Clinical trial NCT03222609
Conditions: Myelofibrosis (MF)
Keywords: Post-polycythemia vera MF (PPV-MF) Post-essential thrombocythemia (PET-MF) ruxolitinib navitoclax splenic volume Primary Myelofibrosis Jakafi enlarged spleen splenomegaly ABT 263 bone marrow fibrosis
Sponsor: AbbVie
Start date: 2017-10-31; Completion date: 2025-01-29
Enrollment: 191 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2 open-label, multicenter study evaluating tolerability and efficacy of navitoclax alone or when added to ruxolitinib in participants with myelofibrosis.

Safety and efficacy data through 16 January 2023 are included in the interim analysis.

Detailed description:

Arms: arm 1: Participants must have received ruxolitinib for at least 12 weeks and on stable dose of ≥10 mg tablets orally twice daily (BID) for ≥8 weeks prior to the 1st dose of navitoclax. Navitoclax tablets are administered once daily (QD) at a starting dose of 50 mg. This was increased after approximately ≥7 days to next dose level if platelet count is ≥75 × 10\^9/L up to a maximum dose of navitoclax 300 mg QD. Participants will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first). arm 2: Those receiving ruxolitinib at Screening must be on a stable dose ≥10 mg tablets orally twice daily (BID) for ≥ 4 weeks prior to 1st dose of navitoclax. Those not receiving ruxolitinib at Screening received 10 mg ruxolitinib BID starting on Day 1. Navitoclax tablets were administered orally once daily (QD) per Baseline platelet count (\>150 × 10\^9/L starting dose of 200 mg; ≤150 × 10\^9/L starting dose of 100 mg, which could be increased to 200 mg QD after 7 days provided platelet count is ≥75 × 10\^9/L). Navitoclax didn't exceed 200 mg QD for first 24 weeks of treatment. After Week 24 disease assessment, navitoclax dose was increased to 300 mg QD at discretion of the Investigator for those with suboptimal spleen response defined as failure to achieve spleen volume reduction of at least 10% per imaging. Participants will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first). arm 3: Participants must have received prior treatment with a Janus Kinase 2 (JAK-2) inhibitor. Those with Baseline platelet count \>150 × 10\^9/L initiated navitoclax film-coated tablets orally once daily (QD) at the starting dose of 200 mg. Those with a Baseline platelet count ≤150 × 10\^9/L initiated navitoclax film-coated tablets orally once daily (QD) at the starting dose of 100 mg, which could be increased to 200 mg once daily after 7 days provided the platelet count is ≥75 × 10\^9/L. Navitoclax didn't exceed 200 mg QD for the first 24 weeks of treatment. After Week 24 disease assessment, navitoclax dose may be increased to 300 mg QD at discretion of the Investigator for those with suboptimal spleen response defined as failure to achieve spleen volume reduction of at least 10% per imaging. Participants will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first). arm 4: Prior treatment with a Janus Kinase 2 (JAK-2) or Bromodomain and Extra-Terminal motif (BET) proteins inhibitor was prohibited. Ruxolitinib tablets administered orally twice daily (BID) based on Baseline platelet count as per the local approved label. Navitoclax tablets were administered orally once daily (QD) per Baseline platelet count (\>150 × 10\^9/L starting dose of 200 mg; ≤150 × 10\^9/L starting dose of 100 mg, which could be increased to 200 mg QD after 7 days provided platelet count is ≥75 × 10\^9/L). Navitoclax didn't exceed 200 mg QD for first 24 weeks of treatment. After Week 24 disease assessment, navitoclax dose may be increased to 300 mg QD at discretion of Investigator for those with suboptimal spleen response defined as failure to achieve spleen volume reduction of at least 10% per imaging. Participants will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first).
Interventions: intervention 1: Ruxolitinib intervention 2: Navitoclax
Intervention descriptions: intervention 1: Tablet; Oral intervention 2: Film-coated tablet; Oral

Protocol documents:
Prot_000.pdf: 
Navitoclax (ABT-263)
M16-109 Protocol Amendment 11
EudraCT 2017-001398-17
1
1.0
Title Page
Clinical Study Protocol M16-109
A Phase 2 Open-Label Study Evaluating Tolerability 
and Efficacy of Navitoclax Alone or in Combination 
with Ruxolitinib in Subjects with Myelofibrosis 
(REFINE)
Incorporating Administrative Changes 1 and 2 
(United States and Puerto Rico Only) and 
Amendments 1, 2, 3, 4, 5, 6, 7, 8, 8.01 (Spain and 
Italy Only), 9, 10, and 11
AbbVie 
Investigational
  Product:
Navitoclax (ABT-263)
Date:
04 October 2021
Development 
Phase:
2
Study Design:
This is a Phase 2 open label, multicenter study evaluating 
tolerability and efficacy of navitoclax alone or in combination 
with ruxolitinib in subjects with myelofibrosis.
EudraCT Number:
2017-001398-17
Investigator:
Investigator information on file at AbbVie.
Sponsor:
AbbVie*
 
NCT03222609




Navitoclax (ABT-263)
M16-109 Protocol Amendment 11
EudraCT 2017-001398-17
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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date
Original
07 April 2017
Protocol Amendment 1
30 June 2017
Protocol Amendment 2
27 July 2017
Protocol Amendment 3
20 February 2018
Protocol Amendment 4
31 March 2018
Administrative Change 1
04 May 2018
Protocol Amendment 5
10 September 2018
Protocol Amendment 6
13 August 2019
Protocol Amendment 7
06 December 2019
Protocol Amendment 8
04 June 2020
Administrative Change 2 (US, PR only)
23 September 2020
Protocol Amendment 8.01 (ES, IT only)
24 September 2020
Protocol Amendment 9
22 October 2020
Protocol Amendment 10
23 June 2021
The purpose of this amendment is to:
●
Revise Section 1.2, Synopsis, Key Exclusion 
Rationale: Clarified that moderate CYP3A inhibitors (e.g., fluconazole) are 
prohibited for Cohort 1b DDI sub-study subjects. 
●
Revise Section 5.2.2, Exclusion Criteria, Rationale for Exclusion Criteria
Rationale:  Corrected that exclusion criteria 13 is due to unknown impact of 
navitoclax on sperm count, the unborn fetus or breastfeeding infant. 
●
Revise Section 5.2.4, Prior and Concomitant Therapy 
Rationale: Clarified that moderate CYP3A4 inhibitors (e.g., fluconazole) 
should be used with caution for subjects receiving ruxolitinib. 
 


Navitoclax (ABT-263)
M16-109 Protocol Amendment 11
EudraCT 2017-001398-17
4
●
Revise Section 5.2.5 Contraception Recommendations
Rationale: 
Removed reference to premenarchal females as subjects must be age 18 or 
older.
Removed "progestogen-only oral hormonal contraception where inhibition of 
ovulation is not the primary mode of action and barrier methods listed as they 
were included in error with Protocol Amendment 10 and are not considered 
highly effective methods of birth control.
Added that if required per local practice, protocol-required birth control 
methods (excluding true abstinence) should be supplemented with barrier 
methods such as male or female condom with or without spermicide OR cap, 
diaphragm or sponge with spermicide. 
●
Revise Section 5.3.1.1, Study Procedures, Pregnancy Testing
Rationale: Clarified that negative pregnancy test prior to dosing on Study 
Day 1 may be determined via urine or serum.
●
Revise Section 5.3.1.1, Study Procedures, Clinical Laboratory Tests
Rationale: Corrected footnote reference for Creatinine Clearance to e, which 
states that it is required at screening but can be performed at investigators 
discretion during the study.
●
Update Appendix G Dynamic International Prognostic Scoring System 
(DIPSS)
Rationale: Footnote * added to Table 14 to specify that in order to report 
constitutional symptoms as yes for DIPSS scoring, at least one of the following 
symptoms must be present: weight loss, fever, or night sweats.
●
Correct typographical errors and minor language or word revisions throughout 
the document.  Update AbbVie contact information throughout the protocol.
 


Navitoclax (ABT-263)
M16-109 Protocol Amendment 11
EudraCT 2017-001398-17
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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M16-109
Name of Study Drug:  Navitoclax (ABT-263) 
Phase of Development:  Phase 2
Name of Active Ingredient:  Navitoclax (ABT-263)
Date of Protocol Synopsis:  04 October 2021
Protocol Title:  A Phase 2 Open-Label Study Evaluating Tolerability and Efficacy of Navitoclax Alone 
or in Combination with Ruxolitinib in Subjects with Myelofibrosis (REFINE)
Objective(s):
The primary objective of the study is:

To evaluate the effect of navitoclax alone or in combination with ruxolitinib on spleen volume
The secondary objectives of the study are:

To assess the effect of navitoclax alone or in combination with ruxolitinib on total symptom 
score (TSS) as assessed by the Myelofibrosis Symptom Assessment Form (MFSAF) version 4.0 
diary

To evaluate the effect of navitoclax alone or in combination with ruxolitinib on bone marrow 
fibrosis

To determine the rate of anemia response associated with navitoclax alone or in combination 
with ruxolitinib

To describe the safety profile and PK profile observed with navitoclax alone or in combination 
with ruxolitinib
Exploratory objectives of the study include, but is not limited to the evaluation of the duration of disease 
response including effects on spleen and anemia, survival, impact on quality of life and translational 
biomarkers.
Investigator(s):  Multi-center
Study Site(s):  Approximately 135 sites
Study Population:  Subjects with primary or secondary (post-polycythemia vera MF [PPV-MF]), post-
essential thrombocythemia [PET-MF]) myelofibrosis who have received prior treatment with ruxolitinib 
(Cohorts 1a and 1b,) or any JAK-2 inhibitor (Cohort 2) OR who have not received prior treatment with a 
JAK2 inhibitor or BET inhibitor (Cohort 3).
Number of Subjects to be Enrolled:  Approximately 174 subjects
 


Navitoclax (ABT-263)
M16-109 Protocol Amendment 11
EudraCT 2017-001398-17
6
Methodology:  
Figure 1.
Study Schema
   
This Phase 2, multicenter, open-label study (Figure 1) evaluates the tolerability and efficacy of navitoclax 
alone or in combination with ruxolitinib in subjects with primary or secondary myelofibrosis.  For 
Cohort 1a, subjects must have received ruxolitinib therapy for at least 12 weeks and currently be on a 
stable dose of ≥ 10 mg twice daily of ruxolitinib.  For Cohorts 1b subjects must have received treatment 
with ruxolitinib.  Cohort 1b will enroll approximately 80 subjects to ensure enrollment of approximately 
70 subjects with prior exposure to ruxolitinib.  For Cohort 2, subjects must have received prior treatment 
with a JAK-2 inhibitor.  For Cohort 3, subjects must not have received prior treatment with a JAK-2 
inhibitor or BET inhibitor.  Navitoclax will be administered at a starting dose of 50 mg once daily 
(Cohort 1a) or at 100 or 200 mg once daily (Cohorts 1b, 2 and 3).
Cohort 1a
The dose of navitoclax may be increased after approximately 7 or more days to the next dose level 
provided the platelet count is ≥ 75 × 109/L up to a maximum dose of navitoclax 300 mg once daily.  
Cohorts 1b, 2 or 3

Baseline Platelet Count >150 × 109/L: 200mg once daily navitoclax starting dose

Baseline platelet count ≤ 150 × 109/L: 100mg once daily navitoclax starting dose
o
The dose of navitoclax may be increased to 200 mg once daily after 7 days provided the 
platelet count is ≥75 × 109/L

The dose of navitoclax should not exceed 200 mg once daily for the first 24 weeks of treatment. 
After the Week 24 disease assessment, the dose of navitoclax may be increased to 300 mg once 
daily at the discretion of the Investigator for subjects with sub-optimal spleen response defined 
as failure to achieve spleen volume reduction of at least 10% as assessed by imaging.  
Subjects in Cohorts 1a, 1b and 3 will receive ruxolitinib administered orally twice daily (BID). Subjects 
in Cohort 1a and 1b receiving ruxolitinib at screening will continue at the current stable dose of ≥10 mg 
twice daily.  Subjects in Cohorts 1b not receiving ruxolitinib at the time of screening will receive 
ruxolitinib at a dose of 10 mg twice daily beginning on Day 1.
Subjects in Cohort 3 will receive ruxolitinib at the individualized starting dose based on baseline platelet 
count as per the local approved ruxolitinib label.
Subjects in Cohort 2 will receive Navitoclax monotherapy.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Navitoclax (ABT-263)
M16-109 Protocol Amendment 11
EudraCT 2017-001398-17
7
Laboratory Visits and Evaluation Schedule
Laboratory visits:

Hematology and Chemistry:  Screening, Pre-dose on Day 1, Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, 24 
and q12 weeks thereafter 

Hematology:  4 hours after the first dose of navitoclax on Day 1, 24 hours post-first-dose on 
Day 2, and prior to navitoclax dose increases, reductions, or re-initiation after interruption.
Clinic/Efficacy Evaluation visits:

Clinic Assessments (including spleen and liver palpation):  Screening, Day 1, Weeks 1, 2, 3, 4, 
6, 8, 12, 16, 20, 24 and q12 weeks thereafter

MFSAF version 4.0 diary:  Daily beginning at the Screening Visit, including pre-dose on Day 1 
through the Week 36 Visit.  For subjects enrolled in Cohorts 1b and 3 the screening period 
should be long enough to ensure at least 7 days to collect the daily MFSAF version 4.0 prior to 
Day 1

EORTC QLQ-C30 QOL questionnaire:  Screening, pre-dose on Day 1, Weeks 4, 8, 12, 24, every 
12 weeks thereafter and at the TCV

PROMIS Fatigue SF 7a questionnaire:  Screening, pre-dose on Day 1, Weeks 4, 8, 12, 24, every 
12 weeks thereafter and at the TCV

PGIC questionnaire:  pre-dose on Weeks 4, 8, 12, 24, every 12 weeks thereafter and at the TCV

Imaging for spleen assessment:  Screening, Weeks 12, 24, 36, 48, 72 and 96.  After 96 weeks of 
treatment, an MRI/CT should be performed if disease progression is suspected. 

Bone marrow biopsy and aspirate:  Screening, Weeks 12, 24, 48 and 96.  After 96 weeks of 
treatment, bone marrow sampling should be performed if disease progression is suspected.

Disease Assessment based on modified IWG:  will be performed at Week 12, 24, 36, 48, 72 and 
96.  Disease assessment should also occur at any other time if disease progression is suspected or 
when imaging/bone marrow sampling is performed.
Pharmacokinetic samples will be collected and analyzed throughout the study.  Additional samples will 
be collected for approximately 10 subjects in Cohort 1b who agree to provide blood samples to assess 
drug-drug interactions between navitoclax and ruxolitinib.
Exploratory biomarker specimens will be collected throughout the study.  Analyses may include, but are 
not limited to allelic burden, mutational status, cytokines, and/or characterization of Bcl-2 and associated 
proteins.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Key Inclusion:

Subjects ≥ 18 years of age

Subjects with documented diagnosis of Primary MF, PPV-MF or PETMF as defined by the 
World Health Organization classification

Subjects classified as intermediate-2 or high-risk MF, as defined by the Dynamic International 
Prognostic Scoring System (DIPSS)

Subject must be ineligible due to age, comorbidities, or unfit for unrelated or unmatched donor 
transplantation or unwilling to undergo stem cell transplantation at time of study entry

ECOG 0, 1, or 2
 


Navitoclax (ABT-263)
M16-109 Protocol Amendment 11
EudraCT 2017-001398-17
8
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Key Inclusion (Continued):

Cohort 1a only:  Subject must have received ruxolitinib therapy for at least 12 weeks and be 
currently on a stable dose of ≥ 10 mg twice daily of ruxolitinib for ≥ 8 weeks prior to the 1st dose 
of navitoclax.
Note:  Subjects with ruxolitinib dose reductions within 8 weeks prior to study enrollment may be 
considered on a stable dose if stable at that decreased dose of ruxolitinib for ≥ 2 weeks prior to 
the 1st dose of navitoclax.  If the dose reduction was due to thrombocytopenia, the platelets must 
be confirmed to be stable by a repeat laboratory test.

Cohort 1b only:  Subject must have received treatment with ruxolitinib and meet at least one of 
the following criteria:
o
Prior or current treatment with ruxolitinib for ≥ 24 weeks with lack of efficacy defined as a 
lack of spleen response (refractory) or a loss of spleen or symptom response (relapsed)
o
Prior or current treatment with ruxolitinib for < 24 weeks with documented disease 
progression while on ruxolitinib as defined by any of the following:

Appearance of new splenomegaly that is palpable to at least 5 cm below the left costal 
margin (LCM) in subjects with no evidence of splenomegaly prior to the initiation of 
ruxolitinib.

A ≥ 100% increase in the palpable distance below the LCM in subjects with measurable 
spleen distance 5 to 10 cm prior to the initiation of ruxolitinib.

A ≥ 50% increase in the palpable distance below the LCM in subjects with measurable 
spleen distance > 10 cm prior to the initiation of ruxolitinib.

A spleen volume increase of ≥ 25% (as assessed by MRI or CT scan) in subjects with a 
spleen volume assessment prior to the initiation of ruxolitinib.
o
Prior or current treatment with ruxolitinib for ≥ 28 days with intolerance defined as new 
RBC transfusion requirement (at least 2 units/month for 2 months), while receiving a total 
daily ruxolitinib dose of ≥ 30 mg but unable to reduce dose further due to lack of efficacy.

Cohort 1b only: Subjects that are receiving ruxolitinib at the time of screening, must currently 
be on a stable dose ≥ 10 mg twice daily of ruxolitinib for ≥ 4 weeks prior to the 1st dose of 
navitoclax.
Note:  Subjects with ruxolitinib dose reductions within 4 weeks prior to study enrollment are 
considered to be on a stable dose if dose of ruxolitinib if the dose is unchanged for ≥ 2 weeks 
prior to Day 1of navitoclax. The current dose must be ≥ 10 mg twice daily. If the dose 
reduction was due to thrombocytopenia, platelet counts must be confirmed to be stable by a 
repeat laboratory test.

Cohort 1b only: Subject must not have received treatment with a BET inhibitor or an alternate 
JAK-2 inhibitor other than ruxolitinib.
 


Navitoclax (ABT-263)
M16-109 Protocol Amendment 11
EudraCT 2017-001398-17
9
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Key Inclusion (Continued):

Cohort 2 only:  Subject must have received prior treatment with JAK-2 inhibitor therapy and 
meet one of the following criteria (a or b):
a.
Prior treatment with JAK-2 inhibitor for at least 12 weeks 
b.
Prior treatment with JAK-2 inhibitor for ≥ 28 days complicated by any of the following:
i.
Development of red blood cell transfusion requirement (at least 2 units/month for 
2 months)
OR
ii. Grade ≥ 3 adverse events of thrombocytopenia, anemia, hematoma and/or hemorrhage 
while on JAK-2 inhibitor treatment

Cohort 3 only:  Subject must not have received prior treatment with a JAK-2 or BET inhibitor

Subject has splenomegaly defined as spleen palpation measurement ≥ 5 cm below costal margin 
or spleen volume ≥ 450 cm3 as assessed by MRI/CT

Cohorts 1b and 3 only: Subject has at least 2 symptoms each with a score ≥ 3 or a total score of 
≥12, as measured by the MFSAF v4.0, on at least 4 out of 7 days during screening, prior to 
study drug dosing.

Subject must meet the following laboratory parameters per local laboratory reference range 
during screening, prior to study drug dosing:
o
Adequate bone marrow reserves; in the absence of growth factors, thrombopoietic factors, 
or platelet transfusions for at least 14 days:

Platelet count ≥ 100 × 109/L (Cohorts 1a, 1b or 3)

Platelet count ≥ 75 × 109/L (Cohort 2)

ANC ≥ 1 × 109/L
o
Renal function:  calculated creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault 
formula
o
Hepatic function and enzymes:

AST and ALT ≤ 3.0 × the upper normal limit (ULN) 

Total Bilirubin ≤ 1.5 × ULN (exception:  subjects with Gilbert's Syndrome may have a 
Bilirubin > 1.5 × ULN)
o
Coagulation:  aPTT and prothrombin time (PT) or INR ≤ 1.5 × ULN
Key Exclusion:

Splenic irradiation within 6 months prior to Screening, or prior splenectomy

Leukemic transformation (> 10% blasts in peripheral blood or bone marrow aspirate/ biopsy)

Subject is currently on medications that interfere with coagulation (including warfarin) or 
platelet function within 3 days prior to the first dose of study drug or during the study treatment 
period with the exception of low dose aspirin (up to 100 mg/day) and low-molecular-weight 
heparin (LMWH).

Prior therapy with a BH3 mimetic compound or stem cell transplantation 
 


Navitoclax (ABT-263)
M16-109 Protocol Amendment 11
EudraCT 2017-001398-17
10
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Key Exclusion (Continued):

Cohort 1b Drug-Drug Interaction (DDI) sub-study subjects only: Subject has received 
strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin) or moderate CYP3A inhibitors
(e.g., fluconazole) within 14 days prior to the administration of the first dose of study drug.
Investigational Product:
Navitoclax (ABT-263)
Cohort 1a Planned Dose(s):
Dose Level –1:  25 mg once daily
Dose Level 1 (Starting Dose):  50 mg once daily
Dose Level 2:  100 mg once daily
Dose Level 3:  200 mg once daily
Dose Level 4:  300 mg once daily
Cohorts 1b, 2 and 3 Planned Dose(s)
Dose Level –3:  25 mg once daily
Dose Level –2:  50 mg once daily
Dose Level –1:  100 mg once daily (Starting dose; 
baseline platelet count ≤150 × 109/L)
Dose Level 1:  200 mg once daily (Starting dose; 
baseline platelet count > 150 × 109/L)
Dose Level 2:  300 mg once daily (after Week 24 
for inadequate response)
Intermediate dose levels (e.g., 150 mg, once daily) may be considered for an individual subject at the 
discretion of the investigator.  If intermediate dose levels are utilized prior to Week 24, consultation with 
the AbbVie TA MD/SD is required prior to implementation.
Mode of Administration:
Oral
Reference Therapy:
Ruxolitinib
Dose(s):
≥ 10 mg twice daily
Mode of Administration:
Oral
Duration of Treatment: Until end of clinical benefit or occurrence of unacceptable toxicity or 
discontinuation criteria have been met.
Toxicity Management for Thrombocytopenia:
Navitoclax accelerates apoptosis of circulating mature platelets whether endogenous or transfused.  This 
mechanism of toxicity differs from the thrombocytopenia caused by ruxolitinib and other conventional 
chemotherapy (i.e., toxicity to platelet progenitors in the bone marrow) and should, therefore, be managed 
according to the guidelines below and presented in detail in the toxicity management section of the 
protocol and Appendix I.  Decisions regarding continued dosing, including the navitoclax or ruxolitinib 
(if applicable) dose level to be administered, for individual subjects will be medically managed by the 
Investigator in consultation with the AbbVie TA MD/SD.
Dose Adjustment Guidelines for Thrombocytopenia:
See Appendix I for comprehensive guidelines. 
 


Navitoclax (ABT-263)
M16-109 Protocol Amendment 11
EudraCT 2017-001398-17
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Criteria for Evaluation:
Efficacy: 
To determine initial disease status, MRI/CT, bone marrow biopsy and aspirate will be obtained at 
Screening for all subjects.  The local bone marrow evaluation will include staining for fibrosis and 
cytogenetics.  To assess for efficacy, bone marrow biopsy, aspirate, MRI/CT, MFSAF and laboratory 
tests will be performed at designated timepoints throughout the study until disease progression is 
documented.
Efficacy will be assessed based on modified International Working Group-Myeloproliferative Neoplasms 
Research and European LeukemiaNet (IWG-MRT/ELN).
Transfusion requirements must be documented during the time period of 12 weeks before the start of 
navitoclax on Day 1.  
Pharmacokinetic:
Pharmacokinetic samples for navitoclax (all cohorts) and ruxolitinib (1a, 1b, and 3) will be collected at 
designated time points throughout the study.
Biomarkers and Translational Research:
Exploratory research may be conducted to identify biomarkers predictive of navitoclax activity.  
Peripheral blood and bone marrow samples will be obtained at study specified time points.  Biomarkers 
(e.g., but not limited to:  allelic burden, mutational status, BCL-2 family profiling, inflammatory cytokine 
reduction) may be assessed to compare subject responses in order to identify markers that may be 
predictive of navitoclax activity alone or in combination with ruxolitinib.
Safety:
Adverse events (AEs), laboratory values, physical examinations, vital signs, and any additional 12-lead 
electrocardiogram (ECG) performed as clinically indicated will be assessed.
Statistical Methods:
Primary Efficacy Endpoint:
At least 35% reduction from baseline in spleen volume at Week 24 (SVR35w24) as measured by MRI/CT.
Secondary Efficacy Endpoints:

At least 50% reduction in total symptom score (TSS) at Week 24 from baseline as measured by 
MFSAF v4. 

Anemia Response.

Change in grade of bone marrow fibrosis.
Sample Size:
For Cohort 1a, approximately 34 subjects will be enrolled; For Cohort 1b, approximately 80 subjects will 
be enrolled to ensure enrolment of approximately 70 subjects with prior exposure to ruxolitinib; For 
Cohorts 2 and 3, approximately 30 subjects to be enrolled into each cohort.
 


Navitoclax (ABT-263)
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EudraCT 2017-001398-17
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Statistical Methods (Continued):
The table below provides point estimate of SVR35w24 Rate and corresponding 95% confidence interval 
(CI) assuming different response rate scenarios given proposed sample sizes.
Cohort
Sample 
size
Number of 
Subjects with 
SVR35w24
Point Estimate 
SVR35w24 Rate 
(%)
Exact 95% CI
Half 
Width of 
CI
Lower 
Limit (%)
Upper 
Limit (%)
1a
34
16
47.06
29.78
64.87
17.55
1a
34
18
52.94
35.13
70.22
17.55
1a
34
20
58.82
40.70
75.35
17.33
1a
34
22
64.71
46.49
80.25
16.88
1b
70
32
45.71
33.74
58.06
12.16
1b
70
34
48.57
36.44
60.83
12.19
1b
70
36
51.43
39.17
63.56
12.19
1b
70
38
54.29
41.94
66.26
12.16
2 or 3
30
12
40.00
22.66
59.40
18.37
2 or 3
30
14
46.67
28.34
65.67
18.67
2 or 3
30
16
53.33
34.33
71.66
18.67
2 or 3
30
18
60.00
40.60
77.34
18.37
  
Based on the table above, this study with proposed sample sizes will provide a reasonable precise 
estimate of the proportion of subjects with SVR35w24 for each cohort.  Also, if true probability of 
experiencing a serious adverse event (SAE) due to the study drug is 10%, then the probability of 
observing at least one SAE in 34 subjects is more than 97% in Cohort 1a; the probability of observing at 
least one SAE in 80 subjects is more than 99% in Cohort 1b; and the probability of observing at least one 
SAE in 30 subjects is more than 95% in either Cohort 2 or 3.  Therefore, from safety assessment 
prospective the proposed sample sizes are adequate.
Pharmacokinetic:
Plasma concentrations and PK parameter values of navitoclax and ruxolitinib will be tabulated for each 
subject, as applicable, and summary statistics will be computed for each sampling time and each 
parameter.
Biomarkers and Translational Research:
Exploratory research may be conducted to identify biomarker predictive of navitoclax activity.  Peripheral 
blood and bone marrow samples will be obtained at study specified time points.  Biomarkers (e.g., but not 
limited to:  allelic burden, mutational status, BCL-2 family profiling, inflammatory cytokine reduction) 
may be assessed to compare subject responses in order to identify markers that may be predictive of 
navitoclax activity alone or in combination with ruxolitinib.
 


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Statistical Methods (Continued):
Safety:
Safety analyses will be performed for all subjects that have received at least one dose of navitoclax unless 
otherwise indicated.  For the study as a whole, AEs will be evaluated by the NCI-CTCAE v. 4.03.  Safety 
will be assessed by evaluating duration of exposure to study drug, adverse events, serious adverse events, 
deaths, and changes in laboratory tests and vital sign parameters.
 


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1.3
List of Abbreviations and Definition of Terms
Abbreviations
AE
Adverse Event
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
BCL-2
B-Cell Lymphoma-2
BCL-XL
B-Cell Lymphoma Extra Large
BET
Bromodomain and Extra-Terminal motif (BET) proteins
BH
Bcl-2 Homology
BID
Two Times a Day
BM
Bone Marrow
BUN
Blood Urea Nitrogen
CI
Confidence Interval
CLL
Chronic Lymphocytic Leukemia
COVID-19
Coronavirus Disease – 2019, SARS-CoV-2
CR
Complete Remission
CRF
Case Report Form
CYP3A
Cytochrome P450 3A
CYP2C8
Cytochrome P450 2C8
CYP2C9
Cytochrome P450 2C9
DIPSS
Dynamic International Prognostic Scoring System
DNA
Deoxyribonucleic acid
DTP
Direct-to-patient
ECG
Electrocardiogram
eCRFs
Electronic Case Report Forms
EDC
Electronic Data Capture
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of Life
ePRO
Electronic Patient Reported Outcome
ET
Essential Thrombocythemia
FDA
Food and Drug Administration
GCP
Good Clinical Practice
 


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IEC
Independent Ethics Committee
IGRA
Interferon-Gamma Release Assay
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IWG-MRT/ELN
International Working Group-Myeloproliferative Neoplasms Research and 
European LeukemiaNet
JAK2/JAK-2
Janus Kinase 2
LDL
Low-density lipoprotein
LMWH
Low-Molecular-Weight Heparin
MCL-1
Myeloid Cell Leukemia 1
MedDRA
Medical Dictionary for Regulatory Activities
MF
Myelofibrosis
MFSAF
Myelofibrosis Symptom Assessment Form
MPN
Myeloproliferative Neoplasm
MRI
Magnetic Resonance Imaging
mRNA
Messenger Ribonucleic Acid
NCI-CTAE
National Cancer Institute Common Terminology Criteria for Adverse Events
ORR
Overall Response Rate
OS
Overall Survival
PET-MF
Post-Essential Thrombocythemia Myelofibrosis
PFS
Progression Free Survival
PG
Pharmacogenetic
PGIC
Patient Global Impression of Change
PK
Pharmacokinetic
PD
Pharmacodynamic
PMF
Primary Myelofibrosis
PPD
Purified Protein Derivative 
PO
Orally
PR
Partial Remission
PRO
Patient-Reported Outcome
PPV-MF
Post-Polycythemia Vera Myelofibrosis
PT
Prothrombin Time
PV
Polycythemia Vera
 


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QD
Once a Day
QTcF
QT interval corrected for heart rate by Fridericia's formula
RBC
Red Blood Cell
RNA
Ribonucleic acid
PRBC
Packed Red Blood Cells
SAE(s)
Serious Adverse Event(s)
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SAP
Statistical Analysis Plan
SLL
Small Lymphocytic Lymphoma
SMF
Secondary Myelofibrosis
SUSAR
Suspected Unexpected Serious Adverse Reactions
SVR
Spleen Volume Reduction
SVR20
Spleen Volume Reduction of at least 20%
SVR35
Spleen Volume Reduction of at least 35%
SVR35w24
Spleen Volume Reduction of at least 35% at Week 24
TA MD/SD
Therapeutic Area Medical Director/Scientific Director
TB
Tuberculosis
TCV
Treatment Completion Visit
TSS
Total System Score
ULN
Upper Limit of Normal
WBC
White Blood Cell Count
WHO
World Health Organization
Pharmacokinetic and Statistical Abbreviations
AUC
Area under the plasma concentration-time curve
AUC∞
Area under the plasma concentration-time curve from time zero to infinity
AUCt
Area under the plasma concentration-time curve from time zero to the last 
measurable concentration
Cmax
Maximum observed plasma concentration
Tmax
Time to maximum observed plasma concentration
 


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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................3
1.2
Synopsis .....................................................................................................5
1.3
List of Abbreviations and Definition of Terms........................................14
2.0
Table of Contents...................................................................17
3.0
Introduction ...........................................................................22
3.1
Myelofibrosis ...........................................................................................22
3.2
BCL-2 Family Proteins............................................................................22
3.3
Navitoclax Activity..................................................................................23
3.4
Navitoclax Clinical Data..........................................................................26
3.5
Differences Statement..............................................................................27
3.6
Benefits and Risks....................................................................................27
4.0
Study Objectives....................................................................29
5.0
Investigational Plan...............................................................30
5.1
Overall Study Design and Plan:  Description ..........................................30
5.2
Selection of Study Population..................................................................34
5.2.1
Inclusion Criteria .....................................................................................34
5.2.2
Exclusion Criteria ....................................................................................38
5.2.3
Enrollment of Subjects Based on Baseline Platelet Count ......................41
5.2.4
Prior and Concomitant Therapy...............................................................42
5.2.5
Contraception Recommendations ............................................................46
5.3
Efficacy, Pharmacokinetic, Biomarker, Exploratory Research and 
Safety Assessments/Variables..................................................................48
5.3.1
Efficacy and Safety Measurements Assessed ..........................................48
5.3.1.1
Study Procedures .....................................................................................49
5.3.1.2
Meals and Dietary Requirements.............................................................66
5.3.1.3
Collection and Handling of Biomarker and Exploratory Research 
Samples....................................................................................................66
5.3.2
Drug Concentration Measurements .........................................................68
5.3.2.1
Collection of Samples for Analysis .........................................................68
5.3.2.2
Handling/Processing of Samples .............................................................69
 


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5.3.2.3
Disposition of Samples ............................................................................69
5.3.2.4
Measurement Methods.............................................................................69
5.3.3
Efficacy Endpoints...................................................................................69
5.3.4
Safety Variables.......................................................................................71
5.3.5
Pharmacokinetic Variables ......................................................................71
5.3.6
Biomarker Variables ................................................................................71
5.4
Removal of Subjects from Therapy or Assessment.................................73
5.4.1
Discontinuation of Individual Subjects....................................................73
5.4.2
Termination of Entire Study ....................................................................74
5.5
Treatments................................................................................................75
5.5.1
Treatments Administered and Dosing......................................................75
5.5.2
Identity of Investigational and Standard of Care Medicinal 
Products....................................................................................................77
5.5.2.1
Identity of Investigation Products............................................................77
5.5.2.2
Identity of Standard of Care Medicinal Products ....................................78
5.5.2.3
Packaging and Labeling...........................................................................78
5.5.2.4
Storage and Disposition of Study Drug ...................................................78
5.5.3
Blinding....................................................................................................79
5.5.4
Treatment Compliance.............................................................................79
5.5.5
Drug Accountability.................................................................................81
5.6
Discussion and Justification of Study Design..........................................81
5.6.1
Appropriateness of Measurements...........................................................82
5.6.2
Suitability of Subject Population .............................................................83
5.6.3
Selection of Doses in the Study ...............................................................83
6.0
Complaints .............................................................................85
6.1
Medical Complaints.................................................................................85
6.1.1
Definitions................................................................................................86
6.1.1.1
Adverse Event..........................................................................................86
6.1.1.2
Serious Adverse Events ...........................................................................87
6.1.1.3
Adverse Events Expected Due to Study Related Endpoints....................88
6.1.1.3.1
Lack of Efficacy or Worsening of Disease ..............................................88
6.1.2
Adverse Event Severity............................................................................88
6.1.3
Relationship to Study Drug......................................................................88
 


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6.1.4
Adverse Event Collection Period.............................................................89
6.1.5
Adverse Event Reporting.........................................................................90
6.1.6
Pregnancy.................................................................................................92
6.1.7
Toxicity Management Guidelines............................................................93
6.1.7.1
Management of Thrombocytopenia and Bleeding Events.......................94
6.1.7.2
Management of Neutropenia....................................................................95
6.1.7.3
Management of Infections .......................................................................96
6.1.7.4
Management of Other Toxicities .............................................................97
6.2
Product Complaint ...................................................................................97
6.2.1
Definition .................................................................................................97
6.2.2
Reporting..................................................................................................98
7.0
Protocol Deviations................................................................98
8.0
Statistical Methods and Determination of Sample 
Size ..........................................................................................99
8.1
Definition of Analysis Populations..........................................................99
8.1.1
Baseline Characteristics.........................................................................100
8.1.2
Pharmacokinetics ...................................................................................100
8.2
Efficacy Endpoints.................................................................................100
8.2.1
Primary Efficacy Endpoint ....................................................................100
8.2.2
Secondary Efficacy Endpoints...............................................................100
8.2.3
Exploratory Efficacy Endpoints.............................................................101
8.3
Statistical Analysis.................................................................................101
8.3.1
Efficacy..................................................................................................101
8.3.2
Safety .....................................................................................................102
8.3.2.1
Duration of Exposure of Study Treatment.............................................102
8.3.2.2
Adverse Events ......................................................................................102
8.3.2.3
Serious Adverse Events .........................................................................103
8.3.2.4
Deaths ....................................................................................................103
8.3.2.5
Laboratory Data .....................................................................................103
8.3.2.6
Vital Signs..............................................................................................103
8.4
Determination of Sample Size ...............................................................104
9.0
Ethics.....................................................................................105
 


