Conditions: Acute Myeloid Leukemia
Keywords: Acute Myeloid Leukemia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 42
Healthy volunteers: no

Brief summary:
This research study is studying a targeted therapy (a form of treatment that uses drugs or other substances to identify and attack specific types of cancer cells with less harm to normal cells) as a possible treatment for high-risk acute myeloid leukemia.

The names of the study interventions involved in this study are:

* Alisertib / MLN8237
* Cytarabine / Cytosine Arabinoside
* Idarubicin / Idarubicin hydrochloride
* Daunorubicin (Can be used in place of idarubicin)

Detailed description:
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied.

As part of this research study, the participant will take alisertib in combination with conventional chemotherapies, idarubicin and cytarabine. Alisertib has not been approved by the FDA (U.S. Food and Drug Administration) for acute myeloid leukemia (AML). However, cytarabine and idarubicin have both been approved by the FDA for treatment of AML. It also means that the FDA (U.S. Food and Drug Administration) has not approved giving alisertib with idarubicin and cytarabine for use in participants, including participants with this type of cancer.

Earlier pre-clinical studies and clinical trials have suggested the alisertib may have clinical promise as a single agent in acute myeloid leukemia. Alisertib is a selective small molecule inhibitor of Aurora A kinase, an enzyme which may play a role in the survival of leukemia cells. Alisertib is being studied for the treatment of advanced malignancies, including AML. Essentially, this means that alisertib may work to halt the growth of malignancy (abnormal cells dividing without control and invading nearby tissues) through a targeted mechanism. By combining alisertib with standard chemotherapy, the hope is to enhance the efficacy of current treatment used for acute myeloid leukemia. An earlier study of this combination has completed accrual, and demonstrated that the regimen is well tolerated.

Through this study, the investigators would like to determine if the addition of alisertib to standard 7+3 chemotherapy improves efficacy as measured by the rate of complete remission (a decreased or disappearance of signs and symptoms of cancer).

Arms:
arm 1: Participants will initially receive 7+3 induction chemotherapy, consisting of cytarabine and concurrent idarubicin (or daunorubicin if appropriate). Oral alisertib, at 30mg twice daily, will begin on day 8, and will continue for 7 days. During induction, patients with residual disease at day 14 may have re-induction with "5+2" chemotherapy, but will not receive additional dosing of alisertib at that time. Following count recovery after induction, if patients proceed to consolidative cycles of therapy with cytarabine, they will receive alisertib at day 6 following conclusion of cytarabine administration. Upon count recovery following consolidation, alisertib will be resumed for 7 days, followed by 14 days off, and will be continued as 21-day cycles of maintenance, for up to 12 cycles.

Interventions: intervention 1: Alisertib intervention 2: Cytarabine intervention 3: Idarubicin intervention 4: Daunorubicin
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: Can be used in place of idarubicin

Protocol document:
Prot_SAP_000.pdf: 




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SYNOPSIS AND SCHEMA 
Patient Population: Adults, over age 18, with newly diagnosed, pathologically-confirmed acute 
myeloid leukemia (AML), eligible for induction chemotherapy, and with higher-risk disease, as 
defined by at least one of the following; a) age  ≥ 65, b) association with poor-risk karyotype, c) 
secondary AML arising out of antecedent myeloid malignancy, d) or due to prior radiation or 
chemotherapy.  
Performance Status: ECOG 0-2 
Primary Objective: 

To determine the rates of complete remission (CR) and complete remission with
incomplete count recovery (CRi) in higher risk patients receiving alisertib in combination
7+3 induction chemotherapy, and to assess whether this is higher than the historical rates
seen in this population with 7+3 induction alone.
Secondary Objectives: 

To determine if the 1-year overall survival (OS) rate, relapse free survival (RFS), remission
duration of higher risk patients receiving alisertib in combination with conventional
intensive cytotoxic chemotherapy, and to assess whether this is higher than the historical
rates seen in this population with  conventional intensive chemotherapy alone.

To describe the frequency and severity of adverse events for patients treated on this study.

To describe the interaction of pretreatment disease and patient characteristics including
morphology, cytogenetics, immunophenotype, molecular/genetic features, WBC count and
hemogram, and performance status on clinical outcomes.

To describe the pharmacodynamic effects of alisertib during treatment with this induction
combination
Phase of Study: II 
Treatment Plan: 
This is a phase II clinical study trial to assess the efficacy of the aurora A kinase alisertib in 
combination with 7+3 induction chemotherapy in patients with higher-risk newly diagnosed AML. 
On day 1 of the trial, all enrolled participants will be initiated on induction chemotherapy with 
conventional AML induction chemotherapy using the “7+3” induction regimen, consisting of 
cyatarabine continuous intravenous infusion for seven days and concurrent idarubicin (or 
daunorubicin if appropriate) as an intravenous bolus for first three days of induction. Oral 
administration with alisertib, at a dose of 30mg twice daily, will begin on day 8, and will continue 
for 7 days after conclusion of IV infusion of induction chemotherapy. The exception will be if 7+3 


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therapy begins in the afternoon or evening, and finishes on Day 8, in which case alisertib may be 
first given in the morning of Day 9. During induction, patients who have residual disease at day 
14 may have re-induction with “5+2” chemotherapy, but they will not receive additional dosing of 
alisertib at that time. Toxicity will be assessed throughout the course of the study, until the final 
study visit. Pharmacodynamic evaluation will be performed prior to treatment, at day 14 of 
induction, at count recovery following induction, and at any time of relapse or suspected relapse. 
Following count recovery after induction, if patients proceed to consolidative chemotherapy with 
cytarabine, they will receive alisertib during consolidation at day 6 following conclusion of 
cytarabine administration, and will continue for 7 days. Upon count recovery, following 
consolidation cycles of therapy, maintenance cycles of alisertib will be started for 7 days, followed 
by 14 days off, and will be continued in this manner as 21-day cycles, for up to 12 cycles, until 
disease progression, or until onset of unacceptable toxicity. We will plan to follow patients for 12 
months after the last patient enrollment. 
 


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Study flowchart 
 
 
TABLE OF CONTENTSSYNOPSIS AND SCHEMA 2 
1. 
OBJECTIVES ......................................................................................................................7 
1.1 
Study Design ............................................................................................................7 
1.2 
Primary Objectives ...................................................................................................7 
1.3 
Secondary Objectives ...............................................................................................7 
2. 
BACKGROUND .................................................................................................................7 
2.1 
Alisertib (MLN8237) ...............................................................................................7 
2.2 
Study Disease: Acute Myeloid Leukemia (AML) .................................................19 
2.3 
Rationale ................................................................................................................20 


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2.4 
Correlative Studies .................................................................................................20 
2.5  
Hypothesis..............................................................................................................21 
3. 
PARTICIPANT SELECTION ...........................................................................................21 
3.1 
Eligibility Criteria ..................................................................................................21 
3.2 
Exclusion Criteria ..................................................................................................22 
3.3 
Inclusion of Women and Minorities ......................................................................25 
4. 
REGISTRATION PROCEDURES ...................................................................................25 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions ...................................25 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions .................................26 
4.3 
General Guidelines for Other Investigative Sites ..................................................27 
4.4 
Registration Process for Other Investigative Sites .................................................27 
5. 
TREATMENT PLAN ........................................................................................................27 
5.1 
Treatment Regimen ................................................................................................27 
5.2 
Agent Administration .............................................................................................28 
5.3 
General Concomitant Medication and Supportive Care Guidelines ......................32 
5.4 
Duration of Therapy ...............................................................................................33 
5.5 
Duration of Follow Up ...........................................................................................33 
5.6  
Criteria for Removal from Study ...........................................................................34 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................34 
6.1 
Alisertib, Dose Modifications/Delays ....................................................................34 
6.2 
Dose Modifications of Idarubicin (or Daunorubicin) for Related 
Hepatotoxicity ........................................................................................................37 
6.3 
Dose Modifications for Treatment with cytarabine consolidation therapy ...........37 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................38 
7.1  
Adverse Event Characteristics ...............................................................................38 
7.1 
Adverse Events Associated with Alisertib .............................................................40 
7.3 
Adverse Events Associated with Idarubicin and Cytarabine .................................47 
7.4  
Adverse Event Reporting Definitions ....................................................................48 
7.5  
Procedures for AE and SAE Recording and Reporting .........................................49 
7.6  
Monitoring of Adverse Events and Period of Observation ....................................53 
7.7 
Product Complaints ................................................................................................54 
8. 
DATA AND SAFETY MONITORING ............................................................................55 
8.1  
Data Reporting .......................................................................................................55 
8.2  
Safety Meetings .....................................................................................................55 


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8.3  
Monitoring .............................................................................................................56 
9. 
REGULATORY CONSIDERATIONS .............................................................................56 
9.1 
Protocol Review and Amendments ........................................................................56 
9.2 
Informed Consent...................................................................................................56 
9.3 
Ethics and Good Clinical Practice (GCP) ..............................................................57 
9.4 
Study Documentation.............................................................................................58 
9.5 
Records Retention ..................................................................................................58 
10. 
PHARMACEUTICAL INFORMATION ..........................................................................58 
10.1  Alisertib (MLN8237) .............................................................................................58 
10.2  Idarubicin ...............................................................................................................59 
10.3  Cytarabine (Cytosine Arabinoside) (Ara-C) ..........................................................60 
11. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................61 
11.1  Laboratory Correlative Studies ..............................................................................61 
12. 
STUDY CALENDAR .......................................................................................................62 
13. 
MEASUREMENT OF EFFECT........................................................................................64 
13.1  Response Criteria ...................................................................................................64 
14. 
STATISTICAL CONSIDERATIONS...............................................................................65 
14.1  Sample Size, Accrual Rate, and Study Duration ...................................................65 
14.2 
Statistical Design/Endpoints ..................................................................................65 
15. 
PUBLICATION PLAN .....................................................................................................66 
16. 
REFERENCES ..................................................................................................................67 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................74 
ADDENDUM B 
EUROPEAN LEUKEMIA NET GUIDELINES ..................................... 70 
 
 


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1. OBJECTIVES 
 
1.1 
Study Design 
This study is a Phase II study which seeks to assess the efficacy of the aurora A kinase inhibitor, 
alisertib, combined with  standard “7+3” induction chemotherapy for patients with newly-
diagnosed, higher risk acute myeloid leukemia (AML). Oral administration with alisertib, at a dose 
of 30mg twice daily, will begin following conclusion of cytarabine continuous infusion, and will 
continue for 7 days during induction chemotherapy. Toxicity will be assessed throughout the 
course of the study, until the final study visit. Pharmacodynamic evaluation will be performed 
prior to treatment, at day 14 of induction, at count recovery following induction, and at the time 
of relapse or suspected relapse. Following count recovery after induction, if patients proceed to 
consolidative chemotherapy with cytarabine, they will receive alisertib during consolidation at day 
6 following conclusion of cytarabine administration, and will continue for 7 days. Upon count 
recovery, following consolidation cycles of therapy, maintenance cycles of alisertib will be started 
for 7 days, followed by 14 days off, and will be continued in this manner as 21-day cycles, for up 
to 12 cycles, until disease progression, or until onset of unacceptable toxicity. 
 
1.2 
Primary Objectives 
 To determine the rates of complete remission (CR), complete remission with incomplete 
count recovery (CRi) in higher risk patients receiving alisertib in combination 7+3 
induction chemotherapy, and to assess whether this is higher than the historical rates seen 
in this population with 7+3 induction alone. 
 
1.3 
Secondary Objectives 
 To determine if the 1-year overall survival (OS) rate, relapse free survival (RFS), remission 
duration of higher risk patients receiving alisertib in combination with chemotherapy, and 
to assess whether this is higher than the historical rates seen in this population with 
conventional intensive chemotherapy alone. 
 To describe the frequency and severity of adverse events for patients treated on this study. 
 To describe the interaction of pretreatment disease and patient characteristics including 
morphology, cytogenetics, immunophenotype, molecular/genetic features, WBC count and 
hemogram, and performance status on clinical outcomes. 
 To describe the pharmacodynamic effects of alisertib during treatment with this induction 
combination  
 
2. BACKGROUND 
 
2.1 
Alisertib (MLN8237) 
 
2.1.1 Alisertib: structure and chemical properties 


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Alisertib is a selective small molecule inhibitor of Aurora A kinase that is being developed for the 
treatment of advanced malignancies. Information regarding the chemical name, structure, and 
properties of MLN8237 is listed below, as is the structure of MLN8237. 
 
Research Name  
 
 
             MLN8237-004  
                                      
 
             ML00653668 
 
Chemical Name                                                    sodium 4- -2- methoxybenzoate hydrate 
 
Common Name                                                            sodium 4-{[9-chloro-7-(2-fluoro-6 
methoxyphenyl) 5H pyrimido[5,4-
d][2]benzazepin-2-yl]amino}-2- 
methoxybenzoate hydrate 
 
 
Generic Name  
 
 
             Not available 
 
Proprietary Name   
 
             Not available 
 
USAN Name  
 
              
             alisertib (free acid), alisertib sodium 
 
pINN Name  
 
 
             alisertib 
 
CAS Registry Number  
                            1208255-63-3 
 
Classification  
 
 
             Aurora A kinase inhibitor 
 
Molecular Formula   
 
             C27H19ClFN4NaO4.H2O 
 
Molecular Weight   
 
             558.92 (sodium salt) 
518.92 (free acid) 


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Structure of MLN8237-004 
 
 
 
 
 
 
 
 
 
Physical, 
Chemical, 
and 
Pharmaceutical 
Properties 
In its solid state, alisertib (MLN8237-004) drug substance is an off-white to yellow solid with an 
assay value of 96.0% to 104.0% (w/w) on an anhydrous basis, as determined by reverse phase high 
performance liquid chromatography (HPLC). The solubility of the drug substance in water (pH = 
8.4) is 8.5mg/mL. The drug substance is a stable monohydrate with a pKa of 4.53 for the free acid. 
 
