Clinical trial NCT02122770
Conditions: Advanced Solid Tumors
Keywords: Drug Therapy
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2014-04-01; Completion date: 2017-06-05
Enrollment: 51 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary purpose of this study is to assess the effect of multiple-dose administration of fluconazole on the single-dose intravenous (IV) pharmacokinetics (PK) of MLN4924; and to assess the effect of multiple-dose administration of itraconazole on the single-dose IV PK of MLN4924.

Detailed description:
The drug being tested in this study is MLN4924. MLN4924 is being evaluated to assess drug-drug interactions (DDIs) with the moderate and strong CYP3A inhibitors, fluconazole and itraconazole, respectively, in participants with advanced solid tumors. This study will look at the blood concentrations of MLN4924 as it relates to treatment with fluconazole and itraconazole.

The study will enroll approximately 52 participants. In Part A, participants will be administered MLN4924 via a 1-hour (+- 5 minutes) intravenous (IV) infusion in combination with either fluconazole or itraconazole administered orally. After participants complete Part A, they will have the opportunity to begin treatment in Part B. In Part B, participants will be administered MLN4924 via a 1-hour (+- 5 minutes) IV infusion in combination with either docetaxel or carboplatin + paclitaxel, the three of which would also be administered intravenously.

This multi-center trial will be conducted in the United States. Participation in Part A of this study will include a screening visit and two weeks of treatment; participation in Part B of this study will include up to an 8-week drug washout period (from last dosing in Part A) and treatment until participants experience symptomatic deterioration, progressive disease, until treatment is discontinued for another reason, or until the study is stopped.

Arms: arm 1: Part A: MLN4924, 8 milligram per square meter (mg/m\^2), intravenously, once on Days 1 and 8; and fluconazole, 400 milligram (mg), tablets, orally, once on Day 4, and 200 mg, once daily on Days 5-10.

Part B: MLN4924, at a dose previously deemed tolerable, given on Days 1, 3, and 5 of each 21-day Cycle (Study C15010, Clinicaltrials.gov Identifier # NCT01862328) in combination with docetaxel or carboplatin + paclitaxel at standard dose regimen on Day 1 of each 21-day Cycle. arm 2: Part A: MLN4924, 8-mg/m\^2, intravenously, once on Days 1 and 8; and itraconazole, 200 mg, oral solution, once daily on Days 4-10.

Part A (safety lead-in step): MLN4924, 15mg/m\^2, intravenously, once on Days 1 and 8; and itraconazole, 200 mg, oral solution, once daily on Days 4-10.

Part A: MLN4924, 20mg/m\^2, intravenously, once on Days 1 and 8; and itraconazole, 200 mg, oral solution, once daily on Days 4-10.

Part B: MLN4924, at a dose previously deemed tolerable given, on Days 1, 3, and 5 of each 21-day Cycle (Study C15010, ClinicalTrails.gov Identifier # NCT01862328) in combination with docetaxel or carboplatin + paclitaxel at standard dose regimen on Day 1 of each 21-day Cycle.
Interventions: intervention 1: MLN4924 intervention 2: Fluconazole intervention 3: Itraconazole intervention 4: Docetaxel intervention 5: Carboplatin intervention 6: Paclitaxel
Intervention descriptions: intervention 1: MLN4924 intravenous solution. intervention 2: Fluconazole tablets. intervention 3: Itraconazole oral solution. intervention 4: Docetaxel intravenous solution. intervention 5: Carboplatin intravenous solution. intervention 6: Paclitaxel intravenous solution.

Protocol documents:
Prot_000.pdf: 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

•
Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 1 Study to Evaluate the Effects of Fluconazole and Itraconazole
CYP3A-Mediated Inhibition on the Pharmacokinetics, Safety, and Tolerability of
MLN4924 in Patients With Advanced Solid Tumors
NCT Number: NCT02122770
Protocol Approve Date: 12 April 2017
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black bar) to protect either personally identifiable information or 
company confidential information. 
Proprietary information, such as scales or coding systems, which are considered confidential
information under prior agreements with license holder.


