A Multicenter, Open-Label, Pilot Study of Alisertib (MLN8237), a Novel Inhibitor of Aurora Kinase A, in Adult Patients With Relapsed/Refractory Acute Megakaryoblastic Leukemia or Myelofibrosis (Including Primary and Post-Essential/Post-Polycythemic Myelofibrosis)
Phase: NA
Conditions: Acute Megakaryoblastic Leukemia, Myelofibrosis, Primary Myelofibrosis
Sponsor: Northwestern University

Amendment 8 March  17, 2017
i
A Multicenter, Open-Label, Pilot Study of Alisertib (MLN8237), A Novel 
Inhibitor of Aurora Kinase A, in Adult Patients with 
Relapsed/Refractory Acute Megakaryoblastic Leukemia or 
Myelofibrosis (Including Primary and Post-Essential/Post-
Polycythemic Myelofibrosis)
Sponsor/Principal Investigator:
Brady L. Stein, MD
Northwestern University Feinberg School of Medicine
Division of Hematology/Oncology
645 N. Michigan Ave, Suite 1020
Chicago, IL 60611
Phone: 312-695-6832
Fax: 312-695-7814
bstein@nmff.org 
NU Sub-Investigator(s):
Jessica Altman, MD
Olga Frankfurt, MD
Shira Dinner, MD
John Crispino, PhD
Participating Site(s):
University of Miami 
Mayo Clinic
Ronan T. Swords, MD, PhD
Naseema Gangat, MD
1475 NW 12th Ave
Division of Hematology
Hope Lodge 311
200 1st Street SW
Sylvester Comprehensive Cancer Center
Rochester, MN 55905
Miller School of Medicine
Phone: 507-284-0527
Miami, FL 33136
gangat.naseema@mayo.edu 
Phone: 305-243-3084
Fax: 305-243-5239
RSwords@med.miami.edu 
Biostatistician:
Alfred Rademaker, PhD
rademaker@northwestern.edu 
IND Number:
127315
IND Holder:
Brady Stein, MD
Funding Source: 
Leukemia & Lymphoma Society
Takeda 
Version Date:
March 17, 2017(Amendment 8)
Lead Site:
Clinical Research Office
Robert H. Lurie Comprehensive Cancer Center 
Northwestern University
676 N. St. Clair, Suite 1200
Chicago, IL  60611
www.cancertrials.northwestern.edu
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TABLE OF CONTENTS
LIST OF ABBREVIATIONS ............................................................................................................1
STUDY SUMMARY .........................................................................................................................2
STUDY SCHEMA ............................................................................................................................4
1.0
INTRODUCTION – BACKGROUND & RATIONALE..........................................................5
1.1
Disease Background .......................................................................................................5
1.2
Pre-clinical Data: Megakaryocytes, AMKL, and PMF......................................................5
1.3
Aurora Kinase A as a Target for Cancer Therapy ...........................................................6
1.4
Preclinical Experience with Alisertib................................................................................7
1.5
Clinical Experience with Alisertib.....................................................................................8
1.6
Rationale for the Current Study.....................................................................................10
2.0
OBJECTIVES & endpoints...............................................................................................11
2.1
Primary Objective & Endpoint........................................................................................11
2.2
Secondary Objectives & Endpoints ...............................................................................11
2.3
Exploratory Objectives & Endpoints ..............................................................................11
3.0
PATIENT ELIGIBILITY......................................................................................................12
3.1
Inclusion Criteria – AMKL Patients................................................................................12
3.2
Inclusion Criteria – MF Patients.....................................................................................13
3.3
Exclusion Criteria – All Patients.....................................................................................14
4.0
TREATMENT PLAN ..........................................................................................................15
4.1
Overview........................................................................................................................15
4.2
Treatment Administration ..............................................................................................15
4.3
Dose Modifications & Delays.........................................................................................16
4.4
Management of Clinical Events.....................................................................................17
4.5
Concomitant Medications/Treatments ...........................................................................19
4.6
Duration of Therapy.......................................................................................................20
4.7
Duration of Follow Up....................................................................................................20
4.8
Termination of Study Treatment and/or Study as a Whole............................................20
5.0
STUDY PROCEDURES.....................................................................................................21
5.1
Schedule of Events for MF Patients ..............................................................................21
5.2
Schedule of Events for AMKL Patients..........................................................................24
6.0
Endpoint assessment......................................................................................................26
6.1
Primary Endpoint ...........................................................................................................26
6.2
Secondary Endpoints ....................................................................................................26
7.0
ADVERSE EVENTS ..........................................................................................................26
7.1
Adverse Event Monitoring .............................................................................................26
7.2
Definitions & Descriptions..............................................................................................26
7.3
Adverse Event Reporting...............................................................................................28
8.0
DRUG INFORMATION ......................................................................................................30
8.1
Alisertib..........................................................................................................................30
9.0
CORRELATIVE STUDIES.................................................................................................33
9.1
Sample Collection..........................................................................................................33
9.2
Transport/Shipment .......................................................................................................33
9.3
Processing and Analysis ...............................................................................................33
10.0
STATISTICAL CONSIDERATIONS ..................................................................................34
10.1
Statistical Analysis.........................................................................................................34
10.2
Sample Size and Accrual ..............................................................................................35
11.0
STUDY MANAGEMENT....................................................................................................35
11.1
Institutional Review Board (IRB) Approval and Consent...............................................35
11.2
Amendments .................................................................................................................35
11.2
Registration Procedures................................................................................................36
11.3
Instructions for Participating Sites .................................................................................36
11.4
Data Submission and Monitoring/Auditing.....................................................................36
11.5
Adherence to the Protocol.............................................................................................37
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11.6
Investigator Obligations.................................................................................................37
11.7
Publication Policy ..........................................................................................................38
REFERENCES ..............................................................................................................................39
Appendix I – International Working Group Response Criteria for AML .................................40
Appendix II – Revised IWG-MRT & ELN Response Criteria for MF.........................................41
Appendix III – CYP 1A2, 2C9, 2C19, 3A4 and UGT 1A1/2/8 Inhibitors and Inducers .............44
Appendix IV – Protocol History of changes ............................................................................444
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LIST OF ABBREVIATIONS
AE
Adverse Event
AMKL
Acute megakaryoblastic leukemia
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AURKA
Aurora A kinase
BID
Twice per daily
CBC
Complete Blood Count
CMP
Comprehensive Metabolic Panel
CR
Complete Response
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
DLT
Dose Limiting Toxicity
ECOG
Eastern Cooperative Oncology Group
H&PE
History & Physical Exam
IV (or iv)
Intravenously
MF
Myelofibrosis
MTD
Maximum Tolerated Dose
NCI
National Cancer Institute
ORR
Overall Response Rate or Objective Response Rate
OS
Overall Survival
PD
Progressive Disease
PFS
Progression Free Survival
PO (or p.o.)
Per os/by mouth/orally
PR
Partial Response
SAE
Serious Adverse Event
SD
Stable Disease
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STUDY SUMMARY
Title
A Multicenter, Open-Label, Pilot Study of Alisertib (MLN8237), A Novel 
Inhibitor of Aurora Kinases, in Adult Patients with Relapsed/Refractory 
Acute Megakaryoblastic Leukemia or Myelofibrosis (Including Primary 
and Post-Essential/Post-Polycythemic Myelofibrosis)
Short Title
Alisertib in Relapsed/Refractory AMKL or MF
Version
March 17, 2017
Study Design
Pilot, two-arm, open-label, multicenter
Study Center(s)

Northwestern University – Robert H. Lurie Comprehensive Cancer 
Center (Lead Site)

Miami University – Sylvester Comprehensive Cancer Center

Mayo Clinic
Objectives
Primary
The primary objective will be to determine the safety profile of alisertib in 
patients with AMKL and in patients with MF. 
Secondary
The secondary objective will be to determine preliminary efficacy of 
alisertib in each population.
Exploratory
Exploratory objectives will include the following:
1.
Describe pharmacodynamics (PD) effects of alisertib in 
peripheral blood and/or bone marrow samples.
2.
Evaluate the relationship between biomarker expression levels 
and response to alisertib.
3.
Evaluate reduction in splenomegaly by palpation (MF arm only)
4.
Evaluate improvement in MF symptoms (MF arm only), as 
assessed by the Myeloproliferative Neoplasm Symptom 
Assessment form (MPN-SAF)
Sample Size
24 total (Maximum 24 subjects, regardless of the disease breakdown of 
MF or AMKL. If all 24 were MF, that would be acceptable).
Diagnosis & Key 
Eligibility Criteria
1.
Confirmed diagnosis of one of the following (as defined by the World 
Health Organization criteria):
a.
Relapsed/refractory acute megakaryoblastic leukemia 
(AMKL)
b.
Myelofibrosis (MF), including primary and post-essential/post-
polycythemic myelofibrosis
2.
Age 18 years or older with ECOG status of 0-2.
3.
Estimated life expectancy of at least 6 months.
*Please see Section 3.0 for complete list, including disease-specific 
criteria for each arm.
Treatment Plan
Alisertib will be administered orally BID on days 1-7 of each cycle (1 cycle 
= 21 days). The starting total daily dose (level 1) for all patients will be 50 
mg BID. Intra-patient dose de-escalations (in -10 mg BID increments 
down to 30 mg BID) may be used in the event that 50 mg BID is too toxic. 
Patients may continue to receive alisertib treatment until progression of 
disease or unacceptable toxicity. 
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Statistical Methodology
All adverse events (AEs) will be summarized using frequencies and 
percentages. Data on type, timing, frequency and attribution of AEs will 
be included. To determine preliminary efficacy, response (defined as 
having at least PR in evaluable patients) will be reported as a proportion 
and 95% confidence interval using exact binomial methods.  Proportions 
for clinical response (defined as having at least PR or stable disease) will 
also be calculated. Please refer to Section 10 for more information 
regarding analysis plan for exploratory objectives. Approximate standard 
errors for the estimated response rate when the true response rate is 
10% are +/- 6% with a sample of 24 patients total, +/- 18% with a sample 
of 18 patients, +/- 9% with 12 patients and +/- 10% to 12% with 6 
patients.  
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STUDY SCHEMA
Patients with relapsed/refractory AMKL 
Patients with relapsed/refractory MF
Treatment with alisertib, 50 mg BID* orally on days 1-7 of each cycle (1 cycle = 21 days).
*Intra-patient de-escalations (in -10 mg BID increments down to 30 mg BID) are permitted if 
needed to manage toxicity.
Response Assessment 
(will be per IWG Criteria by disease – see appendices)
Continue treatment until disease progression or unacceptable toxicity.
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1.0
INTRODUCTION – BACKGROUND & RATIONALE
1.1
Disease Background
1.1.1
Acute Megakaryoblastic Leukemia (AMKL)
Acute Myeloid Leukemia (AML) is a heterogeneous disorder with respect to 
morphology, membrane phenotype, cytogenetics, gene expression profiling and 
natural history. Standard therapy has remained unchanged for the past 4 
decades. According to MRC data, there has been little improvement in survival 
patients for patients with AML during a 30-year period, and improvements noted 
have been largely due to the use of more intensive regimens and better 
supportive care. Within AML, Acute megakaryoblastic leukemia (AMKL) occurs in 
both adults and children but is an uncommon disease comprising approximately 
3–5% of cases of AML. Patients with AMKL present with pancytopenia, 
especially thrombocytopenia, although some may have thrombocytosis. 
Dysplastic features in neutrophils and platelets may be present. Organomegaly, 
e.g. hepatosplenomegaly, is usually infrequent. Morphologically, although AMKL 
may be associated with fibrosis, the histopathology of the biopsy varies from 
cases with a uniform population of poorly differentiated blasts to a mixture of 
poorly differentiated blasts and maturing dysplastic megakaryocytes. A variable 
degree of reticulin fibrosis may be present. Clinically, outcomes for patients with 
AMKL are dismal. Even for those considered eligible for stem cell transplantation, 
the majority will succumb to their disease. Newer more effective therapies are 
urgently needed.
1.1.2
Myelofibrosis (MF)
Myelofibrosis (MF) is a clonal disease of hematopoietic stem cells. It is 
characterized by cytopenias, a leukoerythroblastic blood picture, marrow fibrosis, 
and extramedullary hematopoiesis. Allogeneic hematopoietic cell transplantation 
(HCT) is the only curative treatment for patients with MF at present. Due to 
significant morbidity and mortality associated with HCT, divergent opinions have 
emerged about the application of HCT in MF. Significant regimen-related 
toxicities, graft failure and graft-versus-host disease are major barriers to the 
success of HCT in MF. Since the majority of patients that present with MF are 
older and not transplant candidates, the majority of MF patients will not be cured 
of their disease. Outside of SCT, the goals of therapy in MF are entirely palliative 
and relate to symptoms control. One non-transplant therapy is approved for this 
disease and clinical trials of novel agents are critical.  
1.2
Pre-clinical Data: Megakaryocytes, AMKL, and PMF
Megakaryocytes undergo a modified form of the cell cycle termed endomitosis, in which 
cells skip the late stages of mitosis to become polyploid. Murine and human 
megakaryocytes commonly reach modal ploidy states of 32N and 16N, respectively, and 
can sometimes achieve DNA contents as high as 128N. Polyploidization is associated 
with upregulation of megakaryocyte lineage specific genes, proplatelet formation and 
expression of genes related to apoptosis. Importantly, the choice of a megakaryocyte to 
undergo polyploidization and differentiation is inextricably linked to exit from the 
proliferative cell cycle. Thus, hyperproliferation of megakaryocyte precursors is 
associated within impaired polyploidization and differentiation. 
There are two major hematologic disorders that are characterized by aberrant expansion 
of immature megakaryocytes. The first is AMKL, a rare (3-5%) subtype of AML in which 
megakaryoblasts continue to proliferate and fail to commit to polyploidization or 
differentiation. Outcomes for adult patients with AMKL are dismal. A second malignancy 
with abnormal megakaryocytes is MF, a clonal myeloproliferative neoplasm (MPN) that is 
characterized by fibrotic destruction of the bone marrow accompanied by immature 
megakaryocytes. MF megakaryocytes display defective maturation and an immature 
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gene expression program, and they likely directly contribute to the fibrotic process by 
secreting increased levels of cytokines, including TGF-β.[1] As a consequence of the 
failure of the bone marrow to support normal hematopoiesis, blood cell development 
occurs within the spleen and liver, where it is less effective. Patients with PMF suffer from 
anemia and are at risk of transformation to AML. There are approximately 12,000 PMF 
patients in the US. Recent molecular studies have shown that JAK2 and MPL mutations 
are associated with approximately 50% and 10% of PMF cases respectively[2], while 
most of the remaining patients harbor mutations in calreticulin.[3, 4] Although the JAK 
inhibitor ruxolitinib was approved for MF[5], it primarily provides symptomatic relief. 
Moreover, many patients are intolerant or progress in spite of therapy.[6] Additional 
treatments to be used alone or in combination with ruxolitinib are clearly needed. Another 
disorder with immature megakaryocytes that fail to mature properly is myelodysplastic 
syndrome (MDS). MDS is distinct from the AMKL and MF in that megakaryocytes do not 
appear to be drivers of the disease.
Given that AMKL blasts are hyperproliferative and fail to undergo differentiation or 
polyploidization, we hypothesized that small molecule inducers of polyploidization would 
drive these cells to exit the proliferative cell cycle and undergo terminal differentiation. In 
collaboration with the Broad Institute, we performed a high throughput cell-based screen 
and identified small molecules that induce polyploidization and proliferative arrest of 
malignant megakaryocytes, including those that have MPL or JAK2 mutations. We have 
shown that these compounds, including dimethylfasudil (diMF), selectively increase 
polyploidization, expression of megakaryocyte cell surface markers, and apoptosis of 
megakaryocytes and that diMF blocked the growth of primary human AMKL. Given that 
diMF is known to inhibit multiple kinases, we next performed a multi-pronged target 
identification approach to uncover the specific target of diMF in malignant 
megakaryocytes. These approaches included a biochemical assay, two shRNA screens 
of the kinome, and a SILAC-based proteomic study. Integration of these data revealed 
that aurora A kinase (AURKA) is a major target of diMF[7], and we found that the 
selective AURKA inhibitor alisertib (MLN8237) is a potent anti-AMKL agent. We 
hypothesize that MLN8237 will provide therapeutic benefit to AMKL as well as MF 
patients. In contrast, since these compounds induce polyploidization, but not platelet 
production, they are not an appropriate therapy for MDS.
1.3
Aurora Kinase A as a Target for Cancer Therapy
The Aurora kinases are highly conserved serine/threonine kinases that regulate 
chromosomal alignment and segregation during mitosis and meiosis.[8] Aurora A and 
Aurora B are expressed in all actively dividing cells, while Aurora C expression is largely 
restricted to dividing germ cells.[9] The major function of Aurora A is to coordinate 
centrosome maturation, bipolar spindle assembly and chromosome separation. The 
AURKA gene is located within a region of chromosome 20q13 that is amplified in many 
malignancies. The evidence supporting AURKA as a therapeutic target for the treatment 
of malignancies comes from several sources.  First, the AURKA gene is amplified, 
overexpressed, or both in many tumors, including colon, breast, pancreatic, and bladder 
cancers, as well as certain lymphomas, leukemias, and myeloma.[10-14]  Aurora A 
overexpression in human cancers has been correlated with increased aneuploidy and 
centrosome amplification.[15]  Second, forced overexpression of Aurora A kinase in 
experimental models results in the transformation of normal cells, suggesting that Aurora 
A overexpression may be oncogenic.[10]  Lastly, in a number of different experimental 
systems, Aurora A inhibition leads to mitotic delays and severe chromosome alignment 
and segregation defects, followed by cell death.[16-19]  Overall, the essential role of 
Aurora A in mitotic progression and its dysregulation in certain cancers makes it an 
attractive therapeutic target. 
A variety of AURKA inhibitors have been tested in patients with varied results. The first 
generation drugs showed anti-tumor activity in patients, but also showed unacceptable 
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toxicity. Development of VX-680 was terminated due to its severe toxicities. Given the 
obligatory role of mitosis in tumor proliferation, an AURKA inhibitor would be expected to 
have potential applications across a broad range of human tumors. Indeed, alisertib has 
demonstrated activity against a variety of nonclinical solid tumor and hematological 
malignancy models grown in vitro and in vivo, as described below. Alisertib is also 
expected to be toxic to proliferating normal tissues, such as the bone marrow, 
gastrointestinal epithelium, and hair follicles because any cell that is in mitosis, where 
Aurora A is expressed and active, should be susceptible to the effects of an Aurora A 
kinase inhibitor.
1.4
Preclinical Experience with Alisertib
1.4.1
In Vitro Studies
MLN8237 is a second generation, ATP-competitive, and reversible inhibitor of 
AURKA in vitro with an inhibition constant (Ki) of 0.43 nM.[20] The data from both 
enzymatic and cell-based assays demonstrated that alisertib is a selective and 
potent inhibitor of AURKA. Alisertib inhibited proliferation of a wide variety of 
tumor cell lines grown in culture. Moreover, treatment of tumor cell lines with 
alisertib induced phenotypes consistent with AURKA inhibition, including mitotic 
spindle defects, mitotic delay, and apoptosis.[10-14] Treatment of cells with 
alisertib causes defects in bipolar spindle assembly resulting in chromosomal 
segregation abnormalities. In addition, cells treated with Aurora A inhibitors arrest 
in mitosis due to activation of the mitotic checkpoint. 
1.4.2
In Vivo Studies
Alisertib demonstrated antitumor activity when administered orally on a daily 
basis for approximately 21 days (maximal tumor growth inhibition [TGI] > 90%) in 
several experimental human solid and hematologic tumor models grown as 
xenografts in immunocompromised mice. The maximally efficacious dose (ED) 
for each model varied: between 10 and 30 mg/kg if given once daily (QD) and 20 
mg/kg if given twice daily (BID). Studies in the HCT-116 colon tumor model 
showed that less frequent dosing (eg, 5 days on followed by 5 days off) was also 
efficacious, demonstrating that continuous dosing is not necessary for antitumor 
activity. A single oral dose of alisertib given to nude mice bearing subcutaneous 
HCT-116 human colon tumors resulted in inhibition of activated AURKA and an 
increase in mitotic cells. Therefore, mitotic index (MI) can be used as a 
pharmacodynamic marker of alisertib in some in vivo settings. The relationship 
between pharmacokinetics (PK), pharmacodynamics, and efficacy was further 
studied in HCT-116 xenografts using oral dosing and subcutaneous osmotic 
mini-pumps. Both a pharmacodynamic response and efficacy (antitumor activity) 
were achieved using either route of administration. The data from these studies 
suggest that the maximum pharmacodynamic effect (mitotic accumulation) and 
efficacy are achieved at steady state plasma concentrations of 1-µM. Moreover, 
the maximally efficacious oral doses of alisertib in the HCT-116 model (30 mg/kg 
QD) resulted in plasma concentrations of 1 µM for 8 to 12 hours postdose. 
Plasma concentrations of alisertib associated with saturating levels of 
pharmacodynamic and antitumor activity (1 μM) were exceeded at the 
recommended phase 2 dose (RP2D) of alisertib in patients (50 mg BID).To 
determine whether alisertib would enhance the antitumor effects of standard of 
care agents in solid and hematologic malignancies, nonclinical combination 
studies were performed. Combination therapy with alisertib and docetaxel 
resulted in additive or synergistic effects during the dosing period, with prolonged 
tumor growth delay in multiple solid tumor xenograft models after terminating 
treatment. These effects were also observed in alternative intermittent dosing 
schedules. In DLBCL xenograft models, combination therapy with alisertib and 
rituximab resulted in synergistic, additive, or subadditive effects depending on the 
dose and model; however, prolonged tumor growth delays were observed in 
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every case after terminating treatment, and in some cases complete cures were 
maintained.
1.4.3
Safety Pharmacology, Toxicology, and Drug Metabolism
Safety pharmacology studies with alisertib did not identify significant adverse 
effects in nonclinical studies, including in the central nervous system (CNS) and 
cardiovascular systems. No alisertib-related effects on clinical signs or physical 
examination findings indicative of impaired respiratory function (ie, labored or 
shallow breathing), or microscopic changes in the lungs of animals that survived 
until scheduled termination, were noted at tolerated doses in Good Laboratory 
Practice (GLP)-compliant, repeat-dose, toxicology studies. Alisertib exhibited 
minimal activity against the rapidly activating component of IKr, which is encoded 
by hERG (IC50 and Ki > 100 µM). Alisertib had in vitro activity against the 
GABAAα1 benzodiazepine binding site (Ki = 290 nM).
The dose-limiting toxicities (DLTs) for alisertib in both rats and dogs after repeat 
daily oral dosing for 2 cycles (each cycle consisted of 7 consecutive days 
separated by a 14-day dose holiday) or for 6 cycles (each cycle consisted of 21 
consecutive days of dosing separated by a 7-day dose holiday) were consistent 
with inhibition of AURKA by alisertib. Principal findings in toxicology studies in 
rats and dogs included gastrointestinal (GI) signs, panleukopenia, decreased 
reticulocyte counts, and increased mitotic figures and apoptosis (single-cell 
necrosis) in tissues with a high basal cellular replication rate. These findings are 
indicative of toxicity to rapidly replicating cell populations and are consistent with 
the outcomes associated with Aurora A kinase inhibition. No off-target effects 
were seen in the GLP-compliant toxicology studies. Alisertib was negative in the 
bacterial reverse mutation assay (Ames assay) both in the absence and 
presence of Aroclor™ 1254-induced rat liver S9 fractions. In a rat bone marrow 
micronucleus assay, alisertib was considered to be equivocal for clastogenicity.
Alisertib is metabolized by multiple phase I (cytochrome P450 [CYP] 3A4, 
CYP2C9, CYP2C19, and CYP1A2) and phase II (uridine diphosphate 
glucuronosyltransferase [UGT] 1A1, 1A3, and 1A8) enzymes.  Using human liver 
microsomes with the appropriate cofactors, the percent contribution of CYP and 
UGT was calculated to be 13.1% and 86.9%, respectively, showing that CYP 
isozymes play a minor role in the metabolism of MLN8237.  MLN8237 is unlikely 
to inhibit the 5 major CYP enzymes, 1A2, 2C9, 2C19, 2D6, and 3A4/5 (IC50 > 
100 M) when administered at the projected human efficacious dose.  MLN8237 
is not a mechanism-based inhibitor of CYP3A4/5.  Alisertib inhibited the P 
glycoprotein (Pgp)-mediated efflux of paclitaxel (Taxol®) in Caco 2 cells with an 
IC50 of 4.0 µM.
Detailed information regarding the nonclinical pharmacology and toxicology of 
alisertib may be found in the IB.
1.5 
Clinical Experience with Alisertib
Alisertib for clinical studies is being developed in 2 dosage formulations: enteric-coated-
tablet (ECT) and oral solution (OS). The dose-escalation, phase 1 study, C14007, 
evaluated multiple dose levels from 10 to 60 mg BID for 7 days in repeat, 21-day cycles 
and 50 mg BID has been determined to be the MTD.
Alisertib is structurally related to the benzodiazepines (BZD) (eg, diazepam, lorazepam) 
and also has activity against the GABAAα1
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 BZD receptor. BZD-like effects (eg, 
somnolence, confusion, memory loss) have been observed to be associated with the 
onset of maximal plasma concentration (eg, Tmax [time to maximum plasma 
concentration]). CNS effects associated with peak plasma levels have been generally 

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9
managed by administration of divided doses (eg, BID administration), although dose 
reductions have sometimes been required. While CNS effects attributed to alisertib were 
also generally reversible and manageable by dose delay or reduction, the causal 
relationship, and thus optimal approach to management, were sometimes confounded by 
diverse causes including, but not limited to, concomitant medications (eg, narcotic 
analgesics, antianxiety medications), comorbidities (eg, infection, anemia, electrolyte 
abnormalities), or progressive malignancy (eg, brain metastases). The clinical experience 
with alisertib includes treatment with multiple doses and schedules and is summarized in 
the IB.
1.5.1
Pharmacokinetics
Upon oral administration to patients with advanced nonhematologic 
malignancies, absorption of alisertib was fast, with peak plasma concentrations 
generally achieved by 3 hours postdose. Negligible urinary excretion of alisertib 
was observed in humans. The renal clearance of alisertib in humans was less 
than 0.1% of apparent oral clearance. Steady-state plasma exposures of alisertib 
increased in an approximately dose-proportional manner over the range of 5 to 
200 mg/day in patients with advanced solid tumors. Overall mean steady-state 
terminal half-life following multiple-dose administration in patients with 
nonhematologic malignancies was approximately 22 hours. The overall mean 
peak/trough ratios were 2.6 and 5.0 for BID and QD dosing, respectively. The 
overall mean accumulation ratios were 2.8 and 1.9 for BID and QD dosing, 
respectively. Pharmacokinetic steady-state conditions were approximately 
achieved by Day 7 following daily oral administration. The PK properties of 
alisertib in patients with hematologic malignancies were generally consistent with 
those observed in patients with nonhematologic malignancies. Based on PK and 
genotype data in patients with nonhematologic malignancies, there was a 
substantial overlap in exposures (dose-normalized steady-state area under the 
plasma concentration versus time curve [AUC]) of alisertib in patients with 0, 1, 
or 2 copies of the UGT1A1 *28 allele, indicating the lack of readily apparent 
effects of UGT1A1 genotype on alisertib systemic exposure.
Clinical pharmacokinetic data available as of 20 April 2012 are summarized in 
the IB. Upon oral administration to patients with advanced nonhematologic 
malignancies, absorption of alisertib was fast, with peak plasma concentrations 
generally achieved by 2 hours post dose. Negligible urinary excretion of alisertib 
was observed in humans. The renal clearance of alisertib in humans was less 
than 0.1% of apparent oral clearance. Steady-state plasma exposures of alisertib 
increased in an approximately dose proportional manner over the range of 5 to 
200 mg/day in patients with advanced solid tumors. Overall mean steady-state 
terminal half-life following multiple-dose administration in patients with 
nonhematologic malignancies was approximately 22 hours. The overall mean 
peak/trough ratios were 2.6 and 5.0 for BID and QD dosing, respectively. The 
overall mean accumulation ratios were 2.8 and 1.9 for BID and QD dosing, 
respectively. Pharmacokinetic steady-state conditions were approximately 
achieved by Day 7 following daily oral administration. 
Based on the results of a population PK analysis in 294 adult cancer patients, the 
apparent oral clearance of alisertib CL/F was unaffected by age, body weight, 
BSA, or the UGT1A1 genotype (number of *28 alleles). These results support the 
use of a common fixed starting dose of alisertib independent of UGT1A1 
genotype status, age or body size in the adult patient population, in the ongoing 
and planned clinical trials. The absolute bioavailability of alisertib in humans has 
not been determined; however, the single-dose pharmacokinetics of a prototype 
oral solution formulation of ancomlisertib (25-mg dose) were characterized in a 
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cross-over relative bioavailability evaluation in Study C14010 in 15 patients with 
nonhematologic malignancies. 
The effect of a standardized high-fat meal on the PK of single dose alisertib 
administered as a 50-mg strength was evaluated in 14 patients with advanced 
solid tumors. The lack of an effect of food on alisertib AUCinf observed in this 
study supports the conclusion of the lack of a clinically meaningful effect of food 
on the PK of alisertib. The results of this study, therefore, support a 
recommendation that alisertib may be dosed without regard to the timing of 
meals in future clinical studies.
1.5.2
Potential Risks
Seven-hundred fourteen patients (excluding 13 patients from a company-
sponsored, non-US IND study in Japan) had been treated with alisertib as of 
March 29, 2012. Clinical safety data includes experience from patients who 
received multiple cycles followed by treatment-free periods between each cycle, 
and from patients who reduced or discontinued treatment. Based on the available 
clinical data, drug abuse, dependency, and drug withdrawal effects were not 
observed. 
To date, the observed risks associated with alisertib treatment, as detailed in the 
Safety Management Attachment of the IB, include: (1) reversible 
myelosuppression including leukopenia, neutropenia, febrile neutropenia, 
lymphopenia, thrombocytopenia, and anemia; (2) GI toxicity including 
stomatitis/mucositis/oral pain, nausea, vomiting, anorexia, abdominal pain, 
dyspepsia, diarrhea, and dehydration; (3) sedation, somnolence, confusional 
state, disorientation (and associated memory loss), and gait disturbances; (4) 
alopecia; (5) asthenia/fatigue; (6) fever, (7) infection, (8) abnormal liver function 
tests (including aspartate transaminase [AST], alanine transaminase [ALT], 
bilirubin, alkaline phosphatase [ALP], and gamma glutamyl transferase [GGT]), 
and (9) rash, which may include bullous dermatitis, and palmar-plantar 
erythrodysaesthesia syndrome. While these toxicities are potentially associated 
with risk or discomfort to the patient, they are anticipated to be reversible. 
1.6
Rationale for the Current Study
Alisertib has proven to be effective in preclinical AML studies. Treatment of AML cell 
lines, primary AML cells and mouse models of AML with alisertib decreased their viability 
and colony forming ability on soft agar and increased their apoptosis. In addition, alisertib 
treatment potentiated the anti-leukemic activity of cytarabine in both primary blasts and 
AML cell lines.[21] In humans, a phase 1/2 clinical trial reported a 13% response rate for 
alisertib in relapsed and refractory AML patients. Additionally, in this clinical trial 11% of 
patients had a partial response and 49% of patients achieved stable disease.[22] Based 
on the rarity of AMKL, however, it is highly unlikely likely that any patients with this 
subtype were included in this or other clinical studies of alisertib. Furthermore, there have 
been no studies of alisertib in MF. 
For this reason, while the safety profile is well-documented in other disease sub-groups, 
it has yet to be documented in either of these specific populations. Further, 
hematopoiesis is likely to be sufficiently disturbed in those with refractory AMKL and MF 
(often marked fibrosis and contributions toward hematopoiesis from extramedullary sites), 
increasing the risk for toxicity, necessitating a careful review of safety. More importantly, 
alisertib is being used as a differentiation agent in these two entities, and there exists a 
possibility for a unique differentiation syndrome as can be seen with Acute promyelocytic 
leukemia when using differentiation therapy. Based on these factors, we feel that a pilot 
study to assess safety of alisertib in the AMKL and MF would be appropriate. 
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In summary, our pre-clinical studies show that alisertib has potent activity against both 
AMKL and MF cell lines, primary cells and animal models. Based on these data, we 
expect that the drug will provide therapeutic benefit to patients with both AMKL and MF. 
We propose to conduct a pilot, two-arm trial of alisertib in patients with 
relapsed/refractory AMKL and MF; the overall goals of this study will be to determine the 
safety profile and preliminary efficacy of alisertib in each population.
2.0
OBJECTIVES & ENDPOINTS
2.1
Primary Objective & Endpoint
The primary objective of this pilot study is to determine the safety profile of alisertib in 
patients with AMKL and in patients with MF. 
Adverse events will be defined according to the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. The number, 
frequency, and severity of adverse events will be recorded every cycle for each 
population. All patients who receive at least 1 dose of alisertib will be considered 
evaluable for this endpoint.
2.2
Secondary Objectives & Endpoints
The secondary objective will be to determine preliminary efficacy of alisertib in both 
populations. 
Serial blood and/or bone marrow samples will be collected at specific timepoints for each 
disease (see Section 5) to determine response to alisertib treatment. Responses will be 
categorized according to the revised/modified International Working Group (IWG) 
Response Criteria. Patients who had measureable disease at baseline, receive at least 1 
cycle of treatment, and have at least one post-baseline disease assessment will be 
considered evaluable for this endpoint. Best response will be reported for all evaluable 
patients. 
2.3
Exploratory Objectives & Endpoints
Exploratory objectives will include the following:
2.3.1
Describe pharmacodynamics (PD) effects of alisertib in peripheral blood and/or 
bone marrow samples.
Serial blood and/or bone marrow samples will be collected at specific timepoints. 
Flow cytometry, colony forming assays, AURKA autophosphorylation assays, 
and in vitro cultures of patient specimens to assess the effect of MLN8237 on 
megakaryocytes and other hematopoietic cells will be measured.
2.3.2
Evaluate the relationship between biomarker expression levels and response to 
alisertib.
Changes in biomarker expression levels from baseline will be measured (using 
PD samples) to correlate with response to alisertib therapy. Biomarkers will 
include a) genes encoding key enzymes in Aurora kinase signaling, b) markers of 
cellular aneuploidy and apoptosis, and c) markers of megakaryocytic 
differentiation.
2.3.3
Evaluate reduction in splenomegaly by palpation (MF arm only).
Patients will be examined for splenomegaly by palpation once per cycle and 
change from baseline will be calculated over time.
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2.3.4
Evaluate improvement in MF symptoms (MF arm only), as assessed by the 
Myeloproliferative Neoplasm Symptom Assessment form (MPN-SAF).
The MPN-SAF will be administered to patients in the MF arm only once per 
cycle. Changes in symptom scores over time will be calculated.
2.3.5
Assess change in bone marrow fibrosis in patients in the MF arm. Bone marrow 
will be assessed at screening and after cycle 6 in this population.
3.0
PATIENT ELIGIBILITY
The target population for this study is patients with either AMKL or MF. This will be a multicenter 
trial conducted at Northwestern University, Miami University, and Mayo Clinic. Northwestern 
University will serve as the lead site and coordinating center for this study. 
MF and AMKL are rare diseases with total prevalence (total number of patients with the disease 
in the US at any time) under 15,000. NIH considers prevalence under 200,000 a rare disease. A 
total of 24 subjects  (maximum 24 subjects, regardless of the disease breakdown of MF or AMKL. 
If all 24 were MF, that would be acceptable) will be needed for this pilot trial. Approximately 4 
potentially eligible patients are seen per month, and it is anticipated that at least 1 per month will 
be accrued (once all sites are up and running). Potential patients may be referred to the Principal 
Investigator (PI) at Northwestern University, Dr. Brady Stein (312-695-6832 or 312-695-0990), to 
Dr. Ronan Swords at Miami University, or to Dr. Naseema Gangat at Mayo Clinic.
Eligibility will be evaluated according to the following criteria. Eligibility waivers are not permitted. 
Subjects must meet all of the inclusion and none of the exclusion criteria to be registered to the 
study. Study treatment may not begin until a subject is registered. Please refer to Section 11 for 
complete instructions regarding registration procedures.
3.1
Inclusion Criteria – AMKL Patients
3.1.1
Patients must have a confirmed diagnosis (by blood or bone marrow) of 
relapsed/refractory acute megakaryoblastic leukemia (AMKL), as defined by 
WHO criteria (see appendix I).
NOTE: If diagnosis was performed an outside facility, a copy of the report is 
sufficient for registration purposes; however, local pathology review at one of the 
main sites should still be obtained.
3.1.2
Patients must be age 18 or older.
3.1.3
Patients must have an ECOG status 0-2.
3.1.4
Patients must exhibit adequate organ function within 1 week (7 days) prior to 
registration, defined as:

Total bilirubin ≤ 1.5 x ULN

ALT/AST ≤ 2.5 x ULN

Creatinine < 1.5 x ULN or calculated creatinine clearance > 30 ml/min

PT and PTT ≤ 1.5 x ULN
3.1.5
Patients must have estimated life expectancy of 6 months or greater.
3.1.6
Female patients of child-bearing potential (FOCBP) must have a negative serum 
beta-HCG pregnancy test within 7 days prior to registration.
NOTE: A FOCBP is any woman (regardless of sexual orientation, having 
undergone a tubal ligation, or remaining celibate by choice) who meets the 
following criteria:

Has not undergone a hysterectomy or bilateral oophorectomy

Has had menses at any time in the preceding 12 consecutive months (and 
therefore has not been naturally postmenopausal for > 12 months)
3.1.7
Female patients must meet at least one of the following conditions:
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
Must be post-menopausal for at least 1 year prior to registration (not of child-
bearing potential as described above)

Must be surgically sterilized (as described above) 

Willing to use an acceptable method of birth control (i.e. hormonal 
contraceptive, intra-uterine device, diaphragm with spermicide, condom with 
spermicide, or abstinence) for the duration of the study.
3.1.8
Male patients, even if surgically sterilized (i.e. status post-vasectomy) agrees to 
use an acceptable method for contraception during the entire study treatment 
period through 120 days after the last dose of alisertib. Likewise, female patients 
should agree to use acceptable method for contraception during the entire study 
treatment period through 90 days after the last dose of alisertib.
3.1.9
Patients must be able to understand and willing to sign a written informed 
consent.
3.2
Inclusion Criteria – MF Patients
3.2.1
Patients must have a confirmed diagnosis (by blood or bone marrow) of 
myelofibrosis (MF), as defined by WHO criteria (see appendix II). 
NOTE: If diagnosis was performed an outside facility, a copy of the report is 
sufficient for registration purposes; however, local pathology review at one of the 
main sites should still be obtained.
3.2.2
Patients must be intermediate I risk or beyond and meet the following:

in need of treatment;

intolerant or refractory to ruxolitinib (or other investigational JAK-
inhibitors) OR unlikely to benefit from ruxolitinib

ineligible or refusal to undergo  stem cell transplantation.
3.2.3
Patients must be age ≥ 18 years.
3.2.4
Patients must have an ECOG status 0-2.
3.2.5
Patients must have adequate bone marrow and organ function within 2 weeks 
(14 days prior to registration, defined as: 

Direct bilirubin ≤ 1.5 x ULN≥

ALT/AST ≤ 2.5 x ULN

Creatinine < 1.5 x ULN or calculated creatinine clearance > 30 ml/min

PT and PTT ≤ 1.5 x ULN

ANC ≥ 1000/mm3

Platelets ≥ 50,000/mm3
Note: this must be achieved without transfusion.
3.2.6
Patients must have estimated life expectancy of 6 months or greater.
3.2.7
Female patients of child-bearing potential (FOCBP) must have a negative serum 
beta-HCG pregnancy test within 7 days prior to registration.
NOTE: See section 3.1 for definition of FOCBP.
3.2.8
Female patients must meet at least one of the following conditions:

Must be post-menopausal for at least 1 year prior to registration (not of child-
bearing potential as described above)

Must be surgically sterilized (as described above) 

Willing to use an acceptable method of birth control (i.e. hormonal 
contraceptive, intra-uterine device, diaphragm with spermicide, condom with 
spermicide, or abstinence) for the duration of the study.
3.2.9
Male patients, even if surgically sterilized (i.e. status post-vasectomy) agrees to 
use an acceptable method for contraception during the entire study treatment 
period through 120 days after the last dose of alisertib. Likewise, female patients 
should agree to use acceptable method for contraception during the entire study 
treatment period through 90 days after the last dose of alisertib.
3.2.10
Patients must be able to understand and willing to sign a written informed 
consent.
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3.3
Exclusion Criteria – All Patients
3.3.1
Patients who have received treatment with clinically-significant enzyme inducers 
 within 14 days prior to registration are not eligible. Please refer to Appendix III.
3.3.2
Patients who have received any investigational products, antineoplastic 
therapies, or radiotherapy within 14 days prior to registration are not eligible.
NOTE: Patients actively receiving hydroxyurea are eligible and may continue to 
receive hydroxyurea through cycle 1 of protocol treatment.. If the platelet count 
remains above 1 million after cycle 1, hydroxyurea can be used at the treating 
physician’s discretion, if the platelets are 1000 x 109/L, or more, or if there are 
symptoms from thrombocytosis.
3.3.3
Patients who have received prior administration of an Aurora A kinase-targeted 
agent (including alisertib) are not eligible.
3.3.4
Patients who have received corticosteroids within 7 days prior registration are not 
eligible, UNLESS the patient has been taking a continuous dose of no more than 
15 mg/day of prednisone for at least 1 month prior. 
NOTE: Low dose steroid use for control of nausea and vomiting will be allowed. 
Topical steroid use and inhaled steroids are also permitted.
3.3.5
Patients who are candidates (eligible and willing) for standard and/or potentially 
curative treatments are not eligible.
3.3.6
Patients who have had major surgery within one month (28 days) prior to 
registration are not eligible.
3.3.7
Patients within 60 days of allogenic bone transplant are not eligible; patients with 
solid organ transplant are not eligible.
3.3.8
Patients who have had grade 2 or higher diarrhea, despite optimal antidiarrheal 
supportive care, within 7 days prior to registration are not eligible.
3.3.9
Patients who have had grade 2 or higher peripheral neuropathy within 14 
days prior to registration are not eligible (must have resolved to grade 1 or lower 
to register).
3.3.10
Patients who have had a myocardial infarction within 6 months (24 weeks) prior 
to registration are not eligible. 
3.3.11
Patients who have class III or IV heart failure (as defined by the New York Heart 
Association), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or 
electrocardiographic evidence of acute ischemia or active conduction system 
abnormalities are not eligible. 
3.3.12
Patients who have known GI disease or GI procedures which could interfere with 
the oral absorption or tolerance of alisertib are not eligible. Examples include (but 
are not limited to) partial gastrectomy, history of small intestine surgery, and 
celiac disease.
3.3.13
Patients who have a known history of uncontrolled sleep apnea syndrome and 
other conditions that could result in excessive daytime sleepiness (such as 
severe chronic obstructive pulmonary disease or requirement for supplemental 
oxygen) are not eligible.
3.3.14
Patients who have a requirement for constant administration of proton pump 
inhibitor, H2 antagonist, or pancreatic enzymes are not eligible. Intermittent 
usage of antacids or H2 antagonists are allowed.
3.3.15
Patients with an active, uncontrolled systemic infection are not eligible until 
deemed controlled by the treating physician.
3.3.16
Patients who are known human immunodeficiency virus (HIV) positive are not ‘
eligible.
3.3.17
Patients who are known hepatitis B surface antigen-positive are not eligible.
3.3.18
Patients who have known or suspected active hepatitis C infections are not 
eligible.
NOTE: Patients who are hepatitis C surface antigen-positive are eligible.
3.3.19
Female patients who are pregnant or breast feeding are not eligible. 
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3.3.20
Patients who have any of the following severe acute or chronic medical or 
psychiatric conditions that may increase the risk associated with study 
participation or investigational product administration or may interfere with the 
interpretation of study results and, in the judgment of the investigator, would 
make the patient inappropriate for enrollment in this study are not eligible:

uncontrolled diabetes

malabsorption

resection of the pancreas or upper small bowel

requirement for pancreatic enzymes

any condition that would modify small bowel absorption of oral medications,

other laboratory abnormality.
3.3.21
Patients who have symptomatic CNS involvement are not eligible.
3.3.22
Patients who have been diagnosed or treated for another malignancy within 3 
years prior to registration are not eligible aside from these exceptions: completely 
resected basal cell carcinoma or squamous cell carcinoma of the skin, an in situ 
malignancy, or low-risk prostate cancer after curative therapy. If a patient had a 
prior MPN that evolved to a blast phase, but with treatment, reverted to 
Myelofibrosis at the time of screening, these pts are considered eligible at the 
discretion of the PI, if not considered suitable for stem cell transplantation.
3.3.23
Patients who are unable to swallow oral medication or are unwilling to comply 
with the administration requirements are not eligible.
4.0
TREATMENT PLAN
4.1
Overview
This will be a two arm pilot study of alisertib treatment in patients with AMKL or MF. The 
starting dose (level 1) for all patients will be 50 mg BID, administered orally on days 1-7 
of each cycle (1 cycle = 21 days), based on the MTD from previous studies. Patients may 
continue to receive cycles of alisertib until progression of disease or unacceptable 
toxicity. There will be no long-term follow-up beyond end of treatment, aside from a 
standard end of treatment visit approximately 30 days after the last dose of study drug, 
followed by a final off-study visit approximately 6 months after the last dose. Patients with 
on-going adverse events will be followed until resolution of the event(s), defined as a 
return to baseline or stabilization of the event.
4.2
Treatment Administration
Alisertib will be administered orally BID on days 1-7 of each cycle; one cycle is defined as 
21 days (days 8-21 will be rest days). Patients will be instructed to take each oral dose of 
alisertib with 8 ounces (1 cup, 240 mL) of water, with or without food. Doses on the same 
day should be taken approximately 12 hours apart (but at least 6 hours apart). All tablets 
are to be ingested whole; patients who have difficulty swallowing tablets will be excluded 
from the study. Antiemetogenic agents may be administered at the discretion of the 
investigator. Neutralizing antacids and calcium-containing supplements cannot be taken 
from 2 hours prior to alisertib dosing until up to 2 hours after dosing.
Patients will be dispensed the appropriate number of tablets required for each cycle. 
Treatment compliance will be assessed based on return of unused alisertib tablets and 
completion of a study medication diary; patients will be asked to bring completed diaries 
and pill bottles to each visit, and compliance will be reviewed by the study team each 
cycle. For MF patients only, from Cycle1-6, on Day 1 of each cycle, when the patient 
comes in for clinic visit,  they will be given study drug supply for one cycle (1 cycle=21 
days).  Beyond Cycle 6, if the patient’s condition is stable, then they will be required to 
come in on Day 1 of every odd cycle (every 6 weeks) for study visit. In that case, patients 
will be given study drug supply for 2 cycles. 
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If a dose is missed due to patient error/oversight, they will be instructed to take the dose 
within 6 hours of the normal time. If more than 6 hours have elapsed, that missed dose 
should be omitted, and the patient should resume treatment at the next scheduled dosing 
time point. All missed/omitted doses and the reason will be reported on the diary. If a 
dose is vomited, it should not be re-taken. If a dose is held due to toxicity or investigator’s 
discretion, the patient should be instructed to resume treatment at the investigators 
discretion, taking into account all of the dose modification/discontinuation guidelines 
provided below.
From Cycle1-6, in order for each new cycle of therapy to begin, MF patients must meet 
the following criteria: (if the cytopenias in AMKL patients are considered-disease 
related/due to AMKL then the following neutrophil and platelet count requirements do not 
apply. If cytopenias are considered due to the study drug, then the counts must be

ANC must be ≥ 1000/mm3

Platelet count must be ≥ 50,000/mm3

In addition, all toxicities considered to be related to therapy with alisertib must 
have resolved to ≤ Grade 1or the patient’s baseline values 
For  MF patients only, from Cycle1-6 patients will be required to come in for study visit at 
beginning of every cycle (every 3 weeks) .  Beyond Cycle 6, if the patient’s condition is 
stable, then they will be required to come in on Day 1 of every odd cycle (every 6 weeks) 
for study visit. In that case, for those visits when an MF patient is not coming to clinic for 
study visit, CBC and CMP will be done in an outside laboratory convenient for the patient, 
and results will be have to be faxed to the clinic.
 Patients can start their treatment at home only after the treating physician has reviewed 
the laboratory results and determined that they are able to continue treatment. For these 
cycles, the study coordinator will contact the patient on/prior to Day 1 to inform them if 
they can or cannot  start  the new cycle,  and  also check compliance regarding study 
drug intake. 
4.3
Dose Modifications & Delays
Any patient who receives at least one dose of study therapy will be evaluable for toxicity 
endpoints. Each patient will be assessed for the development of toxicity according to the 
timeframe referenced in Section 5). Toxicity will be evaluated according to the NCI’s 
CTCAE v 4. To manage excessive toxicity, reduction of the total alisertib dose can be 
done by reducing the daily dose administered and/or by interruption of the schedule 
treatment within a cycle.
In general treatment delays of up to 1 week for any reason are permitted. If a patient fails 
to meet the above-cited criteria for a new cycle of therapy, then initiation of the next cycle 
should be delayed for up to 1 week. At the end of that week, the patient should be re-
evaluated to determine whether the criteria for retreatment have been met.  Should 
treatment need to be delayed for more than 1 week because of incomplete recovery from 
treatment-related toxicity, the dose of alisertib will be reduced (see table below) to 40 mg 
BID when therapy resumes. A second dose reduction to 30 mg BID may occur should 
treatment need to be delayed for more than 1 week because of incomplete recovery from 
treatment-related toxicity at the 40 mg BID dose. Patients who require further dose 
reduction will be removed from the study. Should treatment need to be delayed for more 
than 2 weeks at any dose, therapy with alisertib will be discontinued.
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Dose Level
Alisertib1
Level 1
(starting dose)
50 mg
Level -1
40 mg
Level -2
30 mg
Level -3
Discontinue
1 Doses are administered orally, BID on days 1-7 of each cycle.
4.3.1
Dose Modifications for Hematological Toxicities
If a patient experiences any of the following hematological toxicities during the 
dosing period, dosing will be discontinued for the remainder of that cycle and the 
dose will be decreased by 1 level (-10 mg) for all subsequent cycles of treatment.

Grade 4 neutropenia (ANC  500 cells/mm3) lasting more than 7 consecutive 
days

Grade 4 thrombocytopenia (platelet count < 25,000/µL) lasting more than 
7 consecutive days

Platelet count less than 10,000/µL at any time

Grade 3 neutropenia with fever or infection, or both, where fever is defined 
as an oral temperature greater than 38.5C

Grade 3 thrombocytopenia with clinically significant bleeding
4.3.2
Dose Modifications for Non-hematological Toxicities
If a patient experiences any of the following toxicities during the dosing period, 
dosing will be held for the remainder of that cycle and the dose will be decreased 
by 1 level (-10 mg) for all subsequent cycles of treatment, and treatment may 
resume after drug related toxicities have resolved to ≤ Grade 1 or to baseline.

Any Grade 3 non-hematological toxicity that is considered by the investigator 
to be related to study drug other than:
o
Grade 3 or greater nausea or emesis, or both, that occurs in the 
absence of optimal antiemetic therapy (5-hydroxytryptamine 3 [5-
HT3] serotonin receptor antagonist);
o
Grade 3 or greater diarrhea that occurs in the absence of optimal 
supportive therapy with loperamide or a comparable anti-diarrheal;
o
Grade 3 fatigue that lasts less than 1 week

Grade 2 non-hematological toxicities that are considered by the investigator 
to be related to study drug and in the opinion of the investigator require dose 
reduction.

Any grade 4 non-hematological toxicity that is considered by the investigator 
to be related to study drug. If, in the opinion of the investigator and the DMC, 
it is in the patient’s interest to continue therapy with alisertib, the patient may 
resume therapy after recovery from a grade 4 to ≤ Grade 1 or to baseline 
values; the dose of alisertib should be reduced by at least 1 dose level for 
subsequent cycles of therapy.
When intra-patient dose reduction of alisertib is required, no re-escalation of 
dose will be permitted. If a patient requires more than 2 dose reductions, therapy 
with alisertib will be discontinued.
4.4
Management of Clinical Events
4.4.1
Nausea and vomiting
Prophylactic antiemetic therapy will not be used in this study unless it becomes 
clear that alisertib causes acute nausea and vomiting. Although this study will not 
initially employ prophylactic antiemetics, there is no prohibition against antiemetic 
use in the management of a patient who develops nausea or vomiting, or both. If 
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prophylactic antiemetic therapy is needed, 5 HT3 receptor antagonists (without 
corticosteroids) should be tried first. Because of the potential of benzodiazepines 
to cause sedation, the use of benzodiazepines for antiemetic prophylaxis should 
be reserved for patients who cannot be satisfactorily managed otherwise. 
4.4.2
Diarrhea
Antidiarrheal medications will not be used prophylactically; however, patients will 
be instructed to take loperamide, 4 mg, at the occurrence of the first loose stool 
and then 2 mg every 2 hours until they are diarrhea-free for at least 12 hours. 
During the night, patients may take 4 mg of loperamide every 4 hours. Fluid 
intake should be maintained to avoid dehydration.
4.4.3
Central nervous system effects
If a patient experiences excessive sedation believed to be related to alisertib, 
treatment with alisertib should be interrupted. Patients whose sedation is not 
considered immediately life-threatening should be carefully monitored and given 
appropriate supportive care.  Patients and family members/caregivers will be 
explicitly counseled regarding the possibility for sedation during the informed 
consent process, prior to cycle 1, and with each study visit/AE assessment. 
Patients and family members/caregivers will be counseled not to drive, operate 
heavy or dangerous machinery, or perform any other dangerous activities if they 
experience any sedation with alisertib.  
If the patient’s level of consciousness is considered to be life-threatening, 
necessary measures should be instituted to secure the airway, ventilation, and 
intravenous access. Flumazenil (Romazicon®) is a selective benzodiazepine 
receptor antagonist that is intended as an adjunct to, not as a substitute for, the 
proper management of benzodiazepine overdose. Although there is neither 
preclinical nor clinical experience with flumazenil and alisertib, the use of 
flumazenil should be considered if the level of alisertib-associated sedation is 
considered to be life-threatening. Patients treated with flumazenil should be 
monitored for resedation, respiratory depression, and other residual 
benzodiazepine effects for an appropriate period after treatment.  Continued 
monitoring is particularly important in the case of alisertib given its half-life and 
the comparatively brief half-life of flumazenil in the CNS (20-30 minutes). 
Flumazenil should be administered according to its label.
4.4.4
Differentiation syndrome
In this study, alisertib is being used as a differentiation agent in the treatment of 
AMKL and MF, and theoretically, there exists a possibility for a unique 
differentiation syndrome as can be seen with acute promyelocytic leukemia 
when using differentiation therapy.  Therefore, patients will be monitored for 
symptoms of a differentiation syndrome.  Taking from the experience in APL, 
patients will be monitored for the following symptoms or signs:  fever, peripheral 
edema, hypoxemia, respiratory distress, hypotension, renal and hepatic 
dysfunction, and serositis (shortness of breath, pleurisy, abdominal distension)  
The study team will be counseled about the presenting features of this acute 
illness.  With regard to the monitoring plan, with suspected differentiation 
syndrome, alisertib will be held.  Patients will require hospitalization for careful 
monitoring and observation.  Supportive care maneuvers will include 
supplemental oxygen for those with hypoxia, In severe cases, ventilatory support 
will be required. In the presence of volume overload, if hemodynamics permit, 
diuresis can be attempted.  Those with dyspnea or abdominal discomfort will 
require imaging to evaluate for the presence of effusion, pulmonary opacity, and 
ascites.  Patients will be assessed for the presence of coagulopathy, and if 
present, supportive care with fresh frozen plasma, platelet transfusions, or 
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cryoprecipitate will be considered.  Intravenous dexamethasone (10mg IV q12 
hours x 3 days) will be administered in those with differentiation syndrome. 
 
4.5
Concomitant Medications/Treatments
In general, the use of any concomitant medication/therapies deemed necessary for the 
care of the patient is permitted, except as specifically prohibited (see Sections 4.5.1 and 
4.5.2 below),
4.5.1
Prohibited Concomitant Medications/Treatments
The following medications and procedures are prohibited during the study:

Any antineoplastic therapy other than alisertib 

Alternative therapy, including palliative radiotherapy, for treatment of the 
patient’s malignancy 

Any investigational therapy other than alisertib

Requirement for administration of any proton pump inhibitor. Use of any PPI 
in either continued or intermittent use will be prohibited during the conduct of 
the study and patients must discontinue any use of PPI within five days prior 
to the first dose of alisertib. Patients may be administered alternative agents 
to manage gastric acidity or reflux (eg, H2 receptor antagonists, antacids) 
with exceptions described below:
o
Histamine-2 (H2) receptor antagonists are not permitted from the day 
prior (Day -1) through to the end of alisertib dosing (e.g., Day 7)

Strong UGT 1A1/2/8 and CYP 3A4, 2C9, 2C19, and 1A2 enzyme inducers or 
inhibitors, such as the enzyme-inducing antiepileptic drugs phenytoin, 
carbamazepine or phenobarbital, or rifampin, rifabutin, rifapentine unless 
medically necessary (see Appendix III)

Patients should be strongly encouraged to avoid herbal remedies, including:
o
St. John's wort (strong inducer of CYP3A4)
o
Grapefruit juice (strong inhibitor of CYP3A4)
4.5.2
Permitted Concomitant Medications/Treatments

Myeloid growth factors to treat patients with neutropenia according to the 
ASCO guidelines. 

Antiemetic agents may be administered at the discretion of the investigator 
but are not commonly required as a prophylactic agent.

Antacids are permitted; however, they should be administered more than 2 
hours before or 2 hours after administration of alisertib.  

Medications with potential CNS effects are not prohibited in this study, but it 
is recommended that their use be minimized to avoid confusion in the 
interpretation of CNS effects should they occur during the course of 
treatment with alisertib. Because of alisertib’s structural and pharmacological 
similarity to the benzodiazepines, concomitant therapy with benzodiazepines 
is discouraged but not prohibited.

Patients actively receiving hydroxyurea are eligible and may continue to 
receive hydroxyurea through cycle 1 of protocol treatment.
(Note: If the platelet count remains above 1 million after cycle 1, hydroxyurea 
can be used at the treating physician’s discretion, if the platelets are 1000 x 
109/L, or more, or if there are symptoms from thrombocytosis).

Medications that can potentially reduce or increase effectiveness of alisertib, 
UGT 1A1/2/8 and moderate CYP 3A4, 2C9, 2C19, and 1A2 enzyme inducers 
or inhibitors, should be used with caution (see appendix III). 

All other medical conditions should be treated at the discretion of the 
investigator in accordance with local community standards of medical care.
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4.6
Duration of Therapy
Patients may continue to receive alisertib treatment until any of the following occur:

Disease progression

Development of an inter-current illness that prevents further administration of 
treatment

Unacceptable adverse event(s)

Patient decides to withdraw from either study treatment or the as a whole study

The treating investigator determines that the patient should be taken off treatment for 
any reason (i.e. changes in condition, inability to comply with study treatment or 
procedures)
4.7
Duration of Follow Up
Once off treatment for any reason, patients will have an end-of-treatment visit at 
approximately 30 days after their last dose of alisertib. Patients who are experiencing on-
going toxicities at this time will continue to be followed until resolution of the toxicity 
(either return to baseline or stabilization). In addition, there will be a final off-study visit 
approximately 6 months after the last dose of treatment to assess for late-onset toxicity. 
4.8
Termination of Study Treatment and/or Study as a Whole
Patients can be taken off the study treatment and/or study as a whole at any time at their 
own request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation must be clearly 
documented on the appropriate eCRF and may include:

Patient voluntarily withdraws from treatment (follow-up permitted)

Patient withdraws consent (no follow-up permitted)

Patient is unable to comply with protocol requirements

Patient demonstrates disease progression 

Patient experiences unacceptable toxicity 

Patient experiences treatment delay of > 2 weeks due to toxicity 

Treating physician determines that continuation on the study would not be in the 
patient’s best interest

Patient becomes pregnant 

Patient develops a second malignancy that requires treatment which would interfere 
with this study

Patient develops an intercurrent illness that interferes with study treatment.

Patient becomes lost to follow-up (LTF) 
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5.0
STUDY PROCEDURES
5.1
Schedule of Events for MF Patients
Baseline
On-Treatmenti
Off-Treatment
Screening
Cycle 1a
Cycles 2-6q
+/- 2 days
Cycle 
7+m
+/- 2 
days
EOT 
Visito
EOS 
Visitp
D1i
D4
(+/-
1d)
D8
(+/-2 d)
D15
(+/-2 
d)
D1i
D15
D1
Informed consentv
X
Medical historyr
X
Physical examb
X
X
X
X
X
X
X
X
ECOG statuss
X
X
X
X
X
X
X
X
Vital signsc
X
X
X
X
X
X
X
X
12-lead ECGd
X
Hematologye,t
X
X
X
X
X
X
X
X
X
X
Chemistryf,t
X
X
X
X
X
X
X
X
X
X
DIC screeng,t
X
PT(INR)/aPTTg
X
X
X
X
X
Pregnancy testh,t
X
X
Palpation for splenomegalyl
X
X
X
X
MPN-SAFl
X
X
X
X
Bone marrow biopsy & aspiratek
X
Xk
X
Bone marrow collection for PD 
studies i, j
X
Blood collection for PD studies i,j
X
X
X
X
Treatmentn
X
Adverse eventsu
X
X
X
X
X
X
X
X
Concomitant meds
X
X
X
X
X
X
X
a One cycle = 21 days. 
b Includes height (baseline only) and weight. Baseline physical exam within 14 days of registration.
c Vital signs include diastolic and systolic blood pressure, heart rate, and oral temperature;.C1D1 vital signs should be taken pre-dose(+/-30 mins) 
as well as about 2 hours(+/-30mins) post dose.
d A 12-lead ECG will be performed at baseline and thereafter only as clinically indicated. Baseline ECG within 14 days of registration

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22
e Hematology panel to include hematocrit, hemoglobin, white blood cell count with differential, and platelet count. Samples should be collected 
days 1, 4, 8, and 15 of cycle 1, days 1 and 15 of cycles 2-6, and then day 1 of all cycles thereafter (a window of +/- 2 days is permitted for 
all timepoints). See footnote t.
f Chemistry panel to include the following: BUN, creatinine, sodium, potassium, chloride, bicarbonate, glucose, uric acid, LDH, total bilirubin, direct 
bilirubin, ALP, AST (SGOT), ALT (SGPT), albumin, magnesium, phosphate, and calcium. Samples should be collected days 1, 4, 8, and 
15 of cycle1, days 1 and 15 of cycles 2-6, and then day 1 of all cycles thereafter (a window of +/- 2 days is permitted for all timepoints). 
See footnote t. Beyond Cycle 6, magnesium and phosphate testing is not required(as part of the chemistry panel).
g Disseminated intravascular coagulation (DIC) screen should include: PT/INR, aPTTt, fibrinogen, and D-dimer. Cycle 1 day 1 PT/INR/aPTT does 
not need to be performed if the screening DIC was within 3 days of this visit. If the initial DIC is positive follow-up coagulation studies 
should include the full DIC panel (rather than the PT/INR/aPTT alone). See footnote t.
             Note: Beyond Cycle 6, PT/INR,aPTT testing is not required. 
h Serum pregnancy test required for women of child-bearing potential during screening AND pre-dose on Cycle 1 day 1. Results must be available 
and negative prior to dosing. See footnote t.
i  It is strongly preferred that correlative samples be collected and shipped only on Monday – Thursday (with same day shipment preferred).  Friday 
collections/shipments should be avoided to ensure sample stability.  Since these samples are collected on Day 1 of each cycle, it is 
preferred that Day 1 visits be conducted on Monday through Thursday when correlative samples are being collected.  Sites should use the 
available windows to achieve this. Please contact the QAM if there are any questions
.j Peripheral blood (25 ml) and/or bone marrow (bone marrow only if done clinically – will collect about 10-20 ml) samples will be collected for 
determination of alisertib pharmacodynamics (PD studies). Blood samples will be collected at the start of each cycle(D1). Sample 
collection at D15 will be optional.(Samples will be collected for a maximum of 6 cycles). Correlative bone marrow samples should be 
obtained any time bone marrows are collected as clinically indicated during study participation. .  At baseline, correlative bone marrow 
collection is not mandatory for study entry. However, study team should request 3-4 unstained slides from  any prior bone marrow testing 
performed within the last year before study entry. Please refer to laboratory manual for details.
k Bone marrow aspirate and biopsy is required within 1 year prior to registration(provided the PI confirms the diagnosis and there is no suspicion 
for acceleration to blast phase),on C7D1 (+/-14 days)  and thereafter only as clinically indicated.
l Palpation for splenomegaly and MPN-SAF will be done only on MF patients. Baseline MPN-SAF and palpation for Splenomegaly within 14 days 
of registration
m   Beyond Cycle 6, if the patient’s condition is stable, then they will be required to come in only on Day 1 of every even cycle (every 6 weeks) for 
study visit. In that case, for those visits when patient is not coming to clinic for study visit, CBC and CMP only will be done in an outside 
laboratory convenient for the patient, and results will be have to be  faxed to the clinic. Patients can start their treatment at home only after 
the treating physician has reviewed the laboratory results and determined that they are able to continue treatment. For these cycles, the 
study coordinator will contact the patient on/prior to Day 1 to inform them if they can or cannot  start  the new cycle,  and  also check 
compliance regarding study drug intake.
n Patients will be administered orally on days 1-7 of each cycle (1 cycle = 21 days); patients may remain on treatment until development of 
unacceptable toxicity or progression of disease.
o Patients will have an end of treatment (EOT) visit approximately 30 days (+10 days) after the last dose of treatment; if a bone marrow was 
carried out at disease progression, this will be considered the EOT marrow and does not need to be repeated at the EOT visit.
p Patients will have a final end of study (EOS) visit approximately 6 months (+/- 30 days) after the last dose of treatment to assess for late-onset 
toxicity.

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23
q Labs required only on days 1 and 15 of cycles 2-6, but in the event of cycle 1 toxicity or at treating investigator’s discretion, additional interim labs 
  may be performed per standard of care.
r Baseline Medical History within 14 days of registration
s Baseline ECOG Status within 14 days of registration.
t Baseline Hematology, Chemistry, DIC screen, Pregnancy Test, within 14 days of registration
u Baseline Adverse Events and Concomitant Medications within 14 days of registration.
vInformed consent should be obtained  within 28 days of registration.

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24
 5.2
Schedule of Events for AMKL Patients
 
Baseline
On-Treatmenti
Off-Treatment
Screening
Cycle 1a  
Cycles 2-6p
+/- 2 days
Cycle 7+l 
+/- 2 days
EOT 
Visitn
EOS 
Visito
D1i
D4
(+/-1d)  
D8
(+/-2 d)
D15
(+/-2 d)
D1i
D15
Informed consentv
X
Medical historyq
X
Physical examb
X
X
X
X
X
X
X
X
ECOG statusr
X
X
X
X
X
X
X
X
Vital signsc
X
X
X
X
X
X
X
X
12-lead ECGd
X
Hematologye,s
X
X
X
X
X
X
X
X
X
X
Chemistryf,s
X
X
X
X
X
X
X
X
X
X
DIC screeng,s
X
PT(INR)/aPTTg
X
X
X
X
X
Pregnancy testh,s
X
X
Bone marrow biopsy & aspiratek
X
X
X
X
Bone marrow collection for PD 
studies i, j
X
Blood collection for PD studies i,j
X
X
X
X
Buccal swab (Optional)u
X
Treatmentm
X
Adverse eventst
X
X
X
X
X
X
X
X
Concomitant meds
X
X
X
X
X
X
X
a One cycle = 21 days
b Includes height (baseline only) and weight. Baseline physical Exam within 14 days of registration.
c Vital signs include diastolic and systolic blood pressure, heart rate, and oral temperature;  C1D1 vital signs should be taken pre-dose(+/-30 mins) 
as well as about 2 hours(+/-30mins) post dose.
d A 12-lead ECG will be performed at baseline and thereafter only as clinically indicated. Baseline ECG within 14 days of registration
e Hematology panel to include hematocrit, hemoglobin, white blood cell count with differential, and platelet count. Samples should be collected 
days 1, 4, 8, and 15 of cycle 1, days 1 and 15 of cycles 2-6, and then day 1 of all cycles thereafter (a window of +/- 2 days is permitted for 
all timepoints). See footnote s.
f Chemistry panel to include the following: BUN, creatinine, sodium, potassium, chloride, bicarbonate, glucose, uric acid, LDH, total bilirubin, direct 
bilirubin, ALP, AST (SGOT), ALT (SGPT), albumin, magnesium, phosphate, and calcium. Samples should be collected days 1, 4, 8, and 
15 of cycle1, days 1 and 15 of cycles 2-6, and then day 1 of all cycles thereafter (a window of +/- 2 days is permitted for all timepoints). 
See footnote s.

Version Date:March 17, 2017
25
g Disseminated intravascular coagulation (DIC) screen should include: PT/INR, aPTT, fibrinogen, and D-dimer. Cycle 1 day 1 PT/INR/aPTT does 
not need to be performed if the screening DIC was within 3 days of this visit. If the initial DIC is positive follow-up coagulation studies 
should include the full DIC panel (rather than the PT/INR/aPTT alone). See footnote s.
h Serum pregnancy test required for women of child-bearing potential during screening AND pre-dose on Cycle 1 day 1. Results must be available 
and negative prior to dosing. See footnote s.
i It is strongly preferred that correlative samples be collected and shipped only on Monday – Thursday (with same day shipment preferred).  Friday 
collections/shipments should be avoided to ensure sample stability.  Since these samples are collected on Day 1 of each cycle, it is 
preferred that Day 1 visits be conducted on Monday through Thursday when correlative samples are being collected. Sites should use the 
available windows to achieve this. Please contact the QAM if there are any questions.
j Peripheral blood (25 ml) and/or bone marrow (if done will collect about 10-20 ml) samples will be collected for determination of alisertib 
pharmacodynamics (PD studies). Samples will be collected at the start of each cycle(D1). Sample collection at D15 will be optional 
Samples will be collected for a maximum of 6 cycles . Please refer to laboratory manual for details.
k Bone marrow aspirate and biopsy will be performed at screening (within 21 days prior to registration), cycle 2 day 1, and after cycle 4 (between 
days 21 and 35). For patients not yet in CR after cycle 4, bone marrow aspirate and biopsy should be repeated after cycle 6 (between 
days 21 and 35). Thereafter bone marrows should be repeated as clinically indicated. 
l Labs and exam only required on day 1 of cycles 7 and beyond (although additional may be performed as clinically indicated).
m Patients will be administered orally on days 1-7 of each cycle (1 cycle = 21 days); patients may remain on treatment until development of 
unacceptable toxicity or progression of disease.
n Patients will have an end of treatment (EOT) visit approximately 30 days (+10 days) after the last dose of treatment; if a bone marrow was 
carried out at disease progression, this will be considered the EOT marrow and does not need to be repeated at the EOT visit.
o Patients will have a final end of study (EOS) visit approximately 6 months (+/- 30 days) after the last dose of treatment to assess for late-onset 
toxicity.
p Labs required only on days 1 and 15 of cycles 2-6, but in the event of cycle 1 toxicity or at treating investigator’s discretion, additional interim labs 
may be performed per standard of care.
q Baseline Medical History within 14 days of registration
r Baseline ECOG Status within 14 days of registration.
s Baseline Hematology, Chemistry, DIC screen, Pregnancy Test, within 7 days of registration
t Baseline Adverse Events and Concomitant Medications within 14 days of registration.
u For subjects signing optional consent.
vInformed consent should be obtained  within 28 days of registration.

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26
6.0
ENDPOINT ASSESSMENT
6.1
Primary Endpoint
The primary objective of this pilot study is to determine the safety profile of alisertib in 
patients with AMKL and in patients with MF. 
Adverse events will be defined according to the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. The number, 
frequency, and severity of adverse events will be recorded every cycle for each 
population. All patients who receive at least 1 dose of alisertib will be considered 
evaluable for this endpoint.
6.2
Secondary Endpoints
The secondary objective will be to determine preliminary efficacy of alisertib in both 
populations. 
Serial blood and/or bone marrow samples will be collected at specific timepoints for each 
disease (see Section 5) to determine response to alisertib treatment. Responses will be 
categorized according to the revised/modified International Working Group (IWG) 
Response Criteria. Please refer to criteria located in the appendices. Patients who had 
measureable disease at baseline, receive at least 1 cycle of treatment, and have at least 
one post-baseline disease assessment will be considered evaluable for this endpoint. 
Response after cycle 6 (upon completion of C7D1 marrow) will be reported for all 
evaluable patients. 
7.0
ADVERSE EVENTS
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) of the 
Robert H. Lurie Comprehensive Cancer Center of Northwestern University (please refer to 
http://cancer.northwestern.edu/cro/data/DataandSafetyMonitoringPlanMay2014.pdf). The level of 
risk attributed to this study requires high intensity monitoring, as outlined in the DSMP. In 
addition, the study will abide by all safety reporting regulations, as set forth in the Code of Federal 
Regulations and as required by the NCI.  
7.1
Adverse Event Monitoring
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Adverse events are reported in a 
routine manner at scheduled times during a trial (see Section 5 for timepoints). In 
addition, certain adverse events must be reported in an expedited manner to allow for 
optimal monitoring and patient safety and care. 
All patients experiencing an adverse event, regardless of its relationship to study drug, 
will be followed until: 

the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline; 

any abnormal laboratory values have returned to baseline; 

there is a satisfactory explanation other than the study drug for the changes 
observed; or

death.
7.2
Definitions & Descriptions
7.2.1
Adverse Event
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An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an experimental intervention, whether or not related to 
the intervention. 
Recording of AEs should be done in a concise manner using standard, 
acceptable medical terms. In general, AEs are not procedures or measurements, 
but should reflect the reason for the procedure or the diagnosis based on the 
abnormal measurement. Preexisting conditions that worsen in severity or 
frequency during the study should also be recorded (a preexisting condition that 
does not worsen is not an AE). Further, a procedure or surgery is not an AE; 
rather, the event leading to the procedure or surgery is considered an AE.
If a specific medical diagnosis has been made, that diagnosis or syndrome 
should be recorded as the AE whenever possible.  However, a complete 
description of the signs, symptoms and investigations which led to the diagnosis 
should be provided. For example, if clinically significant elevations of liver 
function tests are known to be secondary to hepatitis, “hepatitis” and not 
“elevated liver function tests” should be recorded. If the cause is not known, the 
abnormal test or finding should be recorded as an AE, using appropriate medical 
terminology (e/g/ thrombocytopenia, peripheral edema, QT prolongation).
7.2.2
Severity of AEs
All non-hematologic adverse events will be graded according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The 
CTCAE v4 is available at http://ctep.cancer.gov/reporting/ctc.html
If no CTCAE grading is available, the severity of an AE is graded as follows:

Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities.

Moderate (grade 2): the event causes discomfort that affects normal daily 
activities.

Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status.

Life-threatening (grade 4): the patient was at risk of death at the time of the 
event.

Fatal (grade 5): the event caused death.
7.2.3
Serious Adverse Events (SAEs)
All SAEs, regardless of attribution, occurring from time of signed informed 
consent, through 30 days after the last administration of study drug, must be 
reported upon discovery or occurrence.
An SAE is defined in regulatory terminology as any untoward medical occurrence 
that:

Results in death.
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself.

Is life-threatening.
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The patient was at risk of death at the time of the event; it does not refer to 
an event that hypothetically might have caused death if it were more severe.

Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours.

Results in persistent or significant disability or incapacity.

Is a congenital anomaly/birth defect.

Is an important medical event.
Any event that does not meet the above criteria, but that in the judgment of 
the investigator jeopardizes the patient, may be considered for reporting as a 
serious adverse event. The event may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition of “Serious 
Adverse Event“. 
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency.
7.2.4
Unanticipated Problems Involving Risks to Subject or Others
A UPIRSO is a type of SAE that includes events that meet ALL of the following 
criteria:

Is unanticipated in terms of nature, severity, or frequency

Places the research subject or others at a different or greater risk of harm

Is deemed to be at least possibly related to participation in the study.   
7.3
Adverse Event Reporting
7.3.1
Routine Reporting
All routine adverse events, such as those that are expected, or are unlikely or 
definitely not related to study participation, are to be reported on the appropriate 
eCRF according to the time intervals noted in the appendices. Routine AEs will 
be reviewed by the Data Monitoring Committee (DMC) according to the study’s 
phase and risk level, as outlined in the DSMP. 
7.3.2
Determining if Expedited Reporting is Required
This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of 
treatment and is attributed (possibly, probably, or definitely) to the agent(s) must 
also be reported accordingly.
1)
Identify the type of adverse event using the NCI CTCAE v 4.0.
2)
Grade the adverse event using the NCI CTCAE v 4.0.
3)
Determine whether the adverse event is related to the protocol therapy.  
Attribution categories are as follows:

Definite: AE is clearly related to the study treatment.

Probable: AE is likely related to the study treatment.

Possible: AE may be related to the study treatment.

Unlikely: AE not likely to be related to the study treatment.

Unrelated: AE is clearly NOT related to the study treatment.
4)
Determine the prior experience of the adverse event.
Expected events are those that have been previously identified as 
resulting from administration of the agent. An adverse event is 
considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in:

the current protocol

the current Investigator’s Brochure
7.3.3
Expedited Reporting of SAEs/Other Events
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7.3.3.1 Reporting to the Northwestern University QAM/DMC
All SAEs must be reported to the assigned QAM within 24 hours of 
becoming aware of the event. Completion of the NU CRO SAE Form is 
required.
The completed form should assess whether or not the event qualifies as 
a UPIRSO. The report should also include:

Protocol description and number(s)

The patient’s identification number

A description of the event, severity, treatment, and outcome (if 
known)

Supportive laboratory results and diagnostics

The hospital discharge summary (if available/applicable)
All SAEs will be reported to, and reviewed by, the DMC at their next 
meeting.
7.3.3.2 Reporting to the Northwestern University IRB
The following information pertains to the responsibilities of the lead site 
(Northwestern University). Additional participating sites should follow 
their local IRB guidelines for reporting to their local IRBs.

Any death of an NU subject that is unanticipated in nature and at 
least possibly related to study participation will be promptly reported 
to the NU IRB within 24 hours of notification. 

Any death of an NU subject that is actively on study treatment 
(regardless of whether or not the event is possibly related to study 
treatment)

Any death of a non-NU subject that is unanticipated and at least 
possibly related and any other UPIRSOs will be reported to the NU 
IRB within 5 working days of notification.

All other deaths of NU subjects not previously reported, other non-
NU subject deaths that were unanticipated and unrelated, and any 
other SAEs that were not previously reported as UPIRSOs will be 
reported to the NU IRB at the time of annual continuing review.
7.3.3.3 Reporting to the FDA 
All notifications to the FDA will be handled centrally the QA team at 
Northwestern. 
The FDA will be notified within 7 calendar days of any SAE that is 
associated with study treatment, is unexpected, and is fatal or life-
threatening.
The FDA will be notified within 15 calendar days of any SAE that is 
associated with the study treatment, unexpected, and serious but not 
fatal or life-threatening. This includes any previous SAEs that were not 
initially deemed reportable, but are later determined to meet the criteria 
for reporting (i.e. by the DMC).
All other SAEs will be reported on an annual basis as part of the annual 
FDA report.
7.3.3.4 Reporting to Takeda
Regardless of expectedness or causality, all SAEs must also be reported 
to Takeda or designee:
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
Fatal and Life Threatening SAEs within 24 hours but no later 
than 4 calendar days from observation or awareness of the event

All other serious (non-fatal/non-life threatening) events 
within 4 calendar days of observation or awareness of the event
The NU CRO SAE report form will be completed and submitted for all 
SAEs requiring reporting to Takeda. Reports will include event term(s), 
serious criteria, intensity of the event(s), and causality of the event(s). 
Follow-up information on the SAE may be requested by Takeda.  
The NU PI is responsible to ensure that the SAE reports are sent to 
Takeda (or designee) from all sites participating in the study. Sub-
investigators must report all SAEs to the NU CRO QAM (as outlined 
above). NU must also provide Takeda with a copy of all communications 
with applicable regulatory authorities related to the study product(s) as 
soon as possible but no later than 4 calendar days of such 
communication.
The contact for reporting is:
Takeda or Designee
SAE and Pregnancy Reporting Contact Information
FAX Number 1-800-963-6290
Email: TakedaOncoCases@cognizant.com 
If a woman becomes pregnant or suspects that she is pregnant while 
participating in this study, she must inform the investigator and NU CRO 
QAM immediately and permanently discontinue study drug. The QAM 
must fax a completed Pregnancy Form to Takeda or designee. The 
pregnancy must be followed for the final pregnancy outcome.
If a female partner of a male patient becomes pregnant during the male 
patient’s participation in this study, the QAM must also immediately fax a 
completed Pregnancy Form Takeda or designee. Every effort should be 
made to follow the pregnancy for the final pregnancy outcome.
A product complaint is a verbal, written, or electronic expression that 
implies dissatisfaction regarding the identity, strength, purity, quality, or 
stability of a drug product.  Individuals who identify a potential product 
complaint situation should immediately contact MedComm Solutions 
(see below) and report the event. Whenever possible, the associated 
product should be maintained in accordance with the label instructions 
pending further guidance from a Takeda Quality representative.
For Product Complaints, call MedComm Solutions at:
877-674-3784 (877 MPI DRUG) 
Product complaints in and of themselves are not AEs.  If a product 
complaint results in an SAE, an SAE form should be completed and sent 
to Takeda.
8.0
DRUG INFORMATION
8.1
Alisertib
8.1.1
Other names 
MLN8237
8.1.2
Classification - type of agent
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Alisertib is an adenosine triphosphate (ATP)-competitive and reversible inhibitor 
of Aurora A kinase. 
8.1.3
Mode of action
Consistent with the mechanism of action for an Aurora A kinase inhibitor, alisertib 
treatment results in formation of abnormal mitotic spindles, an accumulation of 
mitotic cells, and a decrease in the proliferation of a broad range of tumor cell 
lines grown in culture.
8.1.4
Storage and stability
Tablets should remain in the bottle provided until use. The container should be 
stored at the investigative site at controlled room temperature (20-25°C; 68-77°F; 
excursions are permitted from 15-30C; 59-86F) and used before the retest 
expiry date provided by Takeda. Containers should be kept closed during 
storage. Patients should be instructed on proper storage, accountability, and 
administration of alisertib, including that alisertib is to be taken as intact tablets.
8.1.5
Protocol dose specifics
The starting dose for patients on both arms will be 50 mg orally BID; each day 
the doses must be taken at least 6 hours apart, with or without food.
8.1.6
Preparation
No preparation is necessary for drug used in this study. Alisertib is an 
investigational agent and therefore should be handled with due care. In case of 
contact with broken tablets, raising dust should be avoided during the cleanup 
operation. The product may be harmful by inhalation, ingestion, or skin 
absorption. Gloves and protective clothing should be worn during preparation 
and the cleanup operation. The area should be ventilated and the spill site 
washed after material pick-up is complete. The spilled material should be 
disposed of as hazardous medical waste in compliance with federal, state, and 
local regulations. In case of contact with the powder (eg, from a broken tablet), 
skin should be washed immediately with soap and copious amounts of water for 
at least 15 minutes. In case of contact with the eyes, copious amounts of water 
should be used to flush the eyes for at least 15 minutes. Medical personnel 
should be notified.
8.1.7
Route of administration for this study
Oral. Patients will be instructed to take each oral dose of alisertib with 8 ounces 
(1 cup, 240 mL) of water. All tablets are to be ingested whole; patients who have 
difficulty swallowing tablets will be excluded from the study.   
8.1.8
Incompatibilities
Patients should not drive, operate dangerous tools or machinery, or engage in 
any other potentially hazardous activity that requires full alertness and 
coordination if they experience sedation while enrolled in this study.
Patients should be instructed to limit the use of alcohol while enrolled in this 
study. Patients should consume no more than 1 standard unit of alcohol per day 
during the study and for 30 days from the last dose of alisertib. A standard unit of 
alcohol is defined as a 12 oz beer (350 mL), 1.5 oz (45 mL) of 80-proof alcohol, 
or one 6-oz (175 mL) glass of wine.
8.1.9
Availability & Supply 
IRB #: STU00200682 Approved by NU IRB for use on or after 2/4/2019 through 2/3/2020.
Alisertib will be provided by Takeda and will be supplied as 10 mg ECT, with the 
dose strength expressed as milligrams of active drug (free acid). Alisertib ECT 
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coil, induction seal, desiccant packs, and a polypropylene child resistant cap. 
Patients will be instructed on the home use of alisertib, including the requirement 
that alisertib be administered as intact tablets.
8.1.10
Side effects
Common
In prior clinical trials, the following have been considered as emerging as a 
consequence of the treatment in ≥ 10% of patients:

Gastrointestinal Disorders
o
Diarrhea
o
Nausea
o
Stomatitis 
o
Vomiting
o
Constipation
o
Abdominal discomfort

Hematological abnormalities
o
Neutropenia
o
Anemia
o
Thrombocytopenia
o
Febrile neutropenia

General abnormalities
o
Fatigue
o
Fever
o
Edema 
o
Asthenia
o
Infection, even in absence of neutropenia (including thrush)

Dermatological abnormalities
o
Alopecia 
o
Rash

Nervous system disorders
o
Somnolence 
o
Headache
o
Dizziness
o
Difficulty walking
o
Psychiatric illness
o
Confusional state/disorientation

Metabolic/Nutritional consequences
o
Dehydration
o
Decreased appetite
o
Low potassium and blood magnesium levels

Respiratory disorders
o
Cough
o
Difficulty breathing
In prior clinical trials, there have been also been reports of eye disorders (not 
further specified), muscle/joint disorders (back and extremity pain), and vascular 
disorders (low blood pressure, sometimes severe (“shock”)
Less common (occurring between 1% and 10% of the time):

Liver function test abnormalities 
Infrequent (occurring less than 1% of the time):

Cardiac abnormalities have been reported in 2 patients, including reduced 
cardiac function, and abnormal heart rhythm (QTc prolongation)
8.1.11
Nursing implications
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Antiemetogenic agents may be administered at the discretion of the investigator.  
Neutralizing antacids and calcium-containing supplements cannot be taken from 
2 hours prior to alisertib dosing until up to 2 hours after dosing.
9.0
CORRELATIVE STUDIES
9.1
Sample Collection
Blood and/or bone marrow samples for PD studies will be collected at multiple timepoints 
for cycles 1-6. Samples will be collected at the time of routine blood and/or bone marrow 
collection on Day 1 of each cycle. Sample collection on Day 15 will be optional. For MF 
patients, only peripheral blood samples will be collected unless bone marrow is deemed 
medically necessary; AMKL patients may include both blood and bone marrow 
procurement. Approximately 25 ml of peripheral blood and 10-20 ml of bone marrow will 
be collected in lavender top EDTA tubes and dark green top tubes respectively, and 
labeled with the patient initials, study number, and date of collection. Samples may sit at 
room temperature until they are picked up or shipped.,.
 As mentioned above, correlative bone marrow samples should be obtained any time 
bone marrows are collected as clinically indicated during study participation. At baseline, 
bone marrow collection is not required for study entry, but study team should request 3-4 
unstained slides from prior bone marrow testing performed within the last year. Unstained 
slides should be shipped at room temperature to Dr. Crispino
It is strongly preferred that correlative samples be collected and shipped only on Monday 
– Thursday (with same day shipment preferred).  Friday collections/shipments should be 
avoided to ensure sample stability.  Since these samples are collected on Day 1 of each 
cycle, it is preferred that Day 1 visits be conducted on Monday through Thursday when 
correlative samples are being collected. Sites should use the available windows to 
achieve this. Please contact the QAM if there are any questions.
9.2
Transport/Shipment
Samples will be picked up by Dr. Crispino’s lab (for NU samples) or shipped at room 
temperature by overnight courier to Dr. Crispino’s laboratory (for University of Miami and 
Mayo Clinic specimens). Samples will be shipped the day of collection(preferred), or 
within the week after collection in the event that additional samples will be collected from 
other patients in the same week. Samples will only be sent Monday through Thursday. 
Any samples collected between Thursday late afternoon and Sunday night will be 
shipped on Monday morning. 
ATTN: Crispino Laboratory
Northwestern University
303 East Superior Street
Lurie Building Room 5-250
Chicago, IL 60611
The phone number to contact Dr. Crispino’s lab for questions or to confirm receipt of 
samples is 312-503-1433. Alternatively, Dr. Crispino may be reached via email at j-
crispino@northwestern.edu. 
9.3
Processing and Analysis
Upon receipt, monocuclear cells will be collected from the samples by Ficoll preparation. 
Aliquots of the cells will be used in the following ways:
1.
To extract RNA for gene expression studies. We will determine the pathways that are 
up or down-regulated upon Alisertib treatment. We anticipate changes in cell cycle 
regulatory and megakaryocyte differentiation pathways. 
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2.
To isolate proteins for analysis of levels of key factors, such as transcription factors, 
ribosome assembly proteins, and signaling molecules. We will use western blot 
assays to determine the changes that occur with Alisertib treatment. 
3.
To perform flow cytometry will be performed to analyze the state of maturation of the 
cells, including CD41, CD42 expression and DNA content. We will use FlowJo 
software to analyze the flow cytometry data to determine the levels of these 
differentiation parameter.  
4.
To perform flow cytometry to assess the state of signaling cascades, such as the 
AKT, ERK, and STAT pathways. We will use FlowJo software to analyze the flow 
cytometry data to determine the levels of activation of these pathways.  
5.
To perform flow cytometry to assess the hematopoietic stem cell compartment. We 
will use FlowJo software to determine the different populations of hematopoietic stem 
and progenitor populations.  
6.
To culture in vitro and in vivo to assess the state and differentiation potential of 
hematopoietic progenitor cells.
7.
We may elect to use samples at a later time point to directly compare differences in 
gene expression and signaling pathways from sequential patient specimens. Thus, 
we will freeze down aliquots of cells, and/or or RNA, and/or protein for future cell 
culture, flow cytometry, DNA, RNA and protein extractions. Samples will be kept for 
up to two years.
8.
An optional correlative study (separate patient consent) will involve exome or whole 
genome sequencing on normal and tumor DNA for patients with AMKL.  DNA from 
tumor samples will be available as in line 7 above; to obtain germline DNA, buccal 
swabs will be obtained.
Samples will be labeled with a number and not the patient names. Identifying information 
will be retained by the PI and co-investigators and not shared with the laboratory staff. 
Identities of the subjects will not be reported in presentations or publications. 
Samples will be retained indefinitely in Dr. Crispino’s laboratory located at Northwestern 
University.
Please refer to laboratory manual for more details.
10.0
STATISTICAL CONSIDERATIONS
10.1
Statistical Analysis
10.1.1
Primary Endpoint
The primary objective of this pilot study is to determine the safety profile. All 
adverse events (AEs) will be summarized using frequencies and percentages. 
These percentages will be subclassified by type of AE, timing of AE in the 
treatment cycle, frequency and attribution of AEs (treatment related or not).   
10.1.2
Secondary Endpoint
To determine preliminary efficacy, response (defined as having at least PR in 
evaluable patients) will be reported as a proportion and 95% confidence interval 
using exact binomial methods. Given that this is a purely descriptive protocol, 
there is no set hypothesis regarding the response rate. Proportions for clinical 
response (defined as having at least PR or stable disease) will also be 
calculated. Please refer to appendices for detailed explanations of the clinical 
response criteria for each population.
10.1.3
Exploratory Endpoints
To describe pharmacodynamic effects, serial measures of megakaryocytes and 
other hematopoietic cells will be summarized using descriptive statistics such as 
means, medians and ranges for each time point. These measures will be plotted 
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for each patient, and these patient specific plots will be plotted for all patients 
together.  Analyses for change over time will be done using repeated measures 
general linear model analysis.
To evaluate the relationship between biomarker expression levels and response, 
changes in biomarker expression levels will be related to response using a 
Wilcoxon rank sum test. To evaluate reduction in splenomegaly by palpation in 
the MF arm, a categorical variable measuring the extent of splenomegaly will be 
tracked over time descriptively, since the small sample size will preclude 
longitudinal analysis. To evaluate improvement in MF symptoms in the MF arm, 
the Myeloproliferative Neoplasm Symptom Assessment (MPN-SAF) score will be 
summarized descriptively over time using means, medians, standard errors and 
ranges.
10.2
Sample Size and Accrual
MF and AMKL are rare diseases with total prevalence (total number of patients with the 
disease in the US at any time) under 15,000. NIH considers prevalence under 200,000 a 
rare disease. A total of 24 subjects (maximum 24 subjects, regardless of the disease 
breakdown of MF or AMKL. If all 24 were MF, that would be acceptable) will be accrued 
to this trial. Approximately 4 potentially eligible patients are seen per month at all sites, 
and it is anticipated that at least 1 per month will be accrued, leading to a 2 year accrual 
period.
. Approximate standard errors for the estimated response rate when the true response 
rate is 10% are +/- 6% with a sample of 24 patients total, +/- 18% with a sample of 18 
patients, +/- 9% with 12 patients and +/- 10% to 12% with 6 patients.  In the event that a 
patient consents and is registered to the study but never begins treatment, that patient 
may be replaced. The QAM must be notified and, if necessary, DMC approval must be 
obtained.   
11.0
STUDY MANAGEMENT
11.1
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol.
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki.
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB approved consent form.
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the 
informed consent discussion.
11.2
Amendments
The Principal Investigator will formally initiate all amendments to the protocol and/or 
informed consent. All amendments will be subject to the review and approval of the 
appropriate local, institutional, and governmental regulatory bodies, as well as by 
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Janssen Scientific Affairs. Amendments will be distributed by the lead institution 
(Northwestern) to all affiliate sites upon approval by the Northwestern University IRB.
11.2
Registration Procedures
Patients may not begin protocol treatment prior to registration. All patient registrations will 
be registered centrally through the Clinical Research Office at Northwestern University 
before enrollment to study. Please contact the assigned Quality Assurance Monitor 
(QAM) or email the QA Department (croqualityassurance@northwestern.edu) for 
questions regarding patient registration. For all potential patients, study teams are asked 
to inform the QAM of the date and time that the patient will need to be registered. 
Prior to registration, eligibility criteria must be confirmed by the assigned QAM. The study 
coordinator will screen all subjects for potential registration via the web-based application 
NOTIS (Northwestern Oncology Trial Information System), which is available at: 
https://notis.nubic.northwestern.edu. Please note that a username and password is 
required to use this program, and will be provided during site activation prior to training 
on the NOTIS system.
BEFORE a patient can be treated on study, please complete and submit the following 
items to confirm eligibility and receive an identification number:

Patient’s signed and dated informed consent form (upload to NOTIS and keep 
original hard copy in a secure location/study chart)

Eligibility checklist (signed and dated by the treating physician – upload to NOTIS)

Eligibility eCRF (complete in NOTIS)

Copy of the pathology report (upload to NOTIS)
The QAM will review all source documentation required to confirm eligibility that is readily 
available in the patient’s electronic medical record (EMR). Any information that is not 
available in the EMR must be de-identified and emailed to the QAM. Once the QAM 
confirms the patient is eligible, he or she will register the patient, assign a subject 
identification number, provide a cohort assignment, and send a confirmation of 
registration to involved personnel. Registration will then be complete and the patient may 
begin study treatment.
11.3
Instructions for Participating Sites
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Research Office at Northwestern University:

Signed and completed Letter of Invitation to participate in the study.

Signed copy of Northwestern University’s Data Monitoring Committee policy 
pertaining to data submission.

Draft informed consent form should for review/approval prior to submission to the 
local IRB

A copy of the official IRB approval letter for the protocol and informed consent. 

CVs and medical licensure for the local PI and any sub-investigators who will be 
involved in the study at the site.

Form FDA 1572 appropriately filled out and signed with appropriate documentation.
Additional activities may be required prior to site activation (i.e. contract execution, study-
specific training). Full requirements will be outlined in a memo upon receipt of the signed 
Letter of Invitation.
11.4
Data Submission and Monitoring/Auditing
Once a subject is confirmed and registered to the study, eCRFs should be submitted 
through NOTIS according to the detailed data submission guidelines (will provided in a 
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separate document). Generally, all data during the first cycle must be submitted on a 
weekly basis. Thereafter data will be due at the end of each cycle.
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) 
of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (please 
refer to Appendices for additional information). The level of risk attributed to this study 
requires high intensity monitoring, as outlined in the DSMP. The assigned QAM, with 
oversight from the Data Monitoring Committee, will monitor this study in accordance with 
the study phase and risk level. 
11.5
Adherence to the Protocol
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol. 
11.5.1
Emergency Modifications
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval. 
For any such emergency modification implemented, an IRB modification form 
must be completed within 5 business days of making the change, and the QAM 
must be notified within 24 hours of such change. 
11.5.2
Other Protocol Deviations
All other deviations from the protocol must be reported to the assigned QAM 
using the appropriate form.
A protocol deviation is any unplanned variance from an IRB approved protocol 
that: 

Is generally noted or recognized after it occurs.

Has no substantive effect on the risks to research participants.

Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected.

Did not result from willful or knowing misconduct on the part of the 
investigator(s). 
A protocol deviation may be considered an instance of RNI(Reportable New 
Information)  if it:

Has harmed or increased the risk of harm to one or more research 
participants.

Has damaged the scientific integrity of the data collected for the study.

Results from willful or knowing misconduct on the part of the investigator(s).

Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies.
11.6
Investigator Obligations
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The PI is responsible for personally overseeing the treatment of all study 
patients. The PI must assure that all study site personnel, including sub-investigators and 
other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion.
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected, entered onto the appropriate eCRFs, and submitted 
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within the study-specific timeframes. Periodically, monitoring visits may be conducted and 
the Principal Investigator will provide access to his/her original records to permit 
verification of proper entry of data. The study may also be subject to routine audits by the 
Audit Committee, as outlined in the DSMP. 
11.7
Publication Policy
All potential publications and/or data for potential publications (e.g. manuscripts, 
abstracts, posters, clinicaltrials.gov releases) must be approved in accordance with the 
policies and processes set forth in the Lurie Cancer Center DSMP. The assigned QAM 
will prepare a preliminary data summary (to be approved by the DMC) no later than 3 
months after the study reaches its primary completion date (the date that the final subject 
is examined or receives an intervention for the purposes of final data collection for the 
primary endpoint). If the investigator’s wish to obtain DMC-approved data prior to this 
point (or prior to the point dictated by study design), the PI must send a written request 
for data to the QAM which includes justification. If the request is approved, data will be 
provided no later than 4 weeks after this request approval. The data will be presented to 
the DMC at their next available meeting, and a final, DMC-approved dataset will be 
released along with any DMC decisions regarding publication. The investigators are 
expected to use only DMC-approved data in future publications. The investigators should 
submit a copy of the manuscript to the biostatistician to confirm that the DMC-approved 
data are used appropriately.  Once the biostatistician gives final approval, the manuscript 
may be submitted to external publishers.
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Chng, W.J., et al., Clinical implication of centrosome amplification in plasma cell neoplasm. 
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Katayama, H., W.R. Brinkley, and S. Sen, The Aurora kinases: role in cell transformation and 
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Marumoto, T., et al., Aurora-A kinase maintains the fidelity of early and late mitotic events in 
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17.
Glover, D.M., et al., Mutations in aurora prevent centrosome separation leading to the formation 
of monopolar spindles. Cell, 1995. 81(1): p. 95-105.
18.
Katayama, H., et al., Interaction and feedback regulation between STK15/BTAK/Aurora-A kinase 
and protein phosphatase 1 through mitotic cell division cycle. Journal of Biological Chemistry, 
2001. 276(49): p. 46219-24.
19.
Hoar, K., et al., MLN8054, a small-molecule inhibitor of Aurora A, causes spindle pole and 
chromosome congression defects leading to aneuploidy. Molecular & Cellular Biology, 2007. 
27(12): p. 4513-25.
20.
Manfredi, M.G., et al., Characterization of Alisertib (MLN8237), an investigational small-molecule 
inhibitor of aurora A kinase using novel in vivo pharmacodynamic assays. Clin Cancer Res, 2011. 
17(24): p. 7614-24.
21.
Kelly, K.R., et al., Targeting Aurora A kinase activity with the investigational agent alisertib 
increases the efficacy of cytarabine through a FOXO-dependent mechanism. Int J Cancer, 2012. 
131(11): p. 2693-703.
22.
Goldberg SL, F.P., Craig MD, Gyan E, Lister J, Kassis J, et al, Phase 2 Study of MLN8237, An 
Investigational Aurora A Kinase (AAK) Inhibitor In Patients with Acute Myelogenous Leukemia 
(AML) or Myelodysplastic Syndromes (MDS), in ASH Annual Meeting. 2010, Blood.  
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Appendix I – International Working Group Response Criteria for AML
Definitions of response criteria are based primary on those given by Cheson et al.
Category
Definition
Complete 
remission (CR)1
Bone marrow blasts <5 percent; absence of blasts with Auer rods; absence of 
extramedullary disease; absolute neutrophil count >1.0 x 109/L (1000/µL); 
platelet count >100 x 109/L (100,000/µL); independence of red cell transfusions
CR with incomplete 
recovery (CRi)2
All CR criteria except for residual neutropenia (<1.0 x 109/L (1000/µL)) or 
thrombocytopenia (<100 x 109/L (100,000/µL))
Morphologic 
leukemia-free 
state3
Bone marrow blasts <5%; absence of blasts with Auer rods; absence of 
extramedullary disease; no hematologic recovery required.
Partial remission 
(PR)
All hematologic criteria of CR; decrease of bone marrow blast percentage to 5 to 
25%; and decrease of pretreatment bone marrow blast percentage by at least 
50%.
Cytogenic CR 
(CRc)4
Reversion to a normal karyotype at the time of morphologic CR (or CRi) in cases 
with an abnormal karyotype at the time of diagnosis; based on the evaluation of 
20 metaphase cells from bone marrow.
Molecular CR 
(CRm)5
No standard definition; depends on molecular target.
Treatment failure
Resistant disease 
(RD)
Failure to achieve CR, CRi or PR; only includes patients surviving ≥7 days 
following completion of initial treatment, with evidence of persistent leukemia by 
blood and/or bone marrow examination.
Death in aplasia
Deaths occurring ≥ 7 days following completion of initial treatment while 
cytopenic; with an aplastic or hypoplastic bone marrow obtained within 7 days of 
death, without evidence of persistent leukemia.
Death from 
indeterminate 
cause
Deaths occurring before completion of therapy, or <7 days following its 
completion; or deaths occurring ≥7 days following completion of initial therapy 
with no blasts in the blood, but no bone marrow examination available.
Relapse6
Bone marrow blasts ≥ 5%; or reappearance of blasts in the blood; or 
development of extramedullary disease.
1 All criteria need to be fulfilled; marrow evaluation should be based on a count of 200 nucleated cells in 
an aspirate with spicules; if ambiguous, consider repeat exam after 5 to 7 days; flow cytometric 
evaluation may help to distinguish between persistent leukemia and regenerating normal marrow; 
a marrow biopsy should be performed in cases of dry tap, or if no spicules are obtained; no 
minimum duration of response required.
2 The criterion of CRi is of value in protocols using intensified induction or double induction strategies, in 
which hematologic recovery is not awaited, but intensive therapy will be continued. In such 
protocols, CR may even not be achieved in the course of the entire treatment plan. In these 
instances, the overall remission rate should include CR and CRi patients. Some patients may not 
achieve complete hematologic recovery upon longer observation times.
3 This category may be useful in the clinical development of novel agents within phase I clinical trials, in 
which a transient morphologic leukemia-free state may be achieved at the time of early response 
assessment.
4 Four studies showed that failure to convert to a normal karyotype at the time of CR predicts inferior 
outcome.
5 As an example, in CBF AML low-level PCR-positivity can be detected in patients even in long-term 
remission. Normalizing to 104 copies of ABL1 in accordance with standardized criteria, transcript 
levels below 10 to 12 copies appear to be predictive for long-term remission.
6 In cases with low blast percentages (5-10%), a repeat marrow should be performed to confirm relapse. 
Appearance of new dysplastic changes should be closely monitored for emerging relapse. In a 
patient who has been recently treated, dysplasia or a transient increase in blasts may reflect a 
chemotherapy effect and recovery of hematopoiesis. Cytogenetics should be tested to distinguish 
true relapse from therapy-related MDS/AML.
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Appendix II – Revised IWG-MRT & ELN Response Criteria for MF
The criteria below are a revision of the International Working Group-Myeloproliferative Neoplasms 
Research and Treatment (IWG-MRT) criteria for treatment response in myelofibrosis (MF) and represents 
a collaborative effort by the IWG-MRT and the European LeukemiaNet to objectively assess the value of 
new drugs in inducing morphologic remission or improvement in MF-associated symptomatic burden (MF-
SB).
Response Categories
Required Criteria1
CR (complete 
remission)

Bone marrow2: age-adjusted normocellularity; < 5% blasts; ≤ grade 1 
MF3 

Peripheral blood: hemoglobin ≥ 100 g/L and < ULN; neutrophil count ≥ 1 
x 109 and < ULN

Platelet count ≥ 100 x 109 and < ULN; < 2% immature myeloid cells4

Clinical: resolution of disease symptoms; spleen and liver not palpable; 
no evidence of EMH.
PR (partial remission)

Peripheral blood: hemoglobin ≥100 g/L and <UNL; neutrophil count ≥1 × 
109/L and <UNL; platelet count ≥100 × 109/L and <UNL; <2% immature 
myeloid cells4 and

Clinical: Resolution of disease symptoms; spleen and liver not palpable; 
no evidence of EMH or

Bone marrow2: Age-adjusted normocellularity; <5% blasts; ≤grade 1 
MF3, and peripheral blood: Hemoglobin ≥85 but <100 g/L and <UNL; 
neutrophil count ≥1 × 109/L and <UNL; platelet count ≥50, but <100 × 
109/L and <UNL; <2% immature myeloid cells4 and

Clinical: Resolution of disease symptoms; spleen and liver not palpable; 
no evidence of EMH
Clinical improvement 
(CI)
The achievement of anemia, spleen or symptoms response without 
progressive disease or increase in severity of anemia, thrombocytopenia, or 
neutropenia5
Anemia response

Transfusion-independent patients: a ≥ 20 g/L increase in hemoglobin 
level6

Transfusion-dependent patients: becoming transfusion independent7
Spleen response8

A baseline splenomegaly that is palpable at 5-10 CM, below the LCM, 
becomes not palpable9
OR

A baseline splenomegaly that is palpable at > 10 cm, below the LCM, 
decreases by ≥ 50%
A baseline splenomegaly that is palpable at <5 cm, below the LCM, is not 
eligible for spleen response
Symptoms response
A ≥ 50% reduction in the MPN-SAF TSS10
Progressive disease11

Appearance of a new splenomegaly that is palpable at least 5 cm below 
the LCM or

A ≥100% increase in palpable distance, below LCM, for baseline 
splenomegaly of 5-10 cm or

A 50% increase in palpable distance, below LCM, for baseline 
splenomegaly of >10 cm or

Leukemic transformation confirmed by a bone marrow blast count of 
≥20% or

A peripheral blood blast content of ≥20% associated with an absolute 
blast count of ≥1 × 10(9)/L that lasts for at least 2 weeks
Stable disease
Belonging to none of the above listed response categories.
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Relapse

No longer meeting criteria for at least CI after achieving CR, PR, or CI, 
or

Loss of anemia response persisting for at least 1 month or

Loss of spleen response persisting for at least 1 month 
Recommendations for assessing treatment-induced cytogenetic and molecular changes
Cytogenetic remission

At least 10 metaphases must be analyzed for cytogenetic response 
evaluation and
requires confirmation by repeat testing within 6 months window
CR: eradication of a preexisting abnormality
PR: ≥50% reduction in abnormal metaphases
Partial response applies only to patients with at least ten abnormal 
metaphases at baseline.
Molecular remission

Molecular response evaluation must be analyzed in peripheral blood 
granulocytes and requires confirmation by repeat testing within 6 
months window

CR: Eradication of a pre-existing abnormality

PR: ≥50% decrease in allele burden
Partial response applies only to patients with at least 20% mutant allele 
burden at baseline.
Cytogenetic/molecular 
relapse
Re-emergence of a pre-existing cytogenetic or molecular abnormality that is 
confirmed by repeat testing.
EMH, extramedullary hematopoiesis (no evidence of EMH implies the absence of pathology- or imaging 
study-proven nonhepatosplenic EMH); LCM, left costal margin; UNL, upper normal limit.
1 For all response categories, benefit must last for ≥12 wk to qualify as a response.
2 Baseline and posttreatment bone marrow slides are to be interpreted at one sitting by a central review process. 
Cytogenetic and molecular responses are not required for CR assignment.
3 Grading of MF is according to the European classification. It is underscored that the consensus definition of a CR 
bone marrow is to be used only in those patients in which all other criteria are met, including resolution of 
leukoerythroblastosis. It should also be noted that it was a particularly difficult task for the working group 
to reach a consensus regarding what represents a complete histologic remission.
4 Immature myeloid cells constitute blasts + promyelocytes + myelocytes + metamyelocytes + nucleated red blood 
cells. In splenectomized patients, <5% immature myeloid cells is allowed.
5 See above for definitions of anemia response, spleen response, and progressive disease. Increase in severity of 
anemia constitutes the occurrence of new transfusion dependency or a ≥20 g/L decrease in hemoglobin 
level from pretreatment baseline that lasts for at least 12 weeks. Increase in severity of thrombocytopenia 
or neutropenia is defined as a 2-grade decline, from pretreatment baseline, in platelet count or absolute 
neutrophil count, according to the CTCAE v 4.0. In addition, assignment to CI requires a minimum platelet 
count of ≥25 000 × 10(9)/L and absolute neutrophil count of ≥0.5 × 10(9)/L.
6 Applicable only to patients with baseline hemoglobin of <100 g/L. In patients not meeting the strict criteria for 
transfusion dependency at the time of study enrollment (see as follows), but have received transfusions 
within the previous month, the pretransfusion hemoglobin level should be used as the baseline.
7 Transfusion dependency before study enrollment is defined as transfusions of at least 6 units of packed red 
blood cells (PRBC), in the 12 weeks prior to study enrollment, for a hemoglobin level of <85 g/L, in the 
absence of bleeding or treatment-induced anemia. In addition, the most recent transfusion episode must 
have occurred in the 28 days prior to study enrollment. Response in transfusion-dependent patients 
requires absence of any PRBC transfusions during any consecutive “rolling” 12-week interval during the 
treatment phase, capped by a hemoglobin level of ≥85 g/L.
8 In splenectomized patients, palpable hepatomegaly is substituted with the same measurement strategy.
9 For the purpose of this study, spleen or liver responses must be confirmed based on palpation/physical 
examination, or ultrasound if the body habitus is prohibitive, in keeping with standard care. 
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(Note: The original criteria mandates the use of imaging studies where a ≥35% reduction in spleen 
volume, as assessed by MRI or CT, is required. Furthermore, a ≥35% volume reduction in the spleen or 
liver, by MRI or CT, constitutes a response regardless of what is reported with physical examination.)
10 Symptoms are evaluated by the MPN-SAF TSS.17 The MPN-SAF TSS is assessed by the patients themselves 
and this includes fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, 
abdominal discomfort, weight loss, and fevers. Scoring is from 0 (absent/as good as it can be) to 10 
(worst imaginable/as bad as it can be) for each item. The MPN-SAF TSS is the summation of all the 
individual scores (0-100 scale). Symptoms response requires ≥50% reduction in the MPN-SAF TSS.
11 Progressive disease assignment for splenomegaly requires confirmation my MRI or computed tomography 
showing a ≥25% increase in spleen volume from baseline. Baseline values for both physical examination 
and imaging studies refer to pretreatment baseline and not to posttreatment measurements.
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Appendix III – CYP 1A2, 2C9, 2C19, 3A4 and UGT 1A1/2/8 Inhibitors and Inducers
CYP 1A2, 2C9, 2C19, 3A4 and UGT1A1/2/8 INHIBITORS
1A2
2C9
2C19
3A4
UGT1A1/2/8
Strong

fluvoxamine

 ciprofloxacin
Weak

cimetidine
Other

amiodarone

efavirenz

fluoroquinolone
s

fluvoxamine

furafylline

interferon

methoxsalen

mibefradil
Strong 

fluconazole
Moderate

amiodarone

miconazole
Other

efavirenz

fenofibrate

fluconazole

fluvastatin

fluvoxamine

isoniazid

lovastatin

metronidazole

paroxetine

phenylbutazone

probenicid

sertraline

sulfamethoxazole

sulfaphenazole

teniposide

voriconazole

zafirlukast
Strong

fluvoxamine

ticlopidine

fluconazole
Moderate

esomeprazole 

fluoxetine  

lansoprazole

omeprazole

voriconazole
Other

pantoprazole

chloramphenicol

cimetidine

felbamate 

indomethacin 

isoniazid

ketoconazole

modafinil

oxcarbazepine

probenicid

topiramate
Strong

indinavir

nelfinavir

ritonavir

clarithromycin

itraconazole

ketoconazole

nefazodone

saquinavir

telithromycin 

grapefruit juice
Moderate

amiodarone 

aprepitant  

erythromycin

fluconazole  

verapamil

diltiazem   
Weak

cimetidine  

chloramphenicol 

boceprevir 

ciprofloxacin 

fluvoxamine 

imatinib

mibefradil 

mifepristone

norfloxacin

norfluoxetine

starfruit 

telaprevir

voriconazole

Atazanavir

Indinavir
  
CYP 1A2, 2C9, 2C19, 3A4 and UGT1A1/2/8 INDUCERS
1A2
2C9
2C19
3A4
UGT1A1/2/8
Moderate

tobacco

Phenytoin
Other

broccoli

brussel sprouts

carbanazepine

char-grilled 
meat

insulin

modafinil

omeprazole

rifampin
Strong

carbamazepine

rifampin
Other

nevirapine

phenobarbital

St. John's Wort
Strong

carbamazepine

rifampin
Moderate

norethindrone

prednisone

St. John's Wort
Strong

carbamazepine

phenytoin

rifampin

St. John's Wort
Moderate 

efavirenz

modafinil

barbiturates

prednisone

oxcarbazepine

phenobarbital

pioglitazone

rifabutin

Carbamazepine

Nicotine
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Note: for full list refer to: http://medicine.iupui.edu/clinpharm/ddis/main-table/ and 
http://www.pharmacologyweekly.com/content/pages/ugt-enzymes-medications-herbs-substrate-
inhibitor-inducer
Reference: Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of 
Medicine (2007). "http://medicine.iupui.edu/clinpharm/ddis/clinical-table/" Accessed 3/25/15.
Appendix IV – Protocol History of Changes
Original Protocol – June 02, 2015
Amendment 1 – Aug 14, 2015 
Section(s) Affected
Prior Version
Amendment 1 Changes
Rationale
Section 4.4 (Management 
of Clinical Events)
1)
Did not have explicit 
description of the 
possibility of 
sedation due to the 
study drug.
2)
N/A
1)
Included a statement 
in section 4.4.3 
(Central nervous 
system effects) that 
potential participants 
will be explicitly 
counseled during the 
consenting process 
on the possible 
effects of sedation 
due to the study drug 
and advise them 
against driving or 
operating heavy 
machinery after 
taking the drug.
2)
Included a section 
(section 4.4.4) on 
clinical management 
of differentiation 
syndrome
Based on Clinical 
deficiencies pointed out 
by FDA reviewers
Amendment 1 – Aug 14, 2015
Amendment 2 – Oct 22, 2015
Section(s) Affected
Prior Version
Amendment 2 Changes
Rationale
Sec 3.1 (Inclusion Criteria for 
AMKL patients)
3.14 -  Prior version included 
the following organ function 
tests as an inclusion criteria:  
adequate bone marrow 
function;  
ANC ≥ 1500/mm3 condition; 
Platelets ≥ 100,000/mm3; 
Hemoglobin > 9 g/dL
3.1.4 -  criteria for organ 
function tests modified to 
delete the following:
adequate bone marrow 
function
ANC ≥ 1500/mm3 condition 
Platelets ≥ 100,000/mm3
Hemoglobin > 9 g/dL
 To broaden the 
inclusion criteria and 
make the study 
available as an option 
for relapsed/refractory 
AMKL patients, who 
otherwise, have 
extremely limited 
treatment options.
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Sec 3.3.7 (Exclusion Criteria) 3.3.7 - Previous version did 
not:  specify an upper 
threshold for excluding 
patients who have had prior 
allogenic bone marrow 
transplant and did not set 
prior solid organ transplant 
as an exclusion criteria
3.3.24 – Previous 
version excluded 
patients who 
required 
administration of 
myeloid growth 
factors/platelet 
f
i
3.3.7 – changed exclusion 
criteria:
1)  to set 60 days as an upper 
threshold for exclusion of 
patients with prior allogenic 
bone marrow 
transplantation.
2) to exclude patients with 
prior solid organ transplants.
3.3.24 – deleted 
criteria to exclude 
patients with a 
requirement for 
administration of 
myeloid growth 
factors/platelet 
transfusions.
 As in the case of the 
inclusion criteria 
(above), changing this 
exclusion criteria also 
can help make the 
study available to this 
patient population.
Sec 4.2 (Treatment 
Administration)
For the statement “In order 
for each ….”,, the previous 
version did not have specific 
criteria with respect to 
cytopenias for MF and 
AMKL patients  
For the statement “In order 
for each ….”, the criteria 
was clarified to be 
applicable to MF patients. 
Also clarified the condition 
for cytopenias in AMKL 
patients.
For clarity and to 
ensure that the 
amended neutrophil 
and platelet count 
criteria can help make 
the study available to 
this patient population.
Section 5.0 (Study Procedures 
– Schdule of events 5.1 and 
5.2)
N/A
Study table footnotes 
updated to include the 
information on windows for 
baseline testing, which was 
clarified via Amnd 1 
clarification memo dt 
09.21.15 that was IRB 
approved on 10.23.15
Optional buccal swab added 
to study table for AMKL (sec 
5.2) 
To integrate 
clarification memo 
information into 
protocol amendment 2.
To incorporate 
optional correlative 
study described in sec
Sec 9.3 (Processing and 
Analysis)
N/A
Description of optional 
correlative study added.
To gain a better 
understanding of 
genetic changes 
underlying the disease.
Amendment 3 – Feb 1, 2016
Section(s) Affected
Prior Version
Amendment 3Changes
Rationale
Cover page, Study Summary, 
Sec 3.0 (Patient Eligibility), 
Sec 9.2 (Transport/Shipment)
N/A
Adds Mayo Clinic as 
affiliate site with Dr. 
Naseema Gangat as the PI 
and Dr. Ayalew Tefferi as 
co-investigator
Mayo Clinic has been 
approved as an affiliate 
site
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Amendment 4 
April 21,  2016
Section(s) Affected
Prior Version
Amendment 4 Changes
Exclusion Criteria
3.3.15
Patients who have a systemic infection 
requiring IV antibiotic therapy within 14
days prior to registration (or other severe 
infection) are not eligible.  
Patients with an active, 
uncontrolled systemic 
infection are not eligible 
until deemed controlled by 
the treating physician.
To increase 
flexibility for 
inclusion of 
such patients
Section 5.1 & 5.2
Study procedures
Footnote i
Urinalysis with
microscopic analysis
(+/-2 PD analysis)  will
be performed days 1, 4,
8, and 15 of cycle 1, days
1 and 15 of cycles 2-6,
and then day 1 of all
cycles thereafter (a
window of +/- 2 days is
permitted for all
time points). 
Removed:
 (+/-2 PD analysis)
Current language:
Urinalysis with
microscopic analysis  will
be performed days 1, 4,
8, and 15 of cycle 1,days
1 and 15 of cycles 2-6,
and then day 1 of all
cycles thereafter (a
window of +/- 2 days is
permitted for all
time points). 
Correction of 
error.
PD analysis is 
not done with 
urine
Section 5.1 and 5.2
         Windows of +/-2 for each cycle was 
mentioned in the footnotes
  Windows of +/-2 is added 
to each cycle in both table 
headings itself to increase 
clarity : e.g Cycle 1(+/-2 
days)
For clarity 
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Amendment 5
July 12,  2016
Section(s) Affected
Prior Version
Amendment 5 Changes
 Rationale
Inclusion criteria 3.1.8 and 3.2.9
Male patients, even if surgically sterilized 
(i.e. status post-vasectomy) agrees to 
use an acceptable method for contraception 
during the entire study treatment period 
through 4 months  after the last dose of 
alisertib
Male patients, even if 
surgically sterilized (i.e. 
status post-vasectomy) 
agrees to 
use an acceptable method 
for contraception during the 
entire study treatment 
period through 120 days 
after the last dose of 
alisertib. Likewise, female 
patients should agree to use 
acceptable method for 
contraception during the 
entire study treatment 
period through 90 days 
after the last dose of 
alisertib.
Per Takeda 
safety board
and current IB
Exclusion Criteria
3.3.22
Patients who have been diagnosed or treated 
for another malignancy within 3 years prior 
to registration are not eligible aside from 
these exceptions: completely resected basal 
cell carcinoma or squamous cell carcinoma 
of the skin, an in situ malignancy, or low-
risk prostate cancer after curative therapy.  
  If a patient had a prior 
MPN that evolved to a blast 
phase, but with treatment, 
reverted to Myelofibrosis at 
the time of screening, these 
pts are considered eligible 
at the discretion of the PI, if 
not considered suitable for 
stem cell transplantation.
In order to 
accommodate 
patients that fall 
within this 
disease 
spectrum
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Section 5.1
Study procedures table 
Footnote J
Peripheral blood (25 ml) and/or bone marrow 
(bone marrow only if done clinically – will 
collect about 10-20 ml) samples will be 
collected for determination of alisertib 
pharmacodynamics (PD studies). Samples 
will be collected in dark green top tubes at 
the start of each cycle and at the time of the 
Day 15 labs, for a maximum of 6 cycles (or 
12 samples total)
Removed: dark 
green top tubes.
Added: Please refer to 
laboratory manual for 
details.
To maintain 
consistency with 
the lab manual. 
Section 5.2
Footnote
Peripheral blood (25 ml) and/or bone marrow 
(if done will collect about 10-20 ml) samples 
will be collected for determination of alisertib 
pharmacodynamics (PD studies). Samples 
will be collected in dark green top tubes 
Removed: dark 
green top tubes.
Added: Please refer to 
laboratory manual for 
details 
To maintain 
consistency with 
the lab manual
at the start of each cycle 
and at the time of the Day 15 labs, 
for a maximum of 6 cycles
 (or 12 samples total).
Section 5.1 and 5.2
Windows of+/-2 days for each visit starting 
from C1D1
Windows of +/-1 day for 
D1D4 and +/- 2 
days for all 
subsequent visits. 
NO WINDOW FOR C1D1
For logistical 
convenience 
and to 
minimize 
protocol 
deviation.
No window for 
C1 D1 as it 
sets up the 
dates for 
subsequent 
visits.
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Section 9.0
Correlatives
Approximately 25 ml of peripheral blood and 
10-20 ml of bone marrow will be collected in 
dark green top tubes, and labeled with the 
patient initials, study number, and date of 
collection. Samples may sit at room 
temperature until they are picked up or 
shipped.
Approximately 25 ml of 
peripheral blood and 10-20 
ml of bone marrow will be 
collected in lavender top 
EDTA tubes and dark 
green top tubes 
respectively, and labeled 
with the patient initials, 
study number, and date of 
collection. Samples may sit 
at room temperature until 
they are picked up or 
shipped.
To maintain 
consistency with 
the lab manual
Appendix II
Footnote 9 
Spleen or liver responses must be confirmed 
using imaging studies where a ≥35% 
reduction in spleen volume, as assessed by 
MRI or CT, is required. Furthermore, a ≥35% 
volume reduction in the spleen or liver, by 
MRI or CT, constitutes a response regardless 
of what is reported with physical 
examination.
In the spleen response section of the table:
“A spleen response requires confirmation by 
MRI or computed tomography showing ≥ 
35% spleen volume reduction.”
In the spleen response section of the table:
“A spleen response requires confirmation by 
MRI or computed tomography showing ≥ 
35% spleen volume reduction.”
Footnote 9 modified.
For the purpose of this 
study, spleen or liver 
responses must be 
confirmed based on 
palpation/physical 
examination, or ultrasound 
if the body habitus is 
prohibitive, in keeping with 
standard care. 
(Note: The original criteria 
mandates the use of 
imaging studies where a 
≥35% reduction in spleen 
volume, as assessed by MRI 
or CT, is required. 
Furthermore, a ≥35% 
volume reduction in the 
spleen or liver, by MRI or 
CT, constitutes a response 
regardless of what is 
reported with physical 
examination.)
Deleted this criteria
Since this study 
is not 
performing CT 
or MRI for for 
assessment of 
spleen response
, due to limited 
resources.
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Previous amendment Summary of 
changes
(dated April 21,2016
Rationale for each change was not inserted in 
the Summary of changes.
Rationale inserted for each 
change in the Summary of 
changes
Correction of 
error and to 
maintain 
protocol/amend
ment format and 
consistency.
Amendment 6
October 12, 2016
Section(s) Affected
Prior Version
Amendment 6 Changes
 Rationale
Section 3.2.5
Eligibility criteria
Adequate bone marrow and organ function 
for eligibility included
ANC ≥1500/mm3
Platelet≥100,000/ mm3
Adequate bone marrow and 
organ function for 
eligibility included
ANC ≥1000/mm3
Platelet ≥50,000/ mm3
Given 
observations in  
NU patients, in 
keeping with 
consistency of 
active MF 
clinical trials in 
, and to include 
patients who 
may have 
limited 
treatment 
options in such 
situations
Section 4.2
Treatment administration
In order for each new cycle of therapy to 
begin, criteria that MF patients must meet 
included:

ANC must be ≥ 1500/mm3

Platelet count must be ≥ 75,000/mm3
These requirements have 
been modified to:

ANC must be ≥ 
1000/mm3

Platelet count must be 
≥ 50,000/mm3
Other language in this 
section modified to align 
with this change. 
In order to the 
make protocol 
more 
specific/explicit, 
and consistent 
across the two 
arms. This is in 
keeping with the 
relaxing of the 
inclusion 
criteria, and also 
to be consistent 
for both MK 
and AMKL 
patients
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Section 5.1 and 5.2
Urinalysis
Urinalysis was scheduled throughout the 
study
Urinalysis to be done only 
at screening. Related 
footnotes modified 
accordingly
Beyond 
screening, there 
is no use for the 
urinalysis.  
There is no 
correlative study 
that requires 
urine.
Section 3.3.2(Eligibility criteria)
& Section 4.5.2(Permitted 
Concomitant medications/treatments)
Patients actively receiving hydroxyurea are 
eligible and may continue to receive 
hydroxyurea through cycle 1 of protocol 
treatment.
Added Note: If the platelet 
count remains above 1 
million after cycle 1, 
hydroxyurea can be used at 
the treating physician’s 
discretion, if the platelets 
are 1000 x 109/L, or more, 
or if there are symptoms 
from thrombocytosis
For clarity
Section 9.1
Details about blood and bone marrow sample 
collection.
Added language:
In addition, following any 
bone marrow procedure, 
two unstained slides should 
be shipped at room 
temperature to Dr. Crispino
Laboratory manual has 
been updated accordingly.
For added 
correlative 
analysis.
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Amendment 7
December 14, 2016
Section(s) 
Affected
Prior Version
Amendment 7 Changes
 Rationale
Study summary 
and Section 
3.0(eligibility) 
and 10.2 
statistics section
Sample size : 24 total (12 with 
MF and 12 with AMKL).
24 total (Maximum 24 subjects, regardless of 
the disease breakdown of MF or AMKL. If all 
24 were MF, that would be acceptable)
To accommodate more patients 
on the MF arm, since there are 
more patients available for MF 
than for  AMKL.
Section 3.2.2
Inclusion criteria 
–MF patients
Patients must be intermediate I 
risk or beyond and meet criteria 
such as : ineligible for stem cell 
transplantation.
Modified to state that patients can be either
 “ineligible or refusal to undergo stem cell 
transplantation” 
For flexibility, so that  various 
scenarios are covered.
Section 5.1, 5.2 
and Section 9.1
 Schedule of 
Events tables 
and Correlative 
studies section.
Footnote j: Peripheral blood 
samples to determine 
pharmacodynamics of 
alisertib(correlative studies) 
were to be collected at D1 and 
D15 of each cycle for  a 
maximum of 6 cycles. 
Footnotej:The D15 sample has been made 
optional.
Also,
Footnote i reworded in tables in 5.1 and 5.2:
“ It is strongly preferred that correlative 
samples be collected and shipped only on 
Monday – Thursday (with same day shipment 
preferred).  Friday collections/shipments 
should be avoided to ensure sample stability.  
Since these samples are collected on Day 1 of 
each cycle, it is preferred that Day 1 visits be 
conducted on Monday through Thursday 
when correlative samples are being collected.  
Sites should use the available windows to 
achieve this. Please contact the QAM if there 
are any questions.”
Same language inserted in Section 9.1
For convenience of patients 
commuting long distances.
To ensure stability of correlative 
samples
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Section 5.1 and 
5.2 
Schedule of 
events tables for 
MF and AMKL 
arms
C1D1 vital signs should be 
taken before and after dosing.
Urinalysis to be done at 
screening
C1D1 vitals to be done pre-dose(+/-30 mins) 
as well as about 2 hours (+/- 30mins) post-
dose.
Urinalysis removed from screening tests. 
Related footnote removed/modified.
For clarity and convenience.
Urinalysis not required for this 
study at any point-per PI
Study summary 
and 
Section 10. 2
(Statistics) 
Approximate standard errors 
for the estimated response rate 
when the true response rate is 
10% are +/- 6% with a sample 
of 24 patients total, and +/- 9% 
with a sample of 12 patients in 
each disease group. 
Approximately 4 potentially 
eligible patients are seen per 
month at both sites
DLT language within the 
statistics section 
 
Approximate standard errors for the estimated 
response rate when the true response rate is 
10% are +/- 6% with a sample of 24 patients 
total, +/- 18% with a sample of 18 patients, 
+/- 9% with 12 patients and +/- 10% to 12% 
with 6 patients.
Both sites corrected to read’all sites’
Removed DLT language
Updated statistics to align with 
modification to disease 
allocation of patients.
Correction of typographical 
error(since there are more than 2 
sites).
Correction of error, since there 
are no DLTs in this study.
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Amendment 8
March17, 2017
Section(s) Affected
Prior Version
Amendment 8 Changes
 Rationale
Section 4.2
Treatment administration
Section 5.1 
Schedule of events for MF patients 
Description of treatment administration
Footnote m: statement that lab and exams 
will be done only on day 1 of Cycle 7 and 
beyond. 
Language modified: 
to state that beyond cycle 6, 
for MF patients who are 
stable, they will be asked to 
come to clinic on D1 of 
every even cycle and they 
will be given drug supply 
for 2 cycles to facilitate 
this. During these 
visits,labs and exams will 
be done as indicated in the 
schedule.During the odd 
numbered cycles, outside 
lab tests(only CBC and 
CMP) will be ordered. 
Patients can start their 
treatment at home only 
after the treating physician 
has reviewed the laboratory 
results and determined that 
they are able to continue 
treatment. For these cycles, 
the study coordinator will 
contact the patient on/prior 
to Day 1 to inform them if 
they can or cannot  start  
the new cycle,  and  also 
check compliance 
regarding study drug 
intake. 
A ‘D1’ added under the 
Cycle 7+ column 
To facilitate 
patient 
treatment 
convenience and 
flexibility.
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Section 5.1
Schedule of events for MF patients
Footnote f: description of chemistry panel 
Footnote g: description of DIC screen and 
coagulation studies.
Added note to state that:
Beyond Cycle 6, 
magnesium and phosphate 
testing is not required(as 
part of the chemistry 
panel).
Added note to state that: 
Beyond Cycle 6, 
PT/INR,aPTT testing is not 
required. 
Per PI: These 
tests are not 
required after 
cycle 6. Hence, 
they have been 
removed for 
convenience.
Footnote j: Description of blood and bone 
marrow samples for PD studies. 
Footnote k: Bone marrow aspirate and biopsy 
is to be done within 1 year prior to 
registration(provided the PI confirms the 
diagnosis and there is no suspicion for 
acceleration to blast phase), and thereafter 
only as clinically indicated.
Added language to clarify 
that :
“Correlative bone marrow 
samples should be obtained 
any time bone marrows are 
collected as clinically 
indicated during study 
participation. At baseline, 
correlative bone marrow 
collection is not mandatory 
for study entry. However, 
study team should request 
3-4 unstained slides from 
 any prior bone marrow 
testing performed within 
the last year before study 
entry”.
Number of slides have been 
increased from 2 to 3-4 
slides(described clearly in 
section 9.1)
Footnote k updated to add 
timepoint C7D1(+/-14 
days) to bone marrow 
aspirate and biopsy.
For clarity 
and convenience
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Section 5.1 
Schedule of events for MF patients
and section 5.2
Schedule of events for AMKL 
patients
Footnote c: Vital signs included supine and 
standing blood pressure measurement.
Footnote g: 3 pt listed as part of DIC screen 
at baseline. 
In both tables, row demonstrating ‘samples 
for PD studies’ which included both blood 
and bone marrow samples
Footnote c:  Removed the 
detail about ‘supine and 
standing’ from the blood 
pressure measurement. 
Footnote g: 3 pt replaced 
by aPTT.
In both tables, this row has 
been removed and replaced 
by  by 2 different rows 
demonstrating ‘Bone 
marrow collection for PD 
studies and ‘Blood 
collection for PD studies’. 
Such detail is 
not required  for 
this study. 
Hence, removed 
in order to 
minimize 
protocol 
deviations.
For clarity
For increased 
clarity
Section 5.1 
Schedule of events for MF patients
and section 5.2
Schedule of events for AMKL 
patients
(contd)
In both tables, window for signing informed 
consent not defined.
Added footnote v in both 
tables stating that informed 
consent should be obtained 
within 28 days of 
registration
For clarity and 
convenience
Section 6.2
Secondary endpoints
Response at 6 months will be reported for all 
evaluable patients.
Modified to state: 
“Response after cycle 6 
(upon completion of C7D1 
marrow) will be reported 
for all evaluable patients.”
For clarity
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Section 9.1
Details about Correlative sample collection.
10-20ml of bone marrow at multiple 
timepoints for cycles 1-6.Two unstained bone 
marrow slides were  required following any 
bone marrow procedure.
Language added to clarify :
1.
Collection of 10-
20ml of bone 
marrow at 
multiple 
timepoints for 
cycles 1-6. 
Collection of 3-4 
unstained slides 
whenever a bone 
marrow collection 
is done at baseline 
or within I year 
prior to study 
entry. 
2.
Language stating 
that bone marrow 
collection for 
correlative testing 
is not mandatory 
for study entry. 
However, study 
team should 
encourage 
collection of 3-4 
unstained slides 
from  bone 
marrow collected 
within the last 
year prior to 
enrollment.
For clarity, 
convenience and 
flexibility.
Section 11.5.2
Study management:
Other protocol deviations
Promptly reportable Non Compliance  
(PRNC) definitions listed
The term Promptly 
reportable Non Compliance 
(PRNC) is replaced by 
Reportable New 
Information (RNI)  
Per NU IRB 
directive
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