will be maintained on case report forms in a RedCap database house by Johns 
Hopkins School of Medicine.   The PI will be responsible for evaluation of data, disease 
response, and weekly overall toxicities.  
 
The investigators will review data to assure the validity of data, as well as, the safety of 
the subjects through internal data review. They will also monitor the progress of the trial. 
The investigators will be responsible for maintaining the clinical protocol. 
 
The principal investigator will be responsible for reporting adverse events, assuring that 
consent is obtained and documented, reporting of unexpected outcomes, and reporting 
the status of the trial in the annual report submitted to the IRB and to the trial monitoring 
review group. 
 
Content of the annual report at a minimum should include year-to-date and full trial data 
on accrual and eligibility, protocol compliance, treatment administration, toxicity and ADR 

46 
 
reports, response, survival, regulatory compliance, compliance with prearranged 
statistical goals. The report should be submitted in a timely manner according to the 
schedule defined by the SKCCC Clinical Research Office. The trial should be placed on 
hold or closed if there is non-compliance with this reporting. This report serves as the 
annual report for the IRB. 
 
The Protocol Chair and SMC will periodically review safety data. Enrollment of 
participants in the trial will be suspended at any time if any of these reviews concludes 
that there are significant safety concerns. 
 
9.2 Adverse Event Reporting 
             9.2.1 Overview 
 
The Principal Investigator is responsible for the detection and documentation of events 
meeting the criteria and definition of an AE (adverse event) or SAE (serious adverse 
event) as described in sections 9.3, 9.4 and 9.5 in this protocol. All AEs and SAEs will be 
recorded in the source documents and on the appropriate electronic CRF(s).  
 
Adverse events that are classified as serious according to the definition of health 
authorities must be reported promptly and appropriately to the Principal Investigator, the 
IRB and health authorities. This section defines the types of AEs and outlines the 
procedures for appropriately collecting, grading, recording and reporting them. 
Information in this section complies with 21CFR 312; ICH Guideline E2A: Clinical Safety 
Data Management: Definitions and Standards for Expedited Reporting; and ICH 
Guideline E-6: Guidelines for Good Clinical Practice; and applies the standards set forth 
in the National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events, 
Version 5.0 (November 27, 2017). 
 
All adverse events will be reported to JHU Institutional Review Board. 
 
             9.2.2 Definitions 
 
An Adverse Event (AE) is defined as any untoward medical occurrence associated with 
the use of a drug in humans, whether or not considered drug related.  
An AE can therefore be  any adverse change or exacerbation from a baseline condition 
or any unfavorable and unintended sign (including abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of investigational 
product which occurs following the initial administration of an investigational product 

47 
 
whether or not the event is considered to be related to the investigational product. 
Examples of this include but are not limited to the following: 
• Adverse changes including new signs and symptoms, intercurrent illness 
modifying the clinical course, or the worsening of a baseline condition including the 
increased frequency of an event or an increased intensity of a condition  
• Concomitant disease with onset or increased severity after the start of study 
product administration 
• A new pattern in a pre-existing condition, occurring after the receipt of 
investigational product that may signal a clinically meaningful change 
• Clinically significant changes in laboratory values 
 
 
                       9.2.2.1 Adverse reaction and suspected adverse reaction 
 
An adverse reaction means any adverse event caused by a drug. Adverse reactions are 
a subset of all suspected adverse reactions for which there is reason to conclude that the 
drug caused the event. 
 
Suspected adverse reaction (SAR) means any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event. For the purposes of safety 
reporting, ‘reasonable possibility’ means there is evidence to suggest a causal 
relationship between the drug and the adverse event. A suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which means 
any adverse event caused by a drug (21 CFR 312.32(a)). 
 
          9.2.2.2 Unexpected adverse events 
 
A SAR is considered “unexpected” if it is not identified in the package insert and/or drug 
label, or protocol, or is not listed at the specificity, or severity that has been observed (21 
CFR 312.32(a)): 
 
“An adverse event or suspected adverse reaction is considered "unexpected" if it is not 
listed in the investigator brochure or is not listed at the specificity or severity that has been 
observed; is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application. For example, under this 
definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the 
investigator brochure referred only to elevated hepatic enzymes or hepatitis. 
"Unexpected," as used in this definition, also refers to adverse events or suspected 

48 
 
adverse reactions that are mentioned in the investigator brochure as occurring with a 
class of drugs or as anticipated from the pharmacological properties of the drug, but are 
not specifically mentioned as occurring with the particular drug under investigation.” 
 
9.2.2.3 Other Adverse Events and  Adverse Events of Special Interest (AESIs) 
 
Adverse events of special interest are events that are being actively monitored as a result 
of a previously identified signal (even if non-serious). Adverse events of special interest 
of Momelotinib will be reported to the PI as defined in this protocol. The PI will ensure that 
if there are any changes to the AESI list, these changes will be updated in the protocol 
as soon as practical.  
Adverse events of special interest (even if non-serious):   
• Cytopenias: ≥ grade 4  
• Severe cutaneous adverse reactions (SCARs) ≥ grade 3 
Other adverse events will be identified by the PI during the evaluation of safety data.  
Significant adverse events of particular clinical importance, other than SAEs and those 
AEs leading to discontinuation of the subject from the study, will be classified as other 
adverse events.  For each, a narrative may be written and included in the clinical study 
report. 
 