MLN4924
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CLINICAL STUDY PROTOCOL C15011 AMENDMENT 2
MLN4924
A Phase 1 Study to Evaluate the Effects of Fluconazole and Itraconazole 
CYP3A-Mediated Inhibition on the Pharmacokinetics, Safety, and Tolerability of 
MLN4924 in Patients With Advanced Solid Tumors 
Protocol Number:
C15011
Indication:
Advanced solid tumors
Phase:
1
Sponsor:
Millennium Pharmaceuticals, Inc.
Therapeutic Area:
Oncology
Protocol History
Original
03 February 2014
Amendment 1
26 February 2015
Amendment 2
12 April 2017
Millennium Pharmaceuticals, Inc.
40 Landsdowne Street
Cambridge, MA 02139 USA  
Telephone: +1 (617) 679-7000
Approved by:
Note: If this document was approved electronically, the electronic approval signatures may 
be found at the end of the document.
Date
Date
Date
Confidentiality Statement
The information contained herein is confidential and the proprietary property of Millennium 
Pharmaceuticals and any unauthorized use or disclosure of such information without the prior 
written authorization of Millennium Pharmaceuticals is expressly prohibited.
PPD
PPD
PPD


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Rationale for Amendment 2
The original protocol was written in 2014 and was designed with procedures and 
assessments requiring many visits. As of 24 February 2017, a total of 3 patients with 
advanced solid tumors remain on treatment after completion of at least 12 cycles. The 
sponsor and investigators have therefore determined, on the basis of the accumulated 
experience to date, that it is appropriate at this time to reduce the frequency of procedures 
and clinic visits with the intention of lessening patient burden, increasing patient retention, 
and more closely aligning with clinical practice. Therefore, the primary reason for 
Amendment 2 is to add flexibility to relieve treatment fatigue for the 3 patients remaining in 
this study beyond the initially planned 12 cycles of treatment.
Minor grammatical, editorial, and formatting changes are included for clarification purposes 
only. For specific descriptions of text changes, the rationale for each change, and where the 
changes are located, see Section 15.12.
Changes in Amendment 2
After completion of Cycle 12, the following changes will be applicable: 
1.
Extend the 2-day window for scheduling issues (eg, inclement weather, holidays, 
vacations, or other administrative reasons) to 2 weeks; treatment breaks of up to 
4 weeks may be permitted after discussion between the investigator and the project 
clinician or designee, and the investigator will confirm patient eligibility for 
continued treatment upon return, before treatment.
2.
Reduce the frequency of disease response assessments from every 3 cycles to every 
6 cycles.
3.
Reduce the frequency of hematology, vital sign, clinical chemistry, and 
electrocardiogram assessments and physical examinations.
4.
Add phosphate to the urinalysis parameters.
5.
Add a ±10-minute window to the MLN4924 infusion duration.
6.
Remove the requirement for independent data monitoring committee monitoring.
7.
Adjust contraception requirements to be consistent with Clinical Trial Facilitation 
Group recommendations.
8.
Update the description of the drug product.
9.
Update the investigator responsibilities for compliance with updated International 
Conference on Harmonisation guidelines.
10.
Update the description of dose-limiting toxicities observed in Study C15003 to be 
consistent with final data.
11.
Update vital signs assessments to allow measurements to be taken with the patient in 
the supine or sitting position.
12.
Clarify the timing of transfusion for red blood cells to at least 1 day before study 
drug administration.


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13.
Remove gamma glutamyl transferase from the serum chemistry parameters.
14.
Remove known breast cancer resistance protein substrates, moderate and strong
inhibitors of cytochrome P450 3A4, and inhibitors of P-glycoprotein from the list of 
excluded concomitant medications.
15.
Replace references to the Safety Management Attachment with references to the 
Development Core Safety Information.
16.
Update the description of the Safety Management Team to be consistent with current 
preferred language and to reflect its cross-functional nature.
17.
Update contact information for product complaints.


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PROTOCOL SUMMARY
Study Title: A Phase 1 Study to Evaluate the Effects of Fluconazole and Itraconazole 
CYP3A-Mediated Inhibition on the Pharmacokinetics, Safety, and Tolerability of MLN4924 in 
Patients With Advanced Solid Tumors
Number of Patients: Up to approximately 52 patients
Study Objectives
Primary

To assess the effect of multiple-dose administration of fluconazole, a moderate cytochrome 
P450 (CYP) 3A inhibitor, on the single-dose intravenous (IV) pharmacokinetics (PK) of 
MLN4924

To assess the effect of multiple-dose administration of itraconazole, a strong CYP3A 
inhibitor, on the single-dose IV PK of MLN4924
Secondary
Part A

