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Supplemental Materials
Long-term Efficacy and Safety of Momelotinib, a JAK1 and JAK2 Inhibitor,
for the Treatment of Myelofibrosis
Animesh Pardanani1, Jason Gotlib2, Andrew W. Roberts3, Martha Wadleigh4, Shireen
Sirhan5, Jun Kawashima6, Julie A. Maltzman6, Lixin Shao6, Vikas Gupta7, and Ayalew
Tefferi1
1Division of Hematology, Mayo Clinic, Rochester, MN, USA; 2Stanford Cancer
Institute, Stanford, CA, USA; 3Clinical Hematology & BMT, Royal Melbourne Hospital,
and University of Melbourne, Parkville, Australia; 4Dept of Medical Oncology, Dana
Farber Cancer Institute, Boston, MA, USA; 5Division of Hematology, Jewish General
Hospital, Montreal, QC, Canada; 6Gilead Sciences, Inc., Foster City, CA, USA; 7Princess Margaret Cancer Centre, Toronto, ON, Canada
Patients and Methods. Study oversight, study design and treatment, eligibility criteria, study endpoints, study assessments and statisticsSupplemental Table 1. Patient disposition in the core and extension studies
Supplemental Table 2. Baseline clinical and demographic characteristics of patients in the core and extension studiesSupplemental Table 3. Symptom response in the core study Supplemental Table 4. Dose reductionsSupplemental Table 5. Study drug-related adverse events by system organ class and preferred term in ≥5% of patients Supplemental Table 6. Neuropathy related to study drugSupplemental Table 7. Adverse events leading to study discontinuationSupplemental Table 8. Treatment-emergent adverse events leading to deathSupplemental Figure 1A, B, C. Duration of response: A) Anemia 8-weeks response; B) Anemia 12-weeks response; C) Spleen response.
Supplemental Figure 2A, B. Best percentage decrease from baseline in splenomegaly. A) Overall in both core and extension studies; B) Presented per dose cohort in both core and extension studies.Supplemental Figure 3. Summary of JAK2V617F over timeSupplemental Figure 4A, B. Kaplan-Meier curves for progression-free survival and overall survival. A) Progression-free survival; B) Overall survival.
Patients and Methods
Study oversight
The study protocol was approved by the independent ethics committee or
institutional review board at each study center prior to study initiation. The study
was conducted in accordance with the International Conference on Harmonisation
guideline for Good Clinical Practice and the principles of the Declaration of Helsinki.
All patients provided written informed consent.
Study design and treatments
The open-label, nonrandomized phase 1/2 core study (NCT00935987) was
conducted in 2 parts. Part 1 was a single-center, open-label, phase 1 dose-
escalation study that aimed to determine the MTD of momelotinib.1 Five successive
cohorts of 3 patients each at increasing oral once-daily doses of momelotinib
capsule (100, 150, 200, 300, and 400 mg) were enrolled. A Data Safety Monitoring
Board (DSMB) authorized the initiation of the next higher-dose cohort based on
safety assessments. A dose-limiting toxicity (DLT) was defined according to the
Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 and the MTD
was defined as the dose level below the DLT level. Cohort expansion was authorized
by the DSMB for doses determined to be safe, tolerable, and producing therapeutic
response per International Working Group for Myelofibrosis Research and Treatment
(IWG-MRT) 2006 consensus criteria.2 The MTD determined in part 1 was 300 mg
once daily, which resulted in expansion of 300 mg once-daily dose cohorts to 20
patients, and addition of a new, 150 mg twice-daily dose cohort of 20 patients.1 The
150 mg once-daily cohort was expanded as well, due to efficacy observed with this
dose. In part 2, a multicenter, dose-confirmation phase 2 study, the 150 mg once-
daily, 300 mg once-daily, and 150 mg twice-daily cohorts were expanded further. In
the absence of toxicity, patients could continue momelotinib treatment for up to
nine 28-day cycles.