Formulation 
MLN8237-004 Enteric-Coated Tablets will be used. 
 The MLN8237-004Tablet: An enteric coated tablet dosage form of MLN8237-004 has been 
developed for use in clinical studies. Three different enteric coated tablet dosage strengths, 10, 
50, and 100 mg, expressed as MLN8237 free acid, were formulated. The key formulation 
excipients that aid in the in vivo absorption of the drug are sodium bicarbonate, sodium lauryl 
sulfate, and enteric coating. The other formulation excipients such as povidone, 
microcrystalline cellulose, croscarmellose sodium, and sodium stearyl fumarate serve as 
manufacturing aids. 
 
Storage 
 Tablet: MLN8237-004 enteric-coated tablets are packaged in HDPE bottles with rayon coil, 
induction seal, desiccant packs, and polypropylene child-resistant cap and stored at USP-
controlled room temperature (20°C to 25ºC) with excursions permitted from 15°C to 30°C. 
 
Handling 
Alisertib (MLN8237-004) drug product is a cytotoxic anticancer drug. As with other potentially 
toxic compounds, caution should be exercised when handling the 3 dosage forms of MLN8237-
004 (capsules, tablets, and oral solution). Refer to published guidelines regarding the proper 
handling and disposal of anticancer agents.[1, 2] 
 


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2.1.2 Alisertib (MLN8237): Pharmacology 
 
2.1.2.1 In Vitro Pharmacology 
The data from both enzymatic and cell-based assays demonstrated that MLN8237 is a selective 
and potent inhibitor of Aurora A kinase.[3-7] Nonclinical studies show that MLN8237 is an 
adenosine triphosphate (ATP)-competitive and reversible inhibitor of Aurora A kinase with an 
inhibition constant (Ki) of 0.43 nM.[3] In HCT-116 human colon cancer cells, MLN8237 inhibited 
Aurora A kinase activity with a half-maximal inhibitory concentration (IC50) of 6.7 nM, and was 
approximately 200-fold more selective for Aurora A than for Aurora B (IC50 = 1534 nM).[4] 
Moreover, MLN8237 was at least 250-fold more selective for Aurora A when compared to other 
kinases tested in vitro.[5] Consistent with the outcomes associated with Aurora kinase inhibition, 
an antimitotic agent, MLN8237 administration in vitro resulted 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.[4, 8-14] 
 
2.1.2.2 In Vivo Pharmacology 
Treatment of nude mice bearing human colon HCT-116 tumor xenografts with MLN8237 resulted 
in increased mitotic cells in the tumor, a phenotype that recapitulates the results in cultured 
cells.[15-17]  In orally dosed mice bearing HCT-116 tumor xenografts, the duration of increased 
mitotic index was longer lasting in the more efficacious dose groups (10 and 30mg/kg) than the 
less efficacious dose group (3mg/kg). MLN8237 was efficacious against a variety of subcutaneous 
solid tumor xenograft models (breast, colon, lung, prostate and neuroblastoma) in mice when 
dosed orally for approximately 21 days.[18-23]  Moreover, MLN8237 demonstrated robust 
antitumor activity in a number of hematologic malignancies, including diffuse large B cell 
lymphomas and acute lymphoblastic leukemias.[21, 22]  The oral dose and schedule that was 
maximally efficacious varied for each model from 10 to 30 mg/kg QD in some models or 20 mg/kg 
BID in other models.[20, 22]  Studies in the HCT-116 colon tumor model demonstrated that less 
frequent dosing (eg, 5 days-on followed by 5 days-off) was also efficacious.[20]  Osmotic mini-
pump studies in HCT-116 tumors showed that the pharmacodynamic effect and efficacy are 
saturated when the plasma concentration reaches approximately 1μM.[15, 17] The relationship 
between PK and pharmacodynamics in orally dosed mice was consistent with this observation. 
The maximally efficacious oral doses of MLN8237 in the HCT-116 model (10 and 30 mg/kg QD) 
resulted in plasma concentrations approximating 1 µM for 8 to 12 hours post-dose. As detailed in 
the discussion of the phase 1 clinical studies, these exposure levels were readily achieved in 
patients with advanced malignancies treated with MLN8237. 
 
2.1.2.3 Safety Pharmacology 
In exploratory safety pharmacology studies, MLN8237 exhibited minimal activity against the 
rapidly activating component of the delayed rectifier potassium current (IKr) encoded by the human 
ether-à-go-go related gene (hERG; IC50 and Ki > 100 μM).[24] MLN8237 had in vitro activity 


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against the gamma aminobutyric acid A alpha-1 (GABAAα1) benzodiazepine binding site (Ki = 
290 nM).[25] In an exploratory non-GLP-compliant single-dose in vivo CNS safety pharmacology 
study, effects consistent with the binding of MLN8237 to the GABAAα1 binding site (gait 
abnormalities) were seen in rats at doses and exposures that exceeded those that were tolerated on 
a daily oral dosing  schedule.[26]  In an exploratory non-GLP-compliant single-dose in vivo 
cardiovascular safety pharmacology study in radio-telemetry-instrumented beagle dogs, effects 
consistent with the binding of MLN8237 to the GABAAα1 binding site (increases in heart rate and 
blood pressure, modest increase in body temperature) were seen in dogs at doses and exposures 
that exceeded those that were tolerated on a daily oral dosing schedule.[27] No MLN8237-related 
effects on clinical signs or physical examination findings indicative of impaired respiratory 
function (i.e., labored our shallow breathing), or microscopic changes in the lungs of animals that 
survived until scheduled termination, were noted at tolerated doses in GLP-compliant repeat-dose 
toxicology studies. 
 
2.1.2.4 Nonclinical Pharmacokinetics and Product Metabolism 
Studies to evaluate the PK of MLN8237 were conducted in nude mice bearing human colon HCT-
116 tumor xenografts and in Sprague-Dawley rats, beagle dogs, cynomolgus monkeys, and 
chimpanzees.[15, 17, 28-31] 
 
Absorption 
MLN8237 was highly permeable in the Caco-2 cell assay, with an apparent permeability (Papp) of 
62.4 and 47.1x10-6 cm/sec in the apical-to-basolateral and basolateral-to-apical directions, 
respectively, at a pH of 7.4.[32] MLN8237 demonstrated good oral bioavailability in all animal 
species tested.[33, 34] 
 
Distribution 
MLN8237 had a moderate volume of distribution at steady state (Vss) in all nonclinical species 
studied, ranging from 0.74 L/kg to 3.5 L/kg.[15, 17, 28-31] MLN8237 is highly bound to plasma 
proteins in all species (percentages of unbound MLN8237 [fu]: 1.9% in mouse, 0.70% in rat, 2.2% 
in dog, 1.7% in chimpanzee, and 2.5% in human plasma).[35] 
 
[14C]MLN8237-derived radioactivity was rapid and extensively distributed to tissues.[36] The 
highest concentrations for most tissues were reached at 0.25 hours after a single oral 
administration. Concentrations of >20μg equiv/g at 0.25 hours post dose were found in the small 
intestine (268.920μg equiv/g), liver (91.860μg equiv/g), adrenal cortex (50.504μg equiv/g), 
stomach (39.040μg equiv/g), adrenal medulla (24.235μg equiv/g), and kidney cortex (23.135μg 
equiv/g). The highest concentrations were observed in contents of the alimentary canal at 0.25 to 
24 hours post-dose (≤67.596 to 2692.620μg equiv/g), which probably reflected the radioactivity 
from the dosing formulation and bile. Bile concentrations were also relatively high (≤831.288μg 


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equiv/g), but concentrations in urine were much lower (0.292μg equiv/g), which suggested that 
biliary excretion was the major route of elimination after PO administration. The concentrations 
observed in the central nervous system were the lowest of all tissues (≤0.525 to 0.726µg equiv/g) 
and were below the quantitation limit (BQL) at 4 hours post-dose. Low concentrations were also 
observed in the testis (≤0.718μg equiv/g), bone (≤0.411μg equiv/g), and the lens of the eye 
(0.124μg equiv/g). 
 
Tissue concentrations in most tissues declined rapidly and were approximately an order of 
magnitude lower at 4 hours post-dose. Concentrations in approximately half of the tissues were 
BQL at 24 hours post-dose and all, except liver and alimentary canal contents, were BQL at 48 
hours post-dose. 
 
Radioactivity was detected by quantitative whole-body autoradiography (QWBA) analysis of 
cardiac blood through 24 hours post-dose (highest at 0.25 hours, 14.770μg equiv/g) and 
concentrations became BQL at 48 hours.[36] Blood-to-plasma ratios were approximately 0.64 
through 4 hours post-dose and had decreased slightly at 24 hours postdose. When analyzed by 
liquid scintillation counting (LSC), blood concentrations of radioactivity closely matched 
concentrations measured by QWBA. 
 
The in vitro blood-to-plasma partitioning of MLN8237 in whole blood from healthy human 
volunteers was determined.[37] At a concentration of 1µM, the mean blood-to-plasma ratios of 
MLN8237 in humans (pooled male and female samples) after 10 and 60 minutes of incubation at 
37°C were 0.46 and 0.55, respectively. At a concentration of 10μM, the mean blood-to-plasma 
ratios of MLN8237 in humans after 10 and 60 minutes of incubation at 37°C were 0.45 and 0.59, 
respectively. MLN8237 (1 to 10μM) was preferentially distributed into human plasma, with a 
mean blood-to-plasma ratio of 0.57 when equilibrium was reached at 60 minutes. 
 
Metabolism 
MLN8237 is metabolized by both glucuronidation and oxidation pathways with no marked species 
differences in metabolism observed from in vitro studies. Urinary excretion of MLN8237 was 
negligible in the rat and chimpanzee (< 1% of the dose).[38] An in vivo metabolic profiling study 
in rats using 14C-MLN8237 showed that unchanged MLN8237 was the predominant circulating 
component in plasma, accounting for approximately 93.0% of the total radioactivity in plasma 
over a 24-hour period.[39] In addition, the major metabolic route of 14C-MLN8237 in rats is acyl 
glucuronidation, with >77.9% of the dose metabolized by this pathway.[40] 
 
The oxidative metabolites (M2 and M3) were formed by CYP3A4, 1A2, 2C9, and 2C19, while 
UGT1A1, 1A3, and 1A8 mediated M1 formation.[38] 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 


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MLN8237.[41] 
 
Excretion 
After oral administration of 14C-MLN8237 to intact rats, radioactivity was eliminated primarily 
in the feces, while radioactivity was eliminated primarily in the bile of bile-duct cannulated 
rats.[39] After IV administration of MLN8237 in rats and chimpanzees, less than 1% of the dose 
was found as the parent form in urine collected over 24 hours post-dose.[29, 31] 
 
Pharmacokinetic Drug Interactions 
The potential of MLN8237 (when administered at the MTD of 50 mg BID) to inhibit the major 
CYP isozymes 1A2, 2C9, 2C19, 2D6, and 3A4/5 is unlikely (IC50>100μM, estimated 
Ki>50μM).[42, 43] Based on the 50-mg BID regimen, with a mean Cmax of ~2.7μM, MLN8237 
is unlikely to produce drug-drug interactions (DDIs) by inhibiting major CYP isozymes. Because 
MLN8237 
is 
metabolized 
by 
multiple 
CYP 
isozymes 
and 
uridine 
diphosphate-
glucuronosyltransferase (UGT) isozymes, CYP-based metabolism plays a minor role in vitro, and 
major UGT-based interactions are less common, it is anticipated that CYP or UGT inhibitors 
would not substantially affect the PK of MLN8237.  
 
In a Caco-2 cell assay, MLN8237 showed excellent permeability and no efflux. MLN8237 is not 
a human P-gp substrate, but inhibited the P-gp-mediated efflux of paclitaxel (Taxol®) in Caco-2 
cells with an IC50 of 4.0µM.[32] MLN8237 is unlikely to produce inhibition of P-gp at systemic 
sites of transport because of the substantially lower steady-state unbound Cmax at the clinical dose 
of 50 mg BID (67nM). However, the potential for inhibition of intestinal P-gp efflux by higher 
intestinal luminal concentrations of MLN8237 cannot be ruled out; therefore, orally administered 
narrow therapeutic range substrates of P-gp (eg, digoxin) should be administered with caution.  
MLN8237 is a weak inhibitor of BCRP, OATP, and MRP2.[32] The potential for co-administered 
MLN8237 to result in drug interactions with chemotherapeutic agents that are known P-gp 
substrates has not been established at the dose and schedules employed in clinical studies. 
 
Other Pharmacokinetics Studies 
On the basis of the GLP-compliant toxicokinetic (TK) evaluations of MLN8237 after repeated 
daily oral dose administration, exposure increased with dose in an approximately dose-
proportional manner from 1 to 50mg/kg in rats and from 0.15 to 1.5mg/kg in dogs. There was no 
obvious accumulation or auto-induction observed throughout the dosing period.[44-46] 
 
2.1.3 MLN8237: Toxicology. 
A series of nonclinical safety assessment studies has been conducted to support the clinical 
development of MLN8237. 
 
Rat Two-Cycle Repeat-Dose Toxicology Study 


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A GLP-compliant study was conducted to evaluate the potential toxicity and toxico-kinetic profile 
of MLN8237 when administered to Sprague Dawley rats once daily via oral gavage for a total of 
2 cycles (each cycle consisting of daily dosing for 7 consecutive days; cycles were separated by a 
14-day non-dosing period), as well as to evaluate the recovery from, persistence, or progression of 
any effects during a minimum 14-day recovery period.[46] Microscopically, the principal change 
observed in all affected tissues was increased mitotic figures (mitotic arrest)/apoptosis, which is 
consistent with the outcomes associated with Aurora A kinase inhibition. This finding was seen in 
tissues/organs of rats dosed with ≥ 5 mg/kg/day, with incidence and severity correlating to basal 
cellular replication rate and increasing with increasing dose. In this study 50 mg/kg/day was 
considered to be the severely toxic dose in 10% of animals administered (STD10) MLN8237. 
Lethality occurred as a result of infections that arose secondary to pharmacologically mediated 
effects on dividing cells in bone marrow and lymphoid tissues. A dosage of 15 mg/kg/day 
generated pharmacologic effects in rats and was clearly tolerated. A dosage of 5 mg/kg/day was 
well tolerated. A dosage of 1 mg/kg/day was the NOEL in both male and female rats. 
 