To further evaluate the safety and tolerability of MLN4924

To further describe the IV PK of MLN4924 before and after multiple oral dosing with 
fluconazole or itraconazole
Part B

To further assess the safety and tolerability of MLN4924 in combination with docetaxel in 
patients with solid tumors

To further assess the safety and tolerability of MLN4924 in combination with carboplatin 
and paclitaxel in patients with solid tumors

To further evaluate disease response that may be observed with the combination of 
MLN4924 and docetaxel

To further evaluate disease response that may be observed with the combination of 
MLN4924, carboplatin, and paclitaxel
Exploratory
Part A
Overview of Study Design: This is an open-label, multicenter, parallel group, 2-arm, phase 1 study 
of MLN4924 designed to assess drug-drug interactions (DDIs) with the moderate and strong CYP3A 
inhibitors fluconazole and itraconazole, respectively, in patients with advanced solid tumors. In the 
Fluconazole Arm, approximately 12 PK-evaluable patients will be enrolled. In the Itraconazole Arm, 
approximately 12 PK-evaluable patients will be enrolled in the 8-mg/m2 and 20-mg/m2 MLN4924 
cohorts, and 3 additional PK-evaluable patients will be needed in the safety lead-in cohort.
CCI


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Part A: Drug-Drug Interaction Assessment
Fluconazole Arm: Patients will receive a single 8-mg/m2 dose of MLN4924 given as a 1-hour 
(5 minutes) IV infusion on Day 1 and Day 8. This low dose of MLN4924 is anticipated to provide 
an adequate safety margin for DDI assessment. Patients will receive concomitant oral fluconazole at 
a dose starting at 400 mg on Day 4 and then 200 mg once daily on Days 5 through 10. 
Pharmacokinetic samples will be taken after the MLN4924 dose on Day 1 and after the Day 8 dose 
of MLN4924 with fluconazole at predetermined time points to assess the effect of fluconazole on the 
PK of MLN4924. Additional samples for determination of MLN4924 concentrations in whole blood 
will be collected on Day 1 only.
Itraconazole Arm: Patients will receive a single dose of MLN4924 given as a 1-hour (5 minutes) 
IV infusion on Day 1 and Day 8 (see dose cohorts defined below). Patients will receive concomitant 
oral itraconazole at a dose of 200 mg once daily on Days 4 through 10. Pharmacokinetic samples 
will be taken after the MLN4924 dose on Day 1 and after the Day 8 dose of MLN4924 with 
itraconazole at predetermined time points (up to 72 hours after dosing) to assess the effect of 
itraconazole on the PK of MLN4924. Additional samples for determination of MLN4924 
concentrations in whole blood will be collected on Day 1 only. The following dose cohorts will be 
enrolled sequentially within the Itraconazole Arm:

Itraconazole Arm, 8-mg/m2 MLN4924 Cohort: Patients will receive a single 8-mg/m2 dose 
of MLN4924 given as a 1-hour (5 minutes) IV infusion on Day 1 and Day 8. This low 
dose of MLN4924 is anticipated to provide an adequate safety margin for DDI assessment. 

Itraconazole Arm, Safety Lead-in 15-mg/m2 MLN4924 Cohort: Patients will receive a single 
15-mg/m2 dose of MLN4924 given as a 1-hour (5 minutes) IV infusion on Day 1 and 
Day 8. Data from this safety lead-in cohort will confirm the anticipated safety margin is 
adequate before any patients are enrolled in the 20-mg/m2 MLN4924 cohort. 