After concluding the core study, eligible patients could enroll in an open-label
extension study (ClinicalTrials.gov ID: NCT01236638) investigating the long-term
efficacy, safety, and tolerability of momelotinib. Enrolled patients continued on the
dose they received during the core study, but dose increases, reductions, or a
change to twice-daily dosing were permitted with consent from both the
investigator and the sponsor. The dose could be escalated to a maximum daily dose
of 300 mg capsule or reduced to a minimum daily dose of 100 mg.
The primary objectives for the combined core and extension studies were
long-term safety and tolerability of momelotinib and the long-term efficacy of
momelotinib as measured by complete remission (CR), partial remission (PR), and
clinical improvement rates according to IWG-MRT 2006 consensus criteria, and
progression-free survival (PFS) and overall survival (OS). Additional endpoints
included change in spleen size (examined by palpation) at each visit, and
improvement in constitutional symptoms. However, as constitutional symptoms
were not uniformly collected throughout the study, the data on constitutional
symptoms improvement have not been presented.
Eligibility criteria
Patient eligibility criteria for the core study have been previously reported.1
Briefly, eligible for enrollment were patients with PMF or post-PV/ET MF (per World
Health Organization and IWG-MRT criteria3), intermediate-2 or high-risk, or
intermediate-1 risk disease (per the International Prognostic Scoring System [IPSS])
with symptomatic hepatosplenomegaly or who were unresponsive to available
therapy.
Patients who completed nine cycles of momelotinib therapy in the core study
were eligible to enroll in the extension study if they tolerated momelotinib
treatment and achieved at least stable disease in the core study.
Study endpoints
The primary objectives for the combined core and extension studies were the
long-term safety and tolerability of momelotinib and long-term efficacy as measured
by complete remission, partial remission, and clinical improvement rates according
to IWG-MRT 2006 consensus criteria, and progression-free survival, and overall
survival.
Study Assessments
Responses were assessed by the investigator every 4 weeks in the core study
and every 3 months in the extension study, and graded per IWG-MRT 2006 criteria.2
Anemia response was defined as no red blood cell transfusions for ≥8 or ≥12 weeks
for those who were transfusion-dependent at baseline, or ≥2 g/dL increase in
hemoglobin that lasted ≥8 or ≥12 weeks for those who were not transfusion-
dependent and had hemoglobin <10 g/dL at baseline. Transfusion dependency at
baseline was defined as receiving ≥2 units of packed red blood cells within the 30
days prior to the first dose of momelotinib. For responders, the time to response
and duration of response were assessed from the date of the first dose of the drug,
not the date of the last transfusion. At each study visit, spleen and liver size was
assessed by physical examination; constitutional symptoms were assessed as well.
However, constitutional symptoms were not uniformly collected throughout the
study. Spleen response was defined as a ≥50% decrease from baseline in palpable
spleen length for baseline splenomegaly ≥10 cm that lasted ≥8 weeks, or
resolution of palpable splenomegaly for baseline splenomegaly >5 cm and <10 cm
that lasted ≥8 weeks. For responders, the time to response and duration of
response were assessed.
In both parts of the core study, patients were evaluated for safety every week
for the first cycle, every 2 weeks during cycle 2, and at the end of each subsequent
28-day cycle for up to 9 cycles of momelotinib treatment.1 Patients enrolled in the
extension study were assessed every 3 months. All patients were followed for 30
days after their last dose of momelotinib. Safety results were summarized for the
combined core and extension studies and treatment-emergent adverse events
(TEAEs) were defined as AEs that occurred on or after the start of momelotinib
treatment, up to the last study visit, or up to 30 days after study discontinuation.
TEAEs could include preexisting events that increase in severity or change in nature
during the study. Clinical and laboratory AEs were coded using the Medical
Dictionary for Regulatory Activities (MedDRA), version 17.1, and the severity of AEs
and shifts in laboratory parameters were graded by the National Cancer Institute
CTCAE version 3.0. Attribution of causality for AEs was the responsibility of the
investigator.
Statistics
The efficacy and safety data of the core and extension studies were
combined and summarized. Continuous variables were summarized using
descriptive statistics, and categorical variables were presented by frequency counts
and percentages. All results were presented based on initial momelotinib capsule
doses assigned at cycle 1 of the core study. The efficacy analysis was based on the
modified intent-to-treat (mITT) population, which consisted of all enrolled patients
who had taken at least 1 dose of study drug and had at least 1 postbaseline efficacy
evaluation of IWG-MRT 2006 consensus criteria in the core study. Median PFS and
OS, time to response, and duration of response along with their 95% confidence
intervals (CIs) were determined using the Kaplan-Meier (KM) method. The change
and percent change from baseline in spleen and liver size (by palpation) at each
visit were summarized using descriptive statistics. Disposition and safety analyses
were based on the safety population that included all patients who received at least
1 dose of momelotinib in the core study.
100 mg QD
n = 3
150 mg QD
n = 52
200 mg QD
n = 3
300 mg QD
n = 60
400 mg QD
n = 6
150 mg BID
n = 42Total
N = 166Patients who completed the core studyb, n (%) 3 (100) 40 (76.9) 2 (66.7) 47 (78.3) 4 (66.7) 28 (66.7) 124 (74.7)
Patients who discontinued the core studyc, n (%)
Disease progressionIntercurrent illnessAdverse eventInvestigator decisionConsent withdrawalOther
0000000
12 (23.1)3 (5.8)1 (1.9)5 (9.6)1 (1.9)1 (1.9)1 (1.9)
1 (33.3)00000
1 (33.3)
13 (21.7)2 (3.3)
08 (13.3)2 (1.7)1 (1.7)
0
2 (33.3)00
2 (33.3)000
14 (33.3)3 (7.1)
07 (16.7)2 (4.8)2 (4.8)
0
42 (25.3)8 (4.8)1 (0.6)
22 (13.3)5 (3.0)4 (2.4)2 (1.2)
Patients who rolled over to the extension study 3 37 2 46 4 28 120
Patients who completed the extension studyd, n (%) 0 10 (27.0) 0 13 (28.3) 1 (25.0) 6 (21.4) 30 (25.0)
Patients who discontinued the extension study
Disease progressionIntercurrent illnessAdverse eventInvestigator decisionConsent withdrawalOther
3 (100)1 (33.3)
01 (33.3)1 (33.3)
00
27 (73.0)7 (18.9)2 (5.4)
7 (18.9)3 (8.1)
5 (13.5)3 (8.1)
2 (100)000
2 (100)00
33 (71.7)7 (15.2)
010 (21.7)7 (15.2)5 (10.9)4 (8.7)
3 (75.0)1 (25.0)
02 (50.0)
000
22 (78.6)9 (32.1)
03 (10.7)6 (21.4)3 (10.7)1 (3.6)
90 (75.0)25 (20.8)
2 (1.7)23 (19.2)19 (15.8)13 (10.8)
8 (6.7)Supplemental Table 2. Patient disposition in the core and extension studiesa
aAll doses of momelotinib represent initial dose cohorts in the core study. bCompleters are those who completed either cycle 9 day 29 in the core study or rolled over to the extension study.cPatients can have only one reason for early discontinuation.
dCompleters are those who rolled over to the open-label long-term study (NCT02124746). BID, twice daily; QD, once daily.