Rat Six-Cycle Repeat-Dose Toxicology Study 
The objectives of this GLP-compliant study were to evaluate the potential toxicity and 
toxicokinetic profile of MLN8237 when administered to Sprague Dawley rats QD via oral gavage 
for a total of 6 cycles (each cycle consisting of daily dosing for 21 consecutive days; cycles were 
separated by a 7-day non-dosing period), as well as to evaluate the recovery from, persistence, or 
progression of any effects during a minimum 28-day recovery period.[47] Administration of 
MLN8237 orally (by gavage) to Sprague Dawley rats for 6 cycles at dosages of 2, 5, or 15 mg/kg 
resulted in the death of 1 male rat from the 5-mg/kg group, as well as 1 male and 1 female rat from 
the 15 mg/kg group. In rats that survived to the scheduled interim and primary ecropsies, 
administration of MLN8237 at 5 mg/kg (primary necropsy only) and 15 mg/kg (interim and 
primary necropsies) resulted in microscopic changes consisting of single-cell necrosis and/or 
lymphoid depletion predominating in tissues/organs with cell populations having a high basal 
cellular replication rate similar to what was noted in the 2-cycle repeat-dose toxicology study. In 
addition, administration of MLN8237 at 5 and 15 mg/kg resulted in hematologic alterations 
secondary to bone marrow suppression of erythrocyte and leukocyte precursors. These test article-
related hematologic and microscopic findings were consistent with outcomes associated with 
Aurora A kinase inhibition.[48] Concomitant test article--related lower body weight gains and 
lower food consumption were noted over the 6 dosing cycles in the 15-mg/kg group. After a 28-
day recovery period, all microscopic findings had completely resolved and hematology alterations 
indicated continuing resolution. 
 
Dog Two-Cycle Repeat-Dose Toxicology Study 
A GLP-compliant study was conducted to evaluate the potential toxicity and toxico-kinetic profile 
of MLN8237 when administered to beagle dogs once daily via oral lavage for a total of 2 cycles 
(each cycle consisting of daily dosing for 7 consecutive days; cycles were separated by a 14-day 


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non-dosing period), as well as to evaluate the recovery from, persistence, or progression of any 
effects during a minimum 16-day recovery period.[45]  In the repeat-dose oral toxicology study in 
dogs, the DLT associated with MLN8237 administration occurred as a result of target-mediated 
effects of mitotic arrest and apoptosis (single-cell necrosis) of replicating cells in the intestine, 
bone marrow, and lymphoid tissues.  A dosage of 1.5 mg/kg/day for 7 consecutive days was 
tolerated in 4 of 6 males. This dosage was adjusted to 1.0 mg/kg/day for the second 7-day dosing 
cycle. Administration of 1.0 mg/kg/day for 7 consecutive days was tolerated by all of the dogs (5 
males and 6 females). Therefore, 1.0 mg/kg/day was the highest non-severely toxic dose 
(HNSTD). A dosage of 0.45 mg/kg/day generated pharmacologic effects and was well-tolerated. 
A dosage of 0.15 mg/kg/day was the NOEL. 
 
Dog Six-Cycle Repeat-Dose Toxicology Study 
The objectives of this GLP-compliant study were to evaluate the potential toxicity and toxico-
kinetic profile of MLN8237 when administered to beagle dogs QD via oral gavage for a total of 6 
cycles (each cycle consisting of daily dosing for 21 consecutive days; cycles were separated by a 
7-day non-dosing period), as well as to evaluate the recovery, persistence, or progression of any 
effects during a minimum 28-day recovery period.[49] Administration of MLN8237 to beagle dogs 
QD via oral gavage at a dosage of 1.0 mg/kg for up to 6 days was not tolerated and resulted in 
lethality and dose reduction to 0.75 mg/kg for the surviving 4 animals for the remainder of the 
dosing period. Cyclical administration of MLN8237 to beagle dogs QD via oral gavage for the 
following 5 complete cycles, was well tolerated at a dosage of 0.75 mg/kg. Cyclical administration 
of MLN8237 to beagle dogs QD via oral gavage for a total of 6 cycles (each cycle consisting of 
daily dosing for 21 consecutive days with cycles separated by a 7-day nondosing period) was well-
tolerated at dosages of 0.45 and 0.15 mg/kg. Test article-related effects were limited to hematology 
and microscopic findings, all of which were consistent with outcomes associated with Aurora A 
kinase inhibition and were similar to what was noted in the 2-cycle repeat-dose toxicology study. 
The microscopic findings in the 0.45- and 1.0/0.75-mg/kg groups had completely resolved at the 
recovery necropsy, and the hematology findings had partially resolved in the 1.0/0.75-mg/kg group 
at the recovery necropsy. 
 
2.1.4 Clinical Experience 
There have been multiple company-sponsored clinical studies of alisertib (MLN8237) that are 
either ongoing or have completed enrollment. The solubility of MLN8237 molecules is low in 
acidic pH; hence, the drug was originally developed as the buffered PIC formulation for the initial 
phase 1 clinical studies. Subsequently, the ECT formulation was developed and has been evaluated 
in multiple studies.  
 
Initial studies enrolled patients with advanced solid tumors. The major goals of each study were 
to evaluate safety, pharmacokinetics, and pharmacodynamics, and to determine the DLT(s) and 
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recovery period. The studies also included cohorts to evaluate longer dosing periods up to 14 or 
21 days. In the first-in-human study phase I study conducted in the United States, 65 patients 
received MLN8237 across dose cohorts evaluating various dose levels and schedules with the PIC 
formulation. 65 pts received 5-150 mg QD for 7 days or 25-70 mg QD for 14 or 21 days. In 
addition, to minimize Cmax-associated somnolence risk, divided treatments were given up to 
maximum administered doses 60 mg BID for 7 days or 40 mg BID for 14 days. Tumors were 
colorectal (14), lung (13), ovary (6), head and neck (6), prostate (4), and others (22). Dose limiting 
toxicities included grades 3-4 neutropenic fever (n=4), thrombopenia (n=3), somnolence (n=2), 
and mucositis (n=1), seen at doses ≥ 110 mg/d x 7 days, ≥ 40 mg BID x 14 days, and in 1 of 11 
pts at 50 mg BID x 7 days. Most common adverse events included nausea (57%), diarrhea (52%), 
fatigue (48%), and alopecia (35%). The recommended phase 2 dose was 50 mg BID for 7 days.  
Durable partials response was documented in one patient with platinum-refractory ovarian cancer 
and treatment was for over 1.5 years (> 30 cycles).  Eight patients continued treatment for ≥ 6 
cycles with stable disease. Alisertib (MLN8237) was deemed to be generally well tolerated.[50] 
 
Concurrent with the above study, data was presented on pharmacokinetic and pharmacodynamic 
results from two phase 1 studies of alisertib (MLN8237) in patients with advanced solid tumors. 
In 117 patients who took MLN8237, the drug was absorbed rapidly (median Tmax, 2h), steady-state 
exposures were achieved by 7 days and were dose-proportional over dosing ranges of 5-200mg 
per day. The recommended phase II dose 50mg BID × 7 days produced steady-state average 
concentrations (geometric mean ~1.7µM), exceeding the efficacious concentration estimated 
preclinically (1µM). Mean t1/2 was ~21h. At steady-state exposures, skin mitotic and apoptotic 
indices and tumor mitotic index increased, and tumor mitotic cell chromosome alignment and 
spindle bipolarity decreased, all demonstrating AAK inhibition. In evaluable pts with paired tumor 
biopsies, exposure-related changes were observed by D7, including decreases in chromosome 
alignment and spindle bipolarity.[51] 
 
Another phase I trial of enteric coated (ECT) alisertib in advanced solid tumors was presented in 
the last year. The agent was administered orally BID for 7 days, followed by 14 days of rest, in 
21-day cycles. 17 pts were treated, with frequent tumor types including sarcoma (n=4), and ovarian 
(n=2). The MTD was identified as 50 mg BID, with a DLT of Grade 4 febrile neutropenia was 
reported at 50 mg BID. The most common adverse events were neutropenia (47%) and fatigue 
(47%), and the most common grade≥3 adverse event was neutropenia (41%), which was 
reversible. Following oral administration, MLN8237 ECT was absorbed at a moderate rate with 
an overall median Tmax of 3 h and with dose-related increase in exposure over ranges of 10–50 mg 
BID. Mean t½ was ~20 h following multiple dosing, consistent with previous results.[52] 
 
Alisertib has also been studied in solid tumor phase II trials as single agent and in combination.[54, 
55] A study in combination with paclitaxel in a phase I/II trial of advanced solid tumor 
malignancies reported grade 4 diarrhea, grade 3 stomatitis (both at paclitaxel 80 mg/m2 with 


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alisertib 20 mg BID) and grade 4 neutropenic fever (at paclitaxel 60 mg/m2 with alisertib 30 mg 
BID). A MTD was not reached. Most common adverse events were neutropenia (n=18), anemia 
(n=13) and nausea (n=12). 21 pts had grade ≥3 drug-related adverse events, with the most common 
being neutropenia (n=15). Eight patients experienced partial responses by RECIST and/or CA125 
levels, and three patients had stable disease for ≥ 6 months.[55] 
 
2.1.4.1 Clinical Studies in Hematologic Malignancies 
Alisertib has also been studied in hematologic malignancies, with promising results. A phase 1 
study of advanced hematologic malignancies was conducted across 6 dose cohorts, evaluating the 
following dose levels and schedules, initially using the PIC formulation of alisertib (initial cohort 
size n = 2-7): 25mg, 35 mg QD x 21 days; and 35, 45, 65, and 90 mg QD x14 days. With the 14-
day schedule, the MTD of alisertib (PIC formulation) was determined to be 45 mg QD in adult 
patients with advanced hematologic malignancies, established following occurrence of DLTs in 
four patients at higher dose levels: grade 4 thrombocytopenia, grade 4 neutropenia (65 mg QD); 
grade 3 febrile neutropenia, grade 4 thrombocytopenia (90 mg QD).  The study was amended and 
expanded to evaluate the ECT formulation of alisertib administered BID with a 7-day schedule, 
specifically to characterize safety and pharmacokinetics with this formulation.  The MTD for the 
ECT formulation was established as 50 mg BID, with four DLTs observed in three patients: at 40 
mg QD for 14 days, one patient had grade 4 febrile neutropenia, and one patient had grade 4 bullous 
dermatitis and grade 4 neutropenia; at 50 mg BID for 7 days, one of nine patients had grade 4 
neutropenia. In total, 55 patients were included (PIC n=28, ECT n=27).  60% of patients had non-
Hodgkin's lymphoma, 35% multiple myeloma, and 5% chronic lymphocytic leukemia/small 
lymphocytic lymphoma. The most common drug-related adverse events (AEs) were neutropenia 
(PIC 46%, ECT 63%), thrombocytopenia (39%, 41%), and diarrhea (29%, 41%). 24 patients (PIC 
n=12, ECT n=12) had serious adverse events; the most common was febrile neutropenia (PIC n=1, 
ECT n=4). Tolerability appeared similar between the PIC and ECT formulations. Six patients (PIC 
n=3, ECT n=3) died during the study, but no deaths were considered related to alisertib.  In the 42 
evaluable patients, five (PIC n=3, ECT n=2) had partial responses, and 11 had a best response of 
stable disease (PIC n=6, ECT n=5).  26 patients had progressive disease (PIC n=14, ECT 
n=12).[56]   
 
In a phase II trial of single agent alisertib in aggressive B-cell and T-cell non-Hodgkin lymphomas, 
patients were treated at a dose of 50mg twice daily for 7 days on 21 day cycles.  48 patients were 
enrolled, of whom 41 were evaluable for response. Most common Grade 3/4 adverse events were 
neutropenia (63%), thrombocytopenia (31%), stomatitis (15%), febrile neutropenia (13%) and 
fatigue (6%). The overall response rate (ORR) was 32%, with response by histology being 20% 
for DLBCL, 23% for MCL 23% and 57% for T- cell NHL. The investigators concluded that the 
generally manageable toxicity profile suggested an opportunity to combine alisertib with other 
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2.1.4.2 Clinical Studies in Myeloid Malignancies 
Relevant to the current study, a phase II, single-arm, multicenter study was performed in patients 
with advanced AML and high-grade myelodysplastic syndrome (MDS). Patients were treated at 
50 mg BID for 7 consecutive days in a 21-day cycle. In all, 57 patients were enrolled, with 46 
having AML, 21 of whom had secondary AML.   49 patients (86%) patients had received prior 
therapies, and 9 (16%) had received 3 prior therapies. Treatment-related grade 3/4 adverse events 
were seen in 24 (42%) patients and included febrile neutropenia (11%), thrombocytopenia (9%), 
anemia (9%), fatigue (7%), neutropenia (7%), and somnolence (4%).  22 on-study deaths were 
reported, caused by events unrelated to alisertib.  Overall, 6 (13%) responses were observed, all in 
AML patients, with 5 patients experiencing a PR, and one documented CR in a 79-year old female 
with no prior therapy, who remained in CR through 16 cycles.  Also, 17 patients with AML (49%) 
and 2 with MDS (20%) achieved stable disease.[58]  
 
At our institution, we have just finished accrual on a phase I, 3+3 cohort dose-escalation study of 
alisertib combined with standard 7+3 induction for newly diagnosed AML. We recently presented 
our data at the oral session during the 2014 American Society of Hematology Conference. For this 
study, those with acute promyelocytic leukemia or with AML and core-binding factor alterations 
were excluded. All patients received 7+3 induction (continuous infusion cytarabine 100mg/m2 x 7 
days and intravenous idarubicin 12mg/m2 x 3 days), after which on day 8, alisertib was 
administered twice daily (BID) for 7 days. Dose escalation occurred via three cohorts (10mg BID, 
20mg BID, 30mg BID). All underwent a mid-induction bone marrow biopsy, following course of 
alisertib, to assess for residual disease, which if present, was to be treated with 5+2 re-induction 
(cytarabine 100mg/m2 x 5 days, idarubicin 12mg/m2 x 2 days) without alisertib. Following 
induction, up to four cycles of consolidation were allowed, using cytarabine (3g/m2 BID days 1,3,5 
for those aged <60 and 2g/m2 daily days 1-5 for those aged ≥60) followed by alisertib, according 
to dose cohort, on days 6-12.  After consolidation, alisertib maintenance was initiated, at cohort 
dose level, for days 1-7 of 21 day cycles, to be continued for 12 months or until disease 
progression. Those eligible for stem cell transplant (SCT), following induction and/or 
consolidation courses, were removed from study for this purpose.   
 
Data on 16 patients were presented (n=3, 10mg BID; n=7, 20mg BID; n=6, 30mg BID). One 
patient (6%) had therapy-related AML and six (38%) had antecedent MDS or myeloproliferative 
neoplasm. Eleven of the 16 patients (69%) had high risk disease, as per older age (age over 65), 
high risk cytogenetics, and /or derived from preceding myeloid malignancy.  FLT3 mutations were 
detected in 3 (19%), NPM1 mutations in 3 (19%), CEBPA mutations in 2 (13%), and IDH1/IDH2 
mutations in 6 patients (38%). One patient in cohort 2 died of sepsis, deemed unrelated to study 
drug, prior to completion of the toxicity assessment period and was replaced. Six (38%) patients 
have gone on to SCT.  All patients received induction, and 9 patients received at least one cycle 
of consolidation, and 3 patients started maintenance therapy. Alisertib was well tolerated. All 
patients experienced expected grade 4 toxicities of anemia, thrombocytopenia, and febrile 


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neutropenia seen during the induction phase of treatment. One DLT was encountered, of delayed 
thrombocytopenia (grade 4 at day 40), was seen in the 20mg BID cohort.  No other DLTs were 
detected, and toxicities which could be possibly or probably be attributed to alisertib were grade 
1/2 rash, nausea, and oral mucositis. [59] 
 
Doses of up to 30mg twice daily were well-tolerated, and this therefore was determined to be the 
recommended phase II dose (RP2D). 14 of 16 (88%) patients achieved remission following 
induction (12 cases of CR and 2 of CRp). During the course of the study, three patients experienced 
relapse, and three have died (two due to disease). Thirteen of 14 evaluable patients had an ablated 
mid-induction marrow biopsy, with the remaining patient showing 6% blasts in a 20% cellular 
marrow at mid-induction.  None of the patients required re-induction with 5+2 at mid-induction. 
Based on this data obtained during dose-escalation, [59] it was deemed that alisertib was well 
tolerated in conjunction with standard induction chemotherapy in newly diagnosed AML, and held 
promise as a therapeutic agent in AML, when combined with induction chemotherapy. Since the 
presentation of this data in abstract form, patient numbers can be updated.  In total, 19 of 22 
patients (86%) have achieved remission. Of these 19 patients, 7 have relapsed during the course 
of the study, and of these, 5 have died of relapsed AML. 
 
2.2 
Study Disease: Acute Myeloid Leukemia (AML) 
AML is characterized by an arrest in differentiation and uncontrolled proliferation of myeloid 
precursors in the bone marrow.  This underlying process frequently leads to hematopoietic 
insufficiency, and when undifferentiated cells escape the marrow, to significant leukocytosis, with 
often devastating and life-threatening sequelae. Unfortunately, successful treatment of AML 
remains a difficult challenge.  Although the majority of adults under age 60 with de novo AML 
achieve a complete remission (CR) with traditional anthracycline and cytarabine based induction 
regimens, the long-term survival rates continue to be poor at approximately 30-40%. [60, 61] 
Remission rates and prognosis are significantly poorer for patients with high-risk AML, which 
includes older patients, those with poor-risk cytogenetic features, and those whose disease has 
arisen from myelodysplastic syndromes (MDS), myeloproliferative disorders (MPD), as well as 
those with secondary AML from environmental exposures or prior chemotherapy.  In such cases, 
a remission is achieved in less than 40% of cases, with very poor long-term survival rates of less 
than 10%.[61, 62] 
 
Anthracyclines and cytarabine have been the primary agents used for AML induction therapy for 
more than two decades.  Early Cancer and Leukemia Group B (CALG-B) studies established the 
utility of these agents in induction regimens.[63]   CALGB-7421 later demonstrated that induction 
with 7 days of cytarabine and 3 days of anthracycline (7+3) was superior to 5 days of cytarabine 
and 2 days of anthracycline (5+2).[64]   Increasing the intensity of the regimen by extending the 
infusion of cytarabine to 10 days was also investigated, and was shown to have no impact in 
complete remission rate.  Since that time, 7+3 has been extensively used as first line induction 


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regimens in AML, although outcomes continue be frequently inadequate and poor, especially in 
older patients and those with high risk AML.[61] 
 
Therefore, there is an urgent need for the development of novel approaches in the treatment of 
AML to improve outcomes for patients, especially those with high-risk disease.  In the last few 
years, a variety of targeted and novel therapies have been combined with standard induction 
therapy, with some promising initial results[65-67], although the majority of advanced phase 
studies to date have failed to show an advantage in outcomes with combination therapies. 
 
2.3 
Rationale 
As mentioned above, there is a pressing need to develop novel approaches to the treatment of 
AML.  Aurora kinases are a family of oncogenic serine-threonine kinases that regulate multiple 
phases of the mitotic signaling cascade. Inhibition of aurora A kinase (AAK) leads to mitotic 
errors, followed by aneuploidy, apoptosis, and senescence, which maybe especially applicable to 
cells recently or concurrently exposed to cytotoxic chemotherapy. Alisertib, also known as 
MLN8237, is an ATP-competitive, orally available inhibitor of AAK, which has been evaluated 
for safety and efficacy in Phase I and II trials of hematological malignancies including AML. [58]  
Recently, we have concluded a phase I study of alisertib in combination with “7+3” conventional 
induction chemotherapy, and found this combination to be safe and well-tolerated.  In addition, 
there was a strong suggestion of efficacy with a significantly less than expected need for “5+2” re-
induction and a significantly higher than expected rate of remission. Of note, the majority of 
patients on this study harbored high risk disease, as defined by age, preceding marrow disease, and 
cytogenetic risk. [59]  The next logical step in establishing the efficacy of alisertib in combination 
with standard induction chemotherapy in patients with higher risk AML, who have particularly 
poor outcomes with standard therapies. 
 
This protocol therefore describes a phase II clinical trial of alisertib, at a dose of 30 mg twice daily, 
combined with induction chemotherapy (7+3 cytarabine- and idarubicin 
-based therapy) for patients with higher risk AML.  30mg twice daily is the RP2D based on a 
recently completed dose-escalation study of this combination.  This will be a highly translational 
project, encouraged by laboratory investigation of AAK activity in myeloid malignancies and 
promising recent clinical data mentioned above, and will be informed by correlative studies 
assessing in vivo pharmacodynamic parameters.   
 
2.4 
Correlative Studies  
We will perform gene panel sequencing on bone marrow aspirate and/or blood samples collected 
at baseline , day 14 of induction (range 13-16), count recovery following induction (range 35-45, 
55-65 if re-induction given), and at any time of relapse or suspicion of relapse. All samples will 
be processed in a CLIA certified lab. De-identified samples obtained from blood, bone marrow, 
and skin biopsies from selected cases will be subjected to broader sequence analysis (whole exome 


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or genome). These exploratory analyses will be performed with several hypotheses in mind. First, 
we will evaluate whether a specific mutational profile is associated with treatment response. 
Second, we will determine whether there is selective sensitivity to therapy among specific 
founding clones and/or subclones.  Third, we will investigate somatic mutation patterns that are 
associated with disease progression.  Additional laboratory studies will be performed to 
characterize the functional consequences of aurora kinase inhibition on leukemic blasts during 
treatment.   
 
2.5  
Hypothesis 
The addition of alisertib to “7+3” induction chemotherapy will enhance the rate of remission and 
other clinical outcomes in patients with high-risk acute myeloid leukemia. 
 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Participants must have pathologically confirmed, newly diagnosed high-risk acute 
myeloid leukemia, as defined by at least one of the following criteria 
 
A. Age ≥65 years 
B. Age ≥ 18 years with adverse risk karyotype, as per European Leukemia Net 
Guidelines (See Addendum B) 
C. Age ≥ 18 years with antecedent or underlying myelodysplastic syndrome, CMML, or 
myeloproliferative neoplasm 
D. Age ≥ 18 years with AML with MDS-related changes 
 
**Note:  
For patients in category A, a sample to evaluate patient cytogenetics will be sent at the 
time of diagnosis per standard clinical care and the absence of favorable risk cytogenetics 
must be confirmed by Day 8. If the cytogenetic analysis reveals that the patient harbors 
favorable risk cytogenetics, or if the cytogenetic results are not received prior to Day 8, 
the participant will be removed from the study. Patients removed due to presence of 
favorable cytogenetics would be considered to be inevaluable and will be replaced. In 
addition, patients who receive less than half of their total alisertib dose during induction 
would be considered to be inevaluable and will be replaced. 
 
3.1.2 Adults, age 18 years or older at the time of diagnosis, eligible for standard induction 
chemotherapy according to their treating physician, who fulfill criteria in section 3.1.1. 
 


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3.1.3 ECOG performance status 0-2 (Karnofsky ≥60%, see Appendix A) 
 
3.1.4 Left ventricular ejection fraction > 50% as measured by echocardiogram or MUGA scan 
 
3.1.5 Must not have received systemic antineoplastic therapy including radiation therapy 
within 14 days of the study enrollment, except hydroxyurea or 6-mercaptopurine for the 
purposes of cytoreduction. Patients may also have received all-trans retinoic acid 
(ATRA) if there is an early suspicion of acute promyelocytic leukemia (APL, M3-AML), 
although if confirmed to have APL these patients will be excluded from the study. 
 
3.1.6 Adequate renal function as defined by: calculated creatinine clearance ≥ 40 mL/min 
(Cockcroft-Gualt Forumla) 
 
3.1.7 Direct bilirubin < 2.0 x upper limit of nomal (ULN), SGOT (AST) and SGPT (ALT)< 2.5 
x ULN. AST and/or ALT may be up to 5X ULN if thought to be secondary to leukemia. 
 
3.1.8 The effects of alisertib on the developing human fetus are unknown.  For this reason and 
because other chemotherapeutic agents are known to be teratogenic, women of child-
bearing potential and men must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) prior to study entry and for the duration of study 
participation.  Should a woman become pregnant or suspect she is pregnant while she or 
her partner is participating in this study, she should inform her treating physician 
immediately.  Men treated or enrolled on this protocol must also agree to use adequate 
contraception for the duration of study participation, and 6 months after completion of 
therapy. 
 
3.1.9 Subject must be able to take oral medication and to maintain a fast as required for 2 hours 
before and 1 hour after alisertib administration.  
 
3.1.10 Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients will be excluded from this study if they are found to harbor  “favorable” risk 
cytogenetics: 
 
3.2.2 Patients with acute bilineal/biphenotypic leukemia 
 


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3.2.3 Participants who have had systemic chemotherapy or radiotherapy within 14 days prior to 
entering the study, except for hydroxyurea or 6-MP as noted. Empiric intrathecal 
chemotherapy during a diagnostic lumbar pucture is allowed, as long as CNS disease is 
not suspected.  
 
3.2.4 Participants who are receiving or have received any other investigational agents within 14 
days of enrollment. 
 
3.2.5 Immunotherapy or therapy with monoclonal antibodies or small tyrosine kinase inhibitors 
within the past 4 weeks prior to treatment with the trial drug 
 
3.2.6 Persistence of clinically relevant therapy related toxicity from previous anti-cancer 
therapy 
 
3.2.7 Prior allogeneic bone marrow or organ transplantation 
 
3.2.8 Individuals with a history of a different malignancy are ineligible except for the 
following circumstances. Individuals with a history of other malignancies are eligible if 
they have been disease-free for at least 3 years and are deemed by the investigator to be 
at low risk for recurrence of that malignancy. Individuals with the following cancers are 
eligible if diagnosed and treated within the past 3 years: cervical cancer in situ, and basal 
cell or squamous cell carcinoma of the skin. 
 
3.2.9 Current clinical central nervous system (CNS) symptoms deemed by the investigator to 
be related to leukemic CNS involvement (no lumbar puncture required, clinical 
assessment per investigator’s judgment is sufficient). 
 
3.2.10 If applicable, patient with ≥ Grade 2 peripheral neuropathy within 14 days before 
enrollment  
 
3.2.11 Prior treatment with alisertib 
 
3.2.12 Known history of hepatitis C infection or suspected currently active hepatitis C infection. 
Known or suspected history of hepatitis B infection will be excluded when any of the 
following conditions are met: 
 Received hematopoietic stem cell transplantation (either allogenic or autologous), or 
 Received any rituximab-containing treatment regimen in the last 12 months before 
entering the study, or Active hepatitis B as deemed by serology or viral load  
 


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3.2.13 Current or history of congestive heart failure New York Heart Association (NYHA) class 
3 or 4, or any history of documented diastolic or systolic dysfunction (LVEF <50%, as 
measured by MUGA scan or echocardiogram). Prior to study entry, any ECG 
abnormality at screening has to be documented by the investigator as not medically 
relevant 
 
3.2.14 Known hypersensitivity to the trial drugs or other contraindication to standard “7+3” 
induction chemotherapy. 
 
3.2.15 Known history of uncontrolled sleep apnea syndrome, or sleep apnea requiring 
supplemental oxygen, and other conditions that could result in excessive daytime 
sleepiness. 
 
3.2.16 A medical condition requiring use of proton pump inhibitors (PPIs); or histamine 2 (H2) 
receptor antagonists. Patients who intermittently use these medications, must meet the 
following criteria: 
 No use of PPIs within 5 days before the first dose of alisertib 
 No use of H2 antagonist or pancreatic enzymes within 24 hours before the first dose of 
alisertib 
 
3.2.17 Patients with mental deficits or psychiatric conditions that preclude them from giving 
informed consent or following protocol. 
 
3.2.18 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection 
requiring intravenous antibiotics, symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements. 
 
3.2.19 Known GI disease or GI procedures that could interfere with the oral absorption or 
tolerance of alisertib. Examples include, but are not limited to partial gastrectomy, history 
of small intestine surgery, and celiac disease. 
 


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3.2.20 Pregnant women are excluded from this study because alisertib, along with standard 
induction chemotherapy, carries the potential for teratogenic or abortifacient effects.  
Because there is an unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother with alisertib as well as cytarabine and idarubicin, 
breastfeeding should be avoided. Confirmation that the subject is not pregnant must be 
established by a negative serum -human chorionic gonadotropin (-hCG) pregnancy test 
result obtained during screening.  Pregnancy testing is not required for post-menopausal 
or surgically sterilized women. 
 
3.2.21 Although not absolute exclusion criteria, because of known drug-drug interactions, below 
are issues that should be considered during enrollment: 
 
Treatment with clinically significant enzyme-inducing drugs, including known P-glycoprotein 
inducers (including St John’s wort and rifampicin) should be used only if absolutely necessary 
and considered to be the best available choice for the patient. If possible, it is recommended that 
alternatives to known substrates, inhibitors or inducers of P-glycoprotein be considered. Cases 
should be discussed with the principal investigator, and may be allowed as per his/her discretion. 
 
3.2.22 Patients with psychological, familial, social, or geographic factors that otherwise 
preclude them from giving informed consent, following the protocol, or potentially 
hamper compliance with study treatment and follow-up. 
 
3.2.23 Patients who are otherwise felt unable to comply with the protocol, in the opinion of the 
investigator. 
 
 
3.3 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups, and any member of an underrepresented 
population, are eligible for this trial. 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions 
 
Institutions will register eligible participants with the DF/HCC Quality Assurance Office for 
Clinical Trials (QACT) central registration system. Registrations must occur prior to the 
initiation of protocol therapy. Any participant not registered to the protocol before protocol 
therapy begins will be considered ineligible and registration will be denied. 


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An investigator will confirm eligibility criteria and a member of the study team will complete the 
QACT protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Notify the QACT Registrar of registration cancellations as soon as 
possible.  
 
 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions 
 
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 5:00 PM 
Eastern Standard Time. In emergency situations when a participant must begin protocol therapy 
during off-hours or holidays, call the QACT registration line at 
 and follow the 
instructions for registering participants after hours. 
 
The registration procedures are as follows: 
 
 Obtain written informed consent from the participant prior to the performance of any 
protocol specific procedures or assessments.  
 
 Complete the QACT protocol-specific eligibility checklist using the eligibility 
assessment documented in the participant’s medical record and/or research chart. To be 
eligible for registration to the protocol, the participant must meet all inclusion and 
exclusion criterion as described in the protocol and reflected on the eligibility 
checklist. 
 
Reminder: Confirm eligibility for ancillary studies at the same time as eligibility for a 
treatment protocol. Registration to both treatment and ancillary protocols will not be 
completed if eligibility requirements are not met for all studies.  
 
 Fax the eligibility checklist(s) and all pages of the consent form(s) to the QACT at 
. For Phase I protocols, attach participant dose level assignment confirmation 
from the sponsor. 
 
 The QACT Registrar will (a) review the eligibility checklist, (b) register the participant 
on the protocol, and (c) randomize the participant when applicable. 


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 An email confirmation of the registration and/or randomization will be sent to the Overall 
PI, study coordinator(s) from the Lead Site, treating investigator and registering person 
immediately following the registration and/or randomization. 
 
4.3 
General Guidelines for Other Investigative Sites 
N/A 
 
4.4 
Registration Process for Other Investigative Sites 
N/A 
 
 
5. TREATMENT PLAN 
 
5.1 
Treatment Regimen 
 
All subjects who meet the inclusion/exclusion criteria will be considered for enrollment.  Subjects 
will only be approached after obtaining permission from their physician and healthcare team at 
that time.  The healthcare team will introduce the study to the patient and obtain permission from 
the patient to be contacted by the study staff.  After permission is obtained, one of the co-
investigators of this study will explain the study to potential subjects in detail.  It will be 
emphasized that the study is entirely optional.  All details of the study will be explained to the 
subject with any questions answered by a co-investigator or a member of the healthcare team.  A 
copy of the study’s consent form will be provided to all participants.  Written informed consent 
will be obtained at that time.  The patient will be ensured that his or her decision to participate in 
the study will not affect his or her individual care. As stated above, all subjects who sign consent 
will be registered via QACT as per standard institutional guidelines. 
 
Enrolled patients will provide blood and urine for assays that are part of standard of care for their 
treatment as well as tests which are required by the study.  Those required by the study are as 
follows, and should occur within 14 days prior to enrollment: complete blood count and 
differential, complete metabolic panel consisting of electrolytes panel, renal function, and hepatic 
function assays, coagulation parameters, LDH, uric acid, hepatitis B/C serologies, and urinalysis.  
EKG and an echocardiogram will also be required prior to initiation of treatment.  A MUGA scan 
can be used in place of an echocardiogram, if necessary.  Standard institutional procedures can be 
followed for imaging and obtaining blood and urine cultures if there is suspicion of infection.  A 
bone marrow biopsy and aspirate will also be performed within 14 days of enrollment.  
 
Induction treatment and cytarabine consolidation will be administered on an inpatient basis. 
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will have a central venous catheter line placed (a peripherally inserted central catheter (PICC) will 
also be allowed) during induction. Patient are not required to have a central line during 
consolidation or maintenance.  Reported adverse events and potential risks for alisertib, cytarabine, 
and idarubicin, as well as appropriate dose modifications for these agents are described in Section 
6. No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
Prior to onset of induction therapy, for patients with significant leukocyotosis, hydroxyurea can be 
administered to lower the WBC, as per discretion of treating physician. Leukapheresis can also be 
used for reduction in the WBC count. It is recommended that patients start allopurinol prior to 
receiving chemotherapy and this be continued until at least day 5. 
 
 
 
 
 
5.2 
Agent Administration 
Treatment on study will be according to the schema outlined below: 


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5.2.1. Remission Induction Therapy: 
On day 1 of the study, all patients will be initiated on the “7+3” induction regimen, which consists 
of the following:  
 Cyatarabine 100mg/m2/day intravenous continuous infusion days 1-7 of induction cycle 
 Idarubicin 12mg/m2/day intravenous bolus days 1-3 of induction cycle. If idarubicin is 
not available, daunorubicin 60mg/m2/day intravenous bolus on days 1-3 will also be 
allowed as an alternative. The dose of idarubicin (or daunorubicin) should be adjusted 
based on bilirubin level as per Section 6.2. 
 
Treatment with alisertib at a dose of 30mg twice daily (every 12 hours) will begin on day 8 (or day 
9), after conclusion of “7+3” induction course. Section 5.2.3 
 
5.2.2. Day 14 Bone Marrow Aspiration and Possible Re-Induction Therapy 


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A bone marrow biopsy will be performed on day 14 (range day 13-16) of induction.   
 If bone marrow cellularity is ≥ 20% and there are greater than 5% myeloblasts present, the 
treating physician is to administer “5+2” re-induction, consisting of the following: 
-Cyatarabine 100mg/m2/day continuous infusion days 1-5 of re-induction 
-Idarubicin 12mg/m2/day bolus days 1-2 of re-induction.  If idarubicin is not available, 
daunorubicin 60mg/m2/day intravenous bolus on days 1-2 will also be allowed as an 
alternative. The dose of idarubicin or daunorubicin should be adjusted based on 
bilirubin level as per Section 6.2.  
-Alisertib will not be given during re-induction 
 
 If regardless of bone marrow cellularity, there are ≤ 5% myeloblasts present, no re-
induction is necessary. 
 
 If bone marrow cellularity is < 20% and there are greater than 5% myeloblasts present, 
re-induction will be at the discretion of the treating physician. 
 
5.2.3 Treatment with Alisertib 
 
During Induction, treatment with alisertib will be as follows:  
-Alisertib 30mg twice daily (every 12 hours) will be given on days 8-14 or 9-15 
 
Alisertib will be begin on day 8, after the conclusion of “7+3” induction course. The exception 
would be if 7+3 therapy begins in the afternoon or evening, and therefore finishes late on day 8, 
in which case the first dose of Alisertib may be given on Day 9,  
 
If “5+2” re-induction is administered, alisertib will not be given during this re-induction.  
 
During Consolidation, treatment with Alisertib will be as follows:  -Alisertib at 30mg PO twice 
daily (every 12 hours) will be administered for  days 6-12 at after the conclusion of Cytarabine. 
Please note . if dose reduction took place for alisertib-related toxicity during induction, that dose-
reduced dose will also be used during consolidation and subsequent maintenance 
 
Following count recovery after induction and/or consolidation course(s), maintenance cycles of 
alisertib will be started.and continued for 12 cycles, or until disease progression or unacceptable 
toxicity. Alisertib delays and dose modification are detailed in Section 6.   
 
During Maintenance, treatment with Alisertib will be as follows:  
 
 
- Alisertib 30mg PO twice daily (every 12 hours) will be administered for days 1-7 followed 


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by 14 days off, in  21 day cycles.  
 
Subjects must be fasting for 2 hours before and 1 hour after Alisertib (MLN8237) administration. 
Only water is allowed during the fasting period. Subjects should take Alisertib within 3 hours of 
a missed dose. If more than 3 hours have passed, then that dose should be omitted, and the 
subject should resume treatment with the next scheduled dose. Vomited or missed doses of 
Alisertib will not be made up or re-dosed on this study. 
 
5.2.4 Remission Bone Marrow Aspiration and Biopsy 
Upon a peripheral blood count recovery of ANC of at least 1000/µL and a platelet count of at least 
100,000/µL, following course of induction (and re-induction, if necessary) chemotherapy, a bone 
marrow aspirate and/or biopsy will be performed to assess and document response to therapy.  A 
bone marrow aspirate and/or biopsy will also be performed if hematologic recovery has not 
occurred by day 42 (Range 35-45) (or day 63 if 5+2 re-induction was given based on day 14 bone 
marrow biopsy, range 55-65), or at any time that AML regeneration is suspected.  
 
Response criteria will be as defined by modified International Working Group (IWG) as per 
Cheson et al [68]. If patient is found to have persistent AML, he/she will be discontinued from the 
study and proceed with additional management off-study per discretion of the treating oncologist. 
 
5.2.5 Remission Consolidation Therapy 
Patients who are eligible for hematopoietic stem cell transplantation (HSCT), per their treating 
physician, or other post-remission strategies, after discussion with and per the discretion of the 
principal investigator, can come off study for this purpose.  
 
Patients in CR or CRi who are unable or unwilling to undergo HSCT can receive up to four cycles 
of remission consolidation therapy, at the discretion of their treating physician. Each consolidation 
cycle is typically four weeks (28 days) in duration, and should begin within two to four weeks 
following hematologic recovery (ANC ≥ 1000/mcL and platelet count ≥ 100,000/mcL), but not 
sooner than four weeks from the beginning of the previous cycle.   
 
Patients who have CRI (ANC ≥ 1000/mcL and platelet count ≤ 100,000/mcL) may undergo 
remission consolidation therapy after discussion with the principal investigator.   
 
Remission consolidation therapy will consist of the following for patients younger than age 60: 
 Cytarabine 3 g/m2 by IV infusion over 3 hours (or institutional standard) given every 12 
hours on Days 1, 3, and 5. (6 doses) 
 Alisertib 30 mg PO given twice daily (every 12 hours) on Days 6-12 
 


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Remission consolidation therapy will consist of the following for patients equal to or greater than 
age 60: 
 Cytarabine 2 g/m2 per day by IV infusion over 3 hours (or institutional standard) on Days 
1-5. (5 doses) 
 Alisertib 30 mg PO given twice daily (every 12 hours) on Days 6-12 
 
Prior to cytarabine infusion, mandatory corticosteroid eye drops will be given per institutional 
standards.  Patients should be monitored closely and a serial fashion for onset of cerebellar deficits 
or central nervous system symptomatology, as per institutional guidelines. 
 
In those patients receiving cycles of consolidation therapy, alisertib (MLN8237) will be started on 
day 6, and given by mouth at a dose of 30mg twice daily, for a period of seven days.  If dose 
reduction took place for alisertib-related toxicity during induction, that dose-reduced dose will also 
be used during consolidation and subsequent maintenance.  Dose reductions for toxicity related to 
alisertib will be as outlined in Section 6.1.   
 
5.2.6 Maintenance Therapy 
Upon count recovery, (ANC ≥ 1000/mcL and/or platelet count ≥ 100,000/mcL), following at least 
2 cycles of consolidation, maintenance therapy with alisertib will be initiated.  The first cycle of 
maintenance should begin within two to four weeks following hematologic recovery (ANC ≥ 
1000/mcL and/or platelet count ≥ 100,000/mcL), but not sooner than four weeks from the 
beginning of the previous cycle.  If the first cycle of maintenance cannot be started within four 
weeks following hematologic recovery (as mentioned above), the patient would be considered off 
study treatment. See section 6.1.1 for further information regarding delay and dose modifications.  
 
  Alisertib will be given at 30mg BID for days 1 through 7 of 21 day cycles.  Maintenance therapy 
will continue for a total of 12 cycles or until disease progression.  A window of up to +/- 3 days is 
allowed to start the successive cycles of maintenance to accommodate patient/provider availability 
and holidays. 
 
5.3 
General Concomitant Medication and Supportive Care Guidelines  
Antiemetics will be used according to standard practices.  Patients will receive prophylaxis 
directed against candidiasis, and/or herpes simplex virus (HSV), and bacterial infection, as needed, 
according to individual institutional practices.  
 
Hematopoietic growth factors may be used with PI approval.  
 
Caution should be used o with the use of proton pump inhibitors, H2 antagonists, antacids, or 
pancreatic enzymes, that could potentially impact the absorption of Alisertib. . 
 


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The following guidelines should be used if using these medications:   
 
 No use of PPI within 5 days prior to Alisertib and while on Alisertib. PPI may be 
restarted after 24hrs after the last dose of Alisertib.  
 No use of H2 antagonist or pancreatic enzymes within 24 hours before the first dose of 
alisertib and  may be restarted 24 hrs after the last dose of  Alisertib.  
 Antacids should not be taken 2hrs prior to Alisertib and for 1 hour after the dose.  
 Carafate should not be taken 6 hrs prior to Alisertib and for 1 hour after the dose 
 
Treatment with clinically significant enzyme-inducing drugs, including known P-glycoprotein 
inducers (including St John’s wort and rifampicin) should be used only if absolutely necessary and 
considered to be the best available choice for the patient. If possible, it is recommended that 
alternatives to known substrates, inhibitors or inducers of P-glycoprotein be considered. Cases 
should be discussed with the principal investigator, and may be allowed as per their discretion. 
  
5.4 
Duration of Therapy 
In the absence of disease progression or unacceptable adverse event, alisertib will be continued for 
a period of up to 12 cycles of maintenance, based on the schedule above.  
 
In the absence of treatment delays due to adverse events, treatment may continue as above until 
one of the following criteria applies:  
 Disease progression,  
 Intercurrent illness that prevents further administration of treatment, 
 Unacceptable adverse event(s)  
 Patient decides to withdraw from the study, or  
 General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
 Patient becomes pregnant or begins breast-feeding   
 Failure to return for follow-up 
 
5.5 
Duration of Follow Up  
Alisertib will be administered as above, until the conclusion of the study, unless relapse, death, 
or intolerable toxicity takes place, at which point treatment will cease.  Patients discontinued 
from therapy for unacceptable adverse events will be followed until resolution or stabilization of 
the adverse event. Also, regardless, all participants will be followed for 30 days after 
removal from study or until death, whichever occurs first.   
Patients will be contacted at least every 3 months for a period of up to 12 months for disease and 
survival status and collection of subsequent anticancer treatment information until death or study 


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closure, whichever occurs first. Results from routine labs will be collected as needed to follow 
patients for peripheral blood count recovery. 
 
  
5.6  
Criteria for Removal from Study  
Patients will be removed from study when any of the criteria listed in Section 5.4 applies, or if the 
study physician determines they cannot comply with the protocol. The reason for study removal 
and the date the patient was removed will be documented in the Case Report Form (CRF). 
Alternative care options will be discussed with the participant. In the event of unusual or life-
threatening complications, participating investigators must immediately notify the Principal 
Investigator, Amir T. Fathi MD, Partners pager 12042. 
 
A QACT Treatment Ended/Off Study Form will be filled out when a participant comes off study. 
This form can be found on the QACT website or obtained from the QACT registration staff.  
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP website 
 http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm.  
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate 
medical treatment should be used (including anti-emetics, anti-diarrheals, etc.). 
 
6.1 Alisertib, Dose Modifications/Delays 
All adverse events experienced by participants will be collected from the time of the first dose of 
study treatment, through the study and until the final study visit. Participants continuing to 
experience toxicity at the off study visit may be contacted for additional assessments until the 
toxicity has resolved or is deemed irreversible. 
 
6.1.1 Management of Toxicity 
It is anticipated that all patients will experience grade 3 or 4 myelosuppression during induction 
and consolidation. There are no dose modifications planned for abnormal blood counts during 
these phases of treatment.  
 
However, during maintenance phase, when concurrent chemotherapy is not administered with 
alisertib, if a patient has grade 4 neutropenia or thrombocytopenia on day 1 the next cycle should 
be delayed until that cytopenia is grade 2 or less, and patients should be followed weekly. Patients 
will be allowed to delay subsequent cycles for up to 2 weeks. If the patient is delayed more than 2 
weeks they will be removed from study.  If during a cycle a patient experiences grade 4 neutropenia 


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or thrombocytopenia, doses should be held until grade 2 or less. Once the patient’s neutropenia or 
thrombocytopenia is at a grade 2 or less,  dosing may be resumed at the next lower dose level as 
per Table 1.  If the cytopenia does not resolve to grade 2 within 2 weeks, the patient will be 
removed from study. If the dose is held during maintenance for this purpose, doses will not be 
made up.   Patients should continue at the lower dose of Alisertib for all subsequent maintenance 
cycles. 
 
If at any time during treatment, patients with CTCAE 4.0 Grade 3  non-hematologic toxicity that 
is possibly, probably or definitely related to alisertib (MLN8237) and persisting for >48 hours 
without resolution to ≤ Grade 2 will have dosing of alisertib interrupted (or sooner at the discretion 
of the investigator if considered necessary for patient safety) with the exception of those Grade 3 
or 4 non-hematologic toxicities that are associated with AML and its treatment with induction or 
consolidation chemotherapy.  
 
If the alisertib-related Grade 3 non-hematologic toxicity reverses to ≤ Grade 1 or baseline within 
7 days of stopping the study drug, then the patient may resume their dosing schedule at one dose 
level lower, according to the dose de-escalation schedule below (See Table 1 below). For example, 
as a scenario, if a patient had been receiving a dose of alisertib 30 mg by mouth twice daily, they 
would then be de-escalated to dose of 20mg by mouth twice daily, and so on per dosing levels 
detailed below.  If the patient develops grade 3 non-hematologic toxicity at a dose of 10mg once 
daily, they will discontinue alisertib.  
 
 Doses will not be made up if days of treatment are missed due to toxicity. If the Grade 3 non-
hematologic toxicity does not resolve within the window provided above, patients will not be re-
dosed with alisertib and will discontinue treatment. 
 
 
 
Patients with non-hematological study drug-related Grade 4 will not be re-dosed with alisertib and 
will discontinue treatment. In addition, dose reduction will be allowed with persistent non-
hematologic grade 2 toxicities, including GI toxicities, at the discretion of the investigator.  Dose 
reductions will be allowed during the induction, consolidation, and maintenance phases of therapy.  
Once a patient’s dose is reduced they should continue at that dose level for the rest of the treatment 
program.   
 
Table 1: Dose de-escalation for toxicity 
Dose Level 
Alisertib Dose 
Level 0 
30 mg by mouth twice daily 
Level -1 
20 mg by mouth twice daily 
Level -2 
10 mg by mouth twice daily 
Level -3 
10 mg by mouth once daily 


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Should unanticipated circumstances arise that might require minor variances from the prescribed 
dosing and schedule of the protocol therapy or recommended supportive care, the principal 
investigator should be contacted in advance for discussion and approval in order to ensure safety 
and determine/allow patients to continue to receive treatment on study. 
 
6.1.1.1 Drug-Drug Interaction Risks 
 
Preliminary results from the recently completed alisertib human ADME Study C14014 
indicate that oxidative metabolism is the predominant route of elimination for alisertib. 
Preliminary results of subsequent in vitro drug metabolism studies suggest that the oxidative 
metabolism of alisertib is mainly mediated via CYP3A4. These findings suggest that 
alisertib systemic exposures may be potentially increased when co-administered with 
clinically significant CYP3A inhibitors. The clinical effect of co-administration of a 
CYP3A inhibitor on the pharmacokinetics of alisertib is unknown at this time and a DDI 
study with itraconazole (a strong CYP3A inhibitor) is planned. Until these results become 
available, it is recommended that the concomitant use of moderate or strong CYP3A 
inhibitors or grapefruit juice/grapefruit-containing products be avoided. Selection of an 
alternate concomitant medication with no or minimal CYP3A inhibition potential is 
recommended. If co-administration of moderate or strong CYP3A inhibitors is medically 
necessary, investigators should monitor for toxicities and follow the dose modifications for 
toxicity per study protocol. 
  
6.1.2 Specific Toxicities and Management 
 
Nausea and Vomiting 
Specifically for in relation to alisertib, prophylactic antiemetic therapy will not be used in this 
study unless it becomes clear that alisertib is causing acute nausea and vomiting.  If prophylactic 
antiemetic therapy is needed, 5-HT3 receptor antagonists (without corticosteroids) should be tried 
first.  Prophylactic anti-emetics can be otherwise used as per institutional guidelines for other 
chemotherapy administered during the study. 
 
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. 
 
Diarrhea 
Specifically for use of alisertib, antidiarrheal medications will not be used prophylactically; 
however, patients can 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 if thought to 
be alisertib-related diarrhea.  Fluid intake should be maintained to avoid dehydration. 


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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. 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 
 
6.1.3 Management of cardiac toxicity 
Given the rare reports of cardiac toxicities in patients receiving alisertib, extra caution will be 
exercised to monitor and manage patients in this regard, as necessary. Alisertib will be 
discontinued if: 
A. There is persistent clinically significant arrhythmia thought to be related to Alisertib. 
B. Onset of congestive heart failure with related symptoms, and which does not respond promptly 
to standard management. 
 
6.2 
Dose Modifications of Idarubicin (or Daunorubicin) for Related 
Hepatotoxicity 
Initial and subsequent idarubicin (or daunorubicin) doses should be modified as follows for 
hepatotoxicity: 
 
Total Bilirubin (mg/dL)  
 
% Dose to Give 
≤ 2  
 
 
 
100% 
> 2 – ≤ 3.0  
 
 
75% (25% dose reduction) 
> 3.0  
 
 
 
50% (50% dose reduction) 
 
Assess total bilirubin daily when administering idarubicin (or daunorubicin) during remission 
induction or re-induction treatment. 
 
6.3 
Dose Modifications for Treatment with cytarabine consolidation therapy 
 
- Contributions of concomitant medications (i.e. psychotropic drugs) to neurotoxicity should be 
assessed and other medications discontinued if possible. 
 
-For neurotoxicity ≥ grade 2 due to cytarabine during consolidation therapy, discontinue high-
dose cytarabine for the remainder of the cycle.  
 
-For patients younger than 60 years, cytarabine may be considered at the subsequent 
consolidation therapy cycle with a dose modification from 3 g/m2 to 2 g/m2 every 12 hours on 
days 1, 3 and 5 if the toxicity has resolved to ≤ grade 1. 


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-For patients equal to or greater than 60 years, cytarabine may be considered at the next 
consolidation therapy cycle with a dose modification from 2 g/m2 to 1 g/m2 daily on days 1 
through 5 of consolidation if the toxicity has resolved to ≤ grade 1. 
 
-For a second occurrence of neurotoxicity ≥ grade 2, cytarabine for consolidation should be 
permanently discontinued. 
 
Should unanticipated circumstances arise that might require minor variances from the prescribed 
dosing of cytarabine or idarubicin (or daunorubicin if indicated) and schedule of the protocol 
therapy, the principal investigator should be contacted in advance for discussion and approval in 
order to ensure safety and determine/allow patients to continue to receive treatment on study. Dose 
reductions for idarubicin (or daunorubicin if indicated) or cytarabine may be implemented if 
clinically indicated, and after discussion with principal investigator of study, for treatment-related 
adverse events that do not meet above dose reduction criteria. 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following definitions of reported and/or potential AEs and the characteristics of an observed AE 
will determine whether the event requires expedited reporting in addition to routine reporting. 
 
7.1 Adverse Event Characteristics 
 
 CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm. 
 
An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient in a clinical investigation who 
received a pharmaceutical product. The event does not necessarily have to have a causal 
relationship with this treatment. 
 
All adverse events occurring during the course of the clinical trial (i.e., from signing the 
informed consent onwards through the observational phase) will be collected, 
documented and reported to the sponsor by the investigator according to the specific 
definitions and instructions detailed in the ‘Adverse Event Reporting’ section of the 


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Investigator Site File. The observational phase for AE reporting is defined from the first 
dose of study treatment until the End of Treatment visit, or 30 days after the last 
administration of study medication, whichever is the latest. 
 
A serious adverse event (SAE) is defined as any AE which results in death, is 
immediately life-threatening, results in persistent or significant disability / incapacity, 
requires or prolongs patient hospitalization, is a congenital anomaly / birth defect, or is to 
be deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the above 
definitions. 
 
Patients may be hospitalized for administrative or social reasons during the trial (e.g. 
days on which infusion takes place, long distance from home to site). These and other 
hospitalizations planned at the beginning of the trial do not need to be reported as an 
SAE. 
 
All adverse events, serious and non-serious, will be fully documented on the appropriate 
CRF(s) / eCRFs. For each adverse event, the investigator will provide the onset, end, 
intensity, treatment required, outcome, seriousness and action taken with the 
investigational drug. The investigator will determine the relationship of the 
investigational drug to all AEs as defined in the 'Adverse Event Reporting' Section of the 
Investigator Site File. 
 
The basis for judging the intensity of the AE as well as the causal relationship between 
the investigational product and the AE is described below. 
 
 For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 
- 
The attribution of any AE to the study drug as “definite,” “probable,” or “possible” 
will be considered as related to the therapy (“yes”), while unlikely and unrelated are 
considered as not related (“no”) for regulatory reporting purposes. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions. 
 
 Attribution of the AE: 


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- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.1 
Adverse Events Associated with Alisertib 
Toxicities have been noted in Phase I and II studies involving alisertib, the majority of grade 3 or 
4 AEs being hematologic in nature.  
 
Experience with alisertib has been in the single-agent and in the combination (with cytotoxic 
chemotherapy) setting. Additionally, 3 alisertib formulations (PIC, ECT, and oral solution) have 
entered clinical studies. The adverse events (AEs) were classified according to the Medical 
Dictionary for Regulatory Activities (MedDRA).   
 
Treatment-emergent adverse events, regardless of causality, occurring in ≥10% of patients are 
displayed, as coded by MedDRA System Organ Class (SOC) and Preferred Term in Table 2 for 
events noted in single agent studies to date, and in Table 3 for events noted specifically in single 
agent studies of hematologic malignancies.   
 
 
 
 
 
 




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Table 3 




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The most common treatment-emergent adverse events of  ≥ grade 3 severity are displayed by 
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Although the majority of treatment-related SAEs reflect mechanistic toxicities of alisertib in 
proliferative tissues (bone marrow, GI epithelium, hair follicles), some SAEs have been reported 
that appear to be possible off-target effects unrelated to already well established Aurora A kinase 
functions. For example, two patients in two separate studies developed cardiac abnormalities 
including left ventricular dysfunction and ejection fraction decrease. In both patients, a significant 
decrease in LVEF was observed during or after the first treatment cycle and prior anthracycline 
therapies were noted in addition to confounding histories and comorbidities.  These events were 
confounded by pre-existing morbidities including prior radiation to the heart, possible tumor 
involvement of the pericardium, and prior treatment-resistant tachycardia. Cardiac toxicity was 
not seen in a phase I study of alisertib in combination 7+3 induction. 
 
In addition, skin rash has been described as an identified risk for treatment with alisertib. Palmar-
plantar erythrodysaesthesia syndrome has been observed predominantly in a pediatric patient 
population, with 2 such serious cases occurring in an adult patient population. One patient 
experienced a serious case of bullous dermatitis. There was no mucous membrane involvement 
and the event improved with antibiotics, methylprednisolone, and local wound care.  
 
7.3 
Adverse Events Associated with Idarubicin and Cytarabine  
Please refer to the appropriate package inserts for the comprehensive list of adverse events for 
each agent. 
 
Idarubicin: Toxicities includes myelosuppression and cardiotoxicity. Cumulative dose beyond 
approximately 150 mg/m2 (and equivalent cumulative doses with other anthracyclines) results in 
increased risk for myocardial injury, and congestive heart failure. Radiation therapy involving the 
heart and previous anthracycline administration increases the risk for cardiomyopathy. Hepatic 
and renal dysfunction may occur. Other reactions include reversible alopecia, nausea and vomiting, 
anorexia, diarrhea and mucositis. If extravasation occurs during administration, tissue necrosis can 
result. Rarely, chills, fever, skin rash and anaphylactoid reactions can occur. The occurrence of 
secondary acute leukemia has been reported rarely in patients treated with anthracycline 
chemotherapy. 
 
Cytarabine: Toxicities include myelosuppression, nausea, vomiting, diarrhea, anorexia, anal 
ulceration, stomatitis, rash, headache, fever, myalgia, malaise, bone pain, chest pain, hepatic and 
renal dysfunction, and alopecia. Central nervous system toxicity, i.e., significant cerebral and 
cerebellar, dysfunction, progression to coma, has been seen with high doses, such as those given 
in consolidation.  Severe cardiomyopathy has been reported with high dose Ara-C in combination 
with cyclophosphamide. Progressive ascending paralysis has occurred in two patients receiving 
IV and intrathecal ara-C. Marked keratoconjunctivitis has also occurred with high doses.  Ara-C 


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can cause fetal harm when administered to a pregnant woman; however, there are no adequate and 
well-controlled studies in pregnant women. 
 
 
 
7.4 Adverse Event Reporting Definitions 
 
7.4.1 Adverse Event (AE): 
An adverse event (AE) is any undesirable sign, symptom or medical condition or experience that 
develops or worsens in severity after starting the first dose of study treatment or any procedure 
specified in the protocol, even if the event is not considered to be related to the study.  
 
Abnormal laboratory values or diagnostic test results constitute adverse events only if they 
induce clinical signs or symptoms or require treatment or further diagnostic tests.  
 
7.4.2 Serious adverse event (SAE): 
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless of 
causality that:  
 Results in death 
 Is life-threatening. Life-threatening means that the person was at 
immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction which hypothetically might have caused death had it 
occurred in a more severe form. 
 Requires or prolongs inpatient hospitalization (i.e., the event required at 
least a 24-hour hospitalization or prolonged a hospitalization beyond the 
expected length of stay). Hospitalization admissions and/or surgical 
operations scheduled to occur during the study period, but planned prior to 
study entry are not considered SAEs if the illness or disease existed before 
the person was enrolled in the trial, provided that it did not deteriorate in 
an unexpected manner during the trial (e.g., surgery performed earlier than 
planned). 
 Results in persistent or significant disability/incapacity. Disability is 
defined as a substantial disruption of a person’s ability to conduct normal 
life functions. 
 Is a congenital anomaly or birth defect; or 
 Is an important medical event when, based upon appropriate medical 
judgment, it may jeopardize the participant and require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of 
such medical events include allergic bronchospasm requiring intensive 


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treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
Events not considered to be serious adverse events are hospitalizations for: 
 routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition, or for elective procedures 
 elective or pre-planned treatment for a pre-existing condition that did not 
worsen 
 emergency outpatient treatment for an event not fulfilling the serious 
criteria outlined above and not resulting in inpatient admission 
 respite care 
 
7.4.3 Expectedness - Adverse events can be 'Expected' or 'Unexpected.'  
 
Expected adverse event 
Expected adverse events are those that have been previously identified as resulting from 
administration of the agent. For the purposes of this study, an adverse event is considered 
expected when it appears in the current adverse event list, the Investigator’s Brochure, the 
package insert or is included in the informed consent document as a potential risk.   
 
Unexpected adverse event 
For the purposes of this study, an adverse event is considered unexpected when it varies in 
nature, intensity or frequency from information provided in the current adverse event list, the 
Investigator’s Brochure, the package insert or when it is not included in the informed consent 
document as a potential risk.   
 
7.4.4 Attribution 
Attribution is the relationship between an adverse event or serious adverse event and the study 
treatment. Attribution will be assigned as follows: 
 
 Definite – The AE is clearly related to the study treatment. 
 Probable – The AE is likely related to the study treatment. 
 Possible – The AE may be related to the study treatment.  
 Unlikely - The AE is doubtfully related to the study treatment. 
 Unrelated - The AE is clearly NOT related to the study treatment. 
 
7.5 Procedures for AE and SAE Recording and Reporting 
 


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Participating investigators will assess the occurrence of AEs and SAEs at all participant evaluation 
time points during the study.  
 
All AEs and SAEs whether reported by the participant, discovered during questioning, directly 
observed, or detected by physical examination, laboratory test or other means, will be recorded in 
the participant’s medical record and on the appropriate study-specific case report forms.  
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0. 
 
A copy of the CTCAE version 4.0 can be downloaded from the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
  
7.5.1 Reporting to the Study Sponsor 
 
7.5.1.1 Serious Adverse Event Reporting: 
All serious adverse events that occur after the initial dose of study treatment, during treatment, or 
within 30 days of the last dose of treatment must be reported to the DF/HCC Overall Principal 
Investigator on the local institutional SAE form. This includes events meeting the criteria 
outlined in Section 7.4.2, as well as the following: 
 
 Grade 2 (moderate) and Grade 3 (severe) Events – Only events that are unexpected and 
possibly, probably or definitely related/associated with the intervention. 
 
 All Grade 4 (life-threatening or disabling) Events – Unless expected AND specifically 
listed in the protocol as not requiring reporting. 
 
 All Grade 5 (fatal) Events – When the participant is enrolled and actively participating in 
the trial OR when the event occurs within 30 days of the last study intervention.  
 
Note: If the participant is in long term follow up, report the death at the time of continuing 
review.  
 
Participating investigators must report each serious adverse event to the DF/HCC Overall Principal 
Investigator within 24 hours of learning of the occurrence. In the event that the participating 
investigator does not become aware of the serious adverse event immediately (e.g., participant 
sought treatment elsewhere), the participating investigator is to report the event within 24 hours 
after learning of it and document the time of his or her first awareness of the adverse event. Report 








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data verification.  
 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or monitoring 
visit to obtain additional case details deemed necessary to appropriately evaluate the SAE report 
(e.g., hospital discharge summary, consultant report, or autopsy report).  
 
Participants should be instructed to report any serious post-study event(s) that might reasonably 
be related to participation in this study. Participating investigators should notify the DF/HCC 
Overall Principal Investigator and their respective IRB of any unanticipated death or adverse event 
occurring after a participant has discontinued or terminated study participation that may reasonably 
be related to the study.   
 
7.7 
Product Complaints 
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 Millennium 
Quality representative. 
For Product Complaints, 
call MedComm Solutions at 
  
(US and International) 
 
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 Millennium Pharmacovigilance (refer to Section 
8.2). 
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 Millennium 
Quality representative. 
A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm.  While overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not.  
Individuals who identify a potential medication error situation should immediately contact 
MedComm Solutions (see below) and report the event. 


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8. DATA AND SAFETY MONITORING 
8.1 Data Reporting 
 
8.1.1 Method  
The QACT will collect, manage, and monitor data for this study.  
 
8.1.2 Data Submission  
The schedule for completion and submission of case report forms (paper or 
electronic) to the QACT is as follows: 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with QACT 
On Study Form 
Within 14 days of registration 
Baseline Assessment Form 
Within 14 days of registration 
Treatment Form 
Within 10 days of the last day of the cycle 
Adverse Event Report Form 
Within 10 days of the last day of the cycle 
Response Assessment Form 
Within 10 days of the completion of the cycle 
required for response evaluation 
Off 
Treatment/Off 
Study 
Form 
Within 14 days of completing treatment or 
being taken off study for any reason 
Follow up/Survival Form 
Within 14 days of the protocol defined follow 
up visit date or call 
8.2 Safety Meetings 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this trial. The committee is composed of clinical specialists with experience 
in oncology and who have no direct relationship with the study. Information that raises any 
questions about participant safety will be addressed with the Principal Investigator and study team. 
 


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The DSMC will meet quarterly and/or more often if required to review toxicity and accrual data.  
Information to be provided to the committee may include:  up-to-date participant accrual; current 
dose level information; DLT information; all grade 2 or higher unexpected adverse events that 
have been reported; summary of all deaths occurring within 30 days for Phase I or II protocols; for 
gene transfer protocols, summary of all deaths while being treated and during active follow-up; 
any response information; audit results, and a summary provided by the study team. Other 
information (e.g. scans, laboratory values) will be provided upon request.  
8.3 Monitoring  
Involvement in this study as a participating investigator implies acceptance of potential audits or 
inspections, including source data verification, by representatives designated by the DF/HCC 
Overall Principal Investigator (or Protocol Chair) or DF/HCC. The purpose of these audits or 
inspections is to examine study-related activities and documents to determine whether these 
activities were conducted and data were recorded, analyzed, and accurately reported in 
accordance with the protocol, institutional policy, Good Clinical Practice (GCP), and any 
applicable regulatory requirements.  
 
All data will be monitored for timeliness of submission, completeness, and adherence to protocol 
requirements. Monitoring will begin at the time of participant registration and will continue 
during protocol performance and completion.  
9. REGULATORY CONSIDERATIONS 
9.1 
Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant information 
related to the study (e.g., advertisements used to recruit participants) and any other 
necessary documents must be submitted, reviewed and approved by a properly 
constituted IRB governing each study location.  
Any changes made to the protocol must be submitted as amendments and must be 
approved by the IRB prior to implementation. Any changes in study conduct must be 
reported to the IRB. The DF/HCC Overall Principal Investigator (or Protocol Chair) 
will disseminate protocol amendment information to all participating investigators.  
All decisions of the IRB concerning the conduct of the study must be made in writing. 
9.2 
Informed Consent 
All participants must be provided a consent form describing this study and 
providing sufficient information for participants to make an informed decision 


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about their participation in this study. The formal consent of a participant, using 
the IRB approved consent form, must be obtained before the participant is 
involved in any study-related procedure. The consent form must be signed and 
dated by the participant or the participant’s legally authorized representative, and 
by the person obtaining the consent. The participant must be given a copy of the 
signed and dated consent document. The original signed copy of the consent 
document must be retained in the medical record or research file.  
 
All patient confidentiality will be respected.  All study members will comply fully with 
all HIPPA regulations and policies in the administration of this study.  All research team 
members are to follow the institutional HIPAA policies and procedures, including the 
‘minimal use’ of protected health information when conducting recruitment activities, 
determining eligibility and retaining research charts.  We will document these discussions 
and file the documentation in the regulatory file. 
9.3 
Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, which 
represent good and sound research practice: 
 
E6 Good Clinical Practice: Consolidated Guidance 
www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129515.pdf  
 
US Code of Federal Regulations (CFR) governing clinical study conduct and 
ethical principles that have their origin in the Declaration of Helsinki 
o Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx 02/21cfr54 02.html  
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx 02/21cfr312 02.html  


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 
State laws 
 
DF/HCC research policies and procedures        
http://www.dfhcc.harvard.edu/clinical-research-support/clinical-research-unit-
cru/policies-and-procedures/  
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, 
the deviation must be reported to the IRB according to the local reporting policy.  
9.4 
Study Documentation 
The investigator must prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each 
research participant. This information enables the study to be fully documented and the 
study data to be subsequently verified. 
 
Original source documents supporting entries in the case report forms include but are not 
limited to hospital records, clinical charts, laboratory and pharmacy records, recorded 
data from automated instruments, microfiches, photographic negatives, microfilm or 
magnetic media, and/or x-rays.  
9.5 
Records Retention 
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.  
 
10. PHARMACEUTICAL INFORMATION 
 
10.1 Alisertib (MLN8237) 
As stated above, in its solid state, alisertib (MLN8237-004) drug substance is an off-white to 
yellow solid with an assay value of 96.0% to 104.0% (w/w) on an anhydrous basis, as determined 
by reverse phase high performance liquid chromatography (HPLC). The solubility of the drug 
substance in water (pH = 8.4) is 8.5mg/mL. The drug substance is a stable monohydrate with a 
pKa of 4.53 for the free acid. 
 
Formulation 
An enteric coated tablet dosage form of MLN8237-004 has been developed for use in clinical 
studies. Three different enteric coated tablet dosage strengths, 10, 50, and 100 mg, expressed as 
MLN8237 free acid, were formulated. The key formulation excipients that aid in the in vivo 
absorption of the drug are sodium bicarbonate, sodium lauryl sulfate, and enteric coating. The 


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other formulation excipients such as povidone, microcrystalline cellulose, croscarmellose sodium, 
and sodium stearyl fumarate serve as manufacturing aids.  
 
The study drug, as provided by Millennium, will be labeled and handled at the investigative site 
as open-label material; packaging labels will fulfill all requirements specified by governing 
regulations.  MLN8237 will be supplied as ECT in 10 mg strength.  The 60-cc HDPE bottles will 
have a child-resistant cap and be labeled for take-home use.  Patients will receive instructions for 
home use of MLN8237, including the requirement that MLN8237 be administered as intact tablets 
 
Storage 
Alisertib (MLN8237-004) enteric-coated tablets are packaged in HDPE bottles with rayon coil, 
induction seal, desiccant packs, and polypropylene child-resistant cap and stored at USP-controlled 
room temperature (20°C to 25ºC) with excursions permitted from 15°C to 30°C. 
 
Handling 
Alisertib (MLN8237-004) drug product is a cytotoxic anticancer drug. As with other potentially 
toxic compounds, caution should be exercised when handling the 3 dosage forms of MLN8237-
004 (capsules, tablets, and oral solution). Refer to published guidelines regarding the proper 
handling and disposal of anticancer agents.[1, 2] 
 
 
10.2 Idarubicin 
 
Desription: (Idarubicin® package insert): Idarubicin HCl Injection contains idarubicin 
hydrochloride and is a sterile, semi-synthetic, preservative-free solution antineoplastic 
anthracycline for intravenous use. Chemically, idarubicin hydrochloride is (1S,3S)-3-Acetyl-
1,2,3,4,6,11-hexahydro-3,5,12-trihydroxy-6,11-dioxo-1-naphthacenyl-3-amino-2,3,6-trideoxy-α-
L-lyxo-hexopyranoside, hydrochloride. 
Molecular weight: 533.95 
Molecular formula: C26H27NO9•HCl 
 
Idarubicin HCl Injection is a sterile, red-orange, isotonic parenteral preservative-free solution, 
available in 5 mL (5 mg), 10 mL (10 mg) and 20 mL (20 mg) single-use-only vials. Each mL 
contains idarubicin HCI 1 mg and the following inactive ingredients: glycerin 25 mg and water for 
injection q.s. Hydrochloric acid is used to adjust the pH to a target of 3.5. 
 
Warnings: Idarubicin is intended for administration under the supervision of a physician who is 
experienced in leukemia chemotherapy. Idarubicin is a potent bone marrow suppressant. 
Idarubicin should not be given to patients with pre-existing bone marrow suppression induced by 
previous drug therapy or radiotherapy unless the benefit warrants the risk. 
 


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Severe myelosuppression will occur in all patients given a therapeutic dose of this agent for 
induction, consolidation or maintenance. Careful hematologic monitoring is required. Deaths due 
to infection and/or bleeding have been reported during the period of severe myelosuppression. 
Facilities with laboratory and supportive resources adequate to monitor drug tolerability and 
protect and maintain a patient compromised by drug toxicity should be available. It must be 
possible to treat rapidly and completely a severe hemorrhagic condition and/or a severe infection. 
 
Pre-existing heart disease and previous therapy with anthracyclines at high cumulative doses or 
other potentially cardiotoxic agents are co-factors for increased risk of idarubicin-induced cardiac 
toxicity and the benefit to risk ratio of idarubicin therapy in such patients should be weighed before 
starting treatment with idarubicin. Myocardial toxicity as manifested by potentially fatal 
congestive heart failure, acute lifethreatening arrhythmias or other cardiomyopathies may occur 
following therapy with idarubicin. Appropriate therapeutic measures for the management of 
congestive heart failure and/or arrhythmias are indicated. Cardiac function should be carefully 
monitored during treatment in order to minimize the risk of cardiac toxicity of the type described 
for other anthracycline compounds. The risk of such myocardial toxicity may be higher following 
concomitant or previous radiation to the mediastinal-pericardial area or in patients with anemia, 
bone marrow depression, infections, leukemic pericarditis and/or myocarditis. While there are no 
reliable means for predicting congestive heart failure, cardiomyopathy induced by anthracyclines 
is usually associated with a decrease of the left ventricular ejection fraction (LVEF) from 
pretreatment baseline values.  
 
Since hepatic and/or renal function impairment can affect the disposition of idarubicin, liver and 
kidney function should be evaluated with conventional clinical laboratory tests (using serum 
bilirubin and serum creatinine as indicators) prior to and during treatment. 
 
Please refer to the product's package insert for full prescribing and toxicity information. 
 
10.3 Cytarabine (Cytosine Arabinoside) (Ara-C) 
 
Description: (Cytarabine® package insert) Cytarabine for Injection, commonly known as ara-C, 
an antineoplastic, is a sterile lyophilized material for reconstitution and intravenous, intrathecal 
or subcutaneous administration. It is available in multi-dose vials containing 100 mg, 500 mg, 1 
g or 2 g sterile cytarabine. The pH of Cytarabine for Injection, is adjusted, when necessary, with 
hydrochloric acid and/or sodium hydroxide. Cytarabine is chemically 4-amino-1-ß-D-
arabinofuranosyl-2(1H)-pyrimidinone. 
Molecular weight: 243.22 
Molecular formula: C9H13N3O5 
 
Cytarabine is an odorless, white to off-white, crystalline powder which is freely soluble in water 
and slightly soluble in alcohol and in chloroform. 


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Warnings: For induction therapy, patients should be treated in a facility with laboratory and 
supportive resources sufficient to monitor drug tolerance and protect and maintain a patient 
compromised by drug toxicity. The main toxic effect of Cytarabine at doses used during induction 
is bone marrow suppression with leukopenia, thrombocytopenia and anemia. Less serious toxicity 
includes nausea, vomiting, diarrhea and abdominal pain, oral ulceration, and hepatic dysfunction. 
The physician must judge possible benefit to the patient against known toxic effects of this drug 
in considering the advisability of therapy with Cytarabine for Injection. 
 
Please refer to the product's package insert for full prescribing and toxicity information. 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record or 
another 
comparable 
drug 
accountability 
form. 
(See 
the 
CTEP 
website 
at 
http://ctep.cancer.gov/protocolDevelopment  for the “Policy and Guidelines for Accountability and 
Storage of Investigational Agents” or to obtain a copy of the drug accountability form.) 
 
11. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
11.1 Laboratory Correlative Studies 
Bone marrow aspirate samples will be obtained prior to treatment, at mid-treatment assessment 
(range day 13-16), and at count recovery (day 42 or day 63 if 5+2 re-induction was given), or 
according to the investigator’s discretion, whichever occurs first, , as well as at any time of 
suspected relapse.  Additionally, although not mandated, if patients agree to a skin biopsy, a single 
6mm punch biopsy will be performed concurrently during the bone marrow aspiration procedure 
on day 14 (window day 13-16).  The punch biopsy will be collected in a specimen cup containing 
saline (NOT formalin). 
 
The study will require the following volumes of aspirated bone marrow in purple top tubes (if 
inaspirable, peripheral blood in purple top tubes may be substituted):  
 
- Pre-treatment: Bone marrow aspirate (5-10 mL) [or Blood (20 mL)] 
- Day 14 (Range days 13-16): Bone marrow aspirate (5-10 mL) [or Blood (20 mL)]; skin biopsy 
(6mm punch)- optional 
- Count recovery or at Day 42 (Range days 35-45) – or day 63 if 5+2 given (Range days  
55-65)): Bone marrow aspirate (5-10) mL [or Blood (20 mL)] 
- In the event of suspected/confirmed relapse: Bone marrow aspirate (5-10 mL) [or Blood (20 mL)] 
 
 
All specimens should be maintained at room temperature and delivered within 1 day to the 
processing laboratories. Specimens may be shipped via FedEx priority overnight Monday through 








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after consolidation therapy). The appearance of new dysplastic changes should be considered 
relapse. The reappearance or development of cytologically proven extramedullary disease 
indicates relapse. Molecular and/or genetic relapse is characterized by reappearance of a 
cytogenetic or molecular abnormality. 
 
14.  STATISTICAL CONSIDERATIONS 
This is a phase II, two-stage, single center, to assess the efficacy of alisertib in combination 7+3 
induction chemotherapy  in the adult higher risk AML population. Higher risk AML patients are 
those that (a) are at least 18 years of age with a poor risk karyotype and/or secondary AML, or 
(b) at least 65 years of age with AML. 
The primary endpoint of this study is the rate of complete remission (CR) or complete remission 
with incomplete count recovery (CRi) in higher risk patients receiving alisertib in combination 
with 7+3 induction chemotherapy. The CR+CRi rate will be compared to the historical rates seen 
in this population with 7+3 induction alone. Secondary endpoints include: 1-year overall survival 
(OS), relapse free survival (RFS), remission duration, and toxicity for patients receiving alisertib 
in combination with conventional cytotoxic chemotherapy. 
14.1 Sample Size, Accrual Rate, and Study Duration 
A total of 39 evaluable patients will be enrolled based on the Simon two-stage design assuming a 
null CR rate of 0.45, a CR+CRi rate of 0.70 for alisertib in combination 7+3 induction 
chemotherapy, a 0.05 significance level, and 90% power. The first stage will accrue 13 patients; 
if more than 6 CR+CRi’s are observed during the first stage, the trial will continue onto the 
second stage accruing 26 more patients. If more than 22 CR+CRi’s are observed out of 39 then 
alisertib in combination 7+3 induction chemotherapy will be considered effective. Under this 
design, the probability of stopping after the first stage is 0.64.  Enrollment for the first stage 
assessment will be held before enrolling the first patient to the second stage. 
Patients removed due to presence of favorable cytogenetics prior to day 8 would be considered to 
be inevaluable and will be replaced. In addition, patients who receive less than half of their total 
alisertib dose during induction would be considered to be inevaluable and will be replaced. We 
anticipate that approximately 3 eligible adults per month will be accrued to this MGH/DFCI for 
an approximate total accrual of 39 evaluable adult high risk AML patients over 13 months.  
14.2 
Statistical Design/Endpoints 
Primary Endpoint 
The primary endpoint of this study is the proportion of patients who achieve a CR or a CRi 
(defined in section 13.1) compared to the historical rate of 0.45. It is hypothesized that the 
CR+CRi rate for alisertib in combination 7+3 induction chemotherapy will be 0.70.  A one-sided 
single proportion test will be used to test the hypothesis that the remission rate of alisertib in 7+3 
chemotherapy is greater than the 7+3 historical rate. 


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Secondary Endpoints 
The one year overall survival and relapse free survival  after treatment will be estimated using 
the Kaplan-Meier method, and presented as a 90% confidence interval using Greenwood’s 
formula for standard errors of the estimate. Overall survival (OS) is defined as the time from 
study entry to death from any cause. Relapse free survival (RFS) is defined as the time from 
achieving a CR to the first of disease recurrence or death. RFS applies only to the subset of 
patients who achieve a CR+CRi at the end of induction therapy. Remission duration will also be 
estimated using the method of Kaplan-Meier. All toxicities encountered during the study will be 
evaluated according to the NCI criteria assigned to the protocol (CTCAE version 4.0).  
 
15. PUBLICATION PLAN 
Dr. Amir T. Fathi holds the primary responsibility for publications related to this study. The 
results should be made public within 24 months of reaching the end of the study. The end of the 
study is the time point at which the last data items are to be reported, or after the outcome data 
are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate and 
Study Duration. If a report is planned to be published in a peer-reviewed journal, then that initial 
release may be an abstract that meets the requirements of the International Committee of Medical 
Journal Editors. A full report of the outcomes should be made public no later than three (3) years 
after the end of the study.  


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grown in immunocompromised mice. . Cambridge (MA, USA): Millennium Pharmaceuticals, 
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24. Doherty C. In vitro binding study of MLN8237 to the hERG channel in HEK-293 cells. . 
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25. Weissman A. Customized screening program prepared for Millennium Pharmaceuticals. 
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26. Silverman L. The acute central nervous system pharmacologic profile of MLN8237-004 
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27. Doherty C. A cardiovascular assessment of MLN8237-004 following oral administration to 
conscious, radio-telemetry-instrumented male beagle dogs. Cambridge, MA: Millennium 
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28. Kim M. A pharmacokinetic study of MLN8237 following intravenous and oral 
administration to non-naïve male beagle dogs. Cambridge, MA: Millennium Pharmaceuticals, 
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29. Leyden A. Pharmacokinetics and oral bioavailability of MLN8237 following administration 
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30. Leyden A. Pharmacokinetics and oral bioavailability of MLN8237 following administration 
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No.: RPT-00953, Amendment 1. 
 


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31. Leyden A. Pharmacokinetics and oral bioavailability of MLN8237 following administration 
of an intravenous dose of 1 mg/kg or an oral administration of 5 mg/kg to naïve male Sprague-
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Assessment after Oral Administration of MLN8237 in Conscious Telemetered Male Beagle 
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rat, chimpanzee, dog, human, and mouse by equilibrium dialysis. Cambridge, MA: Millennium 
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36. Solon E. Quantitative tissue distribution of drug-related material using whole-body 
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40. Pusalkar S. In vitro hepatic metabolism of 14C-MLN8237 in multiple species. Cambridge 
(MA): Millennium Pharmaceuticals, Inc. 2008;Report No.: RPT-01182. 
 
41. Cohen L. In vitro determination of the relative contributions of cytochrome P450 isozymes 
and uridine diphosphate-glucuronosyltransferases to the metabolism of MLN8237. Cambridge 
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2.2. 
 
42. Cohen L. Evaluation of MLN8237 CYP2C9 inhibition potential in human liver microsomes. 
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45. Eapen A. A repeat dose oral toxicity study of MLN8237-004 when administered via oral 
gavage in the beagle dog. . Ashland, OH: WIL Research Laboratories, LLC 2007;Report No.: 
WIL-416033. 
 
46. Padgett E. A repeat dose toxicity study of MLN8237-004 when administered via oral gavage 
in the Sprague-Dawley rat. Ashland, OH: WIL Research Laboratories, LLC. 2007;Report No.: 
WIL-416032. 
 
47. Padgett EL. A 6-month (6-cycle) toxicity study of MLN8237-004 administered via oral 
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57. Friedberg J, Mahadevan D, Jung J, Persky DO, Lossos IS, Danaee H, et al. Phase 2 Trial of 
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9. 
 
 


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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work.
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 


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ADDENDUM B 
 
Adverse Risk Karyotype Groups per European Leukemia Net (ELN) Guidelines
Döhner H et al, Blood 2010;115(3):453-474
 
 Inv(3)(q21q26.2) or t(3;3)(q21;q26.2) 
 t(6;9)(p23;q34) 
 t(v;11)(v;q23), [not including t(9;11)(p22;q23)]* 
 Monosomy 5 or del(5q) 
 Monosomy 7 
 Abnormal 17p 
 Complex karyotype (≥3 abnormalities)