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9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................105
9.2
Ethical Conduct of the Study.................................................................105
9.3
Subject Information and Consent...........................................................106
10.0
Source Documents and Case Report Form 
Completion ...........................................................................107
10.1
Source Documents .................................................................................107
10.2
Case Report Forms.................................................................................108
11.0
Data Quality Assurance ......................................................110
12.0
Use of Information...............................................................111
13.0
Completion of the Study .....................................................112
14.0
Investigator's Agreement....................................................114
15.0
Reference List ......................................................................115
List of Tables
Table 1.
Patient-Reported Outcome Assessments .................................................60
Table 2.
Clinical Laboratory Testsa........................................................................62
Table 3.
Identity of Investigational Products.........................................................77
Table 4.
Identity of Standard of Care Medicinal Products ....................................78
Table 5.
Point Estimates and 95% CI of Rate of SVR35w24 Corresponding 
to Observed Number of Subjects with SVR35w24...................................104
Table 6.
Study Procedures – Navitoclax Alone or in Combination with 
Ruxolitinib .............................................................................................122
Table 7.
Schedule of Pharmacokinetic Assessments for Navitoclax and 
Ruxolitinib .............................................................................................131
Table 8.
Complete Schedule of Pharmacokinetic Assessments for 
Navitoclax and Ruxolitinib in a Subgroup (n ~10) of Cohort 1b 
Subjects for DDI Assessment (DDI cohort is applicable to 
subjects who sign a separate informed consent)....................................134
Table 9.
Summary of Response Criteria ..............................................................135
Table 10.
Summary of Cytogenetic Remission......................................................136
Table 11.
Summary of Molecular Remission ........................................................136
Table 12.
Summary of Progression/Relapse Criteria.............................................137
 


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Table 13.
Consensus on Grading of MF ................................................................138
Table 14.
Dynamic International Prognostic Scoring System (DIPSS).................139
Table 15.
Dynamic International Prognostic Scoring System (DIPSS)-PLUS .....139
List of Figures
Figure 1.
Study Schema...........................................................................................31
Figure 2.
Adverse Event Collection ........................................................................90
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................119
Appendix B.
List of Protocol Signatories....................................................................121
Appendix C.
Study Activities*....................................................................................122
Appendix D.
Evaluation of Potential Drug-Drug Interaction between 
Navitoclax and Ruxolitinib....................................................................133
Appendix E.
Modified IWG-MRT/ELN Response Criteria for Myelofibrosis ..........135
Appendix F.
Bone Marrow:  Grading of Myelofibrosis .............................................138
Appendix G.
Dynamic International Prognostic Scoring System (DIPSS).................139
Appendix H.
Sample List of Excluded and Cautionary Medications..........................140
Appendix I.
Dose Adjustment Guidelines for Thrombocytopenia and 
Neutropenia............................................................................................143
 


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3.0
Introduction
3.1
Myelofibrosis
Myelofibrosis (MF) is an acquired clonal Philadelphia chromosome negative 
myeloproliferative neoplasm (MPN).  It can present as primary MF (PMF) or as 
Secondary MF (SMF) following transformation of Polycythemia Vera (PV) to Post PV-
MF (PPV-MF) or Essential Thrombocythemia (ET) to Post ET-MF (PET-MF).1
MF is characterized by constitutional symptoms, splenomegaly, an increased risk of 
transformation to acute myeloid leukemia (AML) and a shortened life expectancy.2  The 
median age at diagnosis is in the sixth decade and 90% of patients are diagnosed after the 
age of 40 years.3
Ruxolitinib is approved for the treatment of patients with primary myelofibrosis in the 
United States and European Union.  Ruxolitinib induces improvement in splenomegaly 
and disease-related symptoms as compared to placebo or best available alternative 
therapy.4  However, therapy with ruxolitinib does not eradicate the malignant clones, is 
not known to improve bone marrow fibrosis, and patients who stop ruxolitinib rapidly 
become symptomatic again.  Some patients do not respond to ruxolitinib, whereas, others 
develop secondary resistance.5 Current therapy other than hematopoietic stem cell 
transplantation (HSCT) are not able to control all the clinical manifestations of MF, 
therefore, new treatments including combination strategies with ruxolitinib as the 
backbone are a major focus of clinical research.
3.2
BCL-2 Family Proteins
The BCL-2 family proteins are important regulators of the intrinsic apoptosis pathway.  
The BCL2 oncogene was first identified in follicular lymphoma where the t(14;18) 
chromosomal translocation results in significant over-expression of the protein in B-cells.6  
In contrast to other known oncogenes, BCL-2 does not stimulate cellular proliferation, but 
rather inhibits programmed cell death by protecting cells from a wide variety of 
pro-apoptotic stimuli, including cytokine withdrawal, irradiation, cytotoxic drugs, heat 
 


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and deregulated oncogenes.7  The BCL2 family of genes encodes closely related proteins 
that possess either pro-apoptotic or anti-apoptotic activity and share up to four BCL-2 
Homology (BH) domains.8-12  The anti-apoptotic family members (BCL-XL, BCL-2, 
BCL-W, BFL-1/A1 and MCL-1) are characterized by four BH domains that are 
designated BH1 – 4.  The pro-apoptotic family members can be further subdivided into 
multidomain apoptosis effector proteins (BAX, BAK) and the BH3-only proteins (BAD, 
BIK, BID, BIM, HRK, BMF, NOXA, and PUMA).  The interplay between these 
three groups of proteins serves to regulate initiation of the intrinsic apoptosis pathway.
The multidomain pro-apoptotic proteins BAX and BAK are direct mediators of apoptosis 
which, when activated, oligomerize to form pores in the outer membrane of mitochondria, 
enabling the release of apoptogenic factors like cytochrome c into the cytosol.  They are 
absolutely required for the execution of cell death by apoptosis.  Anti-apoptotic BCL-2 
family proteins (e.g., BCL-2, MCL-1 and BCL-XL) inhibit cytochrome c release by 
sequestering BAX and BAK and blocking their activation.13
3.3
Navitoclax Activity
Navitoclax (ABT-263) is a novel small-molecule BCL-2 family protein inhibitor that 
binds with high affinity (Ki ≤ 1 nM) to BCL XL, BCL-2, and BCL-W.  By competitively 
binding to these proteins, navitoclax frees pro-apoptotic family members, thus triggering 
cell death by apoptosis in sensitive populations.  Certain cancer cells are particularly 
sensitive to navitoclax.  For example, navitoclax displays potent mechanism-based 
cytotoxicity (EC50 ≤ 1 µM) against human tumor cell lines derived from small cell lung 
carcinomas and lymphoid malignancies.14  Navitoclax exhibits potent single agent activity 
against 10 of 22 cell lines consisting of multiple leukemia and lymphoma types spanning 
both B-cell and T-cell malignancies.  Navitoclax and its closely related predecessor,
ABT-737,15 have also shown cell killing activity against myeloproliferative neoplasm 
(MPN) patient samples cultured ex vivo16 and MPN-derived cell lines bearing the 
activating JAK2 V617F mutation, which is common in PCV and MF.17,18  Aberrant 
JAK2-STAT3/5 signaling has been linked to over-expression of the well-known 
navitoclax resistance factor MCL-1, and JAK2 inhibitors have been shown to reduce 
 


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MCL-1 expression, likely accounting for the synergistic cell killing observed when they 
were in combination with navitoclax.18  Conversely, BCL-XL elevation has been 
associated with resistance to JAK2 inhibitors, and navitoclax has shown the ability to 
overcome that resistance.17  BCL-XL inhibition alone, achieved using a more selective 
inhibitor (WEHI-539), was shown to be sufficient for overcoming resistance.  
Importantly, ABT-737 has also shown an ability to block the proliferation of MPN cells in 
long-term colony forming assays, which serve as an indicator of malignant precursor/stem 
cell survival and proliferation.  For example, endogenous erythroid colonies representing 
malignant PV clones able to grow in the absence of erythropoietin (EPO) were 
significantly inhibited in the presence of 500 nM ABT-73716 and could be further 
suppressed when 100 – 300 nM ABT-737 was combined with a JAK2 inhibitor.19  These 
data indicate that BCL-2/BCL-XL inhibitors like ABT-737 and navitoclax have the 
potential to kill malignant MPN precursors when combined with a JAK2 inhibitor.  The 
addition of navitoclax to a JAK2 inhibitor has also demonstrated enhanced efficacy in 
animal models of JAK2-mutated malignancies – for example, significantly slowing the 
growth of tumors in mice bearing the Eµ-TEL-JAK2 transgene or patient-derived 
xenograft (PDX) mice bearing JAK2-mutated B-ALL cells.17  The combination was also 
superior to either agent alone in prolonging the survival of mice with JAK2-mutated 
tumors, in some cases effecting cures.17
The anticipated and observed toxicities to date are mechanism-based, in particular, 
BCL-XL mediated decrease in circulating platelet survival and BCL-2 mediated effects on 
lymphocytes.  Nonclinically, testicular germ cell depletion was observed in rats and dogs 
but only after 6 months of dosing at 100 mg/kg/day (the highest dose tested).  The 
testicular effects of navitoclax are thought to be related to Bcl-w inhibition.  Sperm 
evaluation has not been conducted in the clinic and therefore it is unknown if there has 
been any decrease in sperm count or alteration in sperm quality. 
Navitoclax accelerates apoptosis of circulating mature platelets, which differs from typical 
chemotherapy induced thrombocytopenia (i.e., toxicity to platelet progenitors in the bone 
marrow) related to myelosuppression.  Limited human clinical data are available to 
 


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understand the response to infusion of exogenous platelets in the presence of circulating 
drug levels.  Platelet transfusion studies conducted in beagle dogs demonstrated that 
transfusion of one-day old platelets administered near the time of navitoclax Cmax, resulted 
in higher platelet levels than dogs not receiving supplemental platelets.  Platelet 
concentrations remained higher after 24 hours with declining navitoclax concentrations.  
This study suggests that infusion of platelets may have beneficial effects in treating acute 
thrombocytopenia following oral dosing with navitoclax.
From the pre-clinical models, there may be an opportunity in the monotherapy setting to 
increase efficacy without additional platelet toxicity in the setting of continuous dosing.  
In murine xenograft models of small cell lung cancer, 21 days of continuous dosing 
achieves superior tumor growth inhibition, greater increase in life span, and greater 
incidence of complete and overall response rates compared to the intermittent dosing 
schedules or 14 days of dosing and 7 days off drug.  In a dog toxicology study, navitoclax 
was delivered once daily for 28 days.  At doses that achieve plasma concentrations within 
the targeted efficacious exposure range, circulating platelet counts recovered to baseline 
within 14 days of dosing and remained at baseline for the subsequent 14 days of dosing.
This observation of platelet recovery during continued navitoclax dosing has also been 
observed in the Phase 1 clinical studies.  Given that platelet nadirs typically occur in the 
first few days of dosing and circulating platelet counts recover during continued dosing, a 
lead-in dosing period may help reduce the depth of platelet nadir.
Also in dogs at high doses, cardiovascular effects (decrease in cardiac output and increase 
in systemic and pulmonary vascular resistance) have been observed in safety 
pharmacology assessments.  However, results from a follow up 28-day study in dogs 
suggest that the cardiovascular effects are not exacerbated after multiple days of dosing or 
after multiple single infusions of platelets.
 


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3.4
Navitoclax Clinical Data
Three Phase 1/2a clinical trials investigating the safety, pharmacokinetics, and efficacy of 
navitoclax in subjects with relapsed or refractory lymphoid malignancies, subjects with 
small cell lung cancer or other non-hematological malignancies and subjects with chronic 
lymphocytic leukemia (CLL) are underway or completed.
Preliminary aggregate clinical data from 2 ongoing Phase 1 studies support that navitoclax 
is tolerable at doses up to 250 mg in a CLL population and up to 325 mg in a lymphoid 
malignancy population (which includes CLL/SLL subjects).  These studies were utilizing 
a 21/21 day dosing schedule (subjects dosed for 21 consecutive days of a 21-day cycle 
following a 7 to 14 day lead-in period).  Anti-tumor activity has been noted in study 
subjects with CLL/SLL across the dose ranges tested, suggesting that navitoclax may 
provide a clinical benefit to these subjects.
As of 28Feb2020, a total of 34 subjects with MF (Cohort 1a) have been treated in the 
navitoclax in combination with ruxolitinib in Study M16-109.  To date adverse events 
observed occurred at an incidence that appears to be consistent with what has been 
observed in navitoclax clinical studies and with this population of patients with MF.  The 
most common adverse events of any Grade in Study M16-109 to date are 
thrombocytopenia (88%), diarrhea (68%) and fatigue (62%).  Serious adverse events were 
reported in 13 subjects (38%) including pneumonia (n = 4), splenic infarct (n = 2), and the 
following events with 1 occurrence each:  anemia, angina pectoris, abdominal pain, 
colitis, vomiting, chest pain, pyrexia, biliary colic, hyperbilirubinemia, portal vein 
thrombosis, abnormal liver function tests, gout, respiratory failure and deep vein 
thrombosis.
Efficacy data from Study M16-109 is available for 34 subjects (Cohort 1a).  Spleen 
Volume Reductions of ≥ 35% at Week 24 (SVR35w24) were observed in 27% (9/34) of 
subjects.  Improvements in bone marrow fibrosis have been reported in 29% (10/34) of 
subjects.
 


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For further details, please refer to the Investigator's Brochure for additional information 
regarding navitoclax clinical studies, safety and efficacy data, pre-clinical toxicology, 
metabolism, and pharmacology.
3.5
Differences Statement
This is the first study to evaluate navitoclax in subjects with myelofibrosis.
3.6
Benefits and Risks
Conventional treatment includes wait and see approach for asymptomatic patients, 
erythropoiesis-stimulating agents, androgens or immunomodulatory agents for anemia, 
cytoreductive drugs such as hydroxyurea for splenomegaly and constitutional symptoms, 
and splenectomy or radiotherapy for selected patients.20  Currently, ruxolitinib, a dual 
JAK-1 and -2 inhibitor, is the only targeted therapy approved for the treatment of 
myelofibrosis in the United States and European Union.  While the approval of ruxolitinib 
has changed the treatment landscape for patients with myelofibrosis, it is still aimed at 
improving symptoms and quality of life.  The only treatment modality capable of curing 
MF is allogenic HSCT.  The applicability of HSCT is limited by the inherent risks in this 
population, with their attendant comorbidities.  
Fedratinib, a JAK-2 specific inhibitor, is currently in clinical development and has been 
evaluated in patients with MF.  The reported SVR35 with fedratinib in the previously 
untreated population is similar that reported of ruxolitinib at approximately 40%.21,22  A 
recent re-analysis of the JAKARTA-2 study of fedratinib in patients with MF that 
previously failed ruxolitinib treatment reports a SVR35 of 30%.  The most common 
adverse events in the JAKARTA-2 study in the ruxolitinib failure cohort are reported as 
anemia (100%), platelet count decrease (73%), creatinine increased (72%), diarrhea 
(65%), nausea (53%), and ALT increased (52%).  Additionally, among the 600 subjects 
treated with fedratinib in clinical trials, 8 subjects were reported to have potential 
Wernicke's encephalopathy.23
 


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Navitoclax has been evaluated in 25 clinical studies as both single-agent and as 
combination therapy.  Clinical studies have assessed the safety, pharmacokinetics and 
initial efficacy in subjects with hematologic malignancies or in subject with solid tumors.  
There is preclinical data that suggest that the combination of navitoclax with ruxolitinib 
may provide disease-modifying therapy for patients with PMF or SMF.
The preliminary data of the combination of navitoclax and ruxolitinib (Study M16-109) in 
patients with MF that have previously received ruxolitinib are favorable.  The spleen 
response rates of the combination are similar to that observed with fedratinib 
(JAKARTA-2 study) with an acceptable safety profile for this population.  This data 
supports further evaluation of both the combination in patients with MF that have either 
not received ruxolitinib or have failed prior ruxolitinib therapy.  Additional evaluation of 
the single-agent activity of navitoclax is also supported given the response rates observed 
of the combination in a population of patients that had failed prior ruxolitinib treatment.
This study will evaluate the addition of navitoclax to ruxolitinib in patients with PMF or 
SMF (PPV-MF or PET-MF) with persistent splenomegaly while receiving ruxolitinib 
monotherapy in Cohorts 1a and 1b.  Cohort 2 will evaluate navitoclax alone in patients 
with PMF or SMF that have splenomegaly and have received prior treatment with a 
JAK-2 inhibitor.  Cohort 3 will evaluate navitoclax in combination with ruxolitinib in 
patients with PMF or SMF that have not received treatment with a prior JAK-2 inhibitor 
or BET inhibitor.  The initial navitoclax dose and dosing schedule are derived from 
clinical experience in other indications.
Considering the coronavirus (COVID-19) pandemic, the benefit and risk to subjects 
participating in this study has been re-evaluated.  Based on the limited information to 
date, no additional risk to study participants is anticipated with the use of navitoclax. The
Sponsor has evaluated the potential risks of study participation during a global or regional
epidemic and concludes that the potential benefit of the study outweighs the additional 
risk.
 


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4.0
Study Objectives
The primary objective of the study is to:
●
Evaluate the effect of navitoclax alone or in combination with ruxolitinib on 
spleen volume
The secondary objectives of the study are: 
●
To assess the effect of navitoclax alone or in combination with ruxolitinib on 
total symptom score (TSS) as assessed by the Myelofibrosis Symptom 
Assessment Form (MFSAF) version 4.0 diary
●
To evaluate the effect of navitoclax alone or in combination with ruxolitinib on 
bone marrow fibrosis
●
To determine the rate of anemia response associated with navitoclax alone or 
in combination with ruxolitinib
●
To describe the safety profile and PK profile observed with navitoclax alone or 
in combination with ruxolitinib
The exploratory objectives of the study may include but not limited to:
●
To evaluate the effect of navitoclax alone or in combination with ruxolitinib on 
the onset, magnitude and duration of disease response, including effects on 
spleen and anemia. 
●
To evaluate the effect of navitoclax alone or in combination with ruxolitinib on 
measures of health-related quality of life including total symptom score, 
fatigue, and physical functioning. 
●
To evaluate the effect of navitoclax alone or in combination with ruxolitinib on 
overall survival (OS) and progression free survival (PFS). 
●
Exploration of biomarkers predictive of navitoclax activity and response may 
be performed. 
 


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5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 2, multicenter, open-label study designed to evaluate the tolerability and 
efficacy of navitoclax alone or in combination with ruxolitinib in subjects with primary or 
secondary myelofibrosis (PPV-MF, PET-MF).  Subjects enrolled in Cohort 1a must have 
received ruxolitinib therapy for at least 12 weeks and currently be on a stable dose of
≥10 mg twice daily of ruxolitinib.  For Cohort 1b subjects must have received treatment 
with ruxolitinib.  For Cohort 2, subjects must have received prior treatment with a JAK-2 
inhibitor.  For Cohort 3, subjects must not have received prior treatment with a JAK-2 
inhibitor or BET inhibitor.
Approximately 174 subjects at approximately 135 sites globally will be enrolled in the 
following cohorts:
●
Cohort 1a:  34 subjects (fully enrolled as of 10 April 2019)
●
Cohort 1b:  approximately 80 subjects will be enrolled to ensure enrollment of 
approximately 70 subjects with prior exposure to ruxolitinib. 
●
Cohort 2:  approximately 30 subjects
●
Cohort 3:  approximately 30 subjects
The study is designed to meet scientific and regulatory objectives without enrolling an 
undue number of subjects in alignment with ethical considerations.  All efforts will be 
made to adhere to these specific enrollment numbers; however, it might not be ethical to 
deny treatment to subjects in Screening as they may have undergone study related
procedures. Subjects that are enrolled and do not meet the inclusion criteria as outlined in 
Section 5.2 may be replaced at the discretion of the Sponsor.
The study will consist of the following:
●
Screening: Study assessment performed prior to enrollment;
 


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●
Treatment: Study assessments performed from first dose through the 
Treatment Completion Visit (TCV);
●
Follow-up: 
○
Safety Follow-up: approximately 30 days following TCV to assess 
adverse events
○
Post-Treatment Follow-up:  Every 12 weeks after the TCV until disease 
progression is documented or until another therapy for MF is initiated 
○
Survival: Every 6 months follow-up for survival status and collection of 
post-treatment cancer therapy details
Screening
Unless otherwise specified, Screening assessments must be performed within 28 days 
prior to first dose of navitoclax.  For subjects enrolled in Cohorts 1b and 3, the screening 
period should be long enough to ensure there is at least 7 days to collect the daily MFSAF 
v4.0 prior to Day 1.
Treatment
Once Screening procedures are completed and eligibility is confirmed, subjects will begin 
study treatment.  A schematic of the study design is shown below in Figure 1.  
Figure 1.
Study Schema
T2
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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All eligible subjects will initiate navitoclax orally (PO) once daily at the starting dose of 
50 mg once daily (Cohort 1a) or at 100 mg or 200 mg once daily (Cohorts 1b, 2 or 3).
Cohort 1b will enroll approximately 80 subjects to ensure enrollment of approximately 70 
subjects with prior exposure to ruxolitinib.   
Cohort 1a
The dose of navitoclax may be increased after approximately 7 or more days to the next 
dose level provided the platelet count is ≥ 75 × 109/L up to a maximum dose of navitoclax 
300 mg once daily.
Cohorts 1b, 2 or 3
●
Baseline Platelet Count >150 × 109/L: 200 mg once daily navitoclax starting 
dose
●
Baseline platelet count ≤ 150 × 109/L:  100 mg once daily navitoclax starting 
dose
○
The dose of navitoclax may be increased to 200 mg once daily after 7 days 
provided the platelet count is ≥ 75 × 109/L
●
The dose of navitoclax should not exceed 200 mg once daily for the first 
24 weeks of treatment. After the Week 24 disease assessment, the dose of 
navitoclax may be increased to 300 mg once daily at the discretion of the 
Investigator for subjects with sub-optimal spleen response defined as failure to 
achieve spleen volume reduction of at least 10% as assessed by imaging.
If a dose reduction below navitoclax 50 mg once daily is required, the dose of navitoclax 
may be reduced to 25 mg once daily following consultation with the AbbVie Therapeutic 
Area Medical Director/Scientific Director (TA MD/SD) (Section 6.1.5).
Subjects in Cohorts 1a, 1b or 3 will receive ruxolitinib administered orally twice daily 
(BID).  Subjects in Cohort 1a and 1b receiving ruxolitinib at screening will continue at the 
current stable dose of ≥10 mg twice daily.  Subjects in Cohorts 1b not receiving 
 


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ruxolitinib at the time of screening will receive ruxolitinib at a dose of 10 mg twice daily 
beginning on Day 1.  Subjects in Cohort 3 will receive ruxolitinib at the individualized 
starting dose based on baseline platelet count as per the local approved ruxolitinib label.  
The dose of ruxolitinib may be reduced during the study to manage toxicities.
Subjects in Cohort 2 will receive Navitoclax monotherapy.
During treatment, all assessments must be performed on the day of the specified visit 
unless a time window is specified in the schedule of assessments (Appendix C).  Refer to 
Section 3.6 for study visit modifications.
Subjects will continue their treatment until end of clinical benefit, unacceptable toxicity or 
subject meets other protocol criteria for discontinuation (whichever occurs first).  All 
subjects will have a TCV performed when treatment is discontinued.
Response and progression will be assessed by the Investigator based on the modified 
International Working Group-Myeloproliferative Neoplasms Research and European 
Leukemia Net (IWG-MRT/ELN) and as noted in Appendix E.24  Spleen volume will be 
assessed by an independent central review and interpretations will be transmitted to 
investigators, as available, and will be utilized in determining response and progression.  
The evaluation of fibrosis grading and reticulin staining grading may be assessed 
independently by a central pathologist.  Independent interpretations of bone marrow 
samples are not planned to be transmitted to investigators.  Details regarding the 
determination of clinical response and disease progression are provided in Appendix E.
Follow-Up
Safety Follow-Up:  All subjects will have one Safety Follow-up visit approximately 
30 days following TCV. 
Post-Treatment Follow-Up:  For subjects who discontinue study treatment for reasons 
other than disease progression, a Post-Treatment Follow-up visit will be performed 
approximately 12 weeks following TCV, then every 12 weeks thereafter to assess disease 
 


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status until criteria are met for discontinuation from study (e.g., disease progression, 
initiation of post-treatment cancer therapy, or subject refusal of post-treatment follow-up 
visits). 
Once disease progression is confirmed or the subject begins a post-study treatment for MF 
other than the continuation of ruxolitinib (Cohorts 1a, 1b or 3), the subject will enter the 
Survival Follow-up phase. 
Survival Follow-Up:  Survival Follow-up will then be performed approximately every 
6 months for up to 5 years after TCV (provided informed consent has not been withdrawn 
for collection of such information).  Survival information (e.g., date and cause of death, 
details of post-treatment cancer therapies including response and progression) may be 
collected via telephone calls (e.g., to subject or family member), clinic visits, and/or 
public database searches.
5.2
Selection of Study Population
Adult male and female subjects with primary or secondary MF and who meet all inclusion 
criteria and none of the exclusion criteria will be eligible for enrollment into the study.
5.2.1
Inclusion Criteria
A subject will be eligible for study participation if he/she meets the following criteria:
1.
Subject must voluntarily sign and date an informed consent, approved by an 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to 
the initiation of any Screening or study-specific procedures.
2.
Subject must be ≥ 18 years of age.
3.
Subjects with documented diagnosis of Primary MF, PPV-MF, or PET-MF as 
defined by the World Health Organization classification.
4.
Subjects classified as intermediate-2 or high-risk MF, as defined by the Dynamic 
International Prognostic Scoring System (DIPSS).
 


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5.
Subject must be ineligible due to age, comorbidities, or unfit for unrelated or 
unmatched donor transplantation or unwilling to undergo stem cell transplantation 
at time of study entry.
6.
ECOG 0, 1, or 2.
7.
Cohort 1a only:  Subject must have received ruxolitinib therapy for at least 
12 weeks and be on a stable dose of ≥ 10 mg twice daily of ruxolitinib for 
≥8 weeks prior to the 1st dose of navitoclax.
Note:  Subjects with ruxolitinib dose reductions within 8 weeks prior to study 
enrollment may be considered on a stable dose if stable at that decreased dose of 
ruxolitinib for ≥ 2 weeks prior to the 1st dose of navitoclax.  If the dose reduction 
was due to thrombocytopenia, the platelets must be confirmed to be stable by a 
repeat laboratory test.
8.
Cohort 1b only:  Subject must have received treatment with ruxolitinib and meet 
at least one of the following criteria:
a.
Prior or current treatment with ruxolitinib for ≥ 24 weeks with lack of efficacy 
defined as a lack of spleen response (refractory) or a loss of spleen or symptom 
response (relapsed)
b. Prior or current treatment with ruxolitinib for < 24 weeks with documented 
disease progression while on ruxolitinib as defined by any of the following:
i.
Appearance of new splenomegaly that is palpable to at least 5 cm below 
the left costal margin (LCM) in subjects with no evidence of 
splenomegaly prior to the initiation of ruxolitinib.
ii.
A ≥ 100% increase in the palpable distance below the LCM in subjects 
with measurable spleen distance 5 to 10 cm prior to the initiation of 
ruxolitinib.
iii.
A ≥50% increase in the palpable distance below the LCM in subjects 
with measurable spleen distance > 10 cm prior to the initiation of 
ruxolitinib.
 


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iv.
A spleen volume increase of ≥ 25% (as assessed by MRI or CT scan) in 
subjects with a spleen volume assessment prior to the initiation of 
ruxolitinib.
c.
Prior or current treatment with ruxolitinib for ≥ 28 days with intolerance 
defined as new RBC transfusion requirement (at least 2 units/month for 
2 months) while receiving a total daily ruxolitinib dose of ≥ 30 mg but unable 
to reduce dose further due to lack of efficacy.
9.
Cohort 1b only:  Subjects that are receiving ruxolitinib at the time of screening, 
must currently be on a stable dose ≥ 10 mg twice daily of ruxolitinib for ≥ 4 weeks 
prior to the 1st dose of navitoclax.
Note:  Subjects with ruxolitinib dose reductions within 4 weeks prior to study 
enrollment are considered to be on stable dose if dose of ruxolitinib is unchanged
for ≥ 2 weeks prior to Day 1 of navitoclax. The current dose must be ≥ 10 mg 
twice daily. If the dose reduction was due to thrombocytopenia, platelet counts 
must be confirmed to be stable by a repeat laboratory test.
10.
Cohort 1b only:  Subject must not have received treatment with a BET inhibitor or 
an alternate JAK-2 inhibitor other than ruxolitinib.
11.
Cohort 2 only:  Subject must have received prior treatment with JAK-2 inhibitor 
therapy and meet one of the following criteria (a or b):
a.
Prior treatment with JAK-2 inhibitor for at least 12 weeks 
b. Prior treatment with JAK-2 inhibitor for ≥ 28 days complicated by any of the 
following:
i.
Development of red blood cell transfusion requirement (at least 
2 units/month for 2 months
OR
ii.
Grade ≥ 3 adverse events of thrombocytopenia, anemia, hematoma and/or 
hemorrhage while on JAK-2 inhibitor treatment 
 


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12.
Cohort 3 only:  Subject must not have received prior treatment with a JAK-2 or 
BET inhibitor.
13.
Subject has splenomegaly defined as a spleen palpation measurement ≥ 5 cm below 
costal margin or spleen volume ≥ 450 cm3 as assessed by MRI/CT.
14.
Cohorts 1b and 3 only:  Subject has at least 2 symptoms each with a score ≥ 3 or a 
total score of ≥ 12, as measured by the MFSAF v4.0 on at least 4 out of 7 days 
during screening prior to study drug dosing.
15.
Subject must meet the following laboratory parameters per local laboratory 
reference range during screening, prior to study drug dosing:
●
Adequate bone marrow reserve; in the absence of growth factors, 
thrombopoietic factors, or platelet transfusions for at least 14 days: 
○
Platelet count ≥ 100 × 109/L (Cohorts 1a, 1b or 3)
○
Platelet count ≥ 75 × 109/L (Cohort 2)
○
ANC ≥ 1 × 109/L
●
Renal function:  calculated creatinine clearance ≥ 30 mL/min using the 
Cockcroft-Gault formula
●
Hepatic function and enzymes:  
○
AST and ALT ≤ 3.0 × upper normal limit (ULN) 
○
Total Bilirubin ≤ 1.5 × ULN (exception:  subjects with Gilbert's Syndrome 
may have a Bilirubin > 1.5 × ULN)
●
Coagulation:  
○
aPTT ≤ 1.5 × ULN
○
Prothrombin time (PT) or INR ≤ 1.5 × ULN
16.
Female subjects of childbearing potential must practice at least 1 protocol-
specified method of birth control, that is effective from Study Day 1 through at 
least 30 days after the last dose of study drug.
 


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If male, and subject is sexually active with female partner(s) of childbearing 
potential, he must agree, from Study Day 1 through at least 90 days after the last 
dose of study drug, to practice the protocol specified contraception (Section 5.2.5). 
17.
Females of childbearing potential must have a negative serum pregnancy test 
result at Screening, and a negative urine or serum pregnancy test on Study Day 1.  
Negative pregnancy test must be available prior to first dose.
Females of non-childbearing potential (as defined in Section 5.2.5) at Screening do 
not require pregnancy testing.
Rationale for Inclusion Criteria
1
In accordance with Harmonized Good Clinical Practice (GCP)
2 – 12, 14
To select the subject population
13, 15
For the safety of the subjects
16 – 17
The impact of the Navitoclax on pregnancy is unknown
5.2.2
Exclusion Criteria
A subject will not be eligible for study participation if he/she meets any of the following 
criteria:
1.
Splenic irradiation within 6 months prior to Screening, or prior splenectomy.
2.
Leukemic transformation (> 10% blasts in peripheral blood or bone marrow 
aspirate /biopsy).
3.
Subject is currently on medications that interfere with coagulation (including 
warfarin) or platelet function within 3 days prior to the first dose of study drug or 
during the study treatment period with the exception of low dose aspirin (up to 100 
mg/day) and LMWH.
4.
Prior therapy with a BH3 mimetic compound or stem cell transplantation.
 


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5.
Subject has a history of an active malignancy other than MF within the past 2 
years prior to study entry, with the exception of:
●
Adequately treated in situ carcinoma of the cervix uteri
●
Adequately treated basal cell carcinoma or localized squamous cell carcinoma 
of the skin
●
Asymptomatic prostate cancer without known metastatic disease and with no 
requirement for therapy.
6.
Subject has a known positive test for HIV. 
Note:  HIV testing is not required at Screening.
7.
Subject has known hepatitis B (HBV) or hepatitis C (HCV) requiring treatment.  
Subjects with an undetectable viral load within 3 months of screening and those 
with serologic evidence of prior vaccination to HBV [i.e., HBs Ag-, and anti-HBs+] 
may participate (Hepatitis B or C testing is not required at screening unless it is 
required per local guidelines or institutional standards). 
8.
History of an allergic reaction or significant sensitivity to constituents of the study 
drug (and its excipients) and/or other products in the same class.
9.
Clinically relevant or significant ECG abnormalities, including ECG with QT 
interval corrected for heart rate (QTc) using Fridericia's formula (QTcF) > 450 
msec (males) or >470 msec (females).
10.
Subject exhibits evidence of other clinically significant uncontrolled condition(s) 
including, but not limited to:
●
Ongoing systemic infection (viral, bacterial, mycobacterial or fungal)
○
Active SARS-CoV-2 infection.  If a subject has signs/symptoms suggestive 
of SARS-CoV-2 infection, the subject must have a negative molecular 
(e.g., PCR) test result. Note:  SARS CoV-2 diagnostic tests should be 
applied following local requirements/recommendations.     
●
Subjects positive for active SARS-CoV-2 infection may rescreen after 
they meet either criteria a or b indicating SARS-CoV-2 infection has 
resolved with viral clearance:
 


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a.
At least 14 days since first PCR test result have passed in 
asymptomatic patients
OR
b. At least 14 days since recovery, defined as resolution of fever without 
use of antipyretics and improvement in symptoms.
●
Cohorts 1b and 3 only:  Subject has tested positive for tuberculosis prior to 
study entry (subjects must have a negative result per local guidelines or have 
no evidence of latent infection prior to study entry, (see Section 5.3
Tuberculosis Testing for additional details.)
●
Febrile neutropenia
11.
Cohort 1b Drug-Drug Interaction (DDI) sub-study subjects only:  Subject has 
received any of the following within 14 days prior to the first dose of study drug:
●
Strong or moderate CYP3A inhibitors (see Appendix H)
12.
Cohort 1b Drug-Drug Interaction (DDI) sub-study subjects only:  Subject has 
consumed one or more of the following within 3 days prior to the first dose of 
study drug:
●
Grapefruit or grapefruit products
●
Seville oranges (including marmalade containing Seville oranges)
●
Star fruit (carambola)
13.
Female subject who is pregnant, breastfeeding or is considering becoming 
pregnant or donating eggs during the study or for approximately 30 days after the 
last dose of study drug.
Male subject who is considering fathering a child or donating sperm during the 
study or for approximately 90 days after the last dose of study drug.
14.
Subject has history of a cardiovascular, endocrinologic, hepatic, immunologic 
metabolic, neurologic, psychiatric, pulmonary, renal disease, or any other 
condition that in the opinion of the investigator would adversely affect his/her 
participation in this study or interpretation of study results.
 