Supplemental Table 2. Baseline clinical and demographic characteristics of patients in the core and extension studiesa
Characteristic100 mg QD
n = 3150 mg QD
n = 52200 mg QD
n = 3300 mg QD
n = 60400 mg QD
n = 6150 mg BID
n = 42Total
N = 166Age (years)
Mean (SD)MedianMin-max
72.0 (7.94)75.0
63.0–78.0
66.4 (9.20)66.5
34.0–85.0
68.0 (7.81)64.0
63.0–77.0
67.2 (7.49)68.0
46.0–83.0
60.8 (7.57)62.5
51.0–70.0
66.4 (10.14)67.0
47.0–89.0
66.6 (8.77)67.0
34.0–89.0
Sex, n (%)MaleFemale
1 (33.3)2 (66.7)
30 (57.7)22 (42.3)
3 (100.0)0
34 (56.7)26 (43.3)
3 (50.0)3 (50.0)
26 (61.9)16 (38.1)
97 (58.4)69 (41.6)
Diagnosis, n (%)PMFPost-PV MFPost-ET MF
1 (33.3)2 (66.7)
0
38 (73.1)9 (17.3)5 (9.6)
2 (66.7)1 (33.3)
0
38 (63.3)12 (20.0)10 (16.7)
5 (83.3)1 (16.7)
0
21 (50.0)12 (28.6)9 (21.4)
105 (63.3)37 (22.3)24 (14.5)
JAK2V617F status, n (%)PositiveNegativeInconclusiveMissing
2 (66.7)00
1 (33.3)
38 (73.1)10 (19.2)
04 (7.7)
2 (66.7)00
1 (33.3)
37 (61.7)19 (31.7)1 (1.7)3 (5.0)
5 (83.3)1 (16.7)
00
32 (76.2)4 (9.5)
06 (14.3)
116 (69.9)34 (20.5)1 (0.6)
15 (9.0)
Baseline ECOG statusb, n (%)0123
1 (33.3)1 (33.3)1 (33.3)
0
9 (17.3)33 (63.5)7 (13.5)1 (1.9)
1 (33.3)1 (33.3)1 (33.3)
0
11 (18.3)44 (73.3)5 (8.3)
0
05 (83.3)1 (16.7)
0
6 (14.3)29 (69.0)6 (14.3)
0
28 (16.9)113 (68.1)21 (12.7)1 (0.6)
Prior treatment, n (%)JAK2 inhibitorc
IMiDsd0
1 (33.3)5 (9.6)4 (7.7)
2 (66.7)0
8 (13.3)6 (10.0)
1 (16.7)1 (16.7)
7 (16.7)3 (7.1)
23 (13.9)15 (9.0)
Patients RBC transfusion-dependent, n (%) 1 (33.3) 24 (46.2) 0 31 (51.7) 2 (33.3) 15 (35.7) 73 (44.0)
Spleen size (cm) for
spleen-evaluable patientsnMean (SD)MedianMin–max
318.3 (10.41)
15.010.0–30.0
4718.5 (6.59)
17.08.0–34.0
323.0 (6.08)
26.016.0–27.0
5118.3 (6.38)
18.06.0–30.5
422.3 (8.34)
23.512.0–30.0
3717.3 (5.91)
18.06.0–30.0
14518.3 (6.43)
18.06.0–34.0
Hemoglobin (g/dL)Mean (SD)MedianMin–max
9.5 (2.05)8.4
8.3–11.9
9.9 (1.88)9.5
6.8–15.1
11.2 (0.85)11.1
10.4–12.1
9.7 (1.66)9.4
6.7–14.4
9.6 (0.96)9.6
8.5–10.9
9.7 (1.93)9.2
5.9–14.8
9.8 (1.77)9.4
5.9–15.1
Platelet count (x 109/L)Mean (SD)MedianMin–max
178.7 (112.63)
185.063.0–288.0
253.0 (222.91)
174.043.0–1284.0
263.3 (163.86)
334.076.0–380.0
226.8 (187.23)
165.535.0–745.0
165.7 (61.02)160.5
70.0–237.0
267.6 (190.89)
207.549.0–878.0
242.9 (195.25)
182.035.0–1284.0
ANC (x 109/L)nMean (SD)MedianMin–max
316.8 (23.79)
4.61.5–44.2
5111.8 (13.35)
7.90.8–64.2
348.3 (26.55)
60.217.9–66.9
5915.4 (24.47)
7.10.9–129.7
617.5 (23.49)
4.71.1–57.0
4216.4 (15.03)
11.70.9–53.9
16415.2 (19.53)
8.10.8–129.7
aAll doses of momelotinib represent initial dose cohorts in the core study.b2 patients were not assessed in the 150 mg QD group and 1 patient was not assessed in the 150 mg BID group. cJAK2 inhibitors: ruxolitinib (INCB018424), fedratinib (TG101348), pacritinib (SB1518) or unspecified.dIMiDs: lenalidomide, pomalidomide (CC-4047), thalidomide.ANC, absolute neutrophil count; BID, twice daily; BMI, body mass index; DIPSS, Dynamic International Prognostic Scoring System; IMiDs, immunomodulatory drugs; Max, maximum; Min, minimum; PMF, primary myelofibrosis; Post-ET MF, post-essential thrombocythemia myelofibrosis; Post-PV MF, post-polycythemia vera myelofibrosis; QD, once daily; RBC, red blood cells; SD, standard deviation.
Supplemental Table 3. Symptom response in the core study
Constitutional symptom improvement at C6D29*Site 101, n (%) Sites 102-106, n (%)
Fatigue N = 45Complete 2 (4.4)Marked 16 (35.6)None/minimal 27 (60.0)
Pruritis N = 59 N = 45Complete 55 (93.2) 26 (57.8)Marked 2 (3.4) 6 (13.3)None/minimal 2 (3.4) 13 (28.9)
Cough N = 59 N = 45Complete 55 (93.2) 23 (51.1)Marked 2 (3.4) 3 (6.7)None/minimal 2 (3.4) 19 (42.2)
Abdominal discomfort N = 45Complete 19 (42.2)Marked 8 (17.8)None/minimal 18 (40.0)
Peripheral edema N = 24Complete 16 (66.7)Marked 0None/minimal 6 (25.0), 2 not done
Bone pain N = 59 N = 45Complete 51 (86.4) 22 (48.9)Marked 5 (8.5) 6 (13.3)None/minimal 3 (5.1) 17 (37.8)
Fever N = 59 N = 43Complete 59 (100.0) 41 (95.3)Marked 0 0 None/minimal 0 2 (4.7)
Appetite N = 59 N = 44Complete 56 (94.9) 8 (18.2)Marked 0 1 (2.3)None/minimal 3 (5.1) 35 (79.5)
Night sweats N = 59 N = 45Complete 55 (93.2) 26 (57.8)Marked 3 (5.1) 9 (20.0)None/minimal 1 (1.7) 10 (22.2)
Overall QoL N = 45Complete 1 (2.2)Marked 5 (11.1)None/minimal 38 (84.4), 1 not done
Other N = 23Complete 10 (43.5)Marked 7 (30.4)None/minimal 5 (21.7), 1 not done
Percent change from baseline to C6D29 N = 39 N = 43
Median (min, max) -100.0 (-100.0, 0.0) -34.0 (-87.5, 400.0)
*C =cycle 28 days, D = days. C6D29 = 197 days
100 mg QD
n = 3
150 mg QD
n = 52
200 mg QD
n = 3
300 mg QD
n = 60
400 mg QD
n = 6
150 mg BID
n = 42Total
N = 166Patients with decreased doseb, n (%) 3 (100.0) 22 (42.3) 3 (100.0) 41 (68.3) 6 (100.0) 21 (50.0) 96 (57.8)
Reasons for decrease in dose:Adverse eventDisease progressionInvestigator decisionInvestigator discretionLack of responsePatient decisionPatient errorPatient nonadherencePer protocol
3 (100.0)0
1 (33.3)0
1 (33.3)1 (33.3)
000
17 (32.7)1 (1.9)
7 (13.5)0
1 (1.9)0
1 (1.9)00
3 (100.0)00000
1 (33.3)00
34 (56.7)0
4 (6.7)5 (8.3)1 (1.7)
000
2 (3.3)
5 (83.3)0
2 (33.3)00000
2 (33.3)
18 (42.9)1 (2.4)4 (9.5)1 (2.4)
01 (2.4)
01 (2.4)
0
80 (48.2)2 (1.2)
18 (10.8)6 (3.6)3 (1.8)2 (1.2)2 (1.2)1 (0.6)4 (2.4)
Supplemental Table 4. Dose reductionsa
aAll doses of momelotinib represent initial dose cohorts in the core study.bPatients could have more than 1 reason for a dose reduction.BID, twice daily; QD, once daily.