Itraconazole Arm, 20-mg/m2 MLN4924 Cohort: Patients will receive a single 20-mg/m2 dose
of MLN4924 given as a 1-hour (5 minutes) IV infusion on Day 1 and Day 8. This dose of 
MLN4924 falls within the clinically relevant dose range currently evaluated in Phase 1b 
combination studies of MLN4924 plus standard of care therapies. 
Patients will be required to visit the clinic on Day 4 for their first dose of fluconazole or itraconazole. 
For both the Fluconazole and Itraconazole Arms, all doses of fluconazole and itraconazole will be 
administered on an empty stomach with the patient fasting from food and fluids, except water and 
prescribed medications, for 2 hours before and 1 hour after each dose. Patients are encouraged to 
take fluconazole or itraconazole doses at approximately the same time each morning and 
approximately 24 hours apart. On Day 8, patients will take fluconazole or itraconazole together with 
MLN4924 in the morning at the clinic.
In addition to blood sampling for PK, blood samples in the 24-hour postdose window of each arm 
following dosing on Day 1 and Day 8 will be collected to measure pharmacodynamic effects of 
MLN4924. These data will be pooled with data from other MLN4924 clinical studies to contribute to 
an integrated PK-pharmacodynamic analysis across the program.
Part B: Continued Treatment With MLN4924 in Combination With Standard of Care
After completion of the DDI assessment portion of the study, patients will have the opportunity to 
continue in the study by participating in Part B. Patients will receive MLN4924 in combination with 
either docetaxel or carboplatin+paclitaxel at a dose regimen informed from Study C15010 that has 
been deemed tolerable (eg, no dose-limiting toxicities [DLTs] in 3 patients or no more than 1 DLT in 
6 patients). The selected dose may be adjusted based on information obtained from the ongoing 
review of safety data. Safety and disease assessments will be conducted in Part B of the study.


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Study Population: Patients 18 years of age or older who have a histologically or cytologically 
confirmed metastatic or locally advanced solid tumor that is deemed appropriate for treatment with 
1 of the 2 chemotherapy regimens in Part B of this study, or who have progressed despite standard 
therapy, or for whom conventional therapy is not considered effective.
Duration of Study: Patients participating in Part B will be treated (after at least a 2-week [and up to 
8-week] washout period after receiving their last dose of fluconazole or itraconazole in Part A) until 
they experience symptomatic deterioration or progressive disease, or until their treatment is 
discontinued for another reason, or until the study is stopped. After completion of at least 12 cycles 
of treatment, patients will be permitted to take treatment breaks, at the investigator’s discretion, that 
are no longer than 2 weeks in duration (up to 4 weeks after consulting with the sponsor); treatment 
breaks may not be taken consecutively. The investigator will confirm patient eligibility for continued 
treatment (Section 6.4.2) upon return from a treatment break, before treatment.


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STUDY OVERVIEW DIAGRAM 1
Screening Phase
Enrollment Phasea
Fluconazole Arm:
MLN4924 + Fluconazole
Itraconazole Arm:
MLN4924 + Itraconazole
Part A (DDI)
MLN4924 Dose: 8 mg/m2
MLN4924 Dosing Days: 1 and 8
Fluconazole Dosing Days: 4-10
Duration: 24 days
Fluconazole Dose: 400 mg on Day 
4; 200 mg QD on Days 5-10
Number of Patients:  ~12
Safety Lead-In Cohort
MLN4924 Dose: 15 mg/m2
Itraconazole Dose: 200 mg QD
Number of Patients:  3
Part A (DDI)
8 mg/m2 MLN4924 Cohort
MLN4924 Dose: 8 mg/m2
MLN4924 Dosing Days: 1 and 8
Itraconazole Dosing Days: 4-10
Duration: 24 days
Itraconazole Dose: 200 mg QD
Number of Patients: ~12
20 mg/m2 MLN4924 Cohort
MLN4924 Dose: 20 mg/m2
Itraconazole Dose: 200 mg QD
Number of Patients: ~12
Part B (Optional MLN4924 + SoC Treatment:  Cycle 1 and Later)b
MLN4924 Dose:  TBD          MLN4924 Dosing Days:  1, 3, and 5
SoC Treatment: Docetaxel or Carboplatin + Paclitaxel
Cycle Duration:  21 days
End of Study Visit:  30 days after the last dose or before initiating a subsequent anticancer therapy
MLN4924 Dosing Days: 1 and 8
Itraconazole Dosing Days: 4-10
Duration: 24 days
Part A (DDI)
Abbreviations: DDI=drug-drug interaction; QD=once daily; SoC=standard of care; TBD=to be determined
a The first 4-8 patients will be assigned to the Fluconazole Arm (moderate CYP3A inhibitor), then following 
review of the emerging data, patients will be assigned to both the Fluconazole Arm and the Itraconazole 
Arm, 8-mg/m2 MLN4924 Cohort in parallel based on slot availability. Enrollment into the Itraconazole 
Arm, Safety Lead-in 15-mg/m2 MLN4924 Cohort, added per Amendment 1, may begin once the 
amendment is approved at the clinical site. Enrollment into the Itraconazole Arm, 20-mg/m2 MLN4924 
Cohort may begin once the Part A PK and safety data from 3 PK-evaluable patients in the safety lead-in 
cohort have been reviewed and the sponsor has confirmed that the anticipated safety margin for the 
20-mg/m2 dose is adequate. 
b After completing Part A, the patient will be re-evaluated to meet entry criteria to participate in Part B. 