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15.
Subject is concurrently participating in another therapeutic clinical trial or subject 
has previously participated in other AbbVie clinical trials conducted in subjects 
with myelofibrosis.
Rationale for Exclusion Criteria
1 – 5
These criteria were selected to ensure the appropriate subject 
population with sufficient disease severity for evaluation
6 – 12, 14 – 15
These criteria are to ensure general good health and safety of the 
subjects
13
The impact of navitoclax on sperm count, the unborn fetus or breast 
feeding infant is unknown
5.2.3
Enrollment of Subjects Based on Baseline Platelet Count
Cohort 1a only
Given the potential for navitoclax induced thrombocytopenia, the number of subjects with 
a baseline platelet count between 100 – 150 × 109/L and 150 – 200 × 109/L will initially 
be limited to approximately 6 – 8 subjects per platelet range, respectively.  Data from at 
least the first 28 days of enrollment for approximately the first 6 subjects per platelet 
range enrolled in Cohort 1a will be reviewed by the TA MD/SD and Safety Physician.  
Upon review of these initial safety data, the sponsor will determine if further enrollment 
of patients within the specified platelet ranges should continue.
Cohort 2 only
Given the potential for navitoclax induced thrombocytopenia, the number of subjects with 
baseline platelet count between 75 – 100 × 109/L will be limited to approximately 
10 subjects.  Data from at least the first 28 days of treatment for the first 5 to 6 subjects 
with lower platelets enrolled in Cohort 2 will be reviewed by the TA MD/SD and Safety
Physician.  Upon review of these initial safety data, the sponsor will determine if further 
enrollment of patients within the specified platelet ranges should continue.
 


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5.2.4
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements) that the subject is receiving at the time of enrollment, 
or receives during the study, must be recorded along with the reason for use, date(s) of 
administration including start and end dates, and dosage information including dose, route 
and frequency.
Subject must not have received any live vaccine within 4 weeks prior to the first dose of 
study drug or be expected to need of live vaccination during study participation including 
at least 4 weeks after the last dose of study drug.
Best supportive care and treatment will be allowed for each subject (antiemetics, 
antibiotics, transfusions, nutritional support, pain control, etc.) with the exception of the 
following:
●
Clopidogrel, tirofiban and other anticoagulants, drugs or herbal supplements 
that affect platelet.  Administration of low-dose aspirin (≤ 100 mg daily) and 
LMWH are allowed; Dose adjustments for LMWH heparin should be made 
based on the subject's platelet counts and the local label of the agent being 
used.
●
Disulfiram is not allowed during study drug treatment due to potential 
prolongation of prothrombin time (PT).
●
Treatment with NSAIDs for limited duration are permitted during study 
treatment if the platelet counts > 100 × 109/L.
Anti-cancer therapy including chemotherapy, cytoreductive agents, immunotherapy, 
radiotherapy, hormonal (with the exception of hormones for thyroid conditions or 
estrogen replacement therapy), and other investigational agents will not be allowed during 
study treatment.  Hydroxyurea should be discontinued at least 7 days before initiation of 
navitoclax on Day 1.
 


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Treatment with supportive medications for MF such as interferon, erythropoietin, danazol, 
and steroids, is not permitted during study drug treatment.  Steroid therapy for MF or for 
anti-neoplastic intent will not be allowed within 7 days prior to the first dose of study 
treatment or during study drug treatment. If medically indicated, allowed steroid therapy 
includes inhalational steroids for the treatment of asthma or chronic obstructive 
pulmonary disease, topical steroids, and steroids for prevention and/or treatment of 
transfusion related reactions.  Steroids for any other indications should be limited to lower 
dose and /or short duration.
For subjects in Cohort 2 receiving treatment with JAK-2 inhibitor therapy prior to study 
enrollment, a wash-out period is not required.  The last dose of the JAK-2 inhibitor 
therapy must occur ≥ 1 day prior to Day 1 (first dose of navitoclax).
Biologics for MF will not be allowed within 30 days prior to the first dose of study drug 
and during navitoclax administration.
Colony stimulating factors (G-CSF, GM-CSF) may be considered during administration 
of navitoclax if deemed necessary by the investigator.
If clinically indicated, anti-herpes and anti-PCP (Pneumocystis carinii/jiroveci
pneumonia) prophylaxis should be considered.  Although there is a potential for drug-
drug interactions trimethoprim sulfamethoxazole can be considered for PCP prophylaxis 
with close clinical monitoring.
COVID-19 Pandemic-Related Vaccination Guidance
●
Given the ongoing COVID-19 pandemic, selected non-live vaccines (e.g., 
mRNA, non-replicating viral vector, protein subunit, etc.) to prevent SARS-
CoV-2 infection may be administered during screening or the treatment period, 
as long as components of the vaccine are not contraindicated. Investigators are 
to follow the prescribing information for the vaccine.
 


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●
The decision to receive a locally available vaccine should be based on local 
guidance and an individual discussion between the treating physician and the 
subject.
●
The potential impact of navitoclax on SARS-CoV-2 vaccination is unknown. 
Therefore, the timing of administration of vaccine in relation to the study drug 
should be based on the investigator's medical assessment of the subject's 
disease.
Note:  The above guidance applies to all SARS-CoV-2 vaccine doses given as 
part of the complete vaccination course.
●
These recommendations may be subject to change based on the evolving 
knowledge around the use of SARS-CoV-2 vaccines in patients with 
myelofibrosis and as more data are collected in real-world scenarios and 
clinical trials.
●
Any SARS-CoV-2 vaccine information must be documented on the 
COVID-19 vaccine eCRF.
Subjects Receiving Navitoclax
The following concomitant medications are cautionary during study treatment for subjects 
receiving navitoclax as they may potentially lead to drug-drug interaction(s).  The 
investigator should assess whether a potential study subject is taking any of the 
medications in the categories described below and, if so, document the use of medications 
known or suspected to fall in the following medication categories:
●
Strong cytochrome P450 (CYP)-3A inhibitors (e.g., ketoconazole and 
clarithromycin), and foods that inhibit CYP3A such as grapefruit and its juice, 
star fruit, and Seville oranges (due to possible inhibition of the metabolism of 
navitoclax).  NOTE: Strong and moderate CPY3A inhibitors and foods that 
inhibit CYP3A as mentioned above are not allowed for subjects participating 
in the Cohort 1b DDI sub-study.
●
CYP3A inducers such as rifampin and carbamazepine (due to possible 
induction of the metabolism of navitoclax).
 


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●
CYP2C8 substrates such as glitazones and select statins (due to expected 
inhibition of the metabolism of CYP2C8 substrates).
●
CYP2C9 substrates such as phenytoin and tolbutamide (due to expected 
inhibition of the metabolism of CYP2C9 substrates).
●
P-glycoprotein (P-gp) substrates such as digoxin and breast cancer resistance 
protein (BCRP) substrates such as rosuvastatin (due to possible inhibition of 
these transporters by navitoclax).
●
Inhibitors and inducers of P-gp and BCRP (navitoclax is a substrate of P-gp
and BCRP).
A sample list of excluded medications and cautionary medications can be found in 
(Appendix H).  Since a complete list of medications that are excluded or should only be 
used with caution cannot be provided, please refer to the appropriate product label and/or 
contact the AbbVie TA MD/SD whether a specific concomitant medication falls into the 
above mentioned categories.  Information regarding potential drug interactions with 
navitoclax can also be located in the current navitoclax Investigator's Brochure.
If the investigator determines that use of an excluded or cautionary concomitant 
medication is medically indicated, the investigator will notify the AbbVie TA MD/SD and 
discuss the rationale for the use of the concomitant medication and the need to medically 
monitor the potential study subject under consideration.
Subjects Receiving Ruxolitinib
Ruxolitinib is predominantly metabolized by CYP3A4 and to a lesser extent by CYP2C9.  
For subjects who are taking strong CYP3A4 inhibitors (such as ketoconazole and 
clarithromycin) or moderate CYP3A4 inhibitors (such as fluconazole) concurrently with 
ruxolitinib study treatment, the local, approved product label should be referenced for 
ruxolitinib dose reduction, interruption, and discontinuation, or monitoring guidelines.  
The local, approved ruxolitinib product label should also be referenced for monitoring 
guidelines when co-administered with CYP3A inducers or drugs transported by P-gp and 
BCRP.
 


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5.2.5
Contraception Recommendations
While participating in this research study, subjects should not become pregnant, 
breastfeed a baby or father a baby.
Contraception Requirements for Females
Subjects must follow the following contraceptive guidelines as specified:
Females, Non-Childbearing Potential
Females do not need to use birth control during or following study drug treatment if 
considered of non-childbearing potential due to meeting any of the following criteria:
1.
Premenopausal female with permanent sterility or permanent infertility due to one 
of the following:
●
Permanent sterility due to a hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy
●
Non-surgical permanent infertility due to Mullerian agenesis, androgen 
insensitivity, or gonadal dysgenesis; investigator discretion should be applied 
to determining study entry for these individuals.
2.
Postmenopausal female
●
Age > 55 years with no menses for 12 or more months without an alternative 
medical cause.
●
Age ≤ 55 years with no menses for 12 or more months without an alternative 
medical cause AND a follicle-stimulating hormone (FSH) level > 30 IU/L.
Females, of Childbearing Potential
●
Females of childbearing potential should be provided information from study 
staff about cryopreservation of eggs prior to treatment with study drug.
Review and document pregnancy avoidance recommendations with females of 
childbearing potential
 


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●
Females of childbearing potential must avoid pregnancy while taking study 
drugs and for at least 30 days after the last dose of study drug.
●
Females must commit to one of the following methods of birth control:
○
Combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal, injectable) associated with the inhibition of 
ovulation, initiated at least 30 days prior to Study Day 1.
○
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 30 days prior to 
Study Day 1.
○
Bilateral tubal occlusion/ligation (can be via hysteroscopy provided a 
hysterosalpingogram confirms success of the procedure).  
○
Vasectomized partner (provided the vasectomized partner has received
medical confirmation of the surgical success of the vasectomy and is the 
sole sexual partner of the trial subject).
○
Intrauterine device (IUD).
○
Intrauterine hormone-releasing system (IUS).
○
Practice true abstinence defined as:  Refraining from heterosexual 
intercourse when this is in line with the preferred and usual lifestyle of the 
subject [periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable].
If required per local practices, male or female condom with or without 
spermicide OR cap, diaphragm or sponge with spermicide should be used in 
addition to one of the birth control methods listed above (excluding true 
abstinence).
Contraception recommendations related to use of concomitant therapies prescribed should 
be based on the local label.
Contraception Requirements for Males
Male subjects should be provided information to seek advice about cryopreservation of 
sperm prior to treatment with study drug.
 


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Male subjects who are sexually active with a female partner of childbearing potential, 
even if the male subject has undergone a successful vasectomy, must agree to use 
condoms from Study Day 1 through at least 90 days after the last dose of study drug.
His female partner(s) must also use at least 1 of the following methods of birth control:
●
Combined (estrogen and progestogen containing) hormonal birth control (oral, 
intravaginal, transdermal, injectable) associated with inhibition of ovulation 
initiated at least 30 days prior to study Baseline Day 1
●
Progestogen-only hormonal birth control (oral, injectable, implantable) 
associated with inhibition of ovulation initiated at least 30 days prior to study 
Baseline Day 1
●
bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a 
hysterosalpingogram confirms success of the procedure)
●
intrauterine device (IUD)
●
Intrauterine hormone-releasing system (IUS)
●
Vasectomized partner (provided the partner has received medical confirmation 
of the surgical success of the vasectomy, and is the sole sexual partner of the 
trial subject)
Male subject agrees not to donate sperm from Study Day 1 through at least 90 days after 
the last dose of study drug.
5.3
Efficacy, Pharmacokinetic, Biomarker, Exploratory 
Research and Safety Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed
Study procedures described are listed in the following section of this protocol and are 
summarized in tabular format Appendix C.
 


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5.3.1.1
Study Procedures
All study procedures outlined in Appendix C are discussed in detail in this section, with 
the exception of monitoring of treatment compliance (Section 5.5.4), and adverse event 
information (Section 6.1.1.1).  Unscheduled visits may be performed as medically 
indicated (e.g., for monitoring of toxicities).  All study data, including those from 
unscheduled visits, will be recorded on electronic case report forms (eCRFs):  Patient-
Reported Outcome (PRO) assessments will be collected using an electronic and a paper 
process and recorded into the eCRF.
Study visits may be impacted due to the COVID-19 pandemic.  This may include changes 
such as phone or virtual visits, visits at alternative locations, or changes in the visit 
frequency and timing of study procedures, among others.  Additional details are provided 
in the subsequent section.  Every effort should be made to ensure the safety of subjects 
and site staff, while maintaining the integrity of the study.  If visits cannot be conducted 
onsite due to travel restrictions or other pandemic-related reasons, follow the updates 
below on how to proceed.
During the COVID-19 pandemic, if it is not possible for all study procedures to be 
performed as specified due to travel restrictions or other reasons, the following 
modifications are allowed:
Activities performed at site
●
Study Visits and/or activities should be performed as scheduled whenever 
possible.  If an activity, is missed or delayed due to the pandemic, perform the 
activity at the site at the earliest feasible opportunity.
○
Bone marrow biopsy/aspirate and cytogenetic assessment
○
Imaging for spleen volume assessment
○
Biomarker and exploratory research sample collection
○
Disease response assessment
○
Physical examination: full and targeted exams, including skin examination, 
and spleen and liver measurement by palpation at Screening and Treatment 
 


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Completion visits.  A targeted physical examination including skin 
examination, and spleen and liver measurement by palpation will be 
conducted during study visits
Activities performed locally or at site
●
Study Visits and/or activities should be performed as scheduled whenever 
possible.  If activity is missed or delayed due to the pandemic, perform the 
activity at the site or locally at the earliest feasible opportunity.
○
12-Lead Electrocardiogram (may be done locally)
○
Clinical laboratory tests (may be done locally)
Activities performed by Phone/Virtually
●
Some study visits and/or activities may be performed by phone/virtually.
○
Informed consent (if allowed by IRB/EC and/or local guidelines)
○
Adverse event and concomitant medication assessment
○
Transfusion history/status
○
Patient reported outcome assessment PROs eligible for completion by 
interview at such visits are EORTC QLQ-C30 Version 3, Patient Global 
Impression of Change, and PROMIS Fatigue Short Form (SF) 7a).  Note:
The MF-SAF questionnaire should be completed on the ePRO device daily 
by the patient.
○
ECOG performance status
○
Vital signs (may be obtained by the subject or caregiver as needed)
Screening
Procedures performed at Screening will serve as baseline, unless repeated on Day 1 prior 
to dosing, in which case the latter will serve as baseline.
Screening procedures must be performed within 28 days prior to initial study drug 
administration.  The 28 day Screening window starts with the signing of the Informed 
 


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Consent Form.  For subjects enrolled in Cohorts 1b or 3, the screening period should be at 
least 7 days to ensure adequate duration for collection of the daily of MFSAF v4.0 
questionnaire which is needed to calculate a baseline total symptom score.  Subjects not 
meeting inclusion/exclusion criteria will not be enrolled into the study.
Re-Screening
Subjects that initially screen fail for the study may be permitted to re-screen.  All 
Screening procedures, including obtaining informed consent must be repeated, except the 
MRI/CT and bone marrow biopsy/aspirate from the initial Screening period may be 
utilized if collected within 35 days of the first dose of study drug, provided the 
inclusion/exclusion criteria were met.  There is no minimum period of time a subject must 
wait to re-screen for the study.  As appropriate, sites are encouraged to discuss subject 
eligibility with the AbbVie TA MD/SD.
The results of all Screening evaluations must be within medically acceptable limits, upon 
review by the investigator before a subject can be administered study drug.  Subjects will 
not be enrolled in the study if laboratory or other Screening results are medically 
unacceptable.
Informed Consent
Signed informed consent will be obtained from the subject or the subject's legally 
acceptable representative in order to participate in this study.  The Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC) approved informed consent must be 
signed and dated by each subject prior to undergoing any study procedures or before any 
prohibited medications are withheld from the subject in order to participate in this study.  
Informed consent will also be required for the exploratory research sampling portion of 
the study and the drug-drug interaction blood sampling for Cohort 1b.  Refer to 
Section 9.3 for details on obtaining and documenting informed consents.
 


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Following signing of ICF, the IRT will be utilized to assign a subject screening number.  
Subjects who complete all Screening procedures and meet the eligibility criteria in 
Section 5.2.1 and Section 5.2.2 will proceed to enrollment in IRT.
Subjects will be considered screen failures if the informed consent has been signed and a 
study-specific procedure has been performed, but subject was not enrolled into the study.  
The reason for screen failure will be documented in the source and will be captured in the 
eCRF.
Due to the COVID-19 pandemic, it is possible that additional protocol modifications not 
outlined in this protocol may become necessary.  If this situation arises, in addition to the 
study informed consent, additional verbal consent may be obtained prior to these 
adaptations or substantial changes in study conduct in accordance with local regulations.
Medical and Oncologic History
The following will be collected during the Screening Visit per Appendix C:
●
Complete medical history, including documentation of any clinically 
significant medical condition or surgical procedure
●
Detailed prior and concomitant medication usage including dates of usage and 
dosing information for all medications and supplements taken.
●
History of tobacco and alcohol use
●
Detailed MF disease history including, but not limited to:
○
Prior therapy including start and stop dates, dose and response
○
For subjects that have received prior treatment with ruxolitinib, the spleen 
measurement (by palpation or imaging) prior to initiation of ruxolitinib, as 
well as, at the time of response and progression/relapse must be available. 
○
Current disease status including Dynamic International Prognostic Scoring 
System (DIPSS) risk categorization25 and the DIPSS-Plus risk 
categorization26 (Appendix G)
○
Transfusion requirements during the time period of a minimum of 
12 weeks before the start of study treatment
 


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On Day 1, any additional medical history observed after signing of the informed consent 
but prior to initial navitoclax administration and not considered related to study-required 
procedures will be recorded in the subject's medical history.
Tuberculosis (TB) Testing
The TB screening tests are diagnostic test results to be interpreted in the context of the 
subject's epidemiology, history, exam findings, etc., and it is the responsibility of the 
Investigator to determine if a subject has previous, active, or latent TB.  Prior to study 
enrollment, subjects to be enrolled in Cohorts 1b and 3 will be assessed for evidence of 
increased risk for TB and tested for TB infection by a purified protein derivative (PPD) 
skin test and/or interferon-gamma release assay (IGRA).  An alternative approved method 
of testing per local guidelines may also be used.  If a subject had a negative TB test within 
90 days prior to Day 1 and source documentation is available, the test does not need to be 
repeated, provided nothing has changed in the subject's medical history to warrant a repeat 
test.  These cases may be discussed with the AbbVie TA MD/SD.  The results of the TB 
test(s) will be retained at the site as the original source documentation.  The TB test(s) to 
be performed depends on local guidelines.
Additional TB test(s) may be performed during the study at the discretion of the 
investigator per local guidelines. If the test is indeterminate, additional evaluation for 
latent tuberculosis should be completed per local guidelines before starting ruxolitinib or 
continuation of ruxolitinib based on the overall risk-benefit determination.
If TB Skin Test is performed, it should be read by a licensed healthcare professional 
between 48 and 72 hours after administration and the interpretation should be according to 
standard guidelines.  A subject who does not return within 72 hours will need to be 
rescheduled for another skin test.
 


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Adverse Event and Concomitant Medication Assessment
Any adverse events observed from the signing of the informed consent but prior to initial 
navitoclax administration will be reported, as serious or non-serious adverse events, if 
considered by the investigator to be causally related to study-required procedures.
At each visit, the subject's medical history will be reviewed and any changes from 
baseline will be recorded on the adverse event eCRF.
All medications (prescription or over-the-counter, including vitamins and/or herbal 
supplements) will be recorded beginning with the Screening Visit and continuing until 
30 days following the last dose of study drug.
Bone Marrow and Cytogenetic Assessment
A bone marrow biopsy must be collected along with a bone marrow aspirate (provided the 
aspirate sample can be collected) and evaluated locally during Screening and as outlined 
in Appendix C.  Cytogenetic analysis should be evaluated at Screening for determination 
of risk stratification.  If cytogenetic analysis was not performed at Screening, a historical 
result may be utilized for risk stratification determination provided it was obtained within 
6 months of Screening and a new therapy was not initiated between the time of collection 
and Screening.  This evaluation will include staining for fibrosis and staining for reticulin 
grading and cytogenetics.  Cytogenetic results from peripheral blood specimen with an 
adequate number of malignant cells is satisfactory for analysis.  Should peripheral blood 
yield an insufficient number of metaphases analyzed by chromosomal banding analysis 
(<10), a Fluorescence In Situ Hybridization (FISH) panel for MPN may be used to 
determine whether the subject has an "unfavorable karyotype," as defined by the DIPSS+, 
as long as presence of all chromosome abnormalities are assessed: +8; -7/-7q; i(17q); -5/-
5q; 12p-; inv(3);  11q23 rearrangement;  20q-; 13q- and 9.
Historical results from bone marrow samples cannot replace the mandatory bone marrow 
biopsy and aspirate samples obtained and analyzed at Screening.
 


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Bone marrow biopsies and aspirates performed as standard of care during study 
participation should also be captured on the eCRF.  An adequate bone marrow aspirate, if 
available, will be collected for predictive biomarker assessments.
After 96 weeks of treatment, bone marrow sampling is only necessary to be performed if 
disease progression is suspected, or at the discretion of the investigator.
For study visits with bone marrow sampling, chemistry and hematology labs should be 
performed on the same day the bone marrow sample is obtained.
Imaging for Spleen Volume Assessment
Assessment of spleen volume must be performed at Screening with an MRI or a CT scan 
and as outlined in Appendix C.  The scans will be transmitted to the central imaging 
vendor for an independent central review.
The imaging should be acquired as close as possible to the start of study treatment and 
must be during the Screening period.  Image receipt and verification should be received 
from the central imaging vendor before the subject can be treated.  In the event that the 
baseline image is determined by the independent reviewer to have been performed 
incorrectly, the baseline MRI/CT should be rescheduled for the earliest date possible prior 
to dosing.  If imaging is utilized to verify subject eligibility, the baseline spleen volume 
measurement must be requested and the MRI/CT transmitted at least 7 days prior to 
planned Day 1 dosing to allow adequate time for delivery of results from the central 
imaging vendor.
After Week 96, an MRI/CT needs to only be performed if disease progression is 
suspected.
A non-contrast MRI of the abdomen is the preferred imaging modality.  A non-contrast 
CT scan may be performed if MRI is medically contraindicated due to metallic implants 
(e.g., pacemaker, prosthetic valves).  Subjects should have the same imaging modality 
performed throughout the study for consistency and direct comparison unless a subject 
 


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develops a contraindication to MRI during the course of the study, then a change to CT is 
permitted.  All MRI/CT scans performed during the study must be sent to the central 
imaging vendor for an independent central review.
Physical Examination
Complete or symptom-directed physical examinations (PE) will be performed at the study 
visits outlined in Appendix C.
A complete physical examination should include the evaluation of the head, eyes, ears, 
nose, and throat (HEENT); and the following systems:  cardiovascular, respiratory, 
gastrointestinal, musculoskeletal, neurological and dermatological.
A symptom directed physical examination may be limited to those systems associated 
with symptoms.
All physical examinations should include skin examination, spleen and liver measurement 
by palpation.
Abnormalities that represent changes from Screening should be documented at each 
subsequent physical examination.  New or worsened abnormalities should be documented 
as Adverse Events (AEs) if appropriate.
Vital Signs
Body temperature (oral or tympanic), weight, blood pressure, and pulse will be measured 
at the study visits as outlined in Appendix C.
Blood pressure and pulse should be measured after the subject has been sitting for at least 
5 minutes.
Height will be measured only at Screening.  The subject should wear lightweight clothing 
and no shoes during weighing.
 


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ECOG Performance Status
ECOG performance status will be assessed at the study visits outlined in Appendix C as 
follows:
Grade
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light housework, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed 
or chair
Patient-Reported Outcome (PRO) Assessments
Patient-reported outcomes will be assessed using the MFSAF version 4.0, EORTC QLQ 
C30, Version 3, the Patient Global Impression of Change (PGIC) and the PROMIS 
Fatigue Short Form (SF) 7a questionnaires.
Due to the COVID-19 pandemic, subject visits may be conducted via phone or video 
conference.  EORTC QLQ-C30 Version 3, Patient Global Impression of Change, and 
PROMIS Fatigue Short Form (SF) 7a, PROs are eligible for completion by interview at 
the subject visit.  In this situation, sites will read the PRO questions and response options 
to the subject and record the subject's responses.  The subject's ability to view the PRO to 
understand the questions and response options should be preserved.  Sites may share the 
questionnaire by videoconference or send the questionnaires (email or hard copy) to the 
subjects to allow them to read/understand the questions and responses when the subject is 
providing responses over the phone.  The date and time of PRO data collection should be 
recorded along with who collected the information.
 


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MFSAF Version 4.0
MFSAF v4.0 is a symptom diary in which patients rate the following seven MF 
symptoms:  fatigue, night sweats, abdominal discomfort, pruritus, pain under the ribs on 
the left side, early satiety, and bone pain on a daily basis using a scale from 0 (absent) to 
10 (worst imaginable).  The TSS reflects the sum of the scores of these symptoms, for a 
maximum possible score of 70 (ie, most severe symptom experience).
Subjects will be provided with a handheld device at the Screening Visit and should 
complete the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 at home around 
the same time each day during the screening period.  All data entered on the device will 
be immediately stored to the device itself and transmitted to a central server.  The 
investigator and delegated staff will be able to access all uploaded subject entered data via 
a password protected website, up until the generation, receipt, and confirmation of the 
study archive.
For subjects enrolled in Cohorts 1b and 3, the investigator/designee should ensure that 
the subject has completed the MFSAF v4.0 questionnaire on at least 4 of the 7 days prior 
to the first dose of navitoclax (Day 1).  If the investigator believes that the MFSAF v4.0 
score on the day before the first dose of navitoclax (Day 1) is not an accurate reflection of 
the subject's mean symptom score, then the investigator can use the available data to 
calculate a mean weekly score to determine eligibility.  Subjects should then continue to 
complete the MFSAF daily on the handheld device from the Day 1 visit through the Week 
36 visit around the same time each day.
EORTC QLQ-C30 Version 3
Health-related quality of life (HRQoL) and symptoms will also be assessed with the 
EORTC QLQ-C30 version 3.  The EORTC QLQ-C30 is a 30-item subject self-report 
questionnaire composed of both multi-item and single domains/scales, including five 
functional scales (physical, role, emotional, social, and cognitive), three symptom scales 
(fatigue, nausea and vomiting, and pain), a global health status/quality of life scale, and 
 


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six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial 
difficulties).  Subjects will rate items on a four-point scale, with 1 as "not at all" and 4 as 
"very much."  The EORTC QLQ-C30 was developed and validated for use in a cancer 
patient population, and its reliability and validity is highly consistent across different 
language cultural groups.  A change of 5 to 10 points is considered a small change, and 
the lower bound (5) is being used to define the minimum important difference.  A change 
of ≥10 to < 20 points is considered a moderate change.
Patient Global Impression of Change
The Patient Global Impression of Change (PGIC) scale will be utilized to assess patients' 
perceptions of change in their myelofibrosis symptoms over time.  Patients during study 
visits will answer the following question:  "Since the start of the treatment received in this 
study, your myelofibrosis symptoms are (1) Very much improved, (2) Much improved, 
(3) Minimally improved, (4) No change, (5) Minimally worse, (6) Much worse, (7) Very 
much worse."
PROMIS Fatigue Short Form (SF) 7a
PROMIS® is a system of highly reliable, precise measures of patient-reported health 
status for physical, mental, and social well-being.  PROMIS instruments measure 
concepts such as pain, fatigue, physical function, depression, anxiety and social function.  
Fatigue will be assessed using the PROMIS Fatigue SF 7a that has been developed and 
validated for use in oncology populations.  The PROMIS Fatigue SF 7a is a seven item 
questionnaire that assesses the impact and experience of fatigue over the past 7 days.  The 
recommended minimum important difference range is 3 – 5 points; the lower bound (3) is 
being used as the minimum important difference in this study.  All questions employ the 
following five response options:  1 = Never, 2 = Rarely, 3 = Sometimes, 4 = Often, and 
5 = Always. The first six questions are framed in a way that a lower score is associated 
with a lower level of fatigue.  The last question, however, is reverse scored where a lower 
score means a worse outcome.
 


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These PRO assessments will be collected per Appendix C throughout the trial.  PRO 
assessments should be completed prior to any other clinical assessments and prior to 
dosing.
Table 1.
Patient-Reported Outcome Assessments
Administration Order
Test
Administration Time
1
EORTC QLQ-C30 version 3 (paper)
Approximately 12 minutes
2
PROMIS Fatigue SF 7a (paper)
Approximately 5 minutes
3
PGIC (paper)
Approximately 1 minute
4a
MFSAF version 4.0 (electronic)
Approximately 5 minutes
a.
This test is performed on a daily basis and may or may not be completed at the clinic.
Pregnancy Testing
●
Subjects with borderline pregnancy tests at Screening must have a serum 
pregnancy test ≥ 3 days later to document continued lack of a positive result.
●
Females of non-childbearing potential (as defined in Section 5.2.5) at 
Screening do not require pregnancy testing at any time.
●
Females of child bearing potential must have a negative serum pregnancy test 
result at Screening, and a negative urine or serum pregnancy test is required 
prior to dosing on Study Day 1.
●
A urine pregnancy test will also be performed every 4 weeks from Week 4 
through Week 24, and then at all visits (Q12W) through treatment completion.  
Where required by local regulatory authority, urine pregnancy tests will be 
performed every 4 weeks after Week 24 through treatment completion.
●
If the investigator suspects a woman to have become pregnant at any time 
during the study, additional pregnancy testing should be performed.
Clinical Laboratory Tests
All subjects will undergo laboratory assessments listed in Table 2 per the schedule in 
Appendix C.  Certified local laboratories will be utilized to process and provide results for 
all assessments listed in Table 2.  Local laboratory results should be entered into the eCRF 
 


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and these data will be used for all data analysis.  The appropriate certifications will be 
collected from the local laboratories.  Laboratory normal ranges will be provided to the 
AbbVie clinical team, as requested.
The principal investigator or designee should document review (i.e., with initials and date) 
of all laboratory results after receipt from the local laboratories.
Investigators are encouraged to obtain additional laboratory tests if they believe that an 
immediate medical intervention may be needed.
The investigator may consider additional hematology lab collection between 72 to 
96 hours post-dose for subjects with a lower baseline platelet count or for those that 
experience a 24-hour platelet count drop of > 40% from the pre-dose platelet count.
 


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Table 2.
Clinical Laboratory Testsa
Hematology
Clinical Chemistry
Coagulation
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
White Blood Cell (WBC) count
Neutrophils
Bands
Lymphocytes
Monocytes
Basophils
Eosinophils
Blasts (if detected)b
Platelet count (estimate not 
acceptable)
Platelet count by alternate 
methodc
Ferritind
Blood Urea Nitrogen (BUN) or 
Urea
Creatinine
Creatinine Clearancee
Total bilirubin
Conjugated (direct) bilirubinc
Albumin
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphate
Uric acid
Total protein
Glucose
Bicarbonate/CO2
Chloride
C-reactive proteinc
Erythrocyte Sedimentation 
Rate
Gamma-glutamyltransferasec
Lactate dehydrogenase (LDH)f
Prothrombin Time (PT)
Activated partial 
thromboplastin time 
(aPTT)
International Normalized Ratio 
(INR)
Lipid Parameters –
Fasting Stateg
Total Cholesterol
Low-density lipoprotein (LDL)
Triglycerides
Otherh
PPD skin test, or interferon-
gamma release assay or 
other locally approved test 
for Tuberculosis
a.
If travel restrictions or other changes in local regulations in light of the COVID-19 pandemic prevent the subject 
from having blood drawn for laboratory testing at the study site, if possible, arrange for subjects to have laboratory 
work done at a local lab, hospital, or other facility.  Local lab results should be obtained along with reference 
ranges and kept within the subjects' source documentation.  Local lab results should be reviewed by the 
investigator as soon as possible.
If laboratory samples cannot be obtained, study drug administration may be continued provided the investigator has 
reviewed prior laboratory results and confirms and discusses with the subject that there is no safety concern for the 
subject to continue use of the study drug in the absence of current labs.  The subject should be scheduled for 
laboratory draws as soon as feasible.
b.
WBC differential count and peripheral smear examination for blasts should be performed in the absence of Grade 4 
leukopenia.  Smear exam for blasts may not be required when unscheduled labs are performed for monitoring 
thrombocytopenia.
c.
Not required, perform as medically indicated.
d.
For subjects who received ≥ 4 units of PRBC prior to screening and for subjects who received ≥ 4 units during 
study treatment.
e
Required at Screening but can be performed at investigators discretion during the study.
f.
Required at Screening, Week 12, 24, 48, 72, and 96.  Optional at all other visits.
 


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Table 2.
Clinical Laboratory Testsa (Continued)
g.
Required for subjects enrolled in Cohorts 1a, 1b or 3 at Screening and Week 12.
h.
Prior to study enrollment for subjects to be enrolled in Cohorts 1b and 3.
For any laboratory test value outside the reference range that the investigator considers 
clinically significant:
●
The investigator may repeat the test to verify the out-of-range value.
●
The investigator will follow the out-of-range value to a satisfactory clinical 
resolution.
●
A laboratory test value that requires a subject to be discontinued from the 
study or requires a subject to receive treatment, meets protocol specific criteria 
(see Section 6.1.7 regarding toxicity management), and/or the investigator 
considers clinically significant will be recorded as an adverse event.
Chemistry and Hematology
Chemistry and hematology will be performed at the study visits outlined in Appendix C
and as needed throughout the study.  Additionally, hematology will be collected:
●
Predose and 4 hours after the first dose of navitoclax on Day 1 and at 24-hours 
post-first-dose on Day 2,  
●
Prior to navitoclax dose increases, navitoclax reductions (if during a clinic 
visit) or re-initiation of navitoclax after interruption.
●
Additional time points in Appendix C through the end of the study
Chemistry and hematology labs should always be performed on the same day a bone 
marrow sample is obtained.  
 


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Coagulation
Prothrombin time (PT) and activated partial thromboplastin time (aPTT) and International 
Normalized Ratio (INR) samples will be collected as outlined in Appendix C and as 
needed throughout the study.
Lipid Monitoring (Cohorts 1a, 1b or 3 only)
Treatment with ruxolitinib has been associated with increases in lipid parameters 
including total cholesterol, low-density lipoprotein (LDL), and triglycerides.  Any 
clinically significant changes in lipid parameters should be monitored and treated 
according to institutional guidelines for the management of hyperlipidemia.
12-Lead Electrocardiogram (ECG)
A single 12-lead resting ECG will be obtained at Screening, Week 4 (Day 29), Treatment 
Completion Visit, and as clinically needed.  In the event Week 4 or Treatment Completion 
visit ECG cannot be performed due to travel and other restrictions related to the 
COVID-19 pandemic, perform the 12-lead ECG at the next earliest feasible visit or 
arrange to have an alternative acceptable local facility perform the ECG for the subject.
Electrocardiograms will be recorded after the subject has been in the supine position for at 
least 5 minutes.  Subjects will be instructed to remain completely stationary (no talking, 
laughing, deep breathing, sleeping, or swallowing) for approximately 10 seconds during 
the ECG recording.  While ECGs are being acquired, subjects and staff are prohibited 
from having devices (e.g., cellular telephones, fans, heaters, etc.) that emit radiofrequency 
signals in the room.
Each ECG will be printed and evaluated by an appropriately qualified physician at the 
study site (the "local reader") who will determine if any findings outside normal 
physiological variation are clinically significant.  The local reading of the ECG will be 
used by the investigator for subject safety assessments, including adverse event 
 


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determination and management, and decision on whether a subject will be discontinued 
from the study.
The local reader will sign and date the safety ECG and provide a global interpretation 
using the following categories:
●
Normal ECG
●
Abnormal ECG – Not clinically significant (NCS)
●
Abnormal ECG – Clinically significant (CS)
●
Unable to evaluate
All local reader evaluations of ECGs will be entered into the electronic source documents; 
electronic case report forms (CRFs).  If the global interpretation is abnormal (NCS or CS), 
the local reader will provide further information (e.g., sinus bradycardia, arrhythmia).  
The QT interval corrected for heart rate using Fridericia's formula (QTcF) will be 
calculated for all ECGs and documented only if the QT interval is determined to be 
prolonged by the local reader.
All ECG source documentation will be retained at the study site.  The automatic 
cardiograph reading (i.e., cardiograph-generated measurements and interpretations) will 
not be collected for analysis.
Disease Response Assessment
Assessment of disease response will be evaluated based on the modified International 
Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and 
European LeukemiaNet (ELN) consensus report (Appendix E).27  Subject's response is 
based on the most recent physical examination including palpable measurement of spleen 
and liver, bone marrow results, questionnaires, imaging and recent hematology values.  
 


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For disease response assessments performed at Week 36 and 72, a repeat bone marrow 
biopsy is not required unless disease progression is suspected. The prior bone marrow 
assessment may be used for the purposes of assessing disease response.
Assessment of disease response is not required after Week 96 unless disease progression 
is suspected.
5.3.1.2
Meals and Dietary Requirements
The absorption of ruxolitinib is not affected by food and ruxolitinib may be taken with or 
without food.
Food increases the bioavailability of navitoclax independent of meal type (low-fat versus 
high-fat).  Therefore, navitoclax should be taken within 30 minutes of food intake.
Cohort 1b Drug-Drug Interaction (DDI) sub-study subjects only:  Subjects may not 
consume grapefruit or grapefruit products, Seville oranges (including marmalade 
containing Seville oranges) or Star fruit within the 3-day period prior to the first study 
drug administration and until the last day of treatment is completed due to possible 
CYP3A mediated metabolic interaction.
5.3.1.3
Collection and Handling of Biomarker and Exploratory 
Research Samples
Whole blood, plasma, bone marrow aspirate, and bone marrow core biopsy tissue will be 
collected per Appendix C.  Specimens collected for these purposes may be utilized to 
evaluate known and/or novel markers (nucleic acids, peptides/proteins and/or metabolites) 
of disease status, related conditions or to evaluate the association with pharmacokinetics, 
safety or efficacy.  All samples should be prepared, labeled, and shipped as outlined in the 
study-specific laboratory manual.  The biomarker rationale is discussed in the Biomarker 
Research Variables Section (Section 5.3.6).
AbbVie (or people or companies working with AbbVie) will store the biomarker and 
exploratory research samples in a secure storage space with adequate measures to protect 
 


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confidentiality.  The samples will be retained while research on navitoclax (or drugs of 
this class) or this disease and related conditions continues, but for no longer than 20 years 
after study completion.  The procedure for obtaining and documenting informed consent 
is discussed in Section 9.3.
Blood Collections:
Whole blood will be collected into appropriately labeled tubes and processed as outlined 
in the most current version of Study M16-109 Laboratory Manual.
●
Mandatory Blood Collections:
○
Blood for Plasma:  Approximately 4 mL of blood will be collected at the 
study visits as outlined in Appendix C.
○
Blood for Mutational Profiling:  Approximately 4 mL of blood will be 
collected at the study visits as outlined in Appendix C. 
○
Blood for Allelic Burden:  Approximately 4 mL of blood will be collected 
at the study visits as outlined in Appendix C. 
○
Blood for Translational Research-Heparin:  Approximately 6 mL of 
blood will be collected at the study visits as outlined in Appendix C. 
○
Blood for Translational Research-ACD (Females only enrolled at US 
sites):  Approximately 8.5 mL of blood will be collected at the study visits 
as outlined in Appendix C. 
○
Blood for Flow Cytometry:  Approximately 5 mL of blood will be 
collected at the study visits as outlined in Appendix C. 
○
Blood for Viable PBMC:  Approximately 10 mL of blood will be 
collected at the study visits as outlined in Appendix C.
●
Optional Exploratory Research Blood Collections:
○
Blood for Pharmacogenetic Analysis (optional test and requires 
informed consent):  Approximately 6.5 mL of blood will be collected for 
DNA and RNA isolation at the study visits as outlined in Appendix C.  
Sample collection should occur unless precluded by local regulations.
 


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Bone Marrow Aspirate and Biopsy Collections:
Screening and on-treatment bone marrow aspirate (BMA) and bone marrow biopsy should 
be collected into appropriately labeled containers in conjunction with the clinical 
assessments.  A portion of the aspirate must be processed according to the institutional 
standard procedures for clinical evaluation; however, approximately 4 mL of the bone 
marrow aspirate should be collected for biomarker assessments.  Additionally, a portion 
of the biopsy should be collected for biomarker assessments.  Detailed processing will be 
as outlined in the most current version of the Study M16-109 Laboratory Manual for the 
following:
●
BMA Mutational Profiling:  Approximately 1 mL of bone marrow aspirate 
will be collected at study visits as outlined in Appendix C. 
●
BMA Translational Research:  Approximately 3 mL of bone marrow 
aspirate will be collected at study visits as outlined in Appendix C.
●
Bone Marrow Biopsy IHC and Translational Research:  Either an FFPE 
block or 14 to 20 slides from the diagnostic/response assessment biopsy should 
be collected for analysis at study visits as outlined in Appendix C.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples for navitoclax (3 mL for each timepoint) and ruxolitinib, if applicable, 
(3 mL for each timepoint) assay will be collected by venipuncture into 3 mL evacuated 
potassium EDTA-containing collection tubes according to the schedule in Appendix C, 
Table 7.  Subjects in Cohort 1b who agree to participate in the collection of additional 
blood sampling to evaluate drug-drug interactions between ruxolitinib and navitoclax will 
have additional blood samples collected at the times as outlined in Appendix D.  The date 
and time of the PK sample collection and the date and time of the last two doses of 
navitoclax and/or ruxolitinib at each visit will be captured on the eCRF.
 


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5.3.2.2
Handling/Processing of Samples
Blood Samples for Navitoclax PK Assay (All Cohorts)
Detailed sample collection and processing instructions for the navitoclax PK will be 
provided in the current Study M16-109 laboratory manual.
Blood Samples for Ruxolitinib PK Assay (Cohorts 1a, 1b and 3)
Detailed sample collection and processing instructions for the ruxolitinib PK will be 
provided in the current Study M16-109 laboratory manual.
5.3.2.3
Disposition of Samples
The frozen plasma PK samples for navitoclax and possible metabolite(s) assay and frozen 
plasma samples for PK samples for ruxolitinib assay will be packed in dry ice sufficient to 
last during transport and shipped from the study site to a central lab designated by 
AbbVie.  An inventory of the samples included will accompany the package.  Please refer 
to current Study M16-109 laboratory manual for complete shipping instructions.
5.3.2.4
Measurement Methods
Plasma concentrations of navitoclax will be determined by the Bioanalysis Department at 
AbbVie using a validated method.  Plasma concentration of possible navitoclax 
metabolite(s) may be determined with validated or non-validated methods. 
Plasma concentration of ruxolitinib will be determined under the supervision of the 
Bioanalysis Department at AbbVie. 
5.3.3
Efficacy Endpoints
Primary Endpoints
The primary efficacy endpoint is at least 35% reduction from baseline in spleen volume at 
Week 24 (SVR35W24) as measured by MRI/CT.
 


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Secondary Endpoints
Secondary efficacy endpoints are as follows:
●
At least 50% reduction in TSS at Week 24 from baseline as measured by
MFSAF version 4.0
●
The anemia response
●
Change in grade of the bone marrow fibrosis according to the European 
consensus grading system36 (Appendix F)
Exploratory Endpoints
Exploratory efficacy endpoints may include, but are not limited to:
●
At least 35% reduction in spleen volume from baseline (SVR35) as measured 
by MRI or CT scan, per modified IWG criteria at any time point during study
●
Duration of SVR35
●
At least 50% reduction in palpable splenomegaly from baseline per modified
IWG criteria
●
At least 50% reduction in TSS at any time point from baseline as measured by 
MFSAF v4.0
●
Change from baseline in TSS
●
Red blood cell transfusion during study treatment
●
Duration of anemia response 
●
Exploratory analyses of the MFSAF v4.0, PROMIS Fatigue SF 7a, and 
EORTC QLQ-C30
●
Overall response per modified IWG criteria
●
PFS per modified IWG criteria
●
OS
 


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5.3.4
Safety Variables
AbbVie will assess adverse events, laboratory data, physical examinations, vital signs and 
ECGs throughout the study.  Adverse events intensity and laboratory evaluation changes 
will be assessed by utilizing NCI CTCAE Version 4.03.
5.3.5
Pharmacokinetic Variables
Values for the pharmacokinetic parameters of navitoclax, potential navitoclax 
metabolite(s), and ruxolitinib (if applicable), including the maximum observed plasma 
concentration (Cmax), the time to Cmax (peak time, Tmax), and the area under the plasma 
concentration-time curve (AUC) from time 0 to the time of the last measurable 
concentration (AUCt) will be determined using non-compartmental methods.  Other 
parameters such as the terminal phase elimination rate constant (β) and the area under the 
plasma concentration-time curve from time 0 to infinite time (AUC∞) will be determined 
if the data warrants.
5.3.6
Biomarker Variables
Biomarker Samples 
Biospecimens (whole blood, plasma, bone marrow core biopsy and bone marrow aspirate) 
will be collected to conduct exploratory biomarker research.  Types of biomarkers 
analyzed may include, but are not limited to, nucleic acids, proteins, lipids or metabolites.  
These assessments may include biomarkers related to the pathway targeted by the study 
drug or those believed to be related to the disease or to drug response.  The information 
learned from analyzing these samples may be used to investigate factors influencing 
response to treatment, scientific questions related to myelofibrosis, and/or in the 
development of new therapies and diagnostic tests.  The analyses are exploratory in 
nature, may be conducted in non-Good Laboratory Practice (GLP) laboratories, and the 
results may not be included with the clinical study report. 
Plasma may be analyzed for changes in inflammatory cytokines as well as other factors to 
identify predictive or prognostic biomarkers of efficacy.  Additionally, mutational 
 


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analysis can provide critical information on the genes involved in tumorgenesis that may 
be either prognostic or predictive of the response to therapy.  Given the targeted nature of 
navitoclax for a subset of anti-apoptotic proteins (Bcl-2, Bcl XL, and Bcl-w), the 
relationship between sensitivity of cell lines to navitoclax and the expression levels of the 
Bcl-2 family members have been examined in human tumor cell lines.  Bcl-2 expression 
levels (mRNA and protein) exhibited strong correlations with sensitivity, and the protein 
concentrations of Bcl-XL paralleled that of Bcl-2.  Conversely, higher expression levels 
(mRNA and protein) of Mcl-1 were associated with resistance.  Taken together, 
preclinical data suggests that tumor cells sensitive to navitoclax will exhibit high Bcl-2 
and Bcl-XL expression coupled to low Mcl-1 expression whereas the inverse could be 
reflective of navitoclax resistance.  Consequently, tumor specimens obtained from blood, 
and/or bone marrow aspirates/core biopsies prior to therapy and at relapse may be 
evaluated for relative expression of the Bcl-2 family members using 
immunohistochemistry (IHC) or sequencing techniques.  Additionally, reticulin and 
collagen staining of core biopsies may be performed to assess the effect of treatment 
within the bone marrow.
Pharmacogenetic Samples
Pharmacogenetic samples may be analyzed to understand the genetic factors contributing 
to the subject's myelofibrosis and response to treatment.  Genetic factors may include 
sequencing, gene expression and epigenetic analysis of genes associated with 
myelofibrosis, myeloproliferative diseases, drug metabolism, drug transport, the drug 
target pathway, or drug response.  Some genes currently insufficiently characterized or 
unknown may be understood to be important at the time of analysis.  The samples may be 
analyzed as part of a multi-study assessment of genetic factors involved in myelofibrosis, 
myeloproliferative diseases, response to navitoclax or drugs of this class.  The samples 
may also be used for the development of diagnostic tests related to myeloid dysplasia, 
myeloproliferative diseases, navitoclax or drugs of this class.  The results of 
pharmacogenetic analyses may not be reported with the study report.
 


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5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
Each subject has the right to withdraw from the study (study treatment and/or follow-up) 
at any time.  In addition, the Investigator may discontinue a subject from treatment at any 
time for any reason if the Investigator considers it necessary, including the occurrence of 
an adverse event or noncompliance with the protocol.  
During the COVID 19 pandemic, it has been necessary to employ mitigation strategies to 
enable the investigator to ensure subject safety and continuity of care.  Acceptable 
mitigation strategies are identified and included within this protocol.
Each subject will be withdrawn from study treatment (as applicable) if any of the 
following occur:
●
The subject has disease progression as defined in Appendix E, and the 
Investigator feels the subject is no longer benefiting from treatment.
●
The subject requires alternative therapy for treatment of MF.
●
The subject experiences treatment toxicity which, in the Investigator's opinion, 
prohibits further therapy or the Investigator believes it is otherwise in the best 
interest of the subject.
●
Significant subject noncompliance with study drug administration, study 
procedures or study requirements.
●
Subject becomes pregnant or begins breastfeeding.
●
The subject decides to withdraw consent of being treated by study treatment 
for any reason.
●
Any other medical reason that AbbVie or the study Investigator deems 
appropriate.
Discussion with the TA MD/SD is recommended before discontinuing a subject from the 
study for any reason other than described above to ensure all acceptable mitigation steps 
have been evaluated.
 


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In the event that a subject discontinues study treatment, the reason(s) for the 
discontinuation and the primary reason will be recorded and a TCV will be performed as 
soon as possible after discontinuation from study treatment.
If a subject is discontinued from study treatment or the study with an ongoing adverse 
event, the Investigator will attempt to provide follow-up until a satisfactory clinical 
resolution of the adverse event is achieved.
A Safety Follow-Up Visit should be performed for all subjects approximately 30 days 
following last dose of navitoclax.  If the TCV was conducted ≥ 30 days after last dose of 
navitoclax, the Safety Follow-Up visit does not need to be performed.  If the subject 
refuses or is unable to attend the Safety Follow-Up Visit, this should be noted in the 
subject's source documentation.
In the event that a positive result is obtained on a pregnancy test for a subject or a subject 
reports becoming pregnant during the study, the administration of the study drug must be 
discontinued immediately.  The Investigator must report a pregnancy within 1 working 
day of the site being aware to one of the AbbVie representatives listed in Section 6.1.5.
Subjects who permanently discontinue study treatment within the first 28 days on study 
may be replaced at the Sponsor's discretion.
5.4.2
Termination of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or a specific cohort of 
the study or at any study site, for reasonable cause provided that written notice is 
submitted in advance of the intended termination.  The investigator may also terminate the 
study at his/her site for reasonable cause, after providing written notice to AbbVie in 
advance of the intended termination.  Advance notice is not required by either party if the 
study is stopped due to safety concerns.  If AbbVie terminates the study for safety 
reasons, AbbVie will immediately notify the investigator by telephone and subsequently 
provide written instructions for study termination. 
 


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If, in the judgment of the investigator and AbbVie, the continued exposure to the study 
drug represents a significant risk to subjects, the study will be stopped.  The following 
procedures for termination will be followed:
●
If the Sponsor has decided to prematurely terminate the study or a specific 
cohort of the study, the Sponsor will promptly notify in writing each 
Investigator as well as regulatory authorities of the decision and give detailed 
reasons for the discontinuation. 
●
Each Investigator must promptly notify the IRB/IEC and give detailed reasons 
for the termination. 
●
Each Investigator must promptly notify the enrolled subjects of the premature 
termination and administer appropriate treatments such as replacement of 
protocol therapy, if applicable, by other appropriate regimens.
5.5
Treatments
5.5.1
Treatments Administered and Dosing
Navitoclax
Subjects will self-administer navitoclax orally in the morning.  Tablets must be swallowed 
whole and must not be broken, chewed, or crushed.  On days that pre-dose 
pharmacokinetic sampling is required, dosing will occur in the morning in the clinic and, 
if applicable, at the same time as ruxolitinib dosing (Cohorts 1a, 1b, and 3) to facilitate 
pharmacokinetic sampling.  
Subjects will receive the following: 
●
Cohort 1a: Navitoclax at starting dose of 50 mg once daily, then increased 
after approximately 7 days to 100 mg, 200 mg, and 300 mg once daily
depending on individual tolerability and platelet count. 
●
Cohorts 1b, 2 and 3:
○
Baseline Platelet Count > 150 × 109/L: 200 mg once daily navitoclax 
starting dose
 


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○
Baseline platelet count ≤ 150 × 109/L:  100 mg once daily navitoclax 
starting dose
●
The dose of navitoclax may be increased to 200 mg once daily after 
7 days provided the platelet count is ≥ 75 × 109/L
○
The dose of navitoclax should not exceed 200 mg once daily for the first 
24 weeks of treatment. After the Week 24 disease assessment, the dose of 
navitoclax may be increased to 300 mg once daily at the discretion of the 
Investigator for subjects with sub-optimal spleen response defined as 
failure to achieve spleen volume reduction of at least 10% as assessed by 
imaging.  
Dose modifications will be based on the toxicity management guidelines (Section 6.1.7).  
If vomiting occurs within 15 minutes of taking navitoclax and all expelled tablets are still 
intact, another dose may be taken, and this should be documented.  Otherwise, no 
replacement dose is to be taken.  
A missed dose of navitoclax should be taken with food and water within 8 hours of the 
missed dose.  After 8 hours, the missed dose should not be taken.  The next dose of 
navitoclax will be the regularly scheduled dose.
Ruxolitinib (Cohorts 1a, 1b, and 3)
Subjects enrolled in Cohorts 1a, 1b or 3 will self-administer ruxolitinib at prescribed dose.  
For subjects enrolled in Cohort 1a, the current stable dose of ruxolitinib ≥ 10 mg twice 
daily will be continued. 
For subjects enrolled in Cohort 1b, the dose of ruxolitinib will be administered at the 
current stable dose of ruxolitinib ≥ 10 mg twice daily for subjects receiving ruxolitinib at 
screening.  For subjects not taking ruxolitinib at the time of screening, ruxolitinib will be 
administered at a dose of 10 mg twice daily beginning on Day 1.
 


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For subjects enrolled in Cohort 3, ruxolitinib will be administered beginning on Day 1 at 
the individualized starting dose based on baseline platelet count as per local approved 
ruxolitinib label.  The starting dose may be adjusted at investigator discretion as medically 
appropriate in consultation with the TA MD/SD with subsequent increase in dose as 
described in Appendix I.
Dose reductions should be implemented per the approved ruxolitinib local label; refer to 
the management of toxicities (Section 6.1.7).
Decisions regarding continued dosing, including the navitoclax or ruxolitinib dose level to 
be administered and increasing the dose of ruxolitinib higher than the starting dose, for 
individual subjects will be medically managed by the investigator in consultation with the 
AbbVie TA MD/SD.
On days with pre-dose pharmacokinetic sampling required, dosing of navitoclax and 
ruxolitinib will occur in the morning in the clinic to facilitate pharmacokinetic sampling.
5.5.2
Identity of Investigational and Standard of Care Medicinal 
Products
5.5.2.1
Identity of Investigation Products
Information about the navitoclax formulation to be used in this study are presented in 
Table 3.
Table 3.
Identity of Investigational Products
Type of 
Product
Product 
Name
Dosage Form
Strength
Route of 
Administration
Manufacturer
Investigational 
Product
Navitoclax
Film-Coated 
Tablets
25 mg and 
100 mg
oral
AbbVie
AbbVie will provide the investigational product, navitoclax.
 


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5.5.2.2
Identity of Standard of Care Medicinal Products
Information about the ruxolitinib formulation to be used in this study is presented in 
Table 4.
Table 4.
Identity of Standard of Care Medicinal Products
Type of 
Product
Product 
Name
Dosage Form
Strength
Route of 
Administration
Manufacturer
Standard of 
Care 
Medicinal 
Product
Ruxolitinib
Tablets
5, 10, 15, 20, 
and 25 mg
oral
Incyte/Novartis
Ruxolitinib tablets will be sourced locally by sites (from a license pharmacy or 
wholesaler) or provided by AbbVie, depending on country/local regulations.  Each site 
will be responsible for maintaining records including product description, manufacturer, 
and/or lot numbers for all standard of care medicinal products dispensed by the site.
5.5.2.3
Packaging and Labeling
Navitoclax tablets will be packaged in HDPE (high density polyethylene) plastic bottles to 
accommodate the study design.
Study Drug provided by AbbVie will be labeled as required per country requirements.  
Labels must remain affixed to the bottle.  All blank spaces on the label will be completed 
by the site staff prior to dispensing to the subjects.
5.5.2.4
Storage and Disposition of Study Drug
The investigational products supplied in this study are for investigational use only, and are 
to be used only within the context of this study.  All clinical supplies must be maintained 
under adequate security until dispensed to subjects.  All clinical supplies must be stored 
per the conditions specified on the label.
 


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A storage temperature log is to be maintained to document proper storage conditions.  
Malfunctions or temperature excursion must be reported to the Sponsor immediately 
using the AbbVie Temperature Excursion Management System (ATEMS).  Study 
medication should be quarantined and not dispensed until AbbVie (ATEMS) deems the 
medication as acceptable.
Navitoclax 
Navitoclax study drug must be stored at 2° to 25°C (36° to 77°F).
Ruxolitinib
Ruxolitinib tablets must be stored under the conditions specified on the label per local 
requirements or Summary of Product Characteristics (SmPC).
5.5.3
Blinding
This is an open-label study.
5.5.4
Treatment Compliance
The investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol.  The study drug must not be used for reasons other than that described in the 
protocol. Sites may dispense additional study drug when subject is on site, to eliminate 
the need for a visit due to COVID-19.
If a subject is unable to come to the study site to pick up their study drug due to 
COVID-19, a direct-to-patient (DTP) study drug shipment can be made from the study 
site to the subject if allowed by local regulations.  AbbVie will submit any required 
notifications to the regulatory authority as applicable.
Study drug may be shipped from the study site directly to the study subject's home if all 
the following criteria are met:
 


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●
Direct-to-patient (DTP) shipment of study drug is allowed by local regulations 
and the relevant ethics committee
●
Study drug can be administered by the subject (or subject's caregiver) at home
●
Subject agrees to have the study drug shipped directly to their home
●
Shipments may also include other study supplies (e.g., drug dosing diaries, 
paper copies of PROs).  Instructions will be provided by AbbVie as to how a 
study site can initiate a DTP.  Shipments of study drugs from the study site to a 
subject's home will be appropriately temperature controlled (qualified shipper 
or temperature monitoring) within the labeled storage conditions.  Signature is 
required upon delivery; due to COVID-19 related social distancing, this may 
be provided by the courier after delivery.  Documentation of the shipment is to 
be retained by the clinical site.
●
AbbVie will not receive subject identifying information related to these 
shipments, as the site will work directly with the courier.
The study site is responsible for meeting IRB/IEC reporting requirements related to DTP 
shipments of study drug, and for obtaining consent to provide delivery information to the 
courier and documenting this consent in source documents.
An IRT system will assign the study drug provided by AbbVie to be dispensed to a 
subject during the study.  Prior to each scheduled visit, site personnel must contact IRT 
for the next study drug assignment.  AbbVie or its designee will provide specific 
instructions on the use of IRT.
To document compliance with the treatment regimen, subjects will be instructed to return 
all study drug bottles/blister packs (empty, partially filled or full), to the study site 
personnel prior to each visit and at the TCV.  The site staff will document the bottles 
returned and the number of tablets per bottle.  Compliance below 80% will require 
counseling of the subject by study site personnel.
 


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5.5.5
Drug Accountability
The Investigator or his/her designated representatives will administer study drug only to 
subjects enrolled in the study.  Documentation of the receipt of supplies will be supported 
by a signed and dated Proof of Receipt or similar document.  A current (running) and 
accurate inventory of study drug will be kept by the site and will include lot number, 
Proof of Receipt number(s), bottle numbers, and the date on which study drug is 
dispensed to the subject.  An overall accountability of study drug will be performed and 
verified by AbbVie or the designated monitor(s) throughout the study and at the study site 
Closeout Visit.  Upon completion or termination of the study, all original containers 
(containing partially used or unused study drug) will be returned to AbbVie according to 
instructions from AbbVie or the designated monitor(s).  If prearranged between AbbVie 
and the site, destruction of used and unused study drug bottles will be performed at the 
site.  Empty containers will be destroyed at the site.  Labels must remain attached to the 
containers.
The site will record the dose of Ruxolitinib prescribed to each subject in the source 
documents and on the eCRF.  When the Investigator obtains Ruxolitinib commercially, 
site inventory and accountability will not be performed, and drug accountability forms 
will not be provided by the sponsor.
5.6
Discussion and Justification of Study Design
Ruxolitinib has shown clinical benefit in improving splenomegaly and symptoms in 
subjects with intermediate or high-risk primary or secondary MF and is the current 
standard of care.  However, only approximately 40% of patients achieve a reduction in 
spleen volume by ≥ 35% and these improvements are typically observed within the 
first 12 to 24 weeks of administration if they are to occur.21  While ruxolitinib improves 
splenomegaly and disease-related symptoms, it does not impact the underlying fibrosis in 
the bone marrow.  New treatments are still needed with the potential to modify the course 
of the disease.  The combination of navitoclax and ruxolitinib in patients that have failed 
prior ruxolitinib therapy indicates the potential to induce a spleen response as well as 
 


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improve the fibrosis in the bone marrow.  Therefore, the evaluation of the combination in 
patients with MF that have not received prior treatment with a JAK-2 inhibitor represents 
a reasonable combination to be evaluated in Cohort 3.  
Additionally, of those that do derive clinical benefit from ruxolitinib treatment, 
splenomegaly and symptoms may return despite continued ruxolitinib treatment with 
approximately half of MF patients discontinuing ruxolitinib within 2 – 3 years.28,29  In 
order to address this unmet clinical need, the addition of navitoclax to ruxolitinib in 
patients with sub-optimal response to ruxolitinib represents a rational combination to be 
evaluated in Cohorts 1a and 1b.  By enrolling subjects who received at least 12 weeks of 
ruxolitinib or another JAK-2 inhibitor and have an inadequate response, it can be inferred 
that clinical benefits observed while receiving study treatments are likely due to the 
addition of navitoclax because continued improvements after 12 weeks of 
ruxolitinib/JAK-2 inhibitor treatment are unexpected.
The preliminary efficacy analysis of the combination of navitoclax and ruxolitinib in 
patients that have failed prior ruxolitinib therapy is favorable with a spleen response rate 
of 29% at Week 24.  Given this population has received prior ruxolitinib for at least 
12 weeks, no further benefit from ruxolitinib alone was expected.  Therefore, the 
evaluation of navitoclax as a single-agent in Cohort 2 is reasonable to further explore the 
mechanism of navitoclax response.   
5.6.1
Appropriateness of Measurements
Standard PK, statistical, clinical and laboratory procedures will be utilized in this study.  
The efficacy measurements in this study are standard and validated.
The PRO tools chosen for this study have been widely utilized in cancer research.  The 
MFSAF version 4.0 instrument specifically measures Myelofibrosis-specific symptoms 
and was developed on the basis of prior versions of Myelofibrosis symptom assessment 
forms.24,30  EORTC QLQ-C30 was developed and validated for use in a cancer patient 
population, and its reliability and validity is highly consistent across different language 
 


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cultural groups.31  Fatigue will be assessed using the PROMIS Fatigue SF 7a that has been 
developed and validated for use in oncology populations.32,33  The PROMIS Fatigue SF 7a 
is a 7-item questionnaire that assesses the impact and experience of fatigue over the past 
7 days.
5.6.2
Suitability of Subject Population
JAK-2 inhibition induces down-regulation of the anti-apoptotic protein MCL-1 suggesting 
a role for navitoclax, a BCL-XL inhibitor, in the treatment of MPNs including MF.18  
Therefore, subjects diagnosed with MF (PMF or SMF) represent the target population for 
this study.  
5.6.3
Selection of Doses in the Study
Thrombocytopenia observed during ruxolitinib treatment is generally reversible with dose 
reduction or dose interruption.  Subjects enrolled in Cohort 1a and for subjects in 
Cohort 1b receiving ruxolitinib at the time of screening, will continue the stable dose of 
ruxolitinib ≥ 10 mg twice daily.
Subjects enrolled in Cohort 1b that are not receiving ruxolitinib at the time of screening 
will initiate ruxolitinib starting on Day 1 at the dose of 10 mg twice daily.  The dose of 
10 mg twice daily was selected for this population not receiving ruxolitinib based on the 
preliminary analysis of the combination of navitoclax and ruxolitinib in Study M16-109 
(Cohort 1a).  Of the 34 patients enrolled, 25 (74%) patients began study on doses of 
ruxolitinib > 10 mg twice daily.  Of those 25 patients, 22 (88%) patients subsequently 
dose reduced ruxolitinib to ≤ 10 mg during study treatment.  The primary reasons for 
ruxolitinib dose reductions are thrombocytopenia (55.9%) and anemia (11.9%).  The 
preclinical data suggests that navitoclax may overcome JAK-2 resistance and therefore, 
re-sensitizing cells to JAK-2 inhibition from ruxolitinib.17 It is reported that a final 
titrated ruxolitinib dose of 10 mg twice daily induces spleen volume reductions and is 
associated with maximal symptom improvement.34  Therefore, a lower starting dose of 
ruxolitinib at 10 mg twice daily in patients not receiving ruxolitinib prior to entering the 
study, is rational when combining with navitoclax.
 


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Subjects in Cohort 3 will receive ruxolitinib at the individualized starting dose based on 
baseline platelet count as per the local approved ruxolitinib label.
As a BCL-XL inhibitor, navitoclax can also cause thrombocytopenia via intravascular 
apoptosis of platelets.  AbbVie internal data indicates that the effect of navitoclax on 
platelet reduction is exposure-related but may be diminished upon continued 
administration.  Accordingly, thrombocytopenia may occur with navitoclax upon 
exposure to sufficient navitoclax concentrations.  Additionally, thrombocytopenia and 
anemia are the primary reason for ruxolitinib dose reductions.34
Preliminary data from Study M16-109 Cohort 1a showed that weekly navitoclax dose 
escalation from 50 mg QD to 300 mg QD in combination with ruxolitinib at ≥ 10 mg, as 
was initially tested in Study M16-109, was generally safe without clinically relevant 
thrombocytopenia-related bleeding.  In Study M16-109 Cohort 1a, 83% of subjects 
experienced a dose reduction of navitoclax during study treatment with the primary reason 
being thrombocytopenia.  Of the subjects with navitoclax dose reductions for 
thrombocytopenia, 60% received 300 mg of navitoclax.  Therefore, doses of navitoclax 
< 300 mg QD seem to be better tolerated in patients with MF.  In addition, a mechanistic 
PK/PD model was used to evaluate the effect of navitoclax and ruxolitinib on platelet 
counts.  The model incorporated different mechanisms by which navitoclax and 
ruxolitinib cause thrombocytopenia (navitoclax by peripheral platelet apoptosis and 
ruxolitinib by slowing platelet production).  Simulations were conducted at: 
●
Different flat starting doses of navitoclax (100 to 300 mg QD) 
●
Starting at 100 mg QD with a weekly ramp-up to 200 mg QD
Simulations indicate that the maximum decreases in platelet count and incidences of 
Grade 3/4 thrombocytopenia for the weekly ramp-up from 100 to 200 mg QD were either 
similar to or slightly lower than those predicted at a flat starting dose of 200 mg (up to 5% 
difference).  The proposed starting dose of navitoclax in combination with ruxolitinib is 
200 mg QD or 100 mg QD based on baseline platelet counts.
 


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To minimize the risk of relevant thrombocytopenia, a lower starting dose of 100 mg QD 
for subjects with a baseline platelet count ≤ 150 × 109/L was proposed.  For subjects with 
a baseline platelet count of ≤ 150 × 109/L, the dose of navitoclax will be increased to 
200 mg QD after approximately 7 or more days, provided the platelet count remains 
≥75 × 109/L.
6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
The investigational product in this study is defined as navitoclax.  Complaints associated 
with this investigational product must be reported to the Sponsor (Section 6.2.2).  For 
adverse events, please refer to Sections 6.1.2 through 6.1.7.  For product complaints, 
please refer to Section 6.2.
6.1
Medical Complaints
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study drug, the 
investigator will provide another cause of the event.  For adverse events to be considered 
intermittent, the events must be of similar nature and severity.  Adverse events, whether in 
response to a query, observed by site personnel, or reported spontaneously by the subject 
will be recorded.
All adverse events will be followed to a satisfactory conclusion.
 


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6.1.1
Definitions
6.1.1.1
Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, meets protocol specific criteria (see Section 6.1.7 regarding toxicity 
management) and/or if the investigator considers them to be adverse events.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a preexisting condition and 
the surgery/procedure has been pre planned prior to study entry.  However, if the 
preexisting condition deteriorates unexpectedly during the study (e.g., surgery performed 
earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an adverse event.
A treatment-emergent adverse event is defined as any adverse event reported by a subject 
with onset or worsening from the time that the first dose of study drug is administered 
until 30 days have elapsed following discontinuation of study drug administration.
 


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6.1.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
serious adverse event (SAE) within 24 hours of the site being made aware of the serious
adverse event.
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken.  This does not include an event that would have 
been fatal if it had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay. This 
does not include an emergency room visit or admission to an 
outpatient facility, or a hospitalization for respite care.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes 
with the activities of daily living of a study subject.  Disability 
is not intended to include experiences of relatively minor 
medical significance such as headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g., sprained 
ankle).
Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the 
outcomes listed above (i.e., death of subject, life threatening, 
hospitalization, prolongation of hospitalization, congenital 
anomaly, or persistent or significant disability/incapacity).  
Additionally, any elective or spontaneous abortion or stillbirth 
is considered an important medical event.  Examples of such 
events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse.
 


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For serious adverse events with the outcome of death (including death related to disease 
progression), the date and cause of death will be recorded on the appropriate case report 
form.
6.1.1.3
Adverse Events Expected Due to Study Related Endpoints
6.1.1.3.1
Lack of Efficacy or Worsening of Disease
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease are also considered an expected outcome for this study and will not be 
reported as adverse events.
6.1.2
Adverse Event Severity
The investigator will rate the severity of each adverse event according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 
Version 4.03).35  For all reported serious adverse events that increase in severity, the 
supplemental eCRFs also need to be updated to reflect the change in severity.
For AEs not captured by the NCI CTCAE Version 4.03, the following should be used:
Grade 1
The adverse event is transient and easily tolerated by the subject (mild).
Grade 2
The adverse event causes the subject discomfort and interrupts the 
subject's usual activities (moderate).
Grade 3
The adverse event causes considerable interference with the subject's 
usual activities and may be incapacitating (moderate to severe). 
Grade 4
The adverse event is life threatening requiring urgent intervention 
(severe).
Grade 5
The adverse event resulted in death of the subject (severe).
6.1.3
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug:
 


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Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there 
is sufficient evidence (information) to suggest a causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there 
is insufficient evidence (information) to suggest a causal 
relationship
The investigator will assess the relationship of each adverse event to navitoclax and if 
applicable to ruxolitinib.  For causality assessments, events assessed as having a 
reasonable possibility of being related to the study drug will be considered "associated."  
Events assessed as having no reasonable possibility of being related to study drug will be 
considered "not associated."  In addition, when the investigator has not reported a 
causality or deemed it not assessable, AbbVie will consider the event associated to study 
drug.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, an 'other' cause of event must be provided by the investigator for the serious 
adverse event.
6.1.4
Adverse Event Collection Period
All adverse events reported from the time of study drug administration until 30 days, 
following discontinuation of navitoclax administration have elapsed will be collected, 
whether solicited or spontaneously reported by the subject.  In addition, protocol-related 
serious adverse events and protocol-related non-serious adverse events will be collected 
from the time the subject signed the study-specific informed consent.
Adverse event information will be collected as shown in Figure 2.
 


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Figure 2.
Adverse Event Collection
*
Only if considered by the Investigator to be causally related to study-required procedures.
6.1.5
Adverse Event Reporting
In the event of a serious adverse event, whether associated with study drug or not, the 
Investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made 
aware of the serious adverse event by entering the serious adverse event data into the 
electronic data capture (EDC) system.  Serious adverse events that occur prior to the site 
having access to the RAVE® system, or if RAVE is not operable, should be documented 
on the SAE Non-CRF forms and emailed (preferred route) or faxed to Clinical 
Pharmacovigilance within 24 hours of the site being made aware of the serious adverse 
event. 
Email:  PPDINDPharmacovigilance@abbvie.com
FAX to:  +1 (847) 938-0660
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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protocol and above.  The following COVID-19 related supplemental eCRFs should be 
completed (for both serious and non-serious events):
●
COVID-19 Supplemental Signs/Symptoms
●
COVID-19 Status Form
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
global and local guidelines, and Appendix A of the Investigator Brochure will serve as the 
Reference Safety Information (RSI).  The RSI in effect at the start of a DSUR reporting 
period serves as the RSI during the reporting period.  For follow-up reports, the RSI in 
place at the time of occurrence of the 'suspected' Serious Adverse Reaction will be used to 
assess expectedness.  For ruxolitinib, the reference document used for SUSAR reporting 
in the European Union countries will be the most current version of the Summary of 
Product Characteristics (SmPC).
6.1.6
Pregnancy
Pregnancy in a study subject must be reported to an AbbVie representative (Section 6.1.5) 
within 1 working day of the site becoming aware of the pregnancy.  Subjects who become 
pregnant during the study must be discontinued (Section 5.4.1).
All subjects (females and males) should be informed that contraceptive measures (refer to 
Inclusion Criteria for the details on contraception) should be taken throughout the study 
and for at least 30 days for females and 90 days for males after the last dose of navitoclax 
and/or ruxolitinib.  Male subjects should be informed that contraceptive measures should 
be taken by their female partner.  Information regarding a pregnancy occurrence in a study 
subject and the outcome of the pregnancy will be collected.  In the event of a pregnancy 
occurring in the partner of an enrolled subject, written informed consent for release of 
medical information from the partner must be obtained prior to the collection of any 
pregnancy-specific information, and the pregnancy will be followed to outcome.
 


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Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected.
Pregnancy in a study subject is not considered an adverse event.  The medical outcome for 
either mother or infant, meeting any serious criteria including an elective or spontaneous 
abortion, is considered a serious adverse event and must be reported to AbbVie within 
24 hours of the site becoming aware of the event.
6.1.7
Toxicity Management Guidelines
Navitoclax may be associated with cytopenias, notably thrombocytopenia, in patients 
based on observations made during previous clinical trials in other indications and 
preliminary safety data from Cohort 1a of this study.  
The guidelines noted below should be implemented for all subjects unless previously 
discussed and approved with the AbbVie TA MD/SD (Section 6.1.5).
If a navitoclax interruption is necessary, navitoclax may be reintroduced at the same or 
lower dose based on the guidance below.  If a dose reduction below 50 mg once daily is 
required, the dose of navitoclax may be reduced to 25 mg once daily following 
consultation with the AbbVie TA MD/SD.
The same navitoclax dose level shall not be attempted more than twice consecutively 
without prior approval from the AbbVie TA MD/SD.
The local approved ruxolitinib label should be referenced for guidance on ruxolitinib dose 
modifications for subjects with hepatic or renal impairment, drug-drug interactions, 
precautions, monitoring and management of hematologic and non-hematologic toxicities.
For subjects who require interruption of ruxolitinib per the label but are considered to be 
at increased risk for exacerbation of splenomegaly and clinically significant symptoms, 
ruxolitinib dose can be tapered by the Investigator in consultation with the AbbVie TA 
MD/SD followed by interruption. 
 


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Decisions regarding continued dosing, including the navitoclax or ruxolitinib (if 
applicable) dose level to be administered, for individual subjects will be medically 
managed by the Investigator in consultation with the AbbVie TA MD/SD (Section 6.1.5).
Intermediate dose levels (e.g., 150 mg once daily) may be administered at the discretion 
of the investigator.  If intermediate dose levels are utilized prior to Week 24, consultation 
with the AbbVie TA MD/SD is required prior to implementation.  
Decisions to delay or interrupt the study treatment for active COVID-19 infection should 
be made by the treating investigator after considering the subject's clinical assessment of 
the severity of infection, current status of MF and treatment tolerance, as well as the
general medical condition. Treatment interruption longer than 28 days must be discussed 
with the TA MD/SD.
6.1.7.1
Management of Thrombocytopenia and Bleeding Events
Navitoclax accelerates apoptosis of circulating mature platelets whether endogenous or 
transfused.  This mechanism of toxicity differs from the thrombocytopenia caused by 
ruxolitinib and other conventional chemotherapy (i.e., toxicity to platelet progenitors in 
the bone marrow) and should, therefore, be managed according to the guidelines provided 
in Appendix I, for appropriate dosing and management of all subjects for safety.  
Any Grade ≥ 2 bleeding event (without regard to platelet count) will require interruption 
and possible discontinuation of dosing.  Upon resolution of a Grade ≥ 2 bleeding event, 
study treatment may be reintroduced at the same or lower dose level, provided the patient 
is asymptomatic with no evidence of an active bleed.
The investigator should perform additional hematology labs on Day 3 and/or Day 4 for 
subjects with a lower baseline platelet count or for those that experience a 24-hour platelet 
count drop of > 40% from the pre-dose platelet count.  Additional hematology labs should 
be performed based on the platelet counts as medically indicated at the discretion of the 
investigator.
 


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If platelet transfusions are required in response to active bleeding, dosing of navitoclax 
should be interrupted.  It should be noted that platelet response with transfusions may not 
follow typical platelet kinetics of thrombocytopenia as with typical chemotherapy induced 
myelosuppression.  Procedures consistent with local institutional blood banking 
guidelines regarding platelet transfusions should be followed. 
Platelet Transfusion Recommendations:
If platelet transfusion is deemed necessary, the treating physician should be aware that 
due to the rapid apoptotic effect of navitoclax on mature platelets, the initial increase in 
platelet counts post-transfusion may be smaller and the duration of response may be 
shorter.  For this reason, donor platelets collected as recently as possible prior to 
transfusion should be used.  Additional transfusions may be necessary to achieve the 
desired platelet count.  Post transfusion monitoring of platelets should include:
●
A platelet count obtained 10 – 60 minutes post-transfusion
●
A platelet count obtained approximately 24 hours post-transfusion
6.1.7.2
Management of Neutropenia
There is a potential for clinically significant neutropenia given the toxicity profiles of both 
ruxolitinib and navitoclax.  The management of neutropenia guidelines found in 
Appendix I should be implemented for all subjects unless previously discussed and 
approved with the AbbVie TA MD/SD.
For Grade 3 neutropenia, in addition to interruption as listed in Appendix I, support with 
G-CSF and/or prophylaxis with antibiotics may be considered at the discretion of the 
investigator.  For Grade 4 neutropenia, in addition to interruption as listed in Appendix I, 
support with G-CSF and/or prophylaxis with antibiotics may be considered at the 
discretion of the investigator.  If clinically necessary in the opinion of the investigator, 
ruxolitinib dosing, if applicable, may be considered for resumption prior to recovery of 
ANC >1.0 x 109/L.
 


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At any time during the study, if the subject presents with febrile neutropenia, navitoclax 
and ruxolitinib, if applicable, should be interrupted until resolution of the fever or 
infection.  
6.1.7.3
Management of Infections
Subjects who develop clinically significant infections, including COVID-19, should have 
navitoclax held until infection resolves or is controlled.  Subjects may restart navitoclax 
when signs or symptoms of infection have resolved.
If clinically indicated, anti-infective prophylaxis should be implemented at the 
investigator's discretion, including appropriate prophylaxis for viral, fungal, bacterial, or 
Pneumocystis carinii/jiroveci pneumonia infections.  Additionally, the potential for drug-
drug interactions should be considered.  In particular, there is a potential for significant 
drug-drug interactions when administering azole antifungal agents and caution should be 
taken when co-administered with navitoclax.
If study treatment is held in response to a confirmed (viral test positive) or suspected 
COVID-19 infection, study treatment may resume once the following COVID-19 viral 
clearance criteria are met:
●
Symptomatic subjects: 
○
At least 2 negative viral tests in a row, ≥ 24 hours apart after at least 
10 days have passed since recovery, defined as resolution of fever without 
use of antipyretics and improvement in respiratory symptoms (e.g., cough, 
shortness of breath)
●
Asymptomatic subjects: 
○
At least 2 negative viral tests in a row, ≥ 24 hours apart after at least 
10 days have passed since prior positive result (note:  subjects who develop 
symptoms will follow guidance above for symptomatic subjects)
 


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Frequency or timing of COVID-19 testing and intervals between testing for the above 
viral clearance criteria may be adjusted to account for epidemiologic trends, updated 
information regarding infectivity, and local/institutional guidelines.
6.1.7.4
Management of Other Toxicities
If other events occur that are related to navitoclax or ruxolitinib (if applicable), the 
investigator may delay and/or modify dosing of navitoclax and/or ruxolitinib as 
appropriate and clinically indicated.
Grade ≥ 3 non-hematologic toxicity (e.g., nausea, vomiting, and diarrhea when additional 
supportive care fails, neurotoxicity; increase in AST, ALT, bilirubin) that is related to 
navitoclax or ruxolitinib (if applicable) will require interruption and possible 
discontinuation of dosing if toxicity is not resolved.  Study treatment may be reintroduced 
at the same or lower dose level if the toxicity returns to Grade ≤ 1 or to baseline if 
Grade 2 at study entry.
Similarly, during the navitoclax escalation period for Cohort 1a, navitoclax should be 
delayed for the occurrence of any Grade ≥ 3 non-hematologic toxicity related to 
navitoclax.  Navitoclax may be reintroduced at the same or lower dose (in consultation 
with the AbbVie TA MD/SD) if the toxicity returns to Grade ≤ 1 or to baseline if Grade 2 
at study entry.
All subjects should be monitored according to the schedule of assessments (Appendix C) 
for new-onset non-hematologic toxicity and renal toxicities, with dose delay or reduction 
as appropriate.  For ruxolitinib, local, approved product label should be referenced for 
monitoring guidelines.
6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product.
 


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For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, or packaging issues.
Any information available to help in the determination of causality to the events outlined 
directly above should be captured.
6.2.2
Reporting
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 24 hours of the study site's knowledge of the event via the Product 
Complaint form in EDC on the appropriate eCRF.  Product Complaints occurring during 
the study will be followed-up to a satisfactory conclusion.  All follow-up information is to 
be reported to the Sponsor (or an authorized representative) and documented in source as 
required by the Sponsor.  Product Complaints associated with adverse events will be 
reported in the study summary.  All other complaints will be monitored on an ongoing 
basis.
Product Complaints may require return of the product with the alleged complaint 
condition.  In instances where a return is requested, every effort should be made by the 
investigator to return the product within 30 days.  If returns cannot be accommodated 
within 30 days, the site will need to provide justification and an estimated date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol unless when 
necessary to eliminate an immediate hazard to study subjects.  The principal investigator 
is responsible for complying with all protocol requirements, and applicable global and 
local laws regarding protocol deviations.  If a protocol deviation occurs (or is identified, 
 




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●
Set 2:  This set consists all subjects from Cohort 2.
●
Set 3:  This set consists all subjects from Cohort 3. 
8.1.1
Baseline Characteristics
Unless otherwise stated, baseline for a given variable will be defined as the last non-
missing value for that variable obtained prior to the first dose of any component of study 
drug.
Continuous demographic data (e.g., age, height, and weight) will be summarized with 
means, standard deviation, minimum, maximum, and range.  Categorical data (e.g., sex, 
race, etc.) will be summarized with frequencies and percentages.
Frequencies and percentages will be computed for medical history parameters.
8.1.2
Pharmacokinetics
Plasma concentrations of navitoclax, potential navitoclax metabolite(s), and ruxolitinib 
and their available pharmacokinetic parameter values will be tabulated for each subject 
and by visit.  Summary statistics will be computed for each sampling time and each 
parameter.
8.2
Efficacy Endpoints
8.2.1
Primary Efficacy Endpoint
The primary endpoint is at least 35% reduction from baseline in spleen volume at 
Week 24 (SVR35W24) as measured by MRI/CT.
8.2.2
Secondary Efficacy Endpoints
The secondary endpoints are:
●
At least 50% reduction in TSS at Week 24 from baseline as measured by 
MFSAF version 4.0
 


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●
The anemia response rate 
●
Change in the bone marrow fibrosis grade according to the European 
consensus grading system35 (Appendix F)
8.2.3
Exploratory Efficacy Endpoints
Exploratory efficacy endpoints may include, but are not limited to:
●
At least 35% reduction in SVR35 from baseline as measured by MRI or CT 
scan, at any time point during study
●
Duration of SVR35
●
At least 50% reduction in palpable splenomegaly from baseline per modified 
IWG criteria
●
At least 50% reduction in TSS at any time point from baseline as measured by 
MFSAF v4.0
●
Change from baseline in TSS
●
Red blood cell transfusion during study treatment
●
Duration of anemia response 
●
Exploratory analyses of the MFSAF v4.0, PROMIS Fatigue SF 7a, and 
EORTC QLQ-C30 Overall response 
●
PFS per modified IWG criteria
●
OS
8.3
Statistical Analysis 
Unless otherwise noted, all analyses are performed by study treatment for each cohort, no 
formal statistical test will be performed.  Estimation approach will be used.  Details on the 
analysis will be provided in the Statistical Analysis Plan (SAP).
8.3.1
Efficacy
SVR35w24 will be calculated as the proportion of subjects who achieve ≥ 35% reduction 
from baseline in spleen volume at Week 24 (SVR35w24).  The point estimates of SVR35w24
 


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will be provided.  The exact 95% confidence intervals as derived by the Clopper-Pearson 
method will also be presented.  In addition, absolute and percent change from baseline of 
spleen volume will be summarized with mean, standard deviation, median, minimum and 
maximum reported.  TSS response (at least 50% reduction) rate will be calculated as the 
proportion of subjects who achieve at least 50% reduction in TSS at Week 24 from 
baseline.  The point estimates of TSS response rate at Week 24 will be provided and 
corresponding exact 95% confidence intervals as derived by the Clopper-Pearson method 
will be presented.
Anemia response rate and corresponding exact 95% confidence intervals as derived by the 
Clopper-Pearson method will be presented. 
Descriptive statistics for change in grades of bone marrow fibrosis will be reported.
8.3.2
Safety 
The safety of navitoclax alone or in combination with navitoclax and ruxolitinib will be 
assessed by evaluating duration of exposure, adverse events, serious adverse events, 
deaths, and changes in laboratory determinations and vital sign parameters.
8.3.2.1
Duration of Exposure of Study Treatment
Duration of exposure of study treatment will be summarized for both navitoclax and 
ruxolitinib (when applicable), respectively, by the mean, standard deviation, median, min 
and max.
8.3.2.2
Adverse Events
Analyses of adverse events will include only "treatment-emergent" events, i.e., those that 
have an onset on or after the first dose of day of the study drug.  Analyses will not include 
those that have an onset greater than 30 days after the last dose of the study drug.
Treatment-emergent adverse events will be coded and summarized by system organ class 
and preferred term according to the Medical Dictionary for Regulatory Activities 
 


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(MedDRA) adverse event coding dictionary.  The percentage of subjects experiencing an 
adverse event at a given severity, NCI CTCAE version 4.03 toxicity grade and 
relationship to study drug will be provided.
8.3.2.3
Serious Adverse Events
Serious adverse events will be summarized using the same methods as adverse events 
described in the previous section.
8.3.2.4
Deaths
The number of subject deaths will be summarized 1) for deaths occurring while the 
subject was still receiving study drug in this study, 2) for deaths occurring off treatment 
within 30 days after the last dose of study drug, and 3) for all deaths in this study 
regardless of the number of days after the last dose of study drug.
8.3.2.5
Laboratory Data 
Where applicable, laboratory values will be categorized according to the NCI CTCAE 
version 4.03 grades, and shifts from baseline grade to post-baseline maximum grades will 
be assessed.  
Detailed listings of data for subjects experiencing NCI CTCAE Grade 3 to 4, blood 
chemistry and hematology values will be provided.  All measurements collected, 
regardless of the number of days after the last dose of study drug, will be included in these 
listings.
8.3.2.6
Vital Signs 
Detailed listings of data for subjects experiencing potentially clinically significant vital 
sign values according to the AbbVie-defined criteria for vital sign values will be provided.  
All measurements collected, regardless of the number of days after the last dose of study 
drug, will be included in these listings.
 


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8.4
Determination of Sample Size
Approximately 174 subjects in total will be enrolled in this study.  Point estimate and 
exact 95% confidence interval of SVR35w24 rate corresponding to expected observed 
number of subjects with SVR35w24 are presented in Table 5.
Table 5.
Point Estimates and 95% CI of Rate of SVR35w24 Corresponding to 
Observed Number of Subjects with SVR35w24
Cohort
Sample 
size
Number of Subjects 
with SVR35w24
Point Estimate 
(SVR35w24 Rate) 
(%)
Exact 95% CI
Half 
Width 
of CI
Lower 
Limit (%)
Upper 
Limit (%)
1a
34
16
47.06
29.78
64.87
17.55
1a
34
18
52.94
35.13
70.22
17.55
1a
34
20
58.82
40.70
75.35
17.33
1a
34
22
64.71
46.49
80.25
16.88
1b
70
32
45.71
33.74
58.06
12.16
1b
70
34
48.57
36.44
60.83
12.19
1b
70
36
51.43
39.17
63.56
12.19
1b
70
38
54.29
41.94
66.26
12.16
2 or 3
30
12
40.00
22.66
59.40
18.37
2 or 3
30
14
46.67
28.34
65.67
18.67
2 or 3
30
16
53.33
34.33
71.66
18.67
2 or 3
30
18
60.00
40.60
77.34
18.37
Based on the table above, this study with proposed sample sizes will provide a reasonable 
precise estimate of the proportion of subjects with SVR35w24 for each cohort.  According 
to Section 8.1, Set 1 is expected to consist of subjects from Cohorts 1a and 1b.  Also, if 
true probability of experiencing a serious adverse event (SAE) due to the study treatment 
is 10%, then the probability of observing at least one SAE in 34 subjects is more than 
97% in Cohort 1a; the probability of observing at least one SAE in 80 subjects is more 
than 99% in Cohort 1b; the probability of observing at least one SAE in 30 subjects is 
more than 95% in Cohort 2 or 3, respectively.  Therefore, from safety assessment 
prospective the proposed sample size is adequate.
 


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9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent and all other forms of 
subject information related to the study (e.g., advertisements used to recruit subjects) and 
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 
ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain and archive study essential documents according to ICH GCP and all other 
applicable regulatory requirements.
Any serious adverse events that meet the reporting criteria, as dictated by local 
regulations, will be reported to both responsible Ethics Committees and Regulatory 
Agencies, as required by local regulations.  During the conduct of the study, the 
investigator should promptly provide written reports (e.g., ICH Expedited Reports, and 
any additional reports required by local regulations) to the IEC/IRB of any changes that 
affect the conduct of the study and/or increase the risk to subjects. Written documentation 
of the submission to the IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix A.
 


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In the event a significant disaster/crisis (e.g., epidemic/pandemic, natural disaster, 
conflict/combat) occurs leading to difficulties in performing protocol-specified 
procedures, AbbVie may engage with study site personnel in efforts to ensure the safety 
of subjects, maintain protocol compliance, and minimize risks to the integrity of the study 
while trying to best manage subject continuity of care.  This may include alternative 
methods for assessments (e.g., phone contacts or virtual site visits), alternative locations 
for data collection (e.g., use of a local lab instead of a central lab), and shipping 
investigational product and/or supplies direct to subjects to ensure continuity of treatment 
where allowed.  In all cases, these alternative measures must be allowed by local 
regulations and permitted by IRB/IEC.  Investigators should notify AbbVie TA MD/SD if 
any urgent safety measures are taken to protect the subjects against any immediate hazard.
9.3
Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
Screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject, the person who administered the 
informed consent, and any other signatories according to local requirements.  A copy of 
the informed consent form will be given to the subject and the original will be placed in 
the subject's medical record.  An entry must also be made in the subject's dated source 
documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy.
Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the informed consent form.
Optional collection of blood samples to evaluate the potential drug-drug interactions 
between navitoclax and ruxolitinib for subjects in Cohort 1b (Appendix D) will only be 
collected if the subject has voluntarily signed and dated informed consent, approved by 
the IRB/IEC, after the nature of the testing has been explained and the subject has had an 
 


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opportunity to ask questions.  The separate informed consent must be signed before the 
optional blood samples are collected.  If the subject does not consent to the optional blood 
sample collection, it will not impact the subject's participation in the study.
Optional exploratory research sample collection and analysis will only be performed if the 
subject has voluntarily signed and dated informed consent, approved by an IRB/IEC, after 
the nature of the testing has been explained and the subject has had an opportunity to ask 
questions.  The separate informed consent must be signed before the optional exploratory 
research samples are collected.  If the subject does not consent to the optional exploratory 
research testing, it will not impact the subject's participation in the study.
In the event a subject withdraws consent, stored biomarker and exploratory research 
samples will continue to be used for research and analysis.  In the event that a subject 
would like to withdraw consent for future research using these samples, the subject may 
request that their samples be withdrawn.  Once AbbVie receives the request, remaining 
samples will be destroyed.  If the subject changes his/her consent, and the samples have 
already been tested, those results will still remain as part of the overall research data.
Due to the COVID-19 pandemic, it is possible that additional protocol modifications not 
outlined in this protocol may become necessary.  If this situation arises, in addition to the 
study informed consent, additional temporary verbal consent may be obtained prior to 
these adaptations or substantial changes in study conduct in accordance with local 
regulations.  An appropriately signed and dated informed consent form should be obtained 
from the subject afterwards, as soon as possible.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from 
 


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automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded to the appropriate 
source document.  The Investigator Awareness Date (SAE CRF) may serve as the source 
for this data point.  This adverse event data point required for eCRF completion can be 
entered directly in the eCRF.
The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.
During the COVID-19 pandemic, remote monitoring of data may be employed if allowed 
by the local regulatory authority, IRB/IEC, and the study site.
10.2
Case Report Forms
Case report forms (CRF) must be completed for each subject screened/enrolled in this 
study.  These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable.  The CRF data for this study are being 
collected with an electronic data capture (EDC) system called Rave® provided by the 
technology vendor Medidata Solutions Incorporated, NY, USA.  The EDC system and the 
study-specific electronic case report forms (eCRFs) will comply with Title 21 CFR 
Part 11.  The documentation related to the validation of the EDC system is available 
through the vendor, Medidata, while the validation of the study-specific eCRFs will be 
conducted by AbbVie and will be maintained in the Trial Master File at AbbVie.
The investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
The investigator or an authorized member of the investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
 


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be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
principal investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the investigator to make paper printouts from that media.
Patient reported data must be completed for each subject screened/enrolled in this study.  
Some of these data are being collected with an Electronic Patient Reported Outcome 
(ePRO) system called Trialmax, provided by the technology vendor Signant Health of 
Plymouth Meeting, PA, USA.  The ePRO system is in compliance with Title 21 CFR 
Part 11.  The documentation related to the system validation of the ePRO system is 
available through the vendor, Signant Health, while the user acceptance testing of the 
study specific PRO design will be conducted and maintained at AbbVie.
The subject will be entering the data on an electronic device; these data will be uploaded 
to a server.  The data on the server will be considered source, and maintained and 
managed by Signant Health.
Internet access to the ePRO data will be provided by Signant Health for the duration of 
the study.  This access will be available for the duration of the study to the site 
investigator, as well as delegated personnel.  Such access will be removed from 
investigator sites following the receipt of the study archive.  Data from the ePRO system 
will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
investigator at that time as a durable record of the site's ePRO data.  It will be possible for 
the investigator to make paper print-outs from that media.
 


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The ePRO data will be collected by the following methods:
Diary Based
●
MFSAF Version 4.0 will be collected electronically via a handheld device into 
which the patient will record the required pieces of information on a daily 
basis.  The electronic device will be programmed to allow data entry for each 
day. All data entered on the device will be immediately stored to the device 
itself and manually/automatically uploaded to a central server administrated by 
Signant Health.  The Investigator and delegated staff will be able to access all 
uploaded patient entered data via a password protected website, up until the 
generation, receipt and confirmation of the study archive.
11.0
Data Quality Assurance
Prior to enrolling any subject in the study, a Site Training Visit will be held with AbbVie 
personnel, the Investigator(s), and the study coordinators/project manager(s).  This 
meeting will include a detailed discussion and review of the protocol and essential
documents, performance of study procedures, case report form completion and specimen 
collection methods.
The AbbVie monitor will monitor the study site throughout the study.  Source document 
review will be made against entries on the electronic case report forms and a quality 
assurance check will be performed to ensure that the Investigator is complying with the 
protocol and regulations.  In addition, after the case report forms are retrieved, a review of 
the data will be conducted by a physician or representative at AbbVie.
All data hand-entered in the database will be verified at AbbVie.  Any discrepancies will 
be reviewed against the hard-copy case report form and corrected on-line.  After 
completion of the entry process, computer logic and manual checks will be created to 
identify such items as inconsistent study dates.  Any necessary corrections will be made to 
the database via the appropriate change form/electronic CRF.
 


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Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF.
Routine hematology, serum chemistry and serology tests will be conducted using a 
certified clinical laboratory.  Laboratory reference ranges will be obtained prior to the 
initiation of the study and updated as necessary throughout the course of the study.  A 
review of all laboratory results will be conducted by the AbbVie monitor, the Investigator 
and other appropriate personnel from AbbVie.
12.0
Use of Information
All information concerning navitoclax processes, basic scientific data, or formulation 
information, supplied by AbbVie and not previously published is considered confidential 
information.
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by AbbVie in connection with the development of 
navitoclax.  This information may be disclosed as deemed necessary by AbbVie to other 
clinical Investigators, other pharmaceutical companies, and to governmental agencies.  To 
allow for the use of the information derived from this clinical study and to ensure 
complete and thorough analysis, the Investigator is obligated to provide AbbVie with 
complete test results and all data developed in this study and to provide direct access to 
source data/documents for study-related monitoring, audits, IEC/IRB review, and 
regulatory inspection.
This confidential information shall remain the sole property of AbbVie, shall not be 
disclosed to others without the written consent of AbbVie, and shall not be used except in 
the performance of this study.
The Investigator will maintain a confidential subject identification code list of all subjects 
enrolled in the study, including each subject's name, subject number, address, phone 
number and emergency contact information.  This list will be maintained at the study site 
 


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with other study records under adequate security and restricted access, and will not be 
retrieved by AbbVie.
Any research that may be done using biomarker research and/or optional exploratory 
research samples from this study will be experimental in nature and the results will not be 
suitable for clinical decision making or patient management.  Hence, the subject will not 
be informed of individual results, should analyses be performed, nor will anyone not 
directly involved in this research.  Correspondingly, researchers will have no access to 
subject identifiers.  Individual results will not be reported to anyone not directly involved 
in this research other than for regulatory purposes.  Aggregate data from research samples 
may be provided to investigators and used in scientific publications or presented at 
medical conventions.  Research information will be published or presented only in a way 
that does not identify any individual subject.
13.0
Completion of the Study
The investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the investigator and AbbVie.  The investigator will provide a final report to the 
IEC/IRB following conclusion of the study, and will forward a copy of this report to 
AbbVie or their representative.
The investigator must submit, maintain, and archive any records related to the study 
according to ICH GCP and all other applicable regulatory requirements.  If the 
investigator is not able to retain the records, he/she must notify AbbVie to arrange 
alternative archiving options.
AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory investigator for the study will review and sign the final study report in 
 


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accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit or date of last follow-
up contact, whichever is later.
 


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for navitoclax and I am 
familiar with the product labeling for ruxolitinib.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title: 
A Phase 2 Open-Label Study Evaluating Tolerability and Efficacy 
of Navitoclax Alone or in Combination with Ruxolitinib in 
Subjects with Myelofibrosis (REFINE)
Protocol Date:
04 October 2021
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
 


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15.0
Reference List
1.
Beauverd Y, Alimam S, McLornan DP, et al.  Disease characteristics and outcomes 
in younger adults with primary and secondary myelofibrosis.  Br J Haematol.  
2016;175(1):37-42.
2.
Mughal TI, Vaddi K, Sarlis NJ, et al.  Myelofibrosis-associated complications:  
pathogenesis, clinical manifestations, and effects on outcomes.  Int J Gen Med.  
2014;7:89-101.
3.
Tefferi A.  The forgotten myeloproliferative disorder:  myeloid metaplasia.  
Oncologist.  2003;8(3):225-31.
4.
Vannucchi AM, Kantarjian HM, Kiladjian JJ, et al.  A pooled analysis of overall 
survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of 
ruxolitinib for the treatment of myelofibrosis.  Haematologica.  
2015;100(9):1139-45.
5.
Santos FP, Verstovsek S.  What is next beyond janus kinase 2 inhibitors for 
primary myelofibrosis?  Cur Opin Hemato.  2013;20(2):123-9.
6.
Tsujimoto Y, Finger LR, Yunis J, et al.  Cloning of the chromosome breakpoint of 
neoplastic B cells with the t(14;18) chromosome translocation.  Science.  
1984;226(4678):1097-9.
7.
Korsmeyer SJ.  BCL-2 gene family and the regulation of programmed cell death.  
Cancer Res.  1999;59 (7 Suppl):1693s-1700s.
8.
Cory S, Adams JM.  The Bcl2 family:  regulators of the cellular life-or-death 
switch.  Nat Rev Cancer.  2002;2(9):647-56.
9.
Borner C.  The Bcl-2 protein family:  sensors and checkpoints for life-or-death 
decisions.  Mol Immunol.  2003;39(11):615-47.
10.
Cory S, Huang DCS, Adams JM.  The Bcl-2 family:  roles in cell survival and 
oncogenesis.  Oncogene. 2003;22(53):8590-607.
11.
Willis S, Day CL, Hinds MG, et al.  The Bcl-2-regulated apoptotic pathway.  J Cell 
Sci.  2003;116 (Pt 20):4053-6.
 


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12.
Czabotar PE, Lessene G, Strasser A, et al.  Control of apoptosis by the BCL-2 
protein family:  implications for physiology and therapy.  Nat Rev Mol Cell Biol.  
2014;15(1):49-63.
13.
Adams JM, Cory S.  Life or death decisions by the Bcl-2 protein family.  Trends 
Biochem Sci.  2001;26(1):61-6.
14.
Tse C, Shoemaker AR, Adickes J, et al.  ABT-263:  a potent and oral bioavailable 
Bcl-2 family inhibitor.  Cancer Res.  2008;68(9):3421-8.
15.
Oltersdorf T, Elmore SW, Shoemaker AR, et al.  An inhibitor of Bcl-2 family 
proteins induces regression of solid tumours.  Nature.  2005;435(7042):677-81.
16.
Zeuner A, Pedini F, Francescangeli F, et al.  Activity of the BH3 mimetic ABT-737 
on polycythemia vera erythroid precursor cells.  Blood.  2009;113(7):1522-5.
17.
Waibel M, Solomon VS, Knight DA, et al.  Combined targeting of JAK2 and 
Bcl-2/Bcl-xL to cure mutant JAK2-driven malignancies and overcome acquired 
resistance to JAK2 inhibitors.  Cell Rep.  2013;5(4):1047-59.
18.
Guo J, Roberts L, Chen Z, et al.  JAK2V617F drives Mcl-1 expression and 
sensitizes hematologic cell lines to dual inhibition of JAK2 and Bcl-xL.  PLoS 
One.  2015;10(3):e0114363. 
19.
Will B, Siddiqi T, Alberich Jorda M, et al.  Apoptosis induced by JAK2 inhibition 
is mediated by Bim and enhanced by the BH3 mimetic ABT-737 in JAK2 mutant 
human erythroid cells.  Blood.  2010;115(14):2901-9.
20.
Cervantes F.  How I treat myelofibrosis.  Blood.  2014;124(17):2635-42.
21.
Verstovsek S, Mesa R, Gotlib J, et al.  A Double-Blind, Placebo-Controlled Trial 
of Ruxolitinib for Myelofibrosis.  N Engl J Med.  2012;366(9):799-807.
22.
Pardanani A, Harrison C, Cortes JE, et al.  Safety and Efficacy of Fedratinib in 
Patients With Primary or Secondary Myelofibrosis:  a Randomized Clinical Trial.  
JAMA Oncol.  2015;1(5):643-51.
23.
Harrison C, Schaap N, Vannucchi A, et al.  Fedratinib (FEDR) in myelofibrosis 
(MF) patients previously treated with ruxolitinib (RUX):  A reanalysis of the 
 


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JAKARTA-2 study; ASCO Annual Meeting; 2019 May 31-June 4; Chicago, 
Illinois; Abstract No: 7057.
24.
Mesa RA, Schwager S, Radia D, et al.  The Myelofibrosis Symptom Assessment 
Form (MFSAF):  an evidence-based brief inventory to measure quality of life and 
symptomatic response to treatment in myelofibrosis.  Leuk Res.  
2009;33(9):1199-203.
25.
Passamonti F, Cervantes F, Vannucchi A, et al.  A dynamic prognostic model to 
predict survival in primary myelofibrosis:  a study by the IWG-MRT (International 
Working Group for Myeloproliferative Neoplasms Research and Treatment).  
Blood.  2010;115(9):1703-8.
26.
Gangat N, Caramazza D, Vaidya R, et al.  DIPSS plus: a refined Dynamic 
International Prognostic Scoring System for primary myelofibrosis that 
incorporates prognostic information from karyotype, platelet count, and transfusion 
status. J Clin Oncol. 2011 Feb 1;29(4):392-7.
27.
Tefferi A, Cervantes F, Mesa R, et al.  Revised response criteria for myelofibrosis:  
International Working Group-Myeloproliferative Neoplasms Research and 
Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report.  
Blood.  2013;122(8):1395-8.
28.
Palandri F, et al.  Outcome of Patients with Myelofibrosis after Ruxolitinib Failure:  
Role of Disease Status and Treatment Strategies in 214 Patients.  Blood.  
2018;132 (Suppl 1):4277.
29.
Pardanani A, Tefferi A.  Definition and management of ruxolitinib treatment 
failure in myelofibrosis.  Blood Cancer J.  2014;4(12):e268.
30.
Mesa RA, Kantarjian H, Tefferi A, et al.  Evaluating the serial use of the 
Myelofibrosis Symptom Assessment Form for measuring symptomatic 
improvement:  performance in 87 myelofibrosis patients on a JAK1 and JAK2 
inhibitor (INCB018424) clinical trial.  Cancer.  2011;117(21):4869-77.
 


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31.
Aaronson NK, Ahmedzai S, Bergman B, et al.  The European Organization for 
Research and Treatment of Cancer QLQ-C30:  a quality-of-life instrument for use 
in international clinical trials in oncology.  J Natl Cancer Inst.  1993;85(5):365-76.
32.
Garcia SF, Cella D, Clauser SB, et al.  Standardizing patient-reported outcomes 
assessment in cancer clinical trials:  a patient-reported outcomes measurement 
information system initiative.  J Clin Oncol.  2007;25(32):5106-12.
33.
Cella D, Riley W, Stone A, et al.  The Patient-Reported Outcomes Measurement 
Information System (PROMIS) developed and tested its first wave of adult self-
reported health outcome item banks:  2005 - 2008.  J Clin Epidemiol.  
2010;63(11):1179-94.
34.
Verstovsek S, Gotlib J, Gupta V, et al.  Management of cytopenias in patients with 
myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy 
outcomes.  Onco Targets Ther.  2013;7:13-21.
35.
National Cancer Institute.  Common Terminology Criteria for Adverse Events 
(CTCAE), v4.03. 
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Thiele J, Kvasnicka HM, Facchetti F, et al.  European consensus on grading bone 
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2005;90(8):1128-32.
 


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Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices 
(GCP) and local regulations and guidelines governing the study at the site location.  In 
signing the Investigator Agreement in Section 14.0 of this protocol, the investigator is 
agreeing to the following:
1.
Conducting the study in accordance with the relevant, current protocol, making 
changes in a protocol only after notifying AbbVie, except when necessary to 
protect the safety, rights or welfare of subjects.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed 
consent and ethics committees (e.g., independent ethics committee [IEC] or 
institutional review board [IRB]) review and approval of the protocol and 
amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
5.
Reading the information in the Investigator's Brochure/safety material provided, 
including the instructions for use and the potential risks and side effects of the 
investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the 
study about their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making 
those records available for inspection by representatives of AbbVie and/or the 
appropriate regulatory agency, and retaining all study-related documents until 
notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and 
approved the initial clinical investigation and all amendments.
 


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9.
Reporting promptly, all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others, to the appropriate 
individuals (e.g., coordinating investigator, institution director) and/or directly to 
the ethics committees and AbbVie.
10.
Following the protocol and not make any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.
 


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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Clinical
Statistics
Statistical Sciences & Analytics
Clinical Study Leadership
Clinical Pharmacology and Pharmacometrics
 


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Appendix C.
Study Activities*
Table 6.
Study Procedures – Navitoclax Alone or in Combination with Ruxolitinib
Period
Screeninga
Treatment
Follow-Up
Week
–4 to 0
0
0
1
2
3
4
6
8
12
16
20
24
Q12 
Weeks
TCV
30-
Day 
Safety
PTb
Survival
Study Day
Within 
28 days
1
2
8
15
22
29
43
57
85
113
141
169
Visit Window 
(days)
–28
NA
NA
± 1
± 1
± 1
± 1
± 1
± 1
± 2
± 2
± 2
± 3
± 4
NA
NA
± 7
± 14
Activity
LOCAL LABS, EXAMS & ASSESSMENTS
Informed Consent
Xc
Medical/Oncology 
History Assessment
X
Xd
TB Testinge
X
AE/Concomitant 
Medication 
Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Transfusion 
history/status
Xf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Exam 
(including skin, liver 
and spleen 
assessment)g
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGh
X
X
X
 


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Table 6.
Study Procedures – Navitoclax Alone or in Combination with Ruxolitinib (Continued)
Period
Screeninga
Treatment
Follow-Up
Week
–4 to 0
0
0
1
2
3
4
6
8
12
16
20
24
Q12 
Weeks
TCV
30-
Day 
Safety
PTb
Survival
Study Day
Within 
28 days
1
2
8
15
22
29
43
57
85
113
141
169
Visit Window 
(days)
–28
NA
NA
± 1
± 1
± 1
± 1
± 1
± 1
± 2
± 2
± 2
± 3
± 4
NA
NA
± 7
± 14
Activity
Vital Signs
Xi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG performance 
status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
MFSAF version 4.0j
X
X
X
X
X
X
X
X
X
X
X
X
X
Xj
EORTC QLQ-C30K
X
X
X
X
X
X
X
X
PROMIS Fatigue SF 
7aK
X
X
X
X
X
X
X
X
PGICK
X
X
X
X
X
X
Pregnancy Testl
Serum
X
X
X
X
X
X
X
Xl
X
Hematologym
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
X
Xn
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation
X
Lipid Parameters 
(fasting)
X
X
 


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Table 6.
Study Procedures – Navitoclax Alone or in Combination with Ruxolitinib (Continued)
Period
Screeninga
Treatment
Follow-Up
Week
–4 to 0
0
0
1
2
3
4
6
8
12
16
20
24
Q12 
Weeks
TCV
30-
Day 
Safety
PTb
Survival
Study Day
Within 
28 days
1
2
8
15
22
29
43
57
85
113
141
169
Visit Window 
(days)
–28
NA
NA
± 1
± 1
± 1
± 1
± 1
± 1
± 2
± 2
± 2
± 3
± 4
NA
NA
± 7
± 14
Activity
Bone Marrow 
Biopsy and 
Aspiratew
X
X
X
Xw
Xx
Xy
Cytogenetic 
Samplingw,z
X
X
X
Xw
Xx
Disease Response 
Assessment
X
X
Xff
X
Xy
Imaging for spleen 
assessmentee
X
X
X
Xee
Xx
Xy
Survival 
Assessments
Xgg
CENTRAL LABS
Blood for Plasmao
X
X
X
X
X
X
X
X
Xp
X
Blood for Allelic 
Burdeno
X
Xq
Xq
Xr
X
Xs
X
 


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Table 6.
Study Procedures – Navitoclax Alone or in Combination with Ruxolitinib (Continued)
Period
Screeninga
Treatment
Follow-Up
Week
–4 to 0
0
0
1
2
3
4
6
8
12
16
20
24
Q12 
Weeks
TCV
30-
Day 
Safety
PTb
Survival
Study Day
Within 
28 days
1
2
8
15
22
29
43
57
85
113
141
169
Visit Window 
(days)
–28
NA
NA
± 1
± 1
± 1
± 1
± 1
± 1
± 2
± 2
± 2
± 3
± 4
NA
NA
± 7
± 14
Activity
Blood for Mutational 
Profilingo
X
Xq
Xq
Xr
X
Xt
X
Blood for Flow 
Cytometryo
X
X
Xu
Blood for Viable 
PBMCo
X
X
Xu
Blood for 
Translational 
Research-Heparino
X
X
Xv
X
Blood for 
Translational 
Research- ACD 
(female/US only)n
Xhh
X
Xu,v
Optional PG Blood 
Sampleo
X
X
X
 


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Table 6.
Study Procedures – Navitoclax Alone or in Combination with Ruxolitinib (Continued)
Period
Screeninga
Treatment
Follow-Up
Week
–4 to 0
0
0
1
2
3
4
6
8
12
16
20
24
Q12 
Weeks
TCV
30-
Day 
Safety
PTb
Survival
Study Day
Within 
28 days
1
2
8
15
22
29
43
57
85
113
141
169
Visit Window 
(days)
–28
NA
NA
± 1
± 1
± 1
± 1
± 1
± 1
± 2
± 2
± 2
± 3
± 4
NA
NA
± 7
± 14
Activity
Bone Marrow 
Aspirate for 
mutational
profilingo,aa
X
X
X
Xo,w
Xx
Bone Marrow 
Aspirate for 
Translational
researcho,aa
X
Xx
Bone Marrow Core 
Biopsy – IHC and 
Translational
Researcho,aa
X
X
X
Xo,w
Xx
Pharmacokinetic 
Assessments for 
Navitoclax and 
Ruxolitinibbb
Xcc
X
X
Xcc,dd
X
X
X
X
X
 


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Table 6.
Study Procedures – Navitoclax Alone or in Combination with Ruxolitinib (Continued)
Period
Screeninga
Treatment
Follow-Up
Week
–4 to 0
0
0
1
2
3
4
6
8
12
16
20
24
Q12 
Weeks
TCV
30-
Day 
Safety
PTb
Survival
Study Day
Within 
28 days
1
2
8
15
22
29
43
57
85
113
141
169
Visit Window 
(days)
–28
NA
NA
± 1
± 1
± 1
± 1
± 1
± 1
± 2
± 2
± 2
± 3
± 4
NA
NA
± 7
± 14
Activity
TREATMENT
Contact IRT for 
Screening/ 
enrollment
X
X
Dispense and 
administration of 
study treatment
X
X
X
X
X
X
X
X
X
X
X
X
Drug accountability 
assessment and 
compliance
X
X
X
X
X
X
X
X
X
X
X
X
TCV = Treatment Completion Visit; PT = Post Treatment; D = Day
*
Shows the required activities the subject encounters.  The individual activities are described in detail and allowed modifications due to COVID-19 are detailed within 
Section 5.3.1.1. 
a.
Screening procedures must be performed within 28 days prior to initial study drug administration.  The 28 day Screening window starts with the signing of the Informed 
Consent Form.
b.
Post-Treatment visits will be performed every 12 weeks (± 1 week) until the subject has documented disease progression, initiation of post-treatment cancer therapy, or 
subject refusal of post-treatment follow-up visits. 
 


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Table 6.
Study Procedures – Navitoclax Alone or in Combination with Ruxolitinib (Continued)
c.
The informed consent must be obtained prior to performing any Screening or study-specific procedures. 
d.
On Day 1, additional medical history that is observed after signing of the informed consent but prior to initial study drug administration and not considered related to study-
required procedures will be recorded in the subject's medical history.
e.
Subjects to be enrolled in Cohorts 1b and 3 (not applicable for Cohort 1a as it is fully enrolled or Cohort 2, navitoclax monotherapy) will be assessed for evidence of 
increased risk for TB and tested for TB infection, per local guidelines, prior to Day 1.  If TB Skin Test is utilized, it should be read by a licensed healthcare professional 
between 48 and 72 hours after administration.  TB testing may be performed centrally if unable to be performed locally, however, a negative result must be confirmed prior 
to first dose.  
f.
Transfusion must be recorded during the time period of a minimum of 12 weeks before the start of study treatment.
g.
A complete physical exam will be performed at Screening and TCV.  A symptom-directed physical exam may be performed at other study visits at the discretion of the 
investigator.  At a minimum, Spleen and liver palpation and measurement is required, plus skin exam is required for subjects in all Cohorts. 
h.
Additional ECGs may be performed as clinically necessary per the discretion of the investigator.
i.
Height will be measured only at Screening.
j.
MFSAF version 4.0 diary will be performed daily beginning at screening visit, pre-dose on Day 1 through Week 36 visit. For subjects enrolled in Cohorts 1b and 3 the 
screening period should be long enough to ensure at least 7 days to collect the daily MFSAF version 4.0 prior to Day 1.
k.
EORTC QLQ-C30 version 3, PROMIS Fatigue SF 7a and PGIC should be completed prior to any other clinical assessments and prior to dosing.
l.
Females of childbearing potential must have a negative serum pregnancy test result at Screening, and a negative urine or serum pregnancy test at Study Day 1.  Negative 
pregnancy test must be available prior to first dose.  Where required by local regulatory authority, urine pregnancy tests will be performed for females of childbearing 
potential every 4 weeks after Week 24 through treatment completion.
m.
Hematology will be collected pre-dose and 4 hours after the first dose of navitoclax on Day 1; 24-hours post-first-dose on Day 2; additional timepoints indicated above in 
Table 6; and prior to navitoclax dose increases, reductions (if during a clinic visit), or re-initiation after interruption.  Additional monitoring may also be required as per 
Section 6.1.7.1 and Section 6.1.7.2.
n.
Chemistry will be collected pre-dose on Day 1 Week 0
o.
Refer to Section 5.3.1.3 for sample matrix requirements for biomarker and optional exploratory research samples.
p.
Collected at Week 48 (D337) and Week 96 (D673).
q.
Cohort 1a only.
r.
Cohorts 1a and 3 only.
 


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Table 6.
Study Procedures – Navitoclax Alone or in Combination with Ruxolitinib (Continued)
s.
Collected at Week 36 (D253), 48(D337), 60 (D421), 72 (D505), and 96 (D673).
t.
Collected Weeks 48 (D337), 72 (D505), and 96 (D673) for Cohorts 1b and 2, and Weeks 48 (D337), 72 (D505), 96 (D673), 120 (D841), and 144 (D1009) for Cohort 3.
u.
Collected Week 48 (D337) for Cohorts 1b, 2 and 3. 
v.
Collected Week 96 (D673) for Cohorts 1b, 2, and 3.
w.
For visits with bone marrow sampling, hematology and chemistry labs should be performed on the same day as the bone marrow assessment.  Bone marrow biopsy and 
aspirate as well as cytogenetics will be performed at Screening (results from historical bone marrow samples will not be accepted), Weeks 12 (D85), 24 (D169), 48 (D337) 
and 96 (D673).  All bone marrow sampling must be completed within the ± 7 day window for the study visit. Additional bone marrow sampling and cytogenetics should be 
performed if disease progression is suspected, at the discretion of the investigator.
x.
Procedure should be performed if the subject discontinues from the study for a reason other than documented disease progression and if this procedure has not been done 
within the last 12 weeks.
y.
MRI (CT allowed if MRI is medically contraindicated), Bone Marrow sampling and Disease Response Assessments to be performed during Post-Treatment FU visits as 
necessary if disease progression is suspected.
z.
May be obtained from bone marrow or peripheral blood sampling.
aa.
Bone marrow biopsy/aspirate samples for exploratory biomarker analysis should be split from the samples collected for local clinical assessment.  All bone marrow sampling 
must be completed within the ± 7 day window for the study visit.
bb.
See Table 7 and Appendix D for the schedule of Pharmacokinetic Assessments for Navitoclax and Ruxolitinib.
cc.
Cohort 1b-DDI only.  See Appendix D Table 8.
dd.
Cohort 1b-DDI only for Days 7 and 8.  See Appendix D Table 8.
ee.
MRI/CT of the abdomen to determine spleen volume will be conducted at Screening, Weeks 12 (D85), 24 (D169), 36 (D253), 48 (D337), 72 (D505) and 96 (D673).  
Additional MRI/CT should be performed if disease progression is suspected, at the discretion of the investigator.  All MRI/CT assessments must be completed within the 
± 7 day window for the study visit.  All MRI/CT must be sent to a central imaging vendor.
 


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Table 6.
Study Procedures – Navitoclax Alone or in Combination with Ruxolitinib (Continued)
ff.
Disease Response Assessment to be performed at Weeks 12 (D85), 24 (D169), 36 (D253) 48 (D337), 72 (D505) and 96 (D673).  For disease assessments performed at 
Week 36 and 72, a repeat bone marrow biopsy is not required unless disease progression is suspected.  The prior bone marrow assessment may be used for the purposes of 
assessing disease response per modified IWG criteria.
gg. Survival information (e.g., date and cause of death, post-treatment cancer therapies including systemic therapy, radiation therapy, cancer related-procedures and stem-cell 
transplant, response to post-treatment cancer therapies) will be collected via telephone calls (e.g., to subject or family member), clinic visits, and/or public database searched 
every 6 months (± 2 weeks) after the last study visit up to 5 years after TCV (provided informed consent has not been withdrawn for collection of such information).
hh. Sample may be collected at Screening or Week 0 Day 1.
 


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Table 7.
Schedule of Pharmacokinetic Assessments for Navitoclax and Ruxolitinib
Cohort
Visit Schedule
Before Drug Administration
After Drug Administrationa
Sampling Plan
Specimen Matrix
1a
Day 1
Predose
2h, 4h, 6h, 8h
Blood →Plasma
Frozen –20°C or colder
Day 2
Predoseb
Day 8
Day 15
Day 22
Day 29
Day 43
Week 8 (Day 57)
Week 12 (Day 85)
Week 24 (Day 169)
Week 48 (Day 337)
Predose
1b, 2c, 3
Day 1
Predose
Cohort 1b and 3:  4h 
Cohort 2:  2h, 4h, 6h, 8h
Day 2
Predoseb
Day 15
Day 29
Week 8 (Day 57), 
Week 12 (Day 85), 
Week 24 (Day 169)
Predose
h = hours; min = minute
On days when PK samples are collected pre-dose, navitoclax (all cohorts) and ruxolitinib (Cohort 1a, 1b, and 3) should be taken at the same time during the clinic visit following 
the blood sample collection. 
The date and time of each PK sample collection and the date and time of the last two doses of navitoclax and/or ruxolitinib at each visit will be captured on the eCRF. 
a.
Samples for 2h and 4h should be collected within 10% of the scheduled time; Samples for 6h and 8h should be collected with ± 30 min.
 


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Table 7.
Schedule of Pharmacokinetic Assessments for Navitoclax and Ruxolitinib (Continued)
b.
Collection is 24 hours (± 30 min) post-first dose of navitoclax on Day 1 and before dosing of navitoclax and morning dose of ruxolitinib (if applicable, e.g., Cohorts 1a, 1b 
and 3) on Day 2.
c.
Sampling schedule is for navitoclax only.
 


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Appendix D.
Evaluation of Potential Drug-Drug Interaction between Navitoclax 
and Ruxolitinib
A total of approximately 10 subjects from Cohort 1b on a stable dose of ruxolitinib with a 
baseline platelet count > 150 × 109/L at the time of screening will participate in the drug-
drug interaction (DDI) sub-study following informed consent for the collection of 
additional blood samples.  
Navitoclax will be administered at a starting dose of 200 mg once daily beginning on 
Day 1.  Pharmacokinetics (PK) of ruxolitinib when administered alone on Day 0 will be 
compared with its PK when co-administered with navitoclax on Day 7.  Subjects must 
have received a stable dose of navitoclax for at least 4 days before the PK sample 
collection on Day 7.  If navitoclax dose de-escalation has occurred before Day 7, PK 
samples may be taken at a future visit, provided subject has received a stable dose of 
navitoclax for at least 4 days.  Pharmacokinetic samples will be collected prior to dosing 
and at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after dosing on Day 0 (ruxolitinib without 
navitoclax) and Day 7 (ruxolitinib with navitoclax).  Pharmacokinetic schedule for the 
subgroup of subjects participating in DDI evaluation in Cohort 1b is presented in Table 8.
Data from at least 8 subjects receiving navitoclax at the 200 mg dose level and with PK 
samples collected on at least Days 0 and 7 will be required.
 


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Table 8.
Complete Schedule of Pharmacokinetic Assessments for Navitoclax 
and Ruxolitinib in a Subgroup (n ~10) of Cohort 1b Subjects for 
DDI Assessment (DDI cohort is applicable to subjects who sign a 
separate informed consent)
Drug
Visit Schedule
Before Drug 
Administration
After Drug 
Administrationa
Sampling Plan
Specimen Matrix
Ruxolitinib 
Only
Day 0
Predose
0.25h, 0.5h, 1h, 2h, 
4h, 6h, 8h
Blood →Plasma
Frozen –20°C or 
colder
Ruxolitinib + 
Navitoclax
Day 1
Predoseb
4h
Day 2
Predosec
Day 7
Predosed
0.25h,d 0.5h,d 1h,d
2h,d 4h,d 6h,d 8hd
Day 8
Predosec
Day 15
Day 29
Week 8 (Day 57)
Week 12 (Day 85)
Week 24 (Day 169)
Predose
h = hours; min = minute
The date and time of each PK sample collection and the date and time of the last two doses of navitoclax and/or 
ruxolitinib at each visit will be captured on the eCRF.
a.
Samples for 0.25h and 0.5h should be collected with ± 5 min of the scheduled time.  Samples for 1h, 2h and 4h 
should be collected within 10% of the scheduled time; Samples for 6h and 8h should be collected with ± 30 min.
b.
Before dosing of navitoclax and morning dose of ruxolitinib on Day 1.
c.
Collection is 24 hours (± 30 min) post dose of navitoclax on prior day and before dosing of navitoclax and morning 
dose of ruxolitinib.  
d.
Subjects must have received a stable dose of navitoclax for at least 4 days immediately prior Day 7 before PK the 
sampling collection on Day 7.  If not, PK samples may be taken at a future visit, provided subject has received a 
stable dose of navitoclax for at least 4 days.
 


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Appendix E.
Modified IWG-MRT/ELN Response Criteria for Myelofibrosis
Table 9.
Summary of Response Criteria
Response 
Category
Response Requirements (for all response categories, benefit must last 
for ≥ 12 wk to qualify as a response)
Bone Marrow
Peripheral Blood
Clinical
Complete 
Remission (CR)

Age-adjusted 
normocellularity

< 5% blasts

Grade ≤ 1 MF 
(Appendix F)

Hgb ≥ 10g/dL

Neutrophils ≥ 1 × 109/L

Platelets ≥ 100 × 109/L

< 2% immature myeloid 
cells

Resolution of disease 
symptoms

Spleen/Liver not 
palpable

No evidence of EMH
Partial Remission 
(PR)
Not Applicable

Hgb ≥ 10 g/dL

Neutrophils ≥ 1 × 109/L

Platelets ≥ 100 × 109/L

< 2% immature myeloid 
cells

Resolution of disease 
symptoms

Spleen/Liver not 
palpable

No evidence of EMH
OR

Age-adjusted 
normocellularity

< 5% blasts

Grade ≤ 1 MF 
(Appendix F)

Hgb ≥ 8.5 g/dL

Neutrophils ≥ 1 × 109/L

Platelets ≥ 50 × 109/L

< 2% immature myeloid 
cells

Resolution of disease 
symptoms

Spleen/Liver not 
palpable

No evidence of EMH
Clinical 
Improvement
The achievement of anemia, spleen or symptom response without progressive disease or 
increase in severity of anemia, thrombocytopenia or neutropenia*
Anemia Response
Transfusion-independent (baseline Hgb < 10 g/dL):  Hgb increase ≥ 2 g/dL
Transfusion dependent:  becoming transfusion independent**
Spleen Response
A baseline splenomegaly that is palpable at 5 – 10 cm below the LCM, becomes not 
palpable***
A baseline splenomegaly that is palpable at > 10 cm below the LCM, decreases by ≥ 50%***
MRI/CT showing ≥ 35% SVR
Symptoms 
Response
≥ 50% reduction in MF-SAF TSS
Stable Disease
Belonging to none of the above response categories
EMH = extramedullary hematopoiesis; LCM = left costal margin
*
Increase in severity of anemia constitutes the occurrence of new transfusion dependency or a ≥ 2 g/dL decrease in 
Hgb from pretreatment baseline that lasts for ≥ 12 weeks.  Increase in severity of thrombocytopenia or neutropenia 
is defined as a 2-grade decline, from pretreatment baseline, in platelet count or ANC.  In addition, assignment to 
Clinical Improvement requires a minimum platelet count of ≥ 25 × 109/L and ANC ≥ 0.5 × 109/L.
**
Transfusion dependency before study enrollment is defined as transfusions of at least 6 units of packed red blood 
cells (PRBC), in the 12 weeks prior to study enrollment.  In addition, the most recent transfusion episode must 
have occurred in the 28 days prior to study enrollment.  Response in transfusion-dependent patients requires 
absence of any PRBC transfusions during any consecutive "rolling" 12-week interval during the treatment phase.
*** Requires confirmation by MRI/CT with a ≥ 35% SVR.
 


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Table 10.
Summary of Cytogenetic Remission
Cytogenetic Remission 
Category
Cytogenetic Remission Requirements
At least 10 metaphases must be analyzed 
Requires confirmation by repeat testing within 6 months 
Complete Cytogenetic 
Remission
Eradication of a preexisting abnormality
Partial Cytogenetic 
Remission 
≥ 50% reduction in abnormal metaphases
(to qualify for PR:  must have ≥ 10 abnormal metaphases at baseline)
Table 11.
Summary of Molecular Remission
Molecular Remission 
Category
Molecular Remission Requirements
Must be analyzed in peripheral blood granulocytes
Requires confirmation by repeat testing within 6 months
Complete Molecular 
Remission
Eradication of a pre-existing abnormality
Partial Molecular 
Remission 
≥ 50% decrease in allele burden
(to qualify for PR: must have ≥ 20% mutant allele burden at baseline)
 


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Table 12.
Summary of Progression/Relapse Criteria
Progression/Relapse 
Category
Progression/Relapse Criteria
Progressive Disease
At least 1 of the following: 

Appearance of a new splenomegaly that is palpable at least 5 cm 
below the left costal margin (LCM)*

A ≥ 100% increase in palpable distance below LCM, for baseline 
splenomegaly of 5 – 10 cm*

A 50% increase in palpable distance below LCM, for baseline 
splenomegaly of > 10 cm*

MRI/CT showing a ≥ 25% increase in spleen volume from baseline

Leukemic transformation confirmed by a bone marrow blast count of 
≥ 20% 

A peripheral blood blast content of ≥ 20% associated with an 
absolute blast count of ≥ 1 × 109/L that lasts for at least 2 weeks
Relapse
At least 1 of the following: 

No longer meeting criteria for at least Clinical Improvement after 
achieving Complete Response, Partial Response or Clinical 
Improvement

Loss of anemia response persisting for ≥ 1 month

Loss of spleen response persisting for ≥ 1 month
Cytogenetic/Molecular 
Relapse
Re-emergence of a pre-existing cytogenetic or molecular abnormality that 
is confirmed by repeat testing
LCM = left costal margin
*
Requires confirmation by MRI/CT with a ≥ 25% increase in spleen volume from baseline.
 


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Appendix F.
Bone Marrow:  Grading of Myelofibrosis
Table 13.
Consensus on Grading of MF
Grading
Description
MF-0
Scattered linear reticulin with no intersections (cross-overs) corresponding to normal 
bone marrow
MF-1
Loose network of reticulin with many intersections, especially in perivascular areas
MF-2
Diffuse and dense increase in reticulin with extensive intersections, occasionally with 
only focal bundles of collagen and/or focal osteosclerosis
MF-3
Diffuse and dense increase in reticulin with extensive intersections with coarse bundles 
of collagen, often associated with significant osteosclerosis.
Notes:
Thiele J 2005.36
Fiber density should be assessed in hematopoietic (cellular) areas.
 


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Appendix G.
Dynamic International Prognostic Scoring System (DIPSS)
Table 14.
Dynamic International Prognostic Scoring System (DIPSS)
Prognostic Variable
Points
0
1
2
Age, years
≤ 65
> 65
White blood cell count, × 109/L
≤ 25
> 25
Hemoglobin, g/dL
≥ 10
< 10
Peripheral blood blast, %
< 1
≥ 1
Constitutional Symptoms*, Y/N
N
Y
Risk Group
Points
Low
0
Intermediate-1 (INT-1)
1 or 2
Intermediate-2 (INT-2)
3 or 4
High
5 or 6
*
To report constitutional symptoms as Yes, need presence of at least one of the 3 symptoms: weight loss, fever, or 
night sweats.
Notes:
Passamonti F, 2010.25
Table 15.
Dynamic International Prognostic Scoring System (DIPSS)-PLUS
Prognostic Variable
Points
0
1
2
3
DIPSS Risk Score
Low-risk
Int-1
Int-2
High-risk
Platelet Count 
< 100 × 109/L
Transfusion Need, Y/N
N
Y
Unfavorable karyotype,a Y/N
N
Y
Risk Group
Points
Low
0
Intermediate-1 (INT-1)
1
Intermediate-2 (INT-2)
2 or 3
High
4 to 6
a.
Unfavorable karyotype: complex karyotype defined as 3 or more abnormalities OR sole or two abnormalities that 
includes trisomy 8, 7/7q-, i(17q), 5/5q-. 12p-, inv(3), or 11q23 rearrangement.
Notes:
Gangat N, 2011.26
 


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Appendix H.
Sample List of Excluded and Cautionary Medications
Anticoagulation Therapy (Excluded)
Anti-Platelet (Excluded)
coumadin (Warfarin)a and coumarin derivatives 
e.g., phenprocoumon
fondaparinux (Arixtra)
heparinb
melagatran/ximelagatran
rivaroxaban (Xarelto)
apixaban (Eliquis)
acetylsalicylic acid (Aspirin) (> 100 mg qd)
aspirin/extended-release dipyridamole (Aggrenox)
clopidogrel (Plavix)
dipyridamole (Persantine)
ticlopidine (Ticlid)
tirofiban (Aggrastat)
Strong CYP3A Inhibitorsc (Cautionary; Excluded for Cohort 1b DDI sub-study)
boceprevir
clarithromycin
cobicistat
conivaptan
danoprevir/ritonavir
elvitegravir/ritonavir
idelalisib
indinavir
itraconazole
ketoconazole
lopinavir/ritonavir
mibefradil
nefazodone
nelfinavir paritaprevir/ritonavir
posaconazole
ritonavir
saquinavir
telaprevir
telithromycin
tipranavir/ritonavir
troleandomycin
voriconazole
Anticoagulation Therapy (Cautionary)
SSRIs and SNRIs (Cautionary)
dalteparin (Fragmin)
Enoxaparin (Lovenox) and other LMWH
Tinzaparin (Innohep)
citalopram (Celexa)
escitalopram (Lexapro)
fluoxetine (Prozac)
sertraline (Zoloft)
duloxetine (Cymbalta)
vortioxetine (Trintellix)
venlafaxine (Effexor)
desvenlafaxine (Pristiq)
 


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NSAIDSa (Cautionary)
CYP2C9 Substratesc (Cautionary)
Aspirin > 100 mg daily
Diclofenac
Diflunisal
Etodolac
Ibuprofen
Indomethacin
Ketoprofen
Nabumetone
Naproxen
Oxaprozin
Salsalate
Sulindac
Tolmetin
fluvastatin
glipizide
irbesartan
losartan
phenytoin
sulfamethoxazole
sulfinpyrazone
tolbutamide
torsemide
Strong CYP3A Inducersc (Cautionary)
CYP2C8 Substratesc, d(Cautionary)
apalutamide
avasimibe
carbamazepine (Tegretol®)
enzalutamine
mitotane
phenytoin (Dilantin®)
rifampin (Rifadin®)
St. John's wort
amiodarone
amodiaquine
cerivastatin
chloroquine
lovastatine
paclitaxel (Taxol)
pioglitazone
repaglinide
rosiglitazone
simvastatin (Zocor)e
troglitazone
P-gp Substrates (Cautionary)c
BCRP Substrates (Cautionary)c
dabigatran etexilate
digoxin
fexofenadine
rosuvastatin
sulfasalazine
 


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P-gp Inhibitors (Cautionary)c
BCRP Inhibitors (Cautionary)c
amiodarone
carvedilol
clarithromycin
dronedarone
itraconazole
lapatinib
lopinavir and ritonavir
propafenone
quinidine
ranolazine
ritonavir
saquinavir
ritonavir
telaprevir
tipranavir
ritonavir
verapamil
curcumin
cyclosporine A
eltrombopag
P-gp Inducers (Cautionary)f
BCRP Inducers (Cautionary)g
rifampin
phenytoin
carbamazepine
St John's wort
quercetin
curcumin
efavirenz
rifampin
phenytoin
quercetin
curcumin
omeprazole
imatinib
a.
Warfarin and certain NSAIDS are also CYP2C9 substrates.  NSAIDS are allowed for limited duration only if 
platelets >100 x 109/L.
b.
Heparin may be used for patency of a central venous catheter and temporary use for prophylaxis of deep vein 
thrombosis.
c.
This is not an exhaustive list.  For an updated list, see the following link 
http://www fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm0
93664 htm.
d
Only certain statins qualify as CYP2C8 substrates.
e.
Significant increase in AUC by co-administration of gemfibrozile, a potent CYP2C8 inhibitor.  However, the 
involvement of CYP2C8 is unclear.
f.
This is not an exhaustive list.  Elmeliegy M, Vourvahis M, Guo C, et al.  Clin Pharmacokinet.  
2020;59(6):699-714.
g.
This is not an exhaustive list.  Gameiro M, Silva R, Rocha-Pereira C, et al.  Molecules.  2017;22(4):600.
Refer to drug labels as needed for more information.
 


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Appendix I.
Dose Adjustment Guidelines for Thrombocytopenia and Neutropenia

After navitoclax and/or ruxolitinib dose modification, platelet counts should be rechecked approximately 7 days or sooner as clinically 
applicable until at least 2 consecutive laboratory values indicate stable platelet count. 

If treatment is interrupted, recheck platelets approximately every 2 to 3 days until recovery of platelets to ≥ 50 × 109/L.

Navitoclax Dose levels for daily dosing: 200 mg, 150 mg, 100 mg, 75 mg or 50 mg
Hematology Results
Action For 
Navitoclax
Navitoclax
(All Cohorts)
Ruxolitinib Per Approved Local Label
(Cohorts 1a, 1b, and 3)
Dose Modification for Thrombocytopenia
Platelet counts 
≥ 75 × 109/L
No change
OR
Increase dose

Maintain current dose if platelet count ≤ 100× 109/L 

Dose may be increased to 150 mg if the current dose of 
navitoclax is 100 mg and administered for at least 7 days and 
platelets have increased to > 100 × 109/L.

Dose may be increased to 200 mg if the current dose of 
navitoclax is 150 mg and administered for at least 7 days and 
platelets have increased to > 150 × 109/L.

Reduce dose if current dose > 10 mg 
twice daily

Maintain current dose if receiving 10 mg 
twice daily 

Dose may be increased to the label 
recommended dose if the current dose is 
lower than the label recommended dose 
and current dose of ruxolitinib has been 
administered for at least 7 days and 
platelet counts have remained stable at 
> 125 × 109/L with no other dose 
modifications of the regimen
Platelet counts 
≥ 50 × 109/L to 
< 75 × 109/L
Dose 
reduction
OR
No Change

Reduce navitoclax dose if platelets do not return to ≥ 75 × 
109/L OR 

Maintain current dose if counts are stable and no risk for 
bleeding per investigator discretion 

Consider dose reduction.  
 


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
After navitoclax and/or ruxolitinib dose modification, platelet counts should be rechecked approximately 7 days or sooner as clinically 
applicable until at least 2 consecutive laboratory values indicate stable platelet count. 

If treatment is interrupted, recheck platelets approximately every 2 to 3 days until recovery of platelets to ≥ 50 × 109/L.

Navitoclax Dose levels for daily dosing: 200 mg, 150 mg, 100 mg, 75 mg or 50 mg
Hematology Results
Action For 
Navitoclax
Navitoclax
(All Cohorts)
Ruxolitinib Per Approved Local Label
(Cohorts 1a, 1b, and 3)
Dose Modification for Thrombocytopenia
Platelet counts 
< 50 × 109/L
Dose 
interruption

Resume at one dose level lower than prior to interruption once 
platelet counts recover to ≥ 50 × 109/L  

Interrupt per local label.  May taper if 
high risk for exacerbation in discussion 
with TA MD.

Resume per local approved label guidance 
once platelet counts recover ≥ 50 × 109/L  
Dose Modification for Neutropenia
Absolute neutrophil 
count (ANC) 
< 1.0× 109/L to 
0.5 × 109/L
Dose 
interruption

Monitor hematology labs at least weekly until ANC ≥ 1.0 × 
109/L  

Resume at one dose level lower once ANC recover ≥ 1.0 × 
109/L  

Maintain current dose or interrupt if at 
risk for infection per investigator 
discretion. 
Absolute neutrophil 
count (ANC)
< 0.5 × 109/L
Dose 
interruption

Monitor hematology labs at least weekly or often as needed 
until ANC ≥ 1.0 × 109/L.

Resume at one dose level lower once ANC recover ≥ 1.0× 
109/L  

May interrupt per local label.  May taper 
if high risk for exacerbation in discussion 
with TA MD.

Resume at same or lower dose.  
 

SAP_001.pdf: 
Navitoclax/ABT-263
M16-109 – Statistical Analysis Plan
Version 4.0 – 31 January 2023
1
Statistical Analysis Plan for Study M16-109
A Phase 2 Open-Label Study Evaluating Tolerability 
and Efficacy of Navitoclax Alone or in Combination 
with Ruxolitinib in Subjects with Myelofibrosis
Date:  31 January 2023
Version 4.0
 
NCT03222609


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Version 4.0 – 31 January 2023
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Table of Contents
1.0
Introduction...........................................................................6
2.0
Study Design and Objectives ................................................6
2.1
Objectives and Hypotheses..................................................................... 6
2.2
Study Design Overview.......................................................................... 7
2.3
Treatment Assignment and Blinding....................................................... 9
2.4
Sample Size Determination .................................................................... 9
3.0
Endpoints.............................................................................10
3.1
Primary Endpoint ................................................................................. 10
3.2
Secondary Endpoint(s) ......................................................................... 10
3.3
Additional Efficacy Endpoint(s) ........................................................... 10
3.4
Safety Endpoint(s)................................................................................ 11
3.5
Additional Endpoint(s) ......................................................................... 11
4.0
Analysis Populations ...........................................................12
5.0
Subject Disposition..............................................................13
6.0
Study Drug Duration and Compliance ..............................13
6.1
General Considerations......................................................................... 13
6.2
Duration of Study Drug ........................................................................ 13
6.3
Subject-Years of Exposure ................................................................... 14
6.4
Dose intensity (DI) and Relative Dose Intensity (RDI) ......................... 14
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ...................15
7.1
General Considerations......................................................................... 15
7.2
Additional Baseline Definitions............................................................ 16
7.2.1
Baseline TSS Value.............................................................................. 16
7.2.2
Baseline Hemoglobin Laboratory Value ............................................... 16
7.2.3
Baseline Renal Function....................................................................... 17
7.2.4
Baseline Hepatic Function.................................................................... 17
7.2.5
DIPSS+ Score at Study Entry ............................................................... 18
7.3
Demographics and Baseline Characteristics.......................................... 18
7.4
Medical History.................................................................................... 20
7.5
Prior and Concomitant Medications...................................................... 21
 


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8.0
Efficacy Analyses.................................................................21
8.1
General Considerations......................................................................... 21
8.2
Handling of Missing Data..................................................................... 22
8.3
Primary Efficacy Endpoint(s) and Analyses.......................................... 23
8.3.1
Primary Efficacy Endpoint ................................................................... 23
8.3.2
Main Analysis of Primary Efficacy Endpoint........................................ 23
8.4
Secondary Efficacy Analyses ............................................................... 23
8.4.1
Secondary Efficacy Endpoints.............................................................. 23
8.4.1.1
TSS Reduction ≥ 50% at Week 24 (TSS50W24)...................................... 23
8.4.1.2
Anemia Response................................................................................. 24
8.4.1.3
Change in Bone Marrow Fibrosis Grade............................................... 25
8.4.2
Main Analyses of Secondary Efficacy Endpoints.................................. 26
8.5
Exploratory Efficacy Analyses ............................................................. 26
8.5.1
Exploratory Efficacy Endpoints............................................................ 26
8.5.1.1
Spleen Volume Reduction ≥ 10%, ≥ 20%, 30%, and ≥ 35% at 
Any Time (SVR10, SVR20, SVR30 and SVR35), Spleen Volume 
Reduction ≥ 10%, ≥ 20%, and ≥ 30% at Week 24................................. 26
8.5.1.2
Duration of SVR35................................................................................ 27
8.5.1.3
Reduction in Palpable Spleen Length.................................................... 27
8.5.1.4
TSS Reduction ≥ 50% (TSS50).............................................................. 27
8.5.1.5
Change in MFSAF Score...................................................................... 28
8.5.1.6
Post Baseline Red Blood Cell Transfusion............................................ 28
8.5.1.7
Duration of Anemia Response .............................................................. 29
8.5.1.8
Overall Response Rate (ORR).............................................................. 30
8.5.1.9
Progression-Free Survival (PFS)........................................................... 31
8.5.1.10
Overall Survival (OS)........................................................................... 31
8.5.1.11
Change in PROMIS Fatigue Score........................................................ 32
8.5.1.12
Change in EORTC QLQ-C30 Score ..................................................... 32
8.5.2
Main Analyses of Exploratory Efficacy Endpoints................................ 32
8.6
Additional Efficacy Analyses ............................................................... 32
8.6.1
Change in Variant Allele Frequency..................................................... 32
8.6.2
Main Analyses of Additional Endpoints ............................................... 33
8.7
Efficacy Subgroup Analyses................................................................. 33
 


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9.0
Safety Analyses....................................................................33
9.1
General Considerations......................................................................... 33
9.2
Adverse Events..................................................................................... 33
9.2.1
Treatment-Emergent Adverse Events.................................................... 34
9.2.2
Adverse Event Overview...................................................................... 34
9.2.3
Treatment-Emergent Adverse Events by MedDRA SOC and/or 
PT ........................................................................................................ 35
9.2.4
SAEs (including deaths) and Adverse Events Leading to Death............ 35
9.2.5
Safety Topics of Interest....................................................................... 36
9.2.5.1
Time to Onset....................................................................................... 36
9.2.5.2
Incidence and Prevalence by Time........................................................ 36
9.2.5.3
Transfusion Requirements During Study Treatment.............................. 37
9.3
Analysis of Laboratory Data................................................................. 38
9.3.1
Analysis of Shift from Baseline ............................................................ 38
9.3.2
Analysis of Key Laboratory Parameters................................................ 39
9.4
Assessment of Potential Drug-induced Liver Injury.............................. 39
9.5
Analysis of Vital Signs......................................................................... 40
9.6
Analysis of ECG Parameters ................................................................ 40
9.7
Safety Subgroup Analyses.................................................................... 40
10.0
Other Analyses ....................................................................41
10.1
PK Endpoints ....................................................................................... 41
10.2
Main Analyses of PK Endpoints........................................................... 41
11.0
Interim Analyses..................................................................42
11.1
Data Monitoring Committee................................................................. 42
12.0
Overall Type-I Error Control.............................................42
13.0
Version History ...................................................................43
14.0
References............................................................................44
List of Tables
Table 1.
Point Estimates and 95% CI of Rate of SVR35W24 Corresponding 
to Observed Number of Subjects with SVR35W24..................................... 9
Table 2.
Renal Function Group Based on CLcr .................................................. 17
 


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Table 3.
Hepatic Function Group Based on Total bilirubin and AST .................. 17
Table 4.
Demographic and Baseline Characteristics (Categorical Variables) ...... 18
Table 5.
Demographic and Baseline Characteristics (Continuous Variables) ...... 20
Table 6.
Date of First Anemia Response for Duration of Anemia Response ....... 29
Table 7.
Event and Censoring Condition for Duration of Anemia Response ....... 30
Table 8.
SAP Version History Summary ............................................................ 43
List of Figures
Figure 1.
Study Schematic..................................................................................... 8
List of Appendices
Appendix A.
Protocol Deviations .............................................................................. 46
Appendix B.
IWG/MRT/ELN Response Criteria for Myelofibrosis1 ......................... 47
Appendix C.
Patient-Reported Outcome (PRO) Assessments.................................... 50
Appendix D.
Bone Marrow:  Grading Myelofibrosis ................................................. 54
Appendix E.
Safety Topics of Interest....................................................................... 55
 


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1.0
Introduction
This statistical analysis plan (SAP) describes the statistical analyses to be conducted by 
the Data and Statistical Science Department for Navitoclax (ABT-263) Study M16-109.  
The study examines the efficacy and safety of Navitoclax alone or in combination with 
Ruxolitinib in subjects with primary Myelofibrosis (PMF) or secondary MF (Post 
Polycythemia Vera [PPV-MF] or Post Essential Thrombocythemia [PET-MF]).
This SAP provides details to further elaborate statistical methods as outlined in the study 
protocol (amendment 11).  It will not be updated in case of administrative changes or 
amendments to the protocol unless if the changes impact the analysis.  In addition to this 
SAP, Statistical Programming Plan (SPP) will document details to guide the statistical 
programming work.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 (SAS 
Institute Inc., Cary, NC  27513) or later under the UNIX operating system.
2.0
Study Design and Objectives
2.1
Objectives and Hypotheses
The primary objective of the study is to:
●
Evaluate the effect of navitoclax alone or in combination with ruxolitinib on 
spleen volume.
The secondary objectives of the study are:
●
To assess the effect of navitoclax alone or in combination with ruxolitinib on 
total symptom score (TSS) as assessed by the Myelofibrosis Symptom 
Assessment Form (MFSAF) version 4.0 diary.
●
To evaluate the effect of navitoclax alone or in combination with ruxolitinib on 
bone marrow fibrosis.
 


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●
To determine the rate of anemia response associated with navitoclax alone or 
in combination with ruxolitinib.
●
To describe the safety profile and PK profile observed with navitoclax alone or 
in combination with ruxolitinib.
The exploratory objectives of the study are:
●
To evaluate the effect of navitoclax alone or in combination with ruxolitinib on 
the onset, magnitude, and duration of disease response, including effects on 
spleen and anemia.
●
To evaluate the effect of navitoclax alone or in combination with ruxolitinib on 
measures of health-related quality of life including total symptom score, 
fatigue, and physical functioning.
●
To evaluate the effect of navitoclax alone or in combination with ruxolitinib on 
overall survival and progression free survival.
●
Exploration of biomarkers predictive of navitoclax activity and response may 
be performed.
2.2
Study Design Overview
This is a Phase 2, multicenter, open-label study designed to evaluate the tolerability and 
efficacy of navitoclax alone or in combination with ruxolitinib in subjects with primary or 
secondary myelofibrosis (PPV-MF, PET-MF).  Subjects enrolled in Cohort 1a must have 
received ruxolitinib therapy for at least 12 weeks and currently be on a stable dose of 
≥10 mg BID of ruxolitinib.  For Cohort 1b subjects must have received treatment with 
ruxolitinib for at least 24 weeks and currently on stable dose of ≥ 10 mg BID of 
ruxolitinib or had < 24 weeks of ruxolitinib with evidence of disease progression.  For 
Cohort 2, subjects must have received prior treatment with a JAK-2 inhibitor.  For 
Cohort 3, subjects must not have received prior treatment with a JAK-2 inhibitor, BH3 
mimetic or BET inhibitor.
 


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Approximately 174 subjects at approximately 135 sites globally will be enrolled in the 
following cohorts:
●
Cohort 1a:  34 subjects
●
Cohort 1b:  approximately 80 subjects will be enrolled to ensure 
approximately 70 subjects with prior Ruxolitinib exposure.
●
Cohort 2:  approximately 30 subjects
●
Cohort 3:  approximately 30 subjects
Figure 1 is the study schema per protocol.
Figure 1.
Study Schematic
Subjects will continue their treatment until end of clinical benefit, unacceptable toxicity or 
subject meets other protocol criteria for discontinuation (whichever occurs first).  All 
subjects will have a treatment completion visit (TCV) performed when treatment is 
discontinued.
Response and progression will be assessed by the Investigator based on the International 
Working Group-Myeloproliferative Neoplasms Research and Treatment and European 
Leukemia Net (IWG-MRT/ELN).1  Spleen volume will be assessed independently by a 
central imaging vendor and interpretations will be transmitted to investigators, as 
available, and will be utilized in determining response and progression.
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.3
Treatment Assignment and Blinding
This is an open-label and non-randomized study.
2.4
Sample Size Determination
The primary endpoint for each Cohort of the study is SVR35W24 (at least 35% reduction in 
spleen volume by MRI/CT at Week 24 from baseline).  Approximately 174 subjects in 
total will be enrolled in this study across all Cohorts.  Point estimate and exact 95% 
confidence interval of SVR35W24 rate corresponding to observed number of subjects with 
SVR35W24 are presented in Table 1 for each Cohort.
Table 1.
Point Estimates and 95% CI of Rate of SVR35W24 Corresponding to 
Observed Number of Subjects with SVR35W24
Cohort
Sample 
size
Number of 
Subjects with 
SVR35W24
Point Estimate 
(SVR35W24 Rate) 
(%)
Exact 95% CI
Lower 
Limit 
(%)
Upper 
Limit 
(%)
Half Width 
of CI
1a
34
16
47.06
29.78
64.87
17.55
1a
34
18
52.94
35.13
70.22
17.55
1a
34
20
58.82
40.70
75.35
17.33
1a
34
22
64.71
46.49
80.25
16.88
1b
70
32
45.71
33.74
58.06
12.16
1b
70
34
48.57
36.44
60.83
12.19
1b
70
36
51.43
39.17
63.56
12.19
1b
70
38
54.29
41.94
66.26
12.16
2 or 3
30
12
40.00
22.66
59.40
18.37
2 or 3
30
14
46.67
28.34
65.67
18.67
2 or 3
30
16
53.33
34.33
71.66
18.67
2 or 3
30
18
60.00
40.60
77.34
18.37
The study with 34 subjects in Cohort 1a, 70 subjects in Cohort 1b, 30 subjects in Cohort 2 
and 30 subjects in Cohort 3 showed in the above table, respectively, a reasonable 
precision for estimate of SVR35W24.  Also, if true probability of experiencing a serious 
 


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adverse event (SAE) due to the study treatment is 10%, then the probability of observing 
at least one SAE in 34 subjects is more than 97% in Cohort 1a; the probability of 
observing at least one SAE in 80 subjects is more than 99% in Cohort 1b; the probability 
of observing at least one SAE in 30 subjects is more than 95% in Cohort 2 and 3, 
respectively.  Therefore, from safety assessment prospective the proposed sample size is 
adequate.
3.0
Endpoints
3.1
Primary Endpoint
SVR35W24, at least 35% reduction in spleen volume at Week 24 from baseline as measured 
by MRI or CT according to the IWG criteria.1
3.2
Secondary Endpoint(s)
Secondary efficacy endpoints are as follows:
●
TSS50W24, at least 50% reduction in TSS at Week 24 from baseline as 
measured by MFSAF version 4.02
●
Anemia response
●
Change in bone marrow fibrosis grade according to the European consensus 
grading system3
3.3
Additional Efficacy Endpoint(s)
Exploratory efficacy endpoints are as follows:
●
SVR35, at least 35% reduction in spleen volume from baseline as measured by 
MRI or CT according to the IWG criteria1 at any time point during study
●
Duration of SVR35
●
At least 50% reduction in palpable spleen length from baseline 
●
At least 50% reduction in TSS at any time point from baseline as measured by 
MFSAF v4.0
 


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●
Change in TSS and each MFSAF (v4.0) score from baseline
●
Duration of anemia response
●
Change in EORTC-QLQ-C30 score from baseline
●
Change in PROMIS score from baseline
●
Overall response per modified IWG criteria
●
Progression Free Survival (PFS) per modified IWG criteria
●
Overall survival (OS)
●
10%, 20%, and 30% Reduction in spleen volume from baseline as measured 
(SVR10, SVR20, and SVR30) by MRI/CT at any time point during study
●
10%, 20%, and 30% Reduction in spleen volume from baseline as measured 
(SVR10, SVR20, and SVR30) by MRI/CT at Week 24
●
Post-baseline PRBC transfusion independence
3.4
Safety Endpoint(s)
Safety evaluations include the following:
●
AE, Adverse event
●
SAE, serious adverse event
●
Deaths
●
ECG, electrocardiogram variables
●
Vital signs, clinical laboratory testing (hematology and clinical chemistry) 
●
Transfusion requirement for PRBC and platelets
3.5
Additional Endpoint(s)
●
Biomarker endpoints as follows:
○
Change in Variant Allele Frequency
●
Pharmacokinetic (PK) endpoints for navitoclax and ruxolitinib are as follows:
1.
Cmax, maximum observed plasma concentration
 


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2.
Tmax, the time to Cmax
3.
AUCt, the area under the plasma concentration-time curve (AUC) from 
time 0 to the time of the last measurable concentration
4.
β, the terminal phase elimination rate constant, only for navitoclax if the 
data warrants
5.
AUC∞, Area under the plasma concentration-time curve from time 0 to 
infinite time, only for navitoclax if the data warrants
Additional exploratory biomarker and PK endpoints may be evaluated (if required) and 
these will be analyzed without specifying in this study SAP.
4.0
Analysis Populations
In this study, study treatment is navitoclax + ruxolitinib (Cohort 1a, 1b and 3) or 
navitoclax alone (Cohort 2).  Unless otherwise noted, study drug refers to navitoclax and 
ruxolitinib for combination therapy (Cohort 1a, 1b, and 3); and navitoclax for mono 
therapy (Cohort 2).  Cohort 1 refers to Cohort 1a and Cohort 1b together.
The following sets will be used for analyses:
Full Analysis Set (FAS) includes all enrolled subjects who received at least one dose of 
navitoclax.  The FAS will be used for all demographic/baseline analyses. Unless 
otherwise specified, the FAS is also the analysis population for the primary and the 
secondary endpoints.
The Safety Analysis Set includes all enrolled subjects who received at least one dose of 
navitoclax.  The safety analysis set will be used for all safety analyses, unless otherwise 
specified.
The pharmacokinetics (PK) analysis set includes all the enrolled subjects who received at 
least one dose of navitoclax and have at least one post-dose PK assay results.  The PK set 
will be used for PK analyses.
 


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5.0
Subject Disposition
The FAS will be used to summarize subject disposition by cohort.  The total number of 
subjects who were treated will be summarized.
A summary of subject accountability will be provided where the number of subjects in 
each of the following categories will be summarized by cohort.
●
Subjects who were treated with at least one dose of navitoclax
●
Subjects who discontinued study drug- navitoclax (all reasons and primary 
reason)
●
Subjects who discontinued study drug- ruxolitinib (all reasons and primary 
reason)
6.0
Study Drug Duration and Compliance
6.1
General Considerations
Safety analysis set will be used for the analyses of study drug duration and compliance.  
Descriptive statistics (number of non-missing observations, mean, standard deviation, 
median, maximum, and minimum) will be provided for navitoclax and ruxolitinib, 
respectively, by Cohort, unless otherwise stated.  Based on the dosing schedule, for 
Cohort 1 and 3, data from navitoclax and ruxolitinib will be separately summarized, and 
for Cohort 2 data from navitoclax will be summarized.
6.2
Duration of Study Drug
Duration of study drug is calculated for each subject by the following formula, for 
navitoclax and ruxolitinib, respectively:
Duration of study drug (days) = Date of the last dose of study drug -Date of the first dose 
of study drug+1.
 


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The duration of study drug will be categorized as some interval of time (e.g., every 
28-day).  The number and percentage of subjects in each interval will be summarized.
6.3
Subject-Years of Exposure
Subject-years of study drug exposure is calculated as below for navitoclax and ruxolitinib, 
respectively:
Subject-years of exposure (sub-yr) = 
6.4
Dose intensity (DI) and Relative Dose Intensity (RDI)
An observed dose intensity (ODI) will be derived for each subject who receives the study 
drug based on how it was actually administered.  A planned dose intensity (PDI) will also 
be derived based on the protocol-specified schedule of the study drug.
For ODI it is calculated as:
For PDI it is calculated as: 
RDI is defined as:  RDI = (ODI/PDI)×100%.
The RDI will be summarized based on the study drug administration form in EDC.
Ruxolitinib administered before the first dose of navitoclax is considered as prior study 
treatment therapy collected in the Study Cancer Prior Systemic Therapies (Myelofibrosis) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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form in EDC for Cohort 1 (Cohorts 1a and 1b).  Ruxolitinib administered after the last 
dose of navitoclax for Cohort 1 (Cohorts 1a and 1b) is considered as post-study treatment 
collected in Post Study Drug Systemic Therapies form in EDC.
The actual total duration of treatment exposure in the above equations is defined as the 
last dose date minus first dose date + 1 for navitoclax or ruxolitinib, respectively. 
Descriptive statistics will be presented for navitoclax (for all Cohorts) and ruxolitinib (for 
Cohort 3, Cohort 1a and Cohort 1b) respectively.
Number and percentage of subjects who have dose reductions or interruptions, will be 
summarized.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
7.1
General Considerations
Demographics, baseline/disease characteristics, medical history, and prior and 
concomitant medications will be performed on the FAS by Cohort.
Definition of First Date of and Last Date of Study Treatment
First date of study treatment is the date of the first dose of navitoclax.  Last date of study 
treatment is the date of the last dose of navitoclax.
Definition of Baseline
In general, baseline value refers to the last non-missing measurement value collected up to 
the first date of study treatment, unless otherwise specified in Section 7.2.
 


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7.2
Additional Baseline Definitions
7.2.1
Baseline TSS Value
The total symptom score (TSS) will be measured by Myelofibrosis Symptom Assessment 
Form (MFSAF) v4.0. The daily TSS scores will be calculated by summing up scores from 
7 items of the MFSAF. All seven items must be completed for a daily TSS score to be 
computed. The worst (highest) daily TSS score will be considered as the daily TSS for a 
day when multiple responses on the same day were reported.
For subjects who enrolled under Study Protocol Amendment 7 or earlier version, the 
baseline TSS will be calculated by averaging all available daily TSS score collected up to 
the first date of study treatment (including the first date of study treatment).
For subjects who enrolled under Study Protocol Amendment 8 or later version, the 
baseline TSS score is defined as the average of the daily TSS score within 7 days before 
the first date of study treatment (not including the first date of study treatment). At least
4 days of scores are required to calculate the baseline TSS score. If a subject does not
have at least 4 days of scores before the first date of the study treatment (not including the 
first date of study treatment), the subject will not have a baseline TSS score (see detail in 
Appendix C).
7.2.2
Baseline Hemoglobin Laboratory Value
For hemoglobin laboratory test the baseline value will be defined as follows:
For subjects who received PRBC transfusion (for any reason) within 4 Weeks on or 
before the first date of study treatment, the baseline value is the minimum value observed 
before the transfusion, and the last non-missing value on or prior to the first date of study 
treatment.
For subjects who do not receive PRBC transfusion within 4 weeks on or before the first 
date of study treatment, the baseline value is the last observed value on or before the first 
date of study treatment.
 


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7.2.3
Baseline Renal Function
Baseline renal function will be classified based on the estimated creatinine clearance 
(CLcr) per Cockroft-Gault method,4  The last non-missing serum creatine value collected 
on or before the first date of study treatment will be used as baseline (assuming Day 1 
collection is prior to dose as timestamp was not collected).  The following table illustrates 
the classification for renal function:
Table 2.
Renal Function Group Based on CLcr
Renal Function Group
CLcr (mL/min)
Normal
CLcr ≥ 90
Mild Impairment
60 ≤ CLcr < 90
Moderate Impairment
30 ≤ CLcr < 60
Severe Impairment
15 ≤ CLcr < 30
7.2.4
Baseline Hepatic Function
Baseline hepatic function will be classified based on the National Cancer Institute Organ 
Dysfunction Working Group (NCI-ODWG) definition5 using total bilirubin and aspartate 
transaminase (AST) values.  The last observed bilirubin and AST values collected before 
the first date of study treatment (including Day 1 assuming lab parameter collected before 
study treatment on Day 1) will be used as baseline.  The following table illustrates the 
classification of hepatic function:
Table 3.
Hepatic Function Group Based on Total bilirubin and AST
Hepatic Function Group
Total Bilirubin (mg/dL)
AST (IU/L)
Normal
≤ ULN
≤ ULN
Mild Impairment
≤ ULN
> ULN and ≤ 1.5 × ULN
> ULN
any value
Moderate Impairment
> 1.5 × ULN and ≤ 3 × ULN
any value
Severe Impairment
> 3 × ULN
any value
Note:
ULN are based on reported values from each lab.
 


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7.2.5
DIPSS+ Score at Study Entry
For subjects with missing karyotype information at study entry, the DIPSS+ score at study 
entry will be calculated by utilizing the DIPSS risk score, platelet count, read blood cell 
transfusion need collected in EDC form 'DIPSS scoring – Study Entry' according to
DIPSS+ scoring system in protocol Table 15 and by assuming these subjects do not have 
unfavorable karyotype.
7.3
Demographics and Baseline Characteristics
FAS will be used for this analysis.  Categorical variables will be summarized with the 
number and percentage of subjects.  Continuous variables will be summarized with 
descriptive statistics (number of non-missing observations, mean, standard deviation, 
median, minimum, and maximum).
The following categorical demographic and baseline disease characteristics (but not 
limited to) will be summarized as shown in Table 4:
Table 4.
Demographic and Baseline Characteristics (Categorical Variables)
Categorical variable (possible values)
Age (18 - < 65, 65 - < 75, ≥ 75)
Gender (Male, Female)
Race (White, Black or African American, Asian, American Indian or Alaska Native, Native Hawaiian or 
Other Pacific Islander)
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
Region (US, Japan, Rest of World [ROW])
ECOG performance Status (0,1,2)
Baseline Renal Function (Normal, Mild, Moderate, Severe)
Baseline Hepatic Function (Normal, Mild, Moderate, Severe)
Type of MF (Primary MF, Secondary MF)
Prior lines of MF treatment (1,2, 3, > 3)
Response to prior ruxolitinib at screening (Refractory, Relapsed, Disease progression while on therapy, 
intolerance, stable disease, PV progressed to MF, ET prolonged to MF, not applicable, Other)
 


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Table 4.
Demographic and Baseline Characteristics (Categorical Variables)
(Continued)
Categorical variable (possible values)
Reason for treatment change at study entry (Splenomegaly, Worsening symptoms, Increased need for 
transfusions, Anemia, Thrombocytopenia, Increasing WBC, Increasing LDH, Others)
Worsening symptoms as a reason for treatment change at study entry (Fatigue, Altered concentration, 
Early satiety, Inactivity, Night sweats, Itching, Bone pain, Weight loss, Fevers, Edema, Abdominal 
discomfort, Others)
Splenomegaly only as a reason for treatment change at study entry (Yes, No)
Worsening symptoms only as a reason for treatment change at study entry (Yes, No)
Worsening labs only as a reason for treatment change at study entry (Yes, No)
At least one worsening labs as a reason for treatment change at study entry (Yes, No)
Splenomegaly and worsening labs as a reason for treatment change at study entry (Yes, No)
Splenomegaly and worsening symptoms as a reason for treatment change at study entry (Yes, No)
Worsening symptoms and worsening labs as a reason for treatment change at study entry (Yes, No)
Splenomegaly, worsening symptoms, and worsening labs as a reason for treatment change at study entry 
(Yes, No)
Change from nadir in palpable spleen length with prior ruxolitinib/JAK2 inhibitor (< -50%, ≥ -50% to 
< -25%, ≥ -25% to < 0%, 0%, > 0% to < 25%, ≥ 25% to < 50%, ≥ 50%)
Transfusion dependence status based on Investigators (Dependent, Independent)
Mutation status at study entry from central review (JAK2, CALR, MPL, other mutation categories if 
applicable) 
Platelet count (109/L) (< 75, ≥ 75 to < 100, ≥ 100)
Hemoglobin (g/dL) (< 8, ≥ 8 to < 10, ≥ 10)
Unfavorable karyotype at study entry (Yes, No, Not evaluable)
Dynamic international prognostic scoring system (DIPSS) risk at study entry (Low, Intermediate-1, 
Intermediate-2, High)
DIPSS risk at time of diagnosis (Low, Intermediate-1, Intermediate-2, High, Not evaluable)
DIPSS risk at time of ruxolitinib/Jak-2 inhibitor (Low, Intermediate-1, Intermediate-2, High, 
Not evaluable)
DIPSS plus risk at study entry (Low, Intermediate-1, Intermediate-2, High, Not evaluable)
Bone Marrow Fibrosis Grade at baseline (MF-0, MF-1, MF-2, MF-3)
Note:
Worsening labs for prior treatment change includes increased need for transfusions, anemia, 
thrombocytopenia, increasing WBC or increasing LDH.
 


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The following continuous baseline disease characteristics will be summarized as shown in 
Table 5.
Table 5.
Demographic and Baseline Characteristics (Continuous Variables)
Continuous Variable
Age (year)
Body weight (kg)
Body height (cm)
BMI (kg/m2)
Number of prior lines of MF treatments
Number of days from last prior ruxolitinib to study drug start
Time (months) since MF diagnosis
Duration (weeks) of prior ruxolitinib exposure
Spleen length by palpation (cm)
Spleen volume (cm3)
Hemoglobin (g/dL)
Platelet count (109/L)
White blood cell (109/L)
Neutrophil count (109/L)
LDH (U/L)
Baseline TSS
7.4
Medical History
Medical history and ongoing conditions, including MF related conditions and symptoms 
will be summarized and listed.  Separate summaries will be presented for ongoing and 
historical medical conditions.  The summaries will be presented by primary system organ 
class (SOC) and preferred term (PT).  Data will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA).  The actual version of the MedDRA coding dictionary 
will be noted in the statistical tables and clinical study report.  The number and percentage 
of subjects in each medical history category (by MedDRA system organ class and 
preferred term) will be summarized.  The SOC will be presented in alphabetical order, and 
the preferred terms will be presented in alphabetical order within each SOC.  Subjects 
 


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reporting more than one condition/diagnosis will be counted only once in each row (SOC 
or preferred term).
7.5
Prior and Concomitant Medications
Prior and concomitant medications including prior treatments for MF and preceding 
treatment for polycythemia vera or essential thrombocythemia prior to developing 
secondary MF will be summarized by generic name.  A prior medication is defined as any 
medication taken before the first date of study treatment.
A concomitant medication is defined as any medication that started before or after the first 
date of study treatment and continued to be taken after the first date of study treatment, 
but not after the last date of study treatment.  The number and percentage of subjects 
taking medications will be summarized by generic drug name based on the World Health 
Organization (WHO) Drug Dictionary for both prior and concomitant medications.
Subjects who report the use of medications more than one time will be counted only once 
in the summary of any prior or concomitant medication.  Subjects reporting two or more 
uses of the same medication will be counted only once in the total for the associated 
generic drug name.
8.0
Efficacy Analyses
8.1
General Considerations
The primary analysis population for primary endpoint is the Full Analysis Set. Unless 
otherwise specified, the secondary efficacy endpoints and exploratory efficacy endpoints 
will be analyzed in Full Analysis Set.
All efficacy results will be presented by cohort unless stated otherwise.  For all analyses, 
unless otherwise specified, data collected after the cutoff date will be excluded from 
statistical analysis.  All spleen volume related endpoints described in Section 3.0 will be 
based on the assessments from the central review of the radiographic images by an 
Independent Review Committee (IRC) as described in the protocol.
 


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All response rates and the corresponding 95% confidence interval (Cl) using the Clopper-
Pearson method will be provided.
For the analyses of all time-to-event endpoints, survivorship functions will be estimated 
using Kaplan-Meier product-limit methodology.  If reached, median time-to-event and its 
95% CI will be presented.
For the analyses of all continuous endpoints, such as change from baseline in score, the 
scores will be summarized with baseline mean, visit mean, mean change from baseline, 
mean percentage change from baseline, standard deviation, and the corresponding 95% 
CIs.
Baseline measurement related to each efficacy endpoint for analysis has been described in 
Section 7.0.
The post-study treatment refers to Post Study Drug Systemic Therapies for Myelofibrosis, 
Post Study Drug Radiation Therapy and Post Study Drug Transplant.  The disease 
progression (DP) refers to relapse or progressive disease in the Disease Response 
Assessment Form.
8.2
Handling of Missing Data
Missing data for all time-to-event endpoints will be handled by appropriate censoring in 
analysis and the censoring rule will be described in the following sub-sections.
Unless otherwise specified, for the analyses of all response rates, subjects without 
response will be considered as non-responders.
No missing data imputation will be applied for change from baseline in PRO domain 
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8.3
Primary Efficacy Endpoint(s) and Analyses
8.3.1
Primary Efficacy Endpoint
Spleen Volume Reduction ≥ 35% at Week 24 (SVR35W24) per IWG Criteria
SVR35W24 rate is defined as the proportion of subjects who achieved at least 35% 
reduction from baseline spleen volume at Week 24.  The analysis window for Week 24 is 
defined as Day 127 to Day 211 per study activity schedule. Data after the start of post-
study treatment or disease progression (relapse and progressive disease) will be excluded 
from the analyses. Subjects who do not have percent change from baseline (missing 
baseline or missing post-baseline) of spleen volume in the analysis window will be 
considered as non-responders.
Primary analysis population for SVR35W24 is the Full Analysis Set (see Section 4.0 for the 
definition of Full Analysis Set).
8.3.2
Main Analysis of Primary Efficacy Endpoint
The SVR35W24 rate will be estimated, and the corresponding 95% confidence interval (Cl) 
will be provided using the Clopper-Person method.
8.4
Secondary Efficacy Analyses
8.4.1
Secondary Efficacy Endpoints
8.4.1.1
TSS Reduction ≥ 50% at Week 24 (TSS50W24)
TSS50W24 rate is defined as the proportion of subjects who achieved at least 50% reduction 
from baseline in TSS at Week 24.  TSS score at Week 24 is defined as the average of the 
daily scores from a 7-day period closest to Week 24 nominal period. The Week 24 
nominal period is from Day 163 to Day 169 for subjects enrolled before protocol 
amendment 8 and from Day 162 to Day 168 for subjects enrolled after protocol 
amendment 7. The detail of finding the 7-day period closest to the Week 24 nominal 
period from MFSAF data is as follows. Also refer to Appendix C for more details.
 


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1.
Step 1:  Search TSS 7-day period data in Week 24 nominal period, Day 162-168 
(after protocol amendment 7) or Day 163-169 (prior to protocol amendment 8).
2.
Step 2: If Step 1 data are not available, extend the Week 24 nominal period in 
increments of ± 1 day (e.g., for subjects enrolled after protocol Amendment 7: 
Day 163-169 (+1 day expansion), Day 161-167 (-1 day expansion))
3.
Repeat step 2 in increments of ±1 day until ±7 days from Week 24 nominal period 
if data from previous step are not available
4.
The final TSS at Week-24 is the average of 7-day period closest to the Week 24 
nominal period.  The following convention is applied to the situation when a pair 
of 7-day period data has the same distance to Week 24 nominal period: select the 
7-day period data which is before Week 24 nominal period.
Daily TSS will be considered as missing if not all responses for 7 items are provided. The 
worst (highest) daily TSS score will be considered the daily TSS for a day when multiple 
responses were reported on the same day. At least 4 days of scores in the 7-day period of 
Week 24 Visit are required to calculate the TSS score for Week 24. If a subject does not 
have at least 4 days of scores in the 7-day period of Week 24 Visit, the subject will not 
have a TSS score at Week 24.  TSS scores obtained after disease progression or start of 
post-study treatment will not be included in the analysis.
Primary analysis population for TSS50W24 is Full Analysis Set. Subjects with missing 
percent change in TSS at Week 24 (e.g., zero TSS at baseline, or missing either baseline 
or post-baseline) are considered as non-responders of TSS50W24.
8.4.1.2
Anemia Response
Anemia response rate is defined as the proportion of subjects who achieved anemia 
response.
Baseline hemoglobin mentioned below is defined in Section 7.2.2.  The transfusion 
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are based on investigators reporting in the Study Cancer History Form according PRBC 
transfusion events (≥6 units within 12 weeks and ≥1 unit within 28 days) prior to the 
start of study treatment.
For a subject who is transfusion independent (TI) at baseline with hemoglobin value 
< 10 g/dL, the subject will be considered as achieving anemia response if the post baseline 
hemoglobin level increases by ≥ 2 g/dL from baseline without receiving PRBC 
transfusion (for any reason) within 2 weeks and without any erythropoietin, erythropoietin 
mimetics within the last 4 weeks prior to the increase in hemoglobin level by ≥ 2g/dL was 
observed.  Hemoglobin values after 30 days post last date of study treatment, the start of 
post-study treatment or disease progression whichever is earlier will not be considered in 
the analysis of anemia response.
For a subject who is transfusion dependent (TD) at baseline, anemia response is defined as 
a period of at least 12 consecutive weeks without PRBC transfusion after the first dose of
study drug and on or prior to 30 days post last dose of study drug, the start of post-study 
treatment, disease progression or death, whichever occurs earlier.
Subjects who are baseline transfusion independent with baseline hemoglobin of ≥10 g/dL
will not be included in the analysis since these subjects are not evaluable for anemia 
response.
Anemia response rate will also be summarized for all subjects who are evaluable for 
anemia response in the Full Analysis Set and by transfusion dependency status at baseline.
Missing post-baseline anemia response in Full Analysis Set applicable to evaluation of 
anemia response are considered as non-responders of anemia response.
8.4.1.3
Change in Bone Marrow Fibrosis Grade
Grade of bone marrow fibrosis was assessed by investigators according to the European 
consensus grading system.  The proportion of subjects who achieve a reduction of at least 
1 grade in bone marrow fibrosis from baseline at any time will be summarized. The bone 
 


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marrow fibrosis grade reduction of at least 1 grade at Week 24 will also be summarized. 
Data after post-study treatment or disease progression will be excluded from the analysis.
Subjects with missing bone marrow fibrosis grade (either baseline or post-baseline) or 
those with bone marrow fibrosis Grade 0 at baseline are excluded in the analysis for the 
change in bone marrow fibrosis grade.
Time to 1st achieving a reduction of at least 1 grade in bone marrow fibrosis from baseline 
will also be summarized. Mean and median time (week) of time to 1st achieving a 
reduction of at least 1 grade in bone marrow fibrosis from baseline will be provided.
8.4.2
Main Analyses of Secondary Efficacy Endpoints
TSS50W24 rate, anemia response rate and the bone marrow fibrosis grade reduction rate 
will be estimated.  The corresponding 95% confidence interval (Cl) will be provided using 
Clopper-Person method.
Bone marrow fibrosis grades will be tabulated using a shift table with baseline values of 
Grade 0, Grade 1, Grade 2, Grade 3, or missing grade, versus minimum post-baseline of
Grade 0, Grade 1, Grade 2, Grade 3, or missing grade.
8.5
Exploratory Efficacy Analyses
8.5.1
Exploratory Efficacy Endpoints
8.5.1.1
Spleen Volume Reduction ≥10%, ≥ 20%, 30%, and ≥ 35% at 
Any Time (SVR10, SVR20, SVR30 and SVR35), Spleen Volume 
Reduction ≥10%, ≥20%, and ≥30% at Week 24
SVR10, SVR20, SVR30, and SVR35 rates at any time are defined as the proportion of 
subjects who achieved at least 10%, 20%, 30%, and 35% reduction from baseline spleen 
volume any time, respectively.  SVR10, SVR20, and SVR30 at Week 24 are defined as the 
proportion of subjects who achieved at least 10%, 20%, and 30% reduction from baseline 
spleen volume at Week 24, respectively.  Data after the start of post-study treatment or 
disease progression will be excluded from these analyses. Subjects who do not have 
 


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percent change from baseline (missing baseline or missing post-baseline) in spleen 
volume will be treated as non-responders.  In addition, time to first SVR ≥10%, first 
SVR ≥20%, first SVR ≥30%, and first SVR ≥35% will also be summarized.
Above exploratory endpoints will be analyzed in the Full Analysis Set.
8.5.1.2
Duration of SVR35
Only subjects who achieved SVR35 will be included in this analysis for duration of 
SVR35.  The Duration of SVR35 is defined as the number of days from the first date of 
SVR35 achievement to the first date of 1) SVR< 35% AND observing ≥25% spleen 
volume increase from nadir (the lowest spleen volume in the previous assessments) or 
2) disease progression (relapse or progressive disease) per investigator by IWG/MRT
criteria, whichever is earlier. Subjects without the defined event mentioned above will be 
censored at the last date of the following assessments on or before post-study treatment: 
MRI/CT scan for spleen volume assessment, bone marrow assessment, lab assessment, 
disease response assessment.
8.5.1.3
Reduction in Palpable Spleen Length
Rate of reduction in palpable spleen length is defined as the proportion of subjects who 
achieved at least 50% reduction from baseline in palpable spleen length any time during 
the study.
Subjects who had baseline spleen length of greater than 0 (> 0) will be included in this 
endpoint.  Subjects who don't have post baseline spleen length will be excluded from this 
endpoint.  Data after start of post-study treatment or disease progression will not be 
included in the analyses.
8.5.1.4
TSS Reduction ≥ 50% (TSS50)
TSS50 rate is defined as the proportion of subjects who achieved at least 50% reduction 
from baseline in TSS at any week during the study.
 


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Subjects who do not have any post baseline TSS score will be treated as non-responders. 
Subjects with baseline TSS of 0 or without baseline TSS score will also considered as 
non-responders. Data after the start of post-study treatment or disease progression will not 
be included in the analyses.
TSS50 rate will be analyzed in the Full Analysis Set.
8.5.1.5
Change in MFSAF Score
Change in average daily MFSAF score of weekly interval (7-day) for each item and TSS 
(except for Week 23 and Week 25) from baseline will be summarized according to the 
scoring approach provided in Appendix C. Data after the start of post-study treatment, 
disease progression will not be included in the analyses. Change in MFSAF score will be 
analyzed among subjects who had baseline and post-baseline MFSAF score.
8.5.1.6
Post Baseline Red Blood Cell Transfusion
Post Baseline Red Blood Cell transfusion (for any reason) evaluation period is from after 
the first dose of study drug to earliest day of on or before the last dose of study drug + 
30 days, or the start of post-study treatment.
Post baseline transfusion independent rate will be calculated as the proportion of subjects 
who achieved PRBC transfusion independent during the treatment period.  PRBC 
Transfusion independent is defined as a period of at least 12 weeks (≥ 84 days) with no 
PRBC transfusions during the evaluation period.  In addition, the rate of conversion will 
be calculated as proportion of subjects being post-baseline PRBC transfusion independent 
from baseline PRBC transfusion dependent.
The duration of PRBC transfusion independent will also be summarized for overall and 
by transfusion status at baseline (transfusion dependent and transfusion independent).  
The duration of transfusion independence is defined as the first time period that a subject 
received no PRBC transfusions for at least 12 weeks (≥ 84 days).  The descriptive 
 


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statistics (median and range) will be provided for the duration of transfusion 
independence.
Incidence rate of PRBC transfusion/subject/month, defined as total number of PRBC 
transfusion from all subjects divided by total duration of treatment from all subjects 
(months).
Time from first date of study treatment to the first time receiving 2 or more units of PRBC 
transfusion will be summarized.
Above endpoints will be analyzed in the Full Analysis Set.
8.5.1.7
Duration of Anemia Response
Duration of anemia response will be summarized by baseline transfusion status.
For subjects who were transfusion independent at baseline and achieved anemia response, 
the evaluation period for duration of anemia response is from achieving anemia response 
to 30 days after last dose of study treatment. Duration of anemia response is defined as 
number of days from the first date of achieving anemia response described in Table 6 to 
the date of loss anemia response as described in Table 7.
Table 6.
Date of First Anemia Response for Duration of Anemia Response
Transfusion Status
at baseline
Date of First Response
TI
On the first date observing hemoglobin level increase by ≥ 2 g/dL from baseline 
without receiving PRBC transfusion within the last 2 weeks or any 
erythropoietin, erythropoietin mimetics within 4 weeks prior to the increased 
hemoglobin level
TD
On the first date observing no PRBC transfusion for at least 12 weeks
 


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Table 7.
Event and Censoring Condition for Duration of Anemia Response
Transfusion 
Status at 
baseline
Event/Censor
Date of Event/Censor
TI
Event: 1) decrease in hemoglobin 
level by 2 g/dL or more from the 
hemoglobin level at the first 
occurrence of achieving anemia 
response, or 2) need for PRBC 
transfusion before disease 
progression for the bleeding event* 
which was unrelated to 
navitoclax/ruxolitinib or 3) use of 
any erythropoietin, erythropoietin 
mimetics within 30 days of last 
dose of study drug
Earliest date of events
Censor: if no above-mentioned 
events observed within 30 days of 
last dose of study drug
The last date of hemoglobin assessment after 
achieving anemia response, 30 days post last 
dose of study treatment, start of post-study 
treatment, disease progression, or death, 
whichever is earlier.
Date of achieving anemia response will be 
the censor date if no hemoglobin assessment 
is obtained after achieving anemia response.
*
Bleeding event is defined as a treatment emergent hemorrhage event from narrow search of Standardized MedDRA 
Queries (SMQ). PRBC occurring between the start of bleeding event and end/ongoing will be considered as need
for PRBC transfusion for bleeding.
For subjects who were transfusion dependent at baseline, the duration of anemia response 
is defined as the 1st time period that a subject received no PRBC transfusions for at least 
12 weeks (≥84 days).  The descriptive statistics (median and range) will be provided for 
the duration of anemia response.
8.5.1.8
Overall Response Rate (ORR)
ORR is defined as the proportion of subjects who achieve best response of complete 
remission (CR) or partial remission (PR) per IWG criteria.1  Subjects who do not have any 
disease assessment or who have started - post-study treatment prior to achieving best 
response of CR or PR will be considered as non-responders. Responses achieved after 
 


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relapse or progressive disease or starting post-study treatment will not be included.  This 
endpoint will be analyzed in the Full Analysis Set.
8.5.1.9
Progression-Free Survival (PFS)
PFS is defined as time from the first date of study treatment to the date of first 
documented disease progression/relapse per IWG criteria as determined by the 
investigator, or death due to any cause, whichever is earlier.  Disease progression and 
death after start of post-study treatment are not considered as an PFS event.
For subjects who do not experience a PFS event (disease progression, relapse, or death 
due to any cause) on or prior to the start of post-study treatment, PFS will be censored at 
the last adequate disease assessment (where IWG response evaluation is not missing) on 
or prior to the start of post-study treatment.
For subjects without any post baseline disease assessments who did not die, PFS will be 
censored at Day 1.
PFS will be analyzed in the Full Analysis Set.
8.5.1.10
Overall Survival (OS)
OS is defined as time from the first date of study treatment to the date of death due to any 
cause.  If a subject has not died, then the data will be censored on the date when the 
subject was last known alive.
The last known alive date will be determined by selecting the last available date of the 
following study procedures: last dose date of study treatment, start date of adverse event, 
bone marrow collection, disease assessment, spleen assessment, vital signs assessment, 
electrocardiogram assessment, clinical laboratory collection (including COVID-19 test), 
study drug administration, start date of concomitant or post-treatment medicine or 
procedure, last known alive date in survival follow-up, biospecimen sample collection,
quality of life assessments, and performance status.
 


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OS will be analyzed in the Full Analysis Set.
8.5.1.11
Change in PROMIS Fatigue Score
Change in PROMIS fatigue score is defined as the change from baseline score by Visit.  
The scores are collected using PROMIS Fatigue SF7a.  The summary score, symptom and 
impact scores will be calculated according to the scoring algorithm specified in 
Appendix C.  Data after the start of post-study treatment, disease progression will not be 
included in the analyses. Change in PROMIS Fatigue Score will be analyzed among 
subjects who had baseline and post-baseline PROMIS Fatigue Score.
8.5.1.12
Change in EORTC QLQ-C30 Score
Change in EORTC QLQ-C30 score is defined as the change from baseline score by Visit.  
The scores are collected using EORTC QLQ-C30.  The summary score of EORTC 
QLQ-C30 will be calculated according to the scoring algorithm specified in Appendix C. 
Data after the start of post-study treatment, disease progression will not be included in the 
analyses. Change in EORTC QLQ-C30 Score will be analyzed among subjects who had 
baseline and post-baseline EORTC QLQ-C30 score.
8.5.2
Main Analyses of Exploratory Efficacy Endpoints
The data will be analyzed per Section 8.1.
8.6
Additional Efficacy Analyses
8.6.1
Change in Variant Allele Frequency
Change from baseline in variant allele frequency any time during the post baseline period 
will be derived by specific driver gene, which is mutated-JAK2, -CALR, and -MPL, if 
baseline allele frequency and post-baseline allele frequency are available based on the 
Next Generation Sequencing (NGS) method in the peripheral blood. Data after the start of 
post-study treatment, disease progression WILL BE included in the analyses. Change in 
variant allele frequency will be analyzed among subjects who had baseline and post-
baseline variant allele frequency.
 


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Proportion of subjects achieving allele frequency reduction from baseline of ≥20% at 
Week 24 or any time during the study treatment will be summarized among subjects with 
baseline and post-baseline of variant allele frequency for Cohort 1a, Cohort 1b and 
Cohort 3.  Maximum percentage reduction from baseline in allele frequency will be 
presented by the waterfall plot for all cohorts.
8.6.2
Main Analyses of Additional Endpoints
Descriptive statistics with visit mean, mean change from baseline, mean percentage 
change from baseline, standard deviation and range will be provided.
8.7
Efficacy Subgroup Analyses
Subgroup analyses will be performed for the primary SVR35W24 endpoint.
The following subgroups will be used (but not limited to):
●
type of MF (Primary MF and Secondary MF)
●
DIPSS risk at study entry (Inetermediate-1, Intermediate-2 and High risk).
●
Age (18 - < 65 years, ≥ 65 years)
9.0
Safety Analyses
9.1
General Considerations
Safety data will be summarized using the Safety Analysis Set defined in Section 4.0.  The 
safety summaries will be presented by Cohort.  For all safety analyses, unless otherwise 
specified, data collected up to the analysis data cutoff date will be used.
9.2
Adverse Events
Adverse events (AEs) will be summarized and presented using primary MedDRA System 
Organ Classes (SOCs) and preferred terms (PTs) according to the version of the MedDRA 
coding dictionary used for the study at the time of database lock.  The actual version of 
the MedDRA coding dictionary used will be noted in the AE tables and in the clinical 
 


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study report.  Specific adverse events will be counted once for each subject for calculating 
percentages, unless stated otherwise.  In addition, if the same adverse event occurs 
multiple times within a subject, the highest severity and level of relationship to 
investigational product will be reported.
9.2.1
Treatment-Emergent Adverse Events
Treatment-emergent AEs (TEAE) are defined as any AE with the onset that is on or after 
the first dose of navitoclax until 30 days after the last date of study drug.  Events where 
the onset date is the same as the study drug start date are assumed to be treatment 
emergent.  If an incomplete or missing onset date was collected for an AE, the AE will be 
assumed to be treatment-emergent unless there is evidence to the contrary (e.g., the AE 
end date was prior to the date of the first dose of study drug).  All TEAEs will be 
summarized overall, as well as by primary MedDRA SOC and PT.  The SOCs will be 
presented in alphabetical order, and the PTs will be presented in alphabetical order within 
each SOC.
The number and percentage of subjects experiencing TEAEs will be summarized.
9.2.2
Adverse Event Overview
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
●
Any TEAE
●
Any grade 3 TEAE
●
Any grade 4 TEAE
●
Any TEAE with grade 3, or 4
●
Any TEAE with grade 3, 4 or 5
●
Any serious TEAE
●
Any TEAE with reasonable possibility related to navitoclax assessed by the 
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●
Any TEAE with reasonable possibility related to ruxolitinib assessed by the 
investigator
●
Any TEAE leading to discontinuation of navitoclax 
●
Any TEAE leading to discontinuation of ruxolitinib
●
Any TEAE leading to interruption of navitoclax
●
Any TEAE leading to interruption of ruxolitinib
●
Any TEAE leading to dose reduction of navitoclax
●
Any TEAE leading to dose reduction of ruxolitinib
●
Any TEAE leading to death
●
All deaths
●
Deaths occurring ≤ 30 days after last dose of navitoclax
●
Deaths occurring > 30 days after last dose of navitoclax
9.2.3
Treatment-Emergent Adverse Events by MedDRA SOC 
and/or PT
TEAEs listed in Section 9.2.2 will be summarized by MedDRA SOC and PT; Specific 
adverse events will be counted once for each subject for calculating percentages, unless 
stated otherwise.  In addition, if the same adverse event occurs multiple times within a 
subject, the highest grade and level of relationship to investigational product will be 
reported.
In addition, TEAEs will be summarized by PT and sorted by decreasing frequency for 
Cohort 1, and summarized by MedDRA SOC, PT and maximum NCI CTCAE grade.
9.2.4
SAEs (including deaths) and Adverse Events Leading to 
Death
SAEs (including deaths) and AEs leading to death will be summarized by MedDRA SOC 
and PT and in listing format.
 


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9.2.5
Safety Topics of Interest
Safety topics of interest will be identified using the search criteria in Appendix E.
Selected AEs will be summarized by SOC and PT.  The same overview summary as for 
TEAEs and a listing of subjects' data will be provided for each search.
In addition to the searches listed in Appendix E, the torsade de pointes/QT prolongation 
search will be provided. Following analysis may be provided using SMQ Torsade de 
Pointes/QT Prolongation (Broad) search criteria: The incidence of the events by preferred 
term, the same overview summary as for TEAEs and a listing of subjects' data.
9.2.5.1
Time to Onset
Time to onset of the safety topics of interest will be summarized using summary statistics 
(N, mean, standard deviation, median, minimum, and maximum).  Time to onset is 
defined as the time from first dose of Navitoclax to the first occurrence of the event.  
Time to onset will be summarized for each defined event as well as first Grade ≥ 3 event.  
The distribution of time to onset will be summarized for the time period as described in 
Section 6.2.  The time periods may be adjusted to account for sparse data in later time 
periods if necessary.
Additionally, summary statistics (number of subjects, mean, standard deviation, median, 
minimum, and maximum) will be generated for time (in days) to first TEAE leading to 
dose reduction and time (in days) to first TEAE leading to dose interruption.
9.2.5.2
Incidence and Prevalence by Time
Incidence and prevalence for each PT within the search and overall incidence may be 
provided for the time periods based on time from Day 1 of the study treatment to the 
occurrence of the event described in Section 6.2.  The 30 days TEAE window will be 
applied and grouped into the last time period for each subject.  The time periods may be 
adjusted to account for sparse data in later time periods if necessary.
 


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For each time period, the incidence for any given PT will be calculated as follows:
●
The numerator for each time period will be the number of subjects who had the 
first occurrence of an adverse event in that time period
●
The denominator for each time period will be the number of subjects who took 
at least one dose of navitoclax in the time period and did not experience an 
event within any previous period
●
Incidence for each time period = numerator/denominator.
For each time period, the prevalence for any given PT will be calculated as follows:
●
The numerator for each time period will be the number of subjects who had an 
occurrence of an adverse event in that time period or in a previous time period 
and that was ongoing in the current time period
●
The denominator for each time period will be the number of subjects who took 
at least one dose of navitoclax in the time period.
●
Prevalence for each time period = numerator/denominator.
For each TEAE search, a plot capturing the incidence and prevalence (by time period) will 
be displayed.
9.2.5.3
Transfusion Requirements During Study Treatment
Number of subjects who received at least a total of two units (total number of transfusion 
units) of PRBC transfusion or any Platelet transfusions after first dose of Navitoclax to 
30 days after last dose of Navitoclax will be summarized by Transfusion type (platelet, 
PRBC). The Total number of transfusions (Sum of number of transfusion) among all 
subjects will be summarized.
 


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9.3
Analysis of Laboratory Data
9.3.1
Analysis of Shift from Baseline
Data collected from central and local laboratories, including additional laboratory testing 
due to an SAE, will be used in all analysis of laboratory data. Data collected after 30 days 
of last dose of study treatment will be excluded in the analysis of laboratory data.
For shifts relative to National Cancer Institute Common Toxicity Criteria for Adverse
Events, baseline and Maximum post-baseline laboratory observations will be categorized 
as grade 0, grade 1, grade 2, grade 3, or grade 4 according to NCI CTCAE grading. The 
baseline grade is defined as the grade of the last measurement collected on or prior to the 
first dose of study treatment (except baseline hemoglobin – See Section 7.2.2). In cases 
where multiple values are collected on the same day, the minimum grade and maximum 
grade value will be selected as the baseline grade and postbaseline grade, respectively, for
that day. The maximum NCI toxicity grade value is the value with highest NCI toxicity 
grade collected after the first dose of study treatment.
For each graded laboratory test, shift tables will be generated that cross tabulate the 
number of subjects with baseline values of grade 0, grade 1, grade 2, grade 3, or grade 4 
versus maximum or final values of grade 0, grade 1, grade 2, grade 3, or grade 4.
The separate laboratory shifts tables from baseline to the maximum value post baseline 
based on the two criteria below will be generated for each laboratory tests related to 
CTCAE:
●
Shifts from Grade 0 (Normal) at baseline to Grade 1 - 4 Post-baseline 
(maximum), or worsening from an abnormal baseline value of at least one 
grade post- baseline (maximum).
●
Shifts from Grade 0 - 2 at baseline to Grade 3 or 4 Post-baseline (maximum) 
and from grade 3 at baseline value to Grade 4 post-baseline (maximum).
 


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For above shift tables, baseline grade of 0 (normal) will be imputed for all subjects with at 
least one post-baseline but missing a baseline value for each lab test. In above shift table
subjects with a grade 4 baseline value will not be included.
A listing of all relevant laboratory parameters will be provided for each subject who has 
Grade 3 or higher.  All measurements collected, regardless of the number of days after the 
last dose of study treatment, will be included in these listings.
9.3.2
Analysis of Key Laboratory Parameters
For key lab parameters platelet count, lymphocytes, neutrophils, hemoglobin, total 
bilirubin, ALT, AST, and alkaline phosphatase, box plots of laboratory values will be 
displayed at baseline, 1, 4, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96 weeks for each cohort.
9.4
Assessment of Potential Drug-induced Liver Injury
Elevations relative to the upper limit of normal (ULN) in alanine transaminase (ALT), 
AST, total bilirubin, and alkaline phosphatase as outlined in the FDA Guidance for 
Industry6 pertaining to premarketing clinical evaluations for drug-induced liver injury 
(DILI) will be summarized using the maximum post baseline values.  Laboratory values 
collected no more than 30 days following the last date of study treatment will be used in 
the analysis.
The number and percentage of subjects in each Cohort who have at least one observed 
post baseline value meeting the following criteria will be tabulated:
●
ALT: > 3 ×, > 5 ×, > 10 ×, or > 20 × ULN
●
AST: > 3 ×, > 5 ×, > 10 ×, or > 20 × ULN
●
Total bilirubin > 1.5 ×, > 2 × ULN
●
Alkaline phosphatase > 1.5 × ULN
●
ALT and/or AST > 3 × ULN and total bilirubin > 1.5 × ULN at any day
●
ALT and/or AST > 3 × ULN and total bilirubin > 2 × ULN at any day
 


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●
ALT and/or AST > 3 × ULN and total bilirubin > 2 × ULN within 72 hours 
(3 days)
●
ALT and/or AST > 3 × ULN and total bilirubin > 2 × ULN at the same day
An evaluation of Drug Induced Serious Hepatotoxicity (eDISH) plot of the maximum 
post-baseline ALT value (as a multiple of ULN) vs. the maximum post baseline total 
bilirubin value (as a multiple of ULN), not necessarily concurrent, will also be utilized to 
assess for potential hepatotoxicity.  Reference lines will be included at 3 × ULN for ALT 
and at 2 × ULN for total bilirubin.  A similar eDISH plot will be presented for AST vs. 
total bilirubin.
A listing of liver function tests for subjects with observed ALT and/or AST (> 3 × ULN) 
accompanied by total bilirubin (> 2 × ULN) at any time on study will be provided.
9.5
Analysis of Vital Signs
Change from baseline in vital signs will be summarized.  Vital signs values collected no 
more than 30 days following the last date of study treatment will be used in the analysis.
9.6
Analysis of ECG Parameters
A listing will be prepared that will include details about all abnormal ECG findings.
9.7
Safety Subgroup Analyses
The incidence of treatment-emergent AEs overview, by SOC and PT, and selected AEs 
will be assessed for the subgroups defined below:
●
Type of MF (PMF, SMF)
●
Age (18 - < 65 years, ≥65 years)
 


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10.0
Other Analyses
10.1
PK Endpoints
PK samples will be collected following the schedule in protocol Table 7 and Table 8 and 
will be analyzed for navitoclax and ruxolitinib concentrations.  The PK parameters of 
maximum observed plasma concentration (Cmax), the time to Cmax (peak time, Tmax), and 
the area under the plasma concentration-time curve (AUC) from time 0 to the time of the 
last measurable concentration (AUCt) will be determined using non-compartmental 
methods for intensive PK visits (Cohort 1a Week 0 Day 1 for navitoclax and ruxolitinib; 
drug-drug interaction sub cohort within Cohort 1b Week 0 Day 0 for ruxolitinib and 
Week 0 Day 7 for navitoclax and ruxolitinib; Cohort 2 Week 0 Day 1 for navitoclax).  
Other parameters for navitoclax, such as the terminal phase elimination rate constant (β)
and the area under the plasma concentration-time curve from time 0 to infinite time 
(AUC∞) will be determined if the data warrants.
10.2
Main Analyses of PK Endpoints
The analyses of PK endpoints are summarized in following:
●
Tabulation and Summary Statistics
Plasma concentrations of navitoclax and ruxolitinib and their available pharmacokinetic 
parameter values will be tabulated by Cohort and visit.  Summary statistics will be 
computed for each sampling time and each parameter.  Significant pharmacokinetic 
sample time deviations will be identified and listed.
●
Cohort 1b Sub-Study:  Assess the Effect of Navitoclax on Ruxolitinib PK
A repeated measures model will be performed to assess the effect of navitoclax on 
ruxolitinib PK for the following ruxolitinib pharmacokinetic parameters:  the natural 
logarithms of Cmax, AUCt and AUCinf (if appropriate).  The model will include regimen 
 


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(navitoclax in combination with ruxolitinib and ruxolitinib alone) as a fixed effect and 
each subject will be considered as a random effect.
The bioavailability of ruxolitinib in combination with navitoclax relative to ruxolitinib 
alone will be estimated.  Point estimates and corresponding 90% CIs for the ratio of 
ruxolitinib in combination with navitoclax to ruxolitinib alone will be provided.  
Additional analyses may be performed if useful and appropriate.
11.0
Interim Analyses
There is no planned interim analysis.  However, when all subjects from each Cohort 
complete Week 24 disease assessment, or discontinue from study, whichever occurs first, 
primary efficacy analysis will be performed for the corresponding Cohort along with 
summaries for efficacy and safety data from other cohorts.
11.1
Data Monitoring Committee
The study does not have an independent data monitoring committee (DMC), therefore 
safety or efficacy data will be reviewed by the Sponsor.
12.0
Overall Type-I Error Control
There is no formal multiplicity testing will be performed to control type-I error rate in this 
study.
 


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13.0
Version History
Table 8.
SAP Version History Summary
Version
Date
Summary
1.0
24 Nov 2020
Original version
1.1
16 Jun 2021
1.
Clarify exclusion of data beyond new anti MF therapy, 
PD in primary/secondary efficacy analyses.
2.
Clarify BL TSS definition.
3.
Clarify BL Hemoglobin calculation.
4.
Update the definition of anemia response and 
corresponding duration.
5.
Clarify missing data handling in PRO data.
6.
Add regression analyses of SVR35W24 vs baseline DIPSS 
prognostic variables.
7.
Add subgroup analyses by age group.
8.
Add subgroup analyses for DIPSS INT-1 pts in Cohort 1.
9.
Clarify TEAE criteria for AEs on Day 1 and AEs with 
missing/incomplete dates.
10. Add AESI overview summary.
11. Add AE leading to death summary.
12. Add PK set.
13. Add clinically notable QT summary.
14. Add blood pressure shift summary.
15. Update safety topics of interest table.
16. Clarify sample size per protocol amendment.
17. Other editorial changes.
2.0
27 Sep 2021
1.
Efficacy evaluable set added
2.
SVR35W24 analysis window extended to accommodate 
schedule challenges due to COVID19.
3.
Restrict data up to 30 days post last dose of study drug 
for anemia response and duration of anemia response.
4.
Modification of duration of anemia response derivation.
5.
Modify the missing data handling for spleen length to be 
consistent with SVR.
6.
Other editorial changes.
2.1
18 Oct 2021
1.
Modify the definition of duration of SVR35 to 
incorporate other objective measure which may indicates 
the end of response. 
2.
Update safety topics of interest table. 
 


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Version
Date
Summary
3.0 draft
08 May 2022
1.
Modify anemia response, duration of anemia response
2.
Modify PFS and OS
3.
Remove analysis of vital signs
4.
Modify PRBC transfusion analysis
5.
Modify TSS Week 24 derivation
3.0
09 Jan 2023
1.
Fix typo in version 3 draft
2.
Efficacy evaluable set removed
4.0
31 Jan 2023
1.
Add DIPSS+ score at study entry
14.0
References
1.
Tefferi A, Cervantes F, Mesa R, et al.  Revised response criteria for myelofibrosis:  
International Working Group-Myeloproliferative Neoplasms Research and 
Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report.  
Blood.  2013;122(8):1395-8.
2.
Mesa RA, Schwager S, Radia D, et al.  The Myelofibrosis Symptom Assessment 
Form (MFSAF):  an evidence-based brief inventory to measure quality of life and 
symptomatic response to treatment in myelofibrosis.  Leuk Res.  
2009;33(9):1199-203.
3.
Thiele J, Kvasnicka HM, Facchetti F, et al.  European consensus on grading bone 
marrow fibrosis and assessment of cellularity.  Haematologica.  
2005;90(8):1128-32.
4.
Guidance for Industry:  Pharmacokinetics in Patients with Impaired Renal Function 
– Study Design, Data Analysis, and Impact on Dosing and Labeling.  US Food and 
Drug Administration Center for Drug Evaluation and Research.  March 2010.
5.
Ramalingam SS, Kummar S, Saranopoulos J, et al.  Phase I study of vorinostat in 
patients with advanced solid tumors and hepatic dysfunction:  a National Cancer 
Institute Organ Dysfunction Working Group Study.  J Clin Oncol.  
2010;28(29):4507-12.
 


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6.
Guidance for Industry:  Drug-Induced Liver Injury:  Premarketing Clinical 
Evaluation.  US Food and Drug Administration Center for Drug Evaluation and 
Research.  July 2009.
 


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Appendix A.
Protocol Deviations
The number and percentage of subjects who reported at least one of the following 
protocol deviation categories will be provided.
●
Subject entered into the study even though s/he did not satisfy entry criteria.
●
Subject developed withdrawal criteria during the study and was not 
withdrawn.
●
Subject received wrong treatment or incorrect dose of study treatment.
●
Subject took prohibited concomitant medication.
 


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Appendix B.
IWG/MRT/ELN Response Criteria for Myelofibrosis1
Table B-1.
Summary of Response Criteria
Response 
Category
Response Requirements
Bone Marrow
Peripheral Blood
Clinical
Complete 
Remission (CR)

Age-adjusted 
normocellularity

< 5% blasts

Grade ≤ 1 MF

Hgb ≥ 10 g/dL

Neutrophils ≥ 1 × 109/L

Platelets ≥ 100 × 109/L

< 2% immature myeloid cells

Resolution of disease 
symptoms

Spleen/Liver not palpable

No evidence of EMH
Partial 
Remission (PR)
Not Applicable

Hgb ≥ 10 g/dL

Neutrophils ≥ 1 × 109/L

Platelets ≥ 100 × 109/L

< 2% immature myeloid cells

Resolution of disease 
symptoms

Spleen/Liver not palpable

No evidence of EMH
OR

Age-adjusted 
normocellularity

< 5% blasts

Grade ≤ 1 MF

Hgb ≥ 8.5 g/dL

Neutrophils ≥ 1 × 109/L

Platelets ≥ 50 × 109/L

< 2% immature myeloid cells

Resolution of disease 
symptoms

Spleen/Liver not palpable

No evidence of EMH
Clinical 
Improvement
The achievement of anemia, spleen or symptom response without progressive disease or 
increase in severity of anemia, thrombocytopenia or neutropenia*
Anemia 
Response
Transfusion-independent (baseline Hgb < 10 g/dL):  Hgb increase ≥ 2 g/dL
Transfusion dependent:  becoming transfusion independent**
Spleen 
Response
A baseline splenomegaly that is palpable at 5 – 10 cm below the LCM, becomes not 
palpable***A baseline splenomegaly that is palpable at > 10 cm below the LCM, decreases by 
≥50%***MRI showing ≥ 35% SVR
Symptoms 
Response
≥ 50% reduction in MF-SAF TSS
Stable Disease
Belonging to none of the above response categories
EMH = extramedullary hematopoiesis; LCM = left costal margin
*
Increase in severity of anemia constitutes the occurrence of new transfusion dependency or a ≥ 2 g/dL decrease in 
Hgb from pretreatment baseline that lasts for ≥ 12 weeks. Increase in severity of thrombocytopenia or neutropenia 
is defined as a 2-grade decline, from pretreatment baseline, in platelet count or ANC.  In addition, assignment to 
Clinical Improvement requires a minimum platelet count of ≥ 25 × 109/L and ANC ≥ 0.5 × 109/L.
**
Transfusion dependency before study enrollment is defined as transfusions of at least 6 units of packed red blood 
cells (PRBC), in the 12 weeks prior to study enrollment.  In addition, the most recent transfusion episode must 
have occurred in the 28 days prior to study enrollment.  Response in transfusion-dependent patients requires 
absence of any PRBC transfusions during any consecutive "rolling" 12-week interval during the treatment phase.
*** Requires confirmation by MRI with a ≥ 35% SVR.
 


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Table B-2.
Summary of Cytogenetic Remission
Cytogenetic Remission 
Category
Cytogenetic Remission Requirements
At least 10 metaphases must be analyzed Requires confirmation by 
repeat testing within 6 months
Complete Cytogenetic 
Remission
Eradication of a preexisting abnormality
Partial Cytogenetic 
Remission 
≥ 50% reduction in abnormal metaphases (to qualify for PR:  must have 
≥ 10 abnormal metaphases at baseline)
Table B-3.
Summary of Molecular Remission
Molecular Remission 
Category
Molecular Remission Requirements
Must be analyzed in peripheral blood granulocytes Requires confirmation by 
repeat testing within 6 months
Complete Molecular 
Remission
Eradication of a pre-existing abnormality
Partial Molecular 
Remission 
≥ 50% decrease in allele burden (to qualify for PR: must have ≥ 20% mutant 
allele burden at baseline)
 


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Table B-4.
Summary of Progression/Relapse Criteria
Progression/Relapse 
Category
Progression/Relapse Criteria
Progressive Disease
At least 1 of the following:

Appearance of a new splenomegaly that is palpable at least 5 cm 
below the left costal margin (LCM)*

A ≥ 100% increase in palpable distance below LCM, for baseline 
splenomegaly of 5 – 10 cm*

A 50% increase in palpable distance below LCM, for baseline 
splenomegaly of > 10 cm*

MRI showing a ≥ 25% increase in spleen volume from baseline

Leukemic transformation confirmed by a bone marrow blast count 
of ≥ 20%

A peripheral blood blast content of ≥ 20% associated with an 
absolute blast count of ≥ 1 × 109/L that lasts for at least 2 weeks
Relapse
At least 1 of the following:

No longer meeting criteria for at least Clinical Improvement after 
achieving Complete Response, Partial Response or Clinical 
Improvement

Loss of anemia response persisting for ≥ 1 month

Loss of spleen response persisting for ≥ 1 month
Cytogenetic/Molecular 
Relapse
Re-emergence of a pre-existing cytogenetic or molecular abnormality 
that is confirmed by repeat testing
LCM = left costal margin
*
Requires confirmation by MRI with a ≥ 25% increase in spleen volume from baseline.
 


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Appendix C.
Patient-Reported Outcome (PRO) Assessments
MFSAF Version 4.0
MFSAF v4.0 is a symptom diary in which patients rate the following seven MF 
symptoms:  fatigue, night sweats, abdominal discomfort, pruritus, pain under the ribs on 
the left side, early satiety, and bone pain on a daily basis using a scale from 0 (absent) to 
10 (worst imaginable).  The TSS ranges from 0 to 70 and is calculated by summing up the 
scores from the following 7 questions.  The detailed analysis window will be provided in 
the SPP.
●
How Severe Was Worst Bone Pain
●
How Severe Was Worst Fatigue
●
How Severe Was Worst Itching (Pruritus)
●
How Severe Was Worst Night Sweats
●
How Severe Was Worst Abdominal Discomfort
●
Worst Feel Fullness After Beginning Eat (early satiety)
●
Worst Pain Under Ribs Left Side
For each subject, the score will be calculated at each day of a week, and the weekly score 
is calculated by averaging the total scores across all available days in the week.  It is 
important to note that, at least 4 days of scores are required to calculate the weekly score.  
However, for baseline score for subjects enrolled under Amendment 7 or before, at least 
one day of scores are required.
A total of 15 of 7-day period TSS (Table C-1) can be considered as Week 24 TSS. The 
final TSS at Week-24 is the average of 7-day period closest to the Week 24 nominal 
period.
 




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EORTC QLQ-C30
HRQoL and symptoms will be assessed with the EORTC-QLQ-C30 version 3 published 
in 2001.  The QLQ-C30 is 30-item subject self-administered questionnaire composed of 
both multi-item and single-item measures on a four-point scale, with 1 as "not at all" 
and 4 as "very much."  The scoring algorithms for scales will follow the scoring manual, 
except for the summary score defined below.
The EORTC QLQ-C30 Summary Score is calculated by averaging all calculated domain 
scores excluding scores from the domains of Global Health Status and Financial 
Difficulties.  The summary score will be calculated if all of the required 13-domain scores 
are available. Symptom scales will be subtracted from 100 before averaging for summary 
score calculation.
Patient Global Impression of Change
The Patient Global Impression of Change (PGIC) scale will be utilized to assess patients' 
perceptions of change in their myelofibrosis symptoms over time.  Patients during study 
visits will answer the following question:  "Since the start of the treatment received in this 
study, your myelofibrosis symptoms are (1) Very much improved, (2) Much improved, 
(3) Minimally improved, (4) No change, (5) Minimally worse, (6) Much worse, (7) Very 
much worse."
PROMIS Fatigue Short Form (SF) 7a
PROMIS® is a system of highly reliable, precise measures of patient-reported health 
status for physical, mental, and social well-being.  PROMIS instruments measure 
concepts such as pain, fatigue, physical function, depression, anxiety and social function.  
Fatigue will be assessed using the PROMIS Fatigue SF 7a that has been developed and 
validated for use in oncology populations.  The PROMIS Fatigue SF 7a is a seven-item 
questionnaire that assesses the impact and experience of fatigue over the past 7 days. The 
recommended minimum important difference range is 3 – 5 points; the lower bound (3) is 
being used as the minimum important difference in this study.  Five response options for 
 


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question 1-6 are:  1 = Never, 2 = Rarely, 3 = Sometimes, 4 = Often, and 5 = Always, 
whereas question 7 has reversed response options.
Overall total score for PROMIS Fatigue is derived from raw scores according to the 
scoring manual of PROMIS Fatigue SF 7a.  The symptom sub-domain of the PROMIS 
Fatigue SF 7a includes items 1-3 and the Impact domain includes items 4-7.  The scoring 
for each sub-domain is calculated as the averaging the raw scores.
 


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Appendix D.
Bone Marrow:  Grading Myelofibrosis
Table D-1.
Consensus on Grading of MF
Grading
Description
MF-0
Scattered linear reticulin with no intersections (cross-overs) corresponding to normal 
bone marrow
MF-1
Loose network of reticulin with many intersections, especially in perivascular areas
MF-2
Diffuse and dense increase in reticulin with extensive intersections, occasionally with 
only focal bundles of collagen and/or focal osteosclerosis
MF-3
Diffuse and dense increase in reticulin with extensive intersections with coarse bundles 
of collagen, often associated with significant osteosclerosis.
 


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Appendix E.
Safety Topics of Interest
Safety Topics of Interest
Type of 
MedDRA
Query
Broad or
Narrow
Search
Search Criteria
Thrombocytopenia
PT
PTs: 
10043554 Thrombocytopenia
10035528 Platelet count decreased 
Neutropenia
PT
PTs:
10016288 Febrile neutropenia
10029354 Neutropenia
10029366 Neutrophil count decreased
Hemorrhagic Events
SMQ
Narrow
SMQ 20000038 Hemorrhages 
Serious Hemorrhagic Events 
Concurrenta with a Grade 3 or 4 
Thrombocytopenia
SMQ/PT
Narrow
SAEs in the Hemorrhagic Events search 
concurrent with a Grade 3 or 4 AE in 
the Thrombocytopenia search
Serious Infections
SOC
SAEs in the SOC of Infections and 
Infestations 
Serious Infections Concurrenta with 
Grade 3 or 4 Neutropenia
SOC/PT
SAEs in the Serious Infections search 
concurrent with a Grade 3 or 4 AE in 
the Neutropenia search
Drug-Induced Liver Injury (DILI)b
SMQ
Broad/
Narrow
SMQs:
20000006 Drug Related Hepatic 
Disorders – Comprehensive (Broad)
20000007 Drug Related Hepatic 
Disorders – Severe Events Only 
(Narrow)
Skin Cancer or Second 
Malignancies
SMQ
Narrow
SMQs:
20000173 Skin Neoplasms, Malignant 
and Unspecified 
20000194 Malignant tumours 
a.
An AE will be considered concurrent with the cytopenia event if the onset of the event was no more than 7 days 
prior to the onset of the cytopenia event and no more than 7 days after the end of the cytopenia event.
b.
The Drug Related Hepatic Disorders – Comprehensive SMQ (20000006) includes all PTs in the Drug Related 
Hepatic Disorders - Severe Events Only SMQ (20000007).  Summaries will be provided for each SMQ.