9.3 Collecting and recording adverse events 
 
Methods of Collection 
The process of review of all AEs by the PI will be documented on AE collection forms. 
Source documentation, including all available clinic notes, will be reviewed from the time 
a subject signs consent until the participant comes off study or through the End of Study 
visit, whichever comes first.  
 
The methods for collecting AEs will include: 
• 
Observing the participant. 
• 
Questioning the participant in an objective manner. 
• 
Receiving an unsolicited complaint from the participant. 
 
All toxicities, abnormal laboratory results and/or potential adverse events experienced 
by accrued subjects during this time will be assessed by the PI who will do the initial 
determination of the relation, or attribution, of an AE to study participation and will 
record the initial determination on the appropriate AE collection form. The relation of an 

49 
 
AE to study participation will be determined using definitions in section 9.5.1. These 
assessments are to occur regularly for the time period specified and confirmed by the PI 
based on attribution to study intervention(s). 
 
An abnormal value or result from a clinical or laboratory evaluation (e.g., a radiograph, 
an ultrasound, or an electrocardiogram) can also indicate an AE if it is determined by 
the Investigator to be clinically significant. If this is the case, it must be recorded in the 
source document and as an AE on the appropriate AE form(s). The evaluation that 
produced the value or result should be repeated until that value or result returns to 
normal or can be explained and the participant’s safety is not at risk. 
 
Adverse Events 
All AE grades will be defined per NCI-CTCAE version 5.0 criteria unless otherwise 
specified.  
 
9.4 Recording method 
                 
                 9.4.1 Adverse events 
 
Throughout the study, the Investigator will record AEs on the appropriate eCRF 
regardless of their relation to study participation. The Investigator will treat participants 
experiencing AEs appropriately and observe them at suitable intervals until their 
symptoms resolve or their status stabilizes. 
 
                  9.4.2 Serious adverse events 
 
An AE or SAR is considered “serious” if, in the view of the Investigator, it results in any 
of the following outcomes: 
• Death: A death that occurs during the study or that comes to the attention of the 
Principal Investigator receives the first dose of study medication until 30 days 
following cessation of treatment must be reported whether it is considered 
treatment- related or not. 
• A life-threatening event: An AE or SAR is considered “life-threatening” if, in the 
view of the Investigator, its occurrence places the subject at immediate risk of 
death. It does not include an AE or SAR that, had it occurred in a more severe 
form, might have caused death. 
• An event that requires intervention to prevent permanent impairment or damage. 
An important medical event that may not result in death, be life threatening, or 

50 
 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment, it may jeopardize the participant and may require medical or 
surgical intervention to prevent one of the outcomes listed above. 
 
Serious AEs will be recorded and health authorities will be notified as outlined in section 
9.5.2. 
 
9.5 Grading and attribution of adverse events 
                 
                  9.5.1 Grading criteria 
 
The study site will grade the severity of AEs experienced by study participants 
according to the criteria set forth in the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events Version 5.0 (published November 27, 2017). 
This document (referred to herein as the “NCI-CTCAE v. 5.0 manual”) provides a 
common language to describe levels of severity, to analyze and interpret data, and to 
articulate the clinical significance of all AEs. 
 
Severity of adverse events will be graded on a scale from 1 to 5 according to the 
following standards in the NCI-CTCAE v. 5.0 manual: 
• Grade 1 = mild - Does not interfere with routine activities and minimal level of 
discomfort.  
• Grade 2 = moderate- - Interferes with routine activities or moderate level of 
discomfort 
• Grade 3 = severe- Unable to perform routine activities or significant level of 
discomfort 
• Grade 4 = life-threatening or disabling - Hospitalization or ER visit for potentially 
life-threatening event  
• Grade 5 = death. 
 
For additional information and a printable version of the NCI-CTCAE v. 5.0 manual, go 
to https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 
 
FDA guidelines for toxicity will be followed; however, if a subject is evaluated in an 
emergency room for nonlife threatening illness or symptoms (i.e., visits emergency 
department on weekend for mild problems because the physician’s office is closed), the 
information from that visit will be reviewed and severity of the adverse event will be 
assessed according to the subject’s clinical signs and symptoms. 

51 
 
The term “severe” is often used to describe intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself however, may be of 
relatively minor medical significance (such as severe headache). This is not the same as 
“serious”, which is based on subject/event outcome or action criteria usually associated 
with events that pose a threat to a subject’s life or functioning. Seriousness (not severity) 
serves as a guide for defining regulatory reporting obligations. 
There are two categories of reportable adverse events: 1) adverse events that are 
attributable to the use of momelotinib; and 2) adverse events that are not attributable to 
the use of the momelotinib. All reporting of adverse events will be carried out according 
to current IRB and FDA guidelines.  
 
Attribution Definitions 
Adverse events will be categorized for their relation to the investigational treatment. The 
Principal Investigator will do the initial determination of the relation, or attribution, of an 
AE to study participation and will record the initial determination on the appropriate eCRF 
and/or SAE reporting form. The relation of an AE to study participation will be determined 
using definitions in the Attribution of Adverse Events Table below. 
 
 
Attribution of Adverse Events Table 
 
Table 9.5.1 (1) 
Code 
Descriptor 
Relationship (to primary investigational 
product and/or other concurrent mandated 
study therapy) 
Unrelated Categories 
1 
Unrelated 
The adverse event is clearly not related. 
2 
Unlikely 
The adverse event is unlikely related. 
Related Categories 
3 
Possible 
The adverse event has a reasonable possibility 
to be related; there is evidence to suggest a 
causal relationship. 
4 
Probable 
The adverse event is likely related. 
5 
Definite 
The adverse event is clearly related. 
 
 

52 
 
                  9.5.2 Sponsor Responsibilities for Reporting serious adverse events 
 
9.5.2.1 Health Authority 
The sponsor shall be responsible for complying, within the required timelines, with any 
safety reporting obligation towards the competent health authorities, the Ethics 
Committees (EC) or Independent Review Board (IRB) and the participating (co- or sub-) 
investigators. 
9.5.2.2 General 
The Sponsor/Investigator is obligated to report to the FDA suspected adverse reaction 
that is both serious and unexpected. (see 21 CRF, part 312.32): 
• Serious Adverse Event - any adverse experience which is fatal or life-
threatening, permanently disabling, requires inpatient hospitalization, or is a 
congenital anomaly, cancer, or overdose; 
• Unexpected Adverse Event - any adverse experience that is not identified in 
nature, severity or frequency in the current Investigator Brochure. 
 
ALL serious adverse events, regardless of causality must be reported to the following 
entities: 
• IND Sponsor-Investigator – Dr. Jain; 
• IRB (per the IRB’s reporting requirements) 
 
Investigator Reporting Responsibilities 
 
The conduct of the study will comply with all FDA safety reporting requirements. An 
investigator must immediately report to the sponsor-Investigator, Dr. Jain, any serious 
adverse event, whether or not considered drug related, including those listed in this 
protocol or investigator brochure.  This report must include an assessment of whether 
there is a reasonable possibility that the drug caused the event.  Study endpoints that are 
serious adverse events (e.g., all-cause mortality or dose limiting toxicities [DLTs]) and 
show evidence suggesting a causal relationship between the drug and the event (e.g., 
death from anaphylaxis) must also be immediately reported to the IND sponsor-
investigator, who will in turn report these events to GSK, the sponsor of the drug, the JHU 
IRB and the FDA as required. 
 
The sponsor-investigator, Dr. Jain, is responsible for evaluating all adverse events to 
determine whether criteria for “serious” and “unexpected” as defined above are present. 
This SKCCC clinical trial requires maintenance of a study-specific master adverse event 
log to document all nonserious and serious adverse events as well as a protocol deviation 
log. These logs will be reviewed by Dr. Jain throughout the duration of the study, and 
reported to the JHU IRB annually.  
 
The IND sponsor- investigator is required to furnish all reports to GSK, who in turn is 

53 
 
responsible for collecting and evaluating the results obtained. The IND sponsor-
Investigator is also required to submit annual reports to both the FDA and the JHU IRB 
on the progress of the clinical investigations. 
 
Sponsor SAE Reporting to the FDA 
 
All SAEs are reported to the FDA via the IND annual report per 21 CFR 312.33. SAEs 
deemed unexpected and related to the investigational product qualify for expedited 
reporting and must be submitted by the IND Sponsor, Dr. Jain, to the FDA on a FDA Form 
3500A as per 21 CFR 312.32 as shown immediately below. 
 
7 Calendar-Day Telephone or Fax IND Safety Report to FDA 
 
The Sponsor is required to notify the FDA of any fatal or life-threatening adverse event 
that is unexpected and assessed by the Sponsor Investigator to be possibly related to the 
use Momelotinib within 7 calendar-days of first learning of the event. An unexpected 
adverse event deemed possibly related to the use of an investigational study drug is 
defined as any adverse drug experience of which the specificity or severity is not 
consistent with the current investigator brochure, the general investigational plan, or 
elsewhere in the current application, as amended. 
 
Such reports are to be telephoned, faxed or emailed to the FDA within 7 calendar-days 
of first learning of the event. Each transmission should be directed to the FDA new drug 
review division in the Center for Drug Evaluation and Research or in the product review 
division for the Center for Biologics Evaluation and Research, whichever department is 
responsible for the review of the IND and to the Regulatory Project Manager and the 
Chief, Project Management Staff in the FDA review division that has responsibility for 
review of the IND. 
 
15 Calendar-Day Written IND Safety Report to FDA 
 
The IND Sponsor is required to notify the FDA, and all participating investigators, in a 
written IND Safety Report, of any serious, unexpected adverse event considered by the 
IND Sponsor to be possibly related to the use of momelotinib within 15 calendar-days of 
first learning of the event. If applicable, the IND Sponsor must also notify the FDA, and 
all participating investigators of any finding from tests in laboratory animals that suggests 
a significant risk for human subjects including reports of mutagenicity, teratogenicity, or 
carcinogenicity within 15 calendar-days of first learning of the event. 
 
A serious, unexpected adverse event deemed possibly related to the use of an 
investigational study drug is any adverse drug experience of which the specificity or 
severity is not consistent with the current investigator brochure, the general 
investigational plan, or elsewhere in the current application, as amended, and results in 
any of the following outcomes: 
• Death (reported first as a 7-day telephone/fax report); 
• Life-threatening adverse drug experience (reported first as a 7-day phone/fax 

54 
 
report); 
• Inpatient hospitalization or prolongation of existing hospitalization; 
• A persistent or significant disability/incapacity, or a congenital anomaly/birth 
defect; 
 
Or is an important medical event that may not result in death, be life-threatening, or 
require hospitalization but is considered a serious adverse drug experience when, based 
upon appropriate medical judgment, it may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
 
The Principal Investigator is required to notify the Institutional Review Board (IRB) of a 
serious adverse event according to institutional policy. The requirements for IRB Protocol 
Problem Reporting at Johns Hopkins are can be found at this website: 
https://www.hopkinsmedicine.org/institutional-review-board/guidelines-policies 
 
From the time of consent through 30 days following cessation of treatment, all adverse 
events must be reported by the investigator. Such events will be recorded at each 
examination on the Adverse Event case report forms/worksheets. The reporting 
timeframe for adverse events meeting any serious criteria is described below. The 
investigator will make every attempt to follow all subjects with non-serious adverse events 
for outcome. 
Adverse events will not be collected for subjects during the pre-screening period as long 
as that subject has not undergone any protocol-specified procedure or intervention.  If the 
subject requires a blood draw, fresh biopsy etc., the subject is first required to provide 
consent to the main study and AEs will be captured according to guidelines for standard 
AE reporting. All adverse events regardless of CTCAE grade must also be evaluated for 
seriousness. Expected adverse events will be reported using NCI’s Common Terminology 
Criteria for Adverse Events (CTCAE) Version 5.0 at regular intervals as defined in the 
patient monitoring section (section 9.0). 
 
Sponsor-Investigator Notification Requirements to GSK 
All adverse events will be recorded from the time the consent form is signed through 30 
days following cessation of treatment and at each examination on the Adverse Event case 
report forms/worksheets. The reporting timeframe for adverse events meeting any serious 
criteria is described below. All SAEs (regardless of causality), pregnancies, and follow up 
information must be reported to GSK on an GSK specific SAE or Pregnancy Report Form 
within 24 hours of becoming aware of the initial event or follow-up information. The 
Sponsor Institution must provide a causality assessment and must sign and date all SAE 
Report Forms.  

55 
 
If supporting documentation is included in the submission to GSK (e.g., hospital reports, 
consultant reports, death certificates, autopsy reports, etc.), please redact any patient 
identifiers (including Medical Record number). 
GSK SAE and Pregnancy Reporting Information:  
Email: OAX37649@gsk.com or Fax: +44(0) 2081814780 
Unexpected, grade 3-5 adverse events will be reported via an Adverse Event Report form 
to the investigators. Unexpected Grade 3 adverse events must be reported within 3 
business days of knowledge of the event. Unexpected, grade 4-5 adverse events or 
serious adverse events must be reported via an adverse event report form to the study 
PI within one working day of discovery or notification of the event.  
 
Any unexpected, either life threatening or fatal adverse event must be reported within 7 
working days to the Johns Hopkins Institutional Review Board (IRB). Otherwise, 
unexpected serious adverse events must be reported within 15 days. The study staff will 
assume responsibility for reporting to the CRO and IRB, and to other investigators. 
 
                  9.5.3 Protocol-specific expedited adverse event reporting exclusions 
 
Grades 3 and 4 adverse events (including hospitalization/prolonged hospitalization) do 
not require expedited reporting in the following scenarios: 
• 
Progression of the disease should NOT be reported as an AE/SAE unless it is 
considered to be drug related by the investigator. 
• 
Hospitalization due to signs and symptoms of disease progression does NOT 
require reporting as an SAE. 
 
                  9.5.4 Reporting protocol deviation 
 
The term “protocol deviation” is not defined by either the HHS human subjects regulations 
(45 CFR or the FDA human subjects regulations (21 CFR 50). For JHM purposes, a 
protocol deviation is a minor or administrative departure (see definitions below) from the 
protocol procedures approved by the IRB that was made by the PI without prior IRB 
approval. Please note:  Eligibility exceptions for enrollment of a specific individual who 
does not meet the inclusion/exclusion criteria in the IRB approved protocol are not 
deviations. Eligibility exceptions are considered changes in research that require IRB 
review and approval before a subject who does not meet the approved protocol 
inclusion/exclusion criteria may be enrolled. 
 
Reporting Protocol Deviations to the JHM IRB 

56 
 
 
There are several types of deviations from protocol procedures recognized by the JHM 
IRB, and each type has a different IRB reporting requirement: 
 
A. 
Protocol deviations that constitute unanticipated problems involving risks require 
prompt reporting to the JHM IRB: A protocol deviation that constitutes an “unanticipated 
problem involving risks to subjects or to others” (see Policy No. 103.6(b) for the definition 
of an unanticipated problem) must be reported promptly to the IRB, as follows: 
1. Emergency deviations: When a deviation occurs in an emergency situation, such 
as when a departure from the protocol is required to protect the life or physical 
well-being of a participant. The Principal Investigator and the reviewing IRB must 
be notified as soon as possible, but not later than 5 days after the emergency 
situation occurred (21 CFR 812.150(a)(4)). 
 
2. Major, non-emergent deviations without prior approval: A planned deviation that is 
non- emergent and represents a major change in the protocol as approved by the 
IRB. The JHU Principal Investigator and the IRB must approve the request before 
the proposed change is implemented. If a major, non-emergent deviation occurs 
without prior IRB approval the event is considered non-compliance. Non-
compliance must be reported to the IRB promptly. 
 
B. 
Protocol deviations that are only minor or administrative: At JHM, minor or 
administrative protocol deviations are defined as those which do not “affect the scientific 
soundness of the research plan or the rights, safety, or welfare of human subjects.” If a 
protocol deviation occurs which meets this definition, the deviation should be reported to 
the JHM IRB at the time the continuing review application is submitted. Examples of minor 
or administrative deviations could include: follow up visits that occurred outside the 
protocol required time frame because of the participant’s schedule, or blood samples 
obtained at times close to but not precisely at the time points specified in the protocol. 
 
9.6 Toxicity monitoring 
 
We will employ a Bayesian toxicity monitoring strategy to monitor dose-limiting toxicity 
rate, as outlined in section 12.3. 
 
9.7 Data management 
 

57 
 
Data will be maintained on case report forms in REDCap and on appropriate 
spreadsheets. The investigators will be responsible for evaluation of overall toxicities. 
 
10.0 MEASUREMENT OF EFFECT AND ENDPOINTS 
 
This is a non-blinded pilot study. Analysis of response and safety are planned. Exploratory 
analyses of overall survival, feasibility of transplantation, and BMT outcomes are planned.  
 
10.1 Analysis population 
 
All patients who receive at least three cycles will be considered evaluable for efficacy 
analysis, with the exception of patients who discontinue treatment early due to toxicity or 
disease progression, who will be considered as non-responders. Those who receive at 
least 1 one dose of MMB will be considered for safety analysis.  
 
10.2 Sample size 
 
This study includes relatively rare diagnoses of MDS/MPN (CMML, MDS/MPN-N, 
MDS/MPN-NOS) and CNL. Treatment options in these diagnostic entities are limited. 
Johns Hopkins is a tertiary center and a referral center for this rare diagnosis. 
Approximately 100 new patients with these diagnoses are seen at JHU every year. Our 
total sample size is N=18 evaluable patients.  The MDS/MPN disease group is relatively 
uncommon, hence this is essentially a pilot study aimed at gathering information for a 
larger definitive study.  
 
10.3 Response rate  
 
Response rate will be evaluated by the international consortium criteria for MDS/MPN 
and will include complete response, partial remission or clinical benefit per the criteria4. 
This will include assessment of marrow blasts, marrow cellularity, marrow fibrosis, WBC, 
hemoglobin, platelets, neutrophil count, blast %, neutrophilic precursors, monocyte count, 
extramedullary disease including palpable hepatosplenomegaly, and spleen size 
reduction.  
 

58 
 
10.4 Safety and feasibility 
 
Safety and feasibility will be measured by assessment of toxicity using CTCAE version 
5.0. All grade toxicities will be collected and reported.  
 
10.5 Erythroid response  
 
Erythroid response will be measured by improvement in hemoglobin by ≥2 g/dL (relative 
to baseline) in patients who have anemia at the time of enrollment and/or transfusion 
independence for patients requiring at least 4 packed red cells transfusion in the 
previous 8 weeks4. (see Appendix 1) 
 
10.6 Spleen response 
 
Spleen response will be measured by physical exam which will measure the craniocaudal 
dimension of spleen by cm below costal margin in the mid-clavicular line4(see Appendix 
1). Spleen imaging will be done in addition to physical exam for evaluation of reduction in 
spleen volume.  
 
10.7 Patient reported outcomes 
 
Patient reported outcomes (PRO) will be evaluated using MPN-SAF TSS and by PGIC. 
MPN-SAF TSS has been extensively used in MPNs and in MDS/MPN5. PGIC is an 
established metric for oncology patients.  
 
10.8 Overall survival  
 
Interval from Day 0 to date of death from any cause or last patient contact.  
 
10.9 Transplantation  
 
Patients who are able to proceed with transplantation after therapy without increase in 
blasts, splenomegaly or fibrosis will be considered transplant eligible post-MMB-HMA. 
Outcomes following BMT will be evaluated in comparison with a retrospective cohort 
especially focusing on patients with mutations in EZH2, SETBP1, or RUNX112. 

59 
 
 
10.10 Pharmacokinetics 
 
Trough concentrations of MMB and M21 will be listed for each participant at weeks 12 
and 24 for the first 10 patients. Additionally, we will use descriptive statistics to summarize 
trough concentrations of MMB and M21 at the two study visits. Trough concentrations of 
MMB and M21 from this study might be combined with PK from other studies for 
Population PK and Exposure-Response further modeling purposes.   
 
 
11.0 CORRELATIVE STUDIES 
 
Correlative studies will be exploratory aimed at: 
(i) 
Evaluation of the role of NGS mutations at baseline in response with MMB-
HMA especially on those with combination of ASXL1, SRSF2, and SETBP1.  
(ii) 
Evaluation of reduction in somatic mutation burden or clonal reduction with 
treatment using cell free DNA 
(iii) 
Determining the role of CCRL2 in treatment response and impact of treatment 
on CCRL2 mediated signaling of JAK-STAT pathway 
(iv) 
Identifying mechanisms of resistance and relapse using single cell analysis in 
responders and non-responders. 
 
11.1 NGS mutations 
 
While cytogenetics are often normal, somatic mutations are commonly seen in 
MDS/MPN. Our prior work has demonstrated that MDS/MPN with mutations in EZH2, 
RUNX1 or SETBP1 has a very low likelihood of response to commonly HMA 
monotherapy15. We have also recently demonstrated that the co-occurrence of mutations 
in ASXL1, SRSF2, and SETBP1 have a particularly poor prognosis and survival without 
BMT is often under 1 year28. Growing evidence suggests that NGS mutations are likely a 
better in defining individual diagnostic entities of MDS/MPN due to their prognostic value. 
Hence, we hypothesize that responses to therapies such as combination of MMB and 
HMA will be correlated with the driving NGS mutations. In this study, we will correlate 
responses to therapy with underlying mutations at baseline.  
 

60 
 
11.2 Targeted sequencing using cell free DNA  
 
NGS from the marrow can be difficult to obtain frequently due to invasive nature of the 
procedure. While NGS can be performed from peripheral blood mononuclear cells, these 
do not capture the extramedullary hematopoiesis which is common in patients with MPNs 
and MDS/MPNs. Hence, we hypothesize that using cell free DNA from peripheral blood 
can provide both a minimally invasive and comprehensive approach to evaluate clonal 
evolution in MDS/MPN. We will serially monitor for persistent clones using minimally 
invasive cell free DNA assessments in the peripheral blood. For cell free DNA isolation, 
peripheral blood will be spun down in swing-rotor centrifuge at 2000 rpm for 10 min at 
room temperature. Six to 10 mL of plasma will be removed and spun down at 4000 rpm 
for 30 minutes. Supernatant will be aliquoted and stored at -80C. DNA will be isolated 
from fresh plasma using QIAmp MinElute cfDNA kit (Qiagen) per manufacturer protocol. 
This will yield 50-500ng of circulating cell-free DNA obtained from 6-10mL plasma, 
respectively. The targeted deep NGS panel will interrogate for the presence of 50 genes 
most frequently mutated in myeloid malignancies. For somatic variant analysis, the library 
will be prepared using xGen Dual Index UMI Adapters and KAPA Hyper Prep Kit and 
libraries will be sequenced using Illumina novaSeq system (Illumina) using a 2x150 bp 
protocol. We will barcode DNA molecules with unique 8-nucleotide sequence pre-PCR 
amplification to allow recognition of PCR duplicates. We will use a minimum 200ng DNA 
and sequence libraries at a minimum post-PCR deduplication depth of 10000x to achieve 
a sensitivity of 10-2 to 10-3. This will distinguish clonal somatic mutations from background 
variants. Finally, we will analyze this data using Dr. Lukasz Gondek’s (co-investigator) 
custom variant detection pipeline as published59. 
 
11.3 CCRL2 expression on CD34+ cells  
 
Our preliminary data suggest that CCRL2 regulates both JAK1 and JAK2 leading to 
STAT1/3/5 activation in JAK2 mutated and wild-type AML cell lines48,49. Moreover, 
CCRL2 expression promotes the development of resistance to JAK2 selective inhibition 
with fedratinib but is associated with higher sensitivity to the dual JAK1/JAK2 inhibitor 
momelotinib. Our hypothesis is that MDS/MPN patients with high expression of CCRL2 
will demonstrate better response to momelotinib therapy. Bone marrow aspirates will be 
collected before the initiation of treatment and at 6 months following the initiation of 
treatment. The expression of CCRL2 will be measured in CD34+, CD34+CD38-, CD34- 
and blasts populations by flow cytometry. The CCRL2 mean fluorescent intensity (MFI) 
in CD34+ cells and blasts before the initiation of treatment will be correlated with response 
by linear regression analysis. The patients will be stratified as “low CCRL2 expressers” 
and “high CCRL2 expressers” based on the median CCRL2 MFI in CD34+ cells and 

61 
 
blasts before the initiation of treatment. Logistic regression analysis will be also used to 
correlate response and CCRL2 expression in CD34+ cells.   
 
11.4 RNA sequencing analysis 
We propose bulk RNA sequencing on PBMCs derived at week 12 . For this analysis, we 
sort neutrophils for bulk sequencing.  We will also conduct single cell analysis for 
comparison in frequencies and differential expression between cells in responders versus 
non-responders. Bulk RNA sequencing is advantageous because it will provide sufficient 
sequence depth for detailed pathway analysis and prior data show expression in PBMCs 
in MPNs. We will also assess transcriptomes at the single cell level in 3 responders and 
2 non-responders (or at relapse), for the following reasons: 1) First, single cell RNA 
sequencing will allow us to precisely determine differences in frequency of cell identity in 
responders and non-responders, on the transcriptome, 2) single cell RNA sequencing will 
also allow us to identify pathways within distinct cells that persistent after treatment in 
responders and non-responders, and, 3) single cell RNA sequencing provides precision 
that is lost when gene expression from transcriptomes of diverse cells are averaged. To 
this end, we will conduct single cell RNA sequencing on bone marrow CD34+ samples 
from 3 responders and 3 non-responders using our Johns Hopkins transcriptomics core. 
These will be done using matched samples for these patients at baseline and at week 24. 
We will compare transcriptomic profiles of cells derived from responders and non-
responders to identify which genes are dysregulated within single cells. Transcriptomes 
will be clustered and cell identity assigned to each cluster based on published markers. 
 
 
12.0 STATISTICAL DESIGN 
 
12.1 Analysis of primary endpoint 
The primary objective of this study is to obtain an estimate of efficacy of MMB in 
combination with hypomethylating agents (MMB-HMA) in MDS/MPN and CNL. The 
primary endpoint is complete response, partial remission or clinical benefit per 
MDS/MPN IWG criteria4 assessed at 24 weeks. We will combine patients treated at 
momelotinib 150mg and 200mg daily for efficacy evaluation. We will have a sample 
size of N=18 to estimate the efficacy. Assuming response rates of 28-50%, the 90% 
exact binomial confidence intervals would be: 
 
# Responding (out of 18) 
Est (two-sided 90% exact CI) 
5 
0.28 (0.12, 0.50) 

62 
 
6 
0.30 (0.16, 0.55) 
7 
0.39 (0.20, 0.61) 
8 
0.44 (0.24, 0.66) 
9 
0.50 (0.29, 0.71) 
 
 
12.2 Analysis of secondary endpoints 
 
Secondary objectives are (1) to evaluate feasibility and safety of MMB-HMA in 
MDS/MPN and CNL, (2) to evaluate erythroid response with MMB-HMA, (3) to 
evaluate spleen size reduction with MMB-HMA in MDS/MPN and CNL (4) to evaluate 
improvement of MMB-HMA on patient-reported outcomes in MDS/MPN and CNL.   
 
Feasibility will be defined as the proportion of patients who maintain 60% dose 
intensity for 24 weeks. 
 
Incidence, severity and duration of adverse events will be assessed on an ongoing 
basis while patients are on treatment, using CTCAE version 5.0 and evaluated by 
predetermined physical exam, laboratory values for blood counts and chemistries. 
 
Erythroid response will be evaluated at 12 weeks and 24 weeks.  Response would be 
counted as positive if hemoglobin increases by ≥2.0 g/dL at either 12 or 24 weeks or if 
the patient achieves transfusion independence for ≥8 weeks in those requiring at least 
4 PRBC transfusions in the 8 weeks prior to initiation of treatment4. Erythroid response 
will be estimated as a simple proportion along with two-sided 90% exact binomial 
confidence interval.  We will also estimate the change in hemoglobin as a continuous 
variable along with its 90% confidence interval.   
 
Spleen response will be evaluated at 12 weeks and 24 weeks, as reduction in spleen 
volume of ≥ 35% from baseline (we will take the largest of the two reductions) and by 
spleen response by consensus response criteria3,4. Spleen response will be estimated 
as a simple proportion along with two-sided 90% exact binomial confidence interval.  
We will also estimate the change in spleen volume as a continuous variable along with 
its 90% confidence interval.   
 
Patient reported outcomes (PRO) will be evaluated by 50% reduction in MPN-SAF 
TSS from baseline at week 12 and week 24 (the best outcome of the two) and PGIC at 
week 12 and week 245. PRO improvement will be estimated as a simple proportion 
along with two-sided 90% exact binomial confidence interval.  We will also estimate 
the change in PRO scores as continuous variables along with their 90% confidence 
intervals.   
 

63 
 
12.3 Continuous Toxicity monitoring 
We will employ a Bayesian toxicity monitoring strategy to monitor dose-limiting toxicity 
rate during the expansion phase with 12 patients. The DLTs were defined in Section 
8.2.7 occurring within the first cycle of treatment (28 days). If the posterior probability of 
observed toxicity rate being greater than 30% is greater than 0.7, we will pause the 
study. Assuming a Beta (0.5, 0.5) prior distribution for the toxicity response, the Table 
below shows the Bayesian monitoring strategy for N=12 patients (for the MMB 200mg 
daily dose). 
 
Stop if # 
DLTs 
≥ 2 
≥ 3 
≥ 4 
≥ 5 
# patients 
5 
7 
10 
12 
 
The above monitoring strategy has the following operating characteristics: 
 
True Toxicity rate 
Avg samples size (% 
early stop) 
0.1 
11.3 (8.7%) 
0.2 
9.8 (30.4%) 
0.3 
7.9 (55.8%) 
0.4 
6.1 (77.7%) 
0.5 
4.8 (91.5%) 
 
 
 
13.0 ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD 
CLINICAL PRACTICE  
 
13.1 Statement of compliance 
 
This trial will be conducted in compliance with the protocol, current Good Clinical 
Practice (GCP) guidelines—adopting the principles of the Declaration of Helsinki—and 
all applicable regulatory requirements. Prior to study initiation, the protocol and the 
informed consent documents will be reviewed and approved by the sponsor and an 
appropriate ethics review committee or institutional review board (IRB). Any 
amendments to the protocol or consent materials must also be approved by the Sponsor, 

64 
 
the IRB and submitted to FDA before they are implemented. 
 
13.2 Informed consent 
 
The informed consent form is a means of providing information about the trial to a 
prospective participant and allows for an informed decision about participation in the 
study. All participants (or their legally acceptable representative) must read, sign, and 
date a consent form before participating in the study, taking any study drugs, and/or 
undergoing any study-specific procedures. If a participant does not speak and read 
English, the consent materials must be translated into the appropriate language. The 
informed consent form must be updated or revised whenever important new safety 
information is available, whenever the protocol is amended, and/or whenever any new 
information becomes available that may affect participation in the trial. 
 
A copy of the informed consent will be given to a prospective participant for review. The 
attending physician, in the presence of a witness, will review the consent and answer 
questions. The participant will be informed that participation is voluntary and that he/she 
may withdraw from the study at any time, for any reason. 
 
13.3 On-study date 
 
A participant will be considered on study upon the date of signed consent. 
 
13.4 Privacy and confidentiality  
 
A participant’s privacy and confidentiality will be respected throughout the study. Each 
participant will be assigned a sequential identification number. This number, rather than 
the participant’s name, will be used to collect, store, and report participant information. 

65 
 
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69 
 
15.0 APPENDICES 
Appendix 1. International consortium response criteria in MDS/MPN  
Appendix 2: International consortium criteria for progression in MDS/MPN 
Appendix 3: MPN-SAF TSS score 
Appendix 4: Patient Global Impression of Change (PGIC) 
Appendix 5: ECOG Performance status 
Appendix 6: Sample shipping details 
Appendix 7: Contraceptives guidance on the study 
 
 
 
 

70 
 
Appendix 1. International consortium response criteria in MDS/MPN  
 
 
 
 
 

71 
 
Appendix 2: International consortium criteria for progression in MDS/MPN 
 
 
 
 
 

72 
 
Appendix 3: MPN-SAF TSS score 
 
 
 
 

73 
 
Appendix 4: Patient Global Impression of Change (PGIC) 
 
 

74 
 
Appendix 5: ECOG Performance status 
 
 

75 
 
Appendix 6: Specimen collection details 
 
Pharmacokinetics 
(10.11) 
 
Sample collection: 2 mL-3 mL human blood is collected to 
harvest plasma samples, K2 EDTA blood collection tube. 
Sample processing: whole blood samples will be collected 
in K2 EDTA blood collection tube, and placed on ice-water 
bath for up to 120 min to harvest plasma samples. Within 
120 min of blood drawing, centrifuge at 2000 g at 2-8C to 
harvest plasma samples, plasma samples are split into 
primary polypropylene tube and backup tube. Plasma 
samples are stored at -70C cryo freezer for storage before 
shipping.  
Shipping address: Primary samples can be shipped to the 
following address with an electronic manifest.  
Attention:  Stephanie Crutchfield 
700 Pennsylvania Drive, Exton, PA 19341 
Phone:  1-484-878-9739 
Email:  sample_management@frontagelab.com 
 
NGS (11.1): 
Sample collection: 10 mL EDTA tube (lavender) 
Sample processing: DNA will be extracted from total blood 
and NGS sequencing libraries will be prepared using UMI-
UDI library preparation. DNA will be fragmented, and end-
repaired. Unique Molecular Identifiers (UMIs) and Unique 
Dual Indexes (UDIs) will be added during adapter ligation 
to track individual DNA molecules and minimize index 
hopping. Libraries will be amplified, purified, and quality-
checked before sequencing on an Illumina platform. We 
will use DNA hybridization probes to enrich for 50 genes 
most commonly mutated in myeloid malignancies. 
Sequencing data will be processed to remove duplicates 
using UMIs, ensuring accurate variant detection and 
analysis. 
Shipping address: Primary samples can be shipped to the 
following address: 
Gondek Lab, CRB1-216,  
1650 Orleans Street,  
Baltimore, MD 21287 
T: (410) 502-5847 

76 
 
Targeted sequencing 
using cell free DNA 
(11.2) 
Sample collection: 2x 10mL Streck tubes 
Sample processing: described below (in RNA sequencing), 
sequencing as described above but without DNA 
fragmentation. 
Shipping address:  Primary samples can be shipped to the 
following address: 
Gondek Lab, CRB1-216,  
1650 Orleans Street,  
Baltimore, MD 21287 
T: (410) 502-5847 
CCRL2 expression on 
CD34+ cells (11.3) 
Sample collection: total 15 ml of peripheral blood, 2 green 
top tubes. 
Sample processing: If possible, sites can ficoll the cells, 
pellet the MNCs and freeze them and ship them to us as 
frozen MNCs. Cell separation will be performed using 
Ficoll-Paque products and subsequently peripheral blood 
mononuclear cells will be separated to CD34+ and CD34- 
cells using magnetic bead cell separation. Then cells will 
stained for CD34 (FITC), CD38 (BV-605) and CCRL2 (PE) 
and analyzed by flow cytometry.  
Shipping address: Please ship the cells using FedEx 
(Account: 2361-4022-9) to:  
1650 Orleans Street, Baltimore, MD, 21287 
CRB1, Room 238 
Attn: Theodoros Karantanos 
RNA sequencing 
analysis (11.4) 
Sample collection:  we will use cells from NGS samples 
(no additional blood required) 
Sample processing: Peripheral blood mononuclear cells 
(PBMCs) will be isolated via density-gradient centrifugation 
and lymphocytes will be depleted using CD3 and CD19 
antibodies. The remaining myeloid cells will be 
resuspended and loaded onto the 10x Chromium system 
to generate Gel Bead-In-Emulsions (GEMs) containing 
single cells and barcoded primers. After cell lysis and 
reverse transcription, cDNA is amplified, and libraries are 
prepared for sequencing. Libraries are sequenced on an 
Illumina platform, and data are processed with the 10x 
Genomics Cell Ranger pipeline for downstream analysis.  
Shipping address:  Primary samples can be shipped to the 
following address: 

77 
 
Gondek Lab, CRB1-216,  
1650 Orleans Street,  
Baltimore, MD 21287 
T: (410) 502-5847 
 
 
 
 

78 
 
Appendix 7: Contraceptives guidance on the study 
• 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year when used 
consistently and correctly. 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
Intrauterine device (IUD) 
Intrauterine hormone-releasing system (IUS)c 
Bilateral tubal occlusion/ligation 
Azoospermic partner (vasectomized or due to a to medical cause) 
• 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner of 
the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional highly 
effective method of contraception should be used. Spermatogenesis cycle is approximately 90 days. 
Note: documentation of azoospermia for a male participant can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview. 
• 
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when used consistently 
and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulationc 
• oral 
• intravaginal 
• transdermal 
• injectable 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
• oral 
• injectable 
Sexual abstinence 
• 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant. 
a. 
Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods 
for those participating in clinical studies. 
b. 
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when used 
consistently and correctly. 
c. 
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods 
are limited to those that inhibit ovulation as the primary mode of action. 
 
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, 
and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Male condom and female condom 
should not be used together (due to risk of failure from friction).