Supplemental Table 5. Study drug-related adverse events in ≥5% of patients
aThis group
Adverse eventSystem organ class
Preferred term
150 mg QDn = 52
300 mg QDn = 60
150 mg BIDn = 42
Totala
N = 166Grade 1 or 2
Grade 3 or 4
Grade 1 or 2
Grade 3 or 4
Grade 1 or 2
Grade 3 or 4
Grade 1 or 2
Grade 3 or 4
All Grades
Blood and Lymphatic System DisordersThrombocytopenia 14
(26.9)11
(21.2)11
(18.3) 19 (31.7) 5 (11.9) 9 (21.4)31
(18.7)46
(27.7)77 (46.4)
Anemia 2 (3.8) 1 (1.9) 4 (6.7) 3 (5.0) 1 (2.4) 3 (7.1) 8 (4.8) 8 (4.8) 16 (9.6)Neutropenia 0 3 (5.8) 2 (3.3) 4 (6.7) 1 (2.4) 1 (2.4) 3 (1.8) 9 (5.4) 12 (7.2)Leukopenia 0 3 (5.8) 5 (8.3) 1 (1.7) 0 0 5 (3.0) 5 (3.0) 10 (6.0)
Gastrointestinal DisordersDiarrhea
8 (15.4) 021
(35.0) 012
(28.6) 044
(26.5) 044 (26.5)
Nausea 11 (21.2) 0
12 (20.0) 0
10 (23.8) 0
38 (22.9) 0
38 (22.9)
Vomiting 4 (7.7) 0 6 (10.0) 0 4 (9.5) 0 14 (8.4) 0 14 (8.4)Nervous System Disorders
Peripheral neuropathy
10 (19.2) 0
15 (25.0) 0
16 (38.1) 0
44 (26.5) 0
44 (26.5)
Peripheral sensory neuropathy 9 (17.3) 0
18 (30.0) 0
11 (26.2) 0
41 (24.7) 0 41 (24.7)
Dizziness 15 (28.8) 0
14 (23.3) 0 9 (21.4) 0
41 (24.7) 0
41 (24.7)
Headache 10 (19.2) 0
11 (18.3) 1 (1.7) 5 (11.9) 0
26 (15.7) 2 (1.2)
28 (16.9)
InvestigationsIncreased ALT
6 (11.5) 1 (1.9) 9 (15.0) 3 (5.0) 8 (19.0) 024
(14.5) 4 (2.4)28 (16.9)
Increased AST4 (7.7) 1 (1.9) 9 (15.0) 1 (1.7) 6 (14.3) 0
20 (12.0) 2 (1.2)
22 (13.3)
Increased lipase 3 (5.7) 2 (3.8) 7 (11.7) 4 (6.7) 4 (9.5) 0 14 (8.4) 7 (4.2) 21 (12.7)Increased amylase
5 (9.6) 0 9 (15.0) 0 3 (7.1) 017
(10.2) 017 (10.2)
Prolonged APTT 6 (11.5) 0 6 (10.0) 0 2 (4.8) 0 16 (9.6) 0 16 (9.6)Increased blood creatinine 5 (9.6) 0 2 (3.3) 0 4 (9.5) 1 (2.4) 14 (8.4) 1 (0.6) 15 (9.0)Increased blood ALP 3 (5.8) 1 (1.9) 5 (8.3) 1 (1.7) 2 (4.8) 0 11 (6.6) 2 (1.2) 13 (7.8)Increased blood bilirubin 3 (5.8) 0 4 (6.7) 0 1 (2.4) 0 9 (5.4) 0
9 (5.4)
General Disorders and Administration Site ConditionsFatigue 5 (9.6) 0 6 (10.0) 2 (3.3) 3 (7.1) 0 14 (8.4) 2 (1.2) 16 (9.6)
Vascular disordersFlushing 5 (9.6) 0 7 (11.7) 0 1 (2.4) 0 13 (7.8) 0 13 (7.8)Hypotension 4 (7.7) 0 3 (5.0) 0 3 (7.1) 1 (2.4) 10 (6.0) 1 (0.6) 11 (6.6)
Skin and Subcutaneous Tissue Disorders
includes all initial dose cohorts from the core study, including patients treated with momelotinib 100 mg QD (N = 3), 200 mg QD (N = 3), and 400 mg QD (N = 6). ALP, alkaline phosphatase; ALT, alanine aminotransferase; APTT, activated partial thromboplastin time; AST, aspartate aminotransferase; BID, twice daily; QD, once daily.
Supplemental Table 6. Neuropathy related to study druga
Presented as n (%). aAll doses of momelotinib represent initial dose cohorts in the core study.
bPatients can have multiple AEs of the same type under preferred term, but the AE is only counted once under high-level term.cNo grade 3, 4 or 5 peripheral neuropathy or peripheral sensory neuropathy was reported.AE, adverse event; BID, twice daily; NEC, not elsewhere classified; QD, once daily.
Preferred term100 mg QD
n = 3150 mg QD
n = 52200 mg QD
n = 3300 mg QD
n = 60400 mg QD
n = 6150 mg BID
n = 42Totala
N = 166
Peripheral neuropathyc 0 10 (19.2) 0 15 (25.0) 3 (50.0) 16 (38.1) 44 (26.5)Grade 1 0 8 (15.4) 0 15 (25.0) 3 (50.0) 12 (28.6) 38 (22.9)Grade 2 0 2 (3.8) 0 0 0 4 (9.5) 6 (3.6)
Peripheral sensory neuropathyc 1 (33.3) 9 (17.3) 2 (66.7) 18 (30.0) 0 11 (26.2) 41 (24.7)Grade 1 1 (33.3) 9 (17.3) 2 (66.7) 15 (25.0) 0 8 (19.0) 35 (21.1)Grade 2 0 0 0 3 (5.0) 0 3 (7.1) 6 (3.6)
Supplemental Table 7. Summary of adverse events leading to study discontinuation for at least 2 patients
All values are n (%) unless otherwise indicated.
Type of event100 mg
QD(n =3)
150 mg QD
(n = 52)
200 mg QD
(n = 3)
300 mg QD
(n = 60)
400 mg QD
(n = 6)
150 mg BID
(n = 42)Total
(n = 166)Thrombocytopenia 0 0 0 3 (5.0) 0 2 (4.8) 5 (3.0)Peripheral sensory neuropathy 0 2 (3.8) 0 1 (1.7) 0 1 (2.4) 4 (2.4)Disease progression 0 1 (1.9) 0 1 (1.7) 0 0 2 (1.2)Sepsis 0 0 0 1 (1.7) 1 (16.7) 0 2 (1.2)Subdural hematoma 1 (33.3) 0 0 0 0 1 (2.4) 2 (1.2)Peripheral neuropathy 0 1 (1.9) 0 0 0 1 (2.4) 2 (1.2)
Supplemental Table 8. Treatment-emergent adverse events leading to deatha
100 mg QD
n = 3
150 mg QD
n = 52
200 mg QD
n = 3
300 mg QD
n = 60
400 mg QD
n = 6
150 mg BID
n = 42
TotalN = 166
Patients with ≥1 TEAE leading to death, n (%) 1 (33.3) 10 (19.2) 1 (33.3) 11 (18.3) 3 (50.0) 6 (14.3) 32 (19.3)
Disease progression 3 (5.8) 3 (5.0) 1 (2.4) 7 (4.2)Death (sudden) 1 (33.3) 2 (3.3) 3 (1.8)Respiratory failure 1 (1.9) 1 (1.7)b 1 (16.7) 3 (1.8)Sepsis 1 (1.7) 1 (16.7) 2 (1.2)Subdural hematoma 1 (33.3) 1 (2.4) 2 (1.2)Acute myeloid leukemia 1 (1.9) 1 (0.6)Acute renal failure 1 (1.9) 1 (0.6)CNS hemorrhage 1 (2.4) 1 (0.6)Endocarditis 1 (1.7) 1 (0.6)Fall 1 (1.7) 1 (0.6)GI hemorrhage 1 (1.9) 1 (0.6)Infectious colitis 1 (1.9) 1 (0.6)Infection 1 (1.7) 1 (0.6)Interstitial lung disease 1 (1.9) 1 (0.6)Intracranial hemorrhage 1 (1.7) 1 (0.6)Localized infection 1 (2.4) 1 (0.6)Myelofibrosis 1 (2.4) 1 (0.6)Pneumonitis 1 (1.9) 1 (0.6)Pulmonary mass 1 (2.4) 1 (0.6)Restrictive cardiomyopathy 1 (16.7) 1 (0.6)
Adverse events were coded using MedDRA version 17.1 preferred term. If a patient experienced ≥1 episode of an adverse event, that patient was counted once within a preferred term, high-level term, and system organ class.aAll doses of momelotinib represent initial dose cohorts in the core study. Deaths are reported within 30 days of completing studybIn the source document, this event was previously listed as “uncoded” due to misspelling of the verbatim term. BID, twice daily; CNS, Central Nervous System; GI, gastrointestinal; QD, once daily; TEAE, treatment-emergent adverse event.
Supplemental Figure 1A, B, C. Duration of response. A) Anemia 8-weeks response; B) Anemia 12-weeks response; C) Spleen response
A.
65 (0)
45 (18)
31 (29)
26 (33)
23 (35)
18 (38)
16 (38)
14 (39)
11 (40)
10 (41)
9 (42)
6 (43)
4 (44)
2 (44)
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 450
20
40
60
80
100
Time (Months)
% R
espo
nder
s
8-Week Anemia Response
Number at Risk (Events)
B.
60 (0)
53 (6)
34 (21)
28 (26)
24 (29)
20 (31)
18 (31)
16 (32)
12 (33)
9 (36)
8 (37)
5 (38)
4 (39)
2 (39)
Number at Risk (Events)
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 450
20
40
60
80
100
Time (Months)
% R
espo
nder
s
12-Week Anemia Response
C.
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 540
20
40
60
80
100
Time (Months)
% R
espo
nder
sSpleen Response
59 (0)
54 (3)
42 (8)
38 (10)
30 (12)
29 (12)
28 (13)
24 (14)
22 (15)
18 (16)
14 (16)
12 (16)
9 (16)
5 (16)
3(16)
1(16)
Number at Risk (Events)
Supplemental Figure 2 A, B. Best percentage decrease from baseline in splenomegaly. A) Overall in both core and extension studies; B) Presented per dose cohort in both core and extension studies
A.
-100
-80
-60
-40
-20
0
20
40
60
80
100
Bes
t % C
hang
e in
SPD
Momelotinib Core + Extension
B.
-100
-80
-60
-40
-20
0
20
40
60
80
100
Bes
t % C
hang
e in
SPD
100 mg QD
200 mg QD300 mg QD150 mg BID400 mg QD
150 mg QD
Supplemental Figure 4. Summary of JAK2V617F over time. N is the number of patients
included in each analysis. Zero denotes baseline.
Supplemental Figure 4 A, B. Kaplan-Meier curves for progression-free survival and overall survival. A) Progression-free survival; B) Overall survival
A.
B.
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 540
20
40
60
80
100
Time (Months)
% P
rogr
essi
on-F
ree
Progression-Free Survival
165 (0)
156 (6)
134 (15)
115 (22)
101 (26)
89 (30)
81 (34)
75 (37)
65 (39)
59 (40)
50 (45)
37 (50)
29 (50)
15 (52)
5 (53)
1 (53)
Number at Risk (Events)
165 (0)
157 (5)
134 (12)
115 (16)
102 (19)
89 (19)
81 (21)
75 (23)
65 (25)
59 (26)
51 (28)
37 (30)
29 (30)
15 (31)
5 (32)
1 (32)
Number at Risk (Events)
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 540
20
40
60
80
100
Time (Months)
% S
urvi
ving
Overall Survival