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STUDY FLOW DIAGRAM 2
Abbreviations: D=Day; DDI=drug-drug interaction; IV=intravenous; QD=once daily; PO=oral.
Note: As of Amendment 2, a ±10-minute window will be applied to the MLN4924 IV infusion time.


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SCHEDULES OF EVENTS
Schedule of Events for Drug-Drug Interaction (Part A)
Baseline
Treatment Period
Washout
End of 
Studye
Screeninga
Week 1
Week 2
Week 3
Day 1 
Predose
Day 1
Day 2
Day 4
Days
5-7b
Day 8 
Predose
Day 8
Days
9-10c
Day 11
Day 24d
Study Drug Administration
MLN4924 
administrationf
X
Xg
CYP3A inhibitor 
administrationh
X
Xi
Xg
X
Provide and review 
patient diaryj
X
X
Study Procedures
Informed consent
X
Inclusion/exclusion 
criteria
X
Demographics
X
Medical history/prior 
therapy
X
Full physical 
examination
X
X
X
Symptom-directed 
physical examination
X
X
X
X
X
X
Height
X
Weight
X
Xk
X
Vital signsl
X
Xk
X
X
X
X
X
X
X
X
X
ECOG performance 
status
X
Xk
X
X


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Schedule of Events for Drug-Drug Interaction (Part A)
Baseline
Treatment Period
Washout
End of 
Studye
Screeninga
Week 1
Week 2
Week 3
Day 1 
Predose
Day 1
Day 2
Day 4
Days
5-7b
Day 8 
Predose
Day 8
Days
9-10c
Day 11
Day 24d
12-lead ECGm
X
Xk
X
X
X
X
X
X
Echocardiogram 
X
Adverse event reporting
Recorded from first dose of study drug through 30 days (+ 10 days) after the last dose of study drug
Serious adverse events will be reported from signing of the informed consent form through 
30 days (+ 10 days) after the last dose of study drug.
Concomitant 
medications, therapies,
and procedures
Recorded from first dose of study drug through 30 days (+ 10 days) after the last dose of study drug
Laboratory Assessments
Pregnancy test
X
Hematologyn
X
Xk
X
X
X
X
X
X
X
Clinical chemistry panelo
X
Xk
X
X
X
X
X
X
X
X
X
Coagulationp
X
Xk
Urinalysis with 
microscopic analysisq
X
Xk
X
X
X
X
Blood sample for PKr
X
X
Blood sample for PDs
X
X
Abbreviations: aPTT=activated partial thromboplastin time; CYP=cytochrome P450; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; 
EOS=End of Study; INR=international normalized ratio; IV=intravenous; PD=pharmacodynamic(s); PK=pharmacokinetic(s); PT=prothrombin time; 
SoC=standard of care.
a Unless otherwise noted, the Screening visit must occur within 28 days before the day of the first dose of study drug in Part A.
b Study Days 5-7 are patient home dosing days, and no visit to the clinic is required. 
c Each assessment is to occur on Day 9 and on Day 10.
d Patients will require at least a 2-week (and up to 8-week) drug washout period after their last dose of fluconazole or itraconazole (SPORANOX®) in Part A 
before starting Part B (dosing with MLN4924+SoC). The Day 24 visit should occur on Day 24 (2 days). For patients to be eligible for dosing in Part B, they 


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Schedule of Events for Drug-Drug Interaction (Part A)
Baseline
Treatment Period
Washout
End of 
Studye
Screeninga
Week 1
Week 2
Week 3
Day 1 
Predose
Day 1
Day 2
Day 4
Days
5-7b
Day 8 
Predose
Day 8
Days
9-10c
Day 11
Day 24d
must meet certain entry criteria; refer to Section 7.4.20. If the criteria in Section 7.4.20 are met on Day 24 of Part A, the patient will be eligible for Part B 
dosing immediately. If the criteria in Section 7.4.20 are NOT met on Day 24, see footnote a in the Schedule of Events for Continued Treatment With 
MLN4924+Standard of Care (Part B): Cycle 1 Through Cycle 12 for requirements to begin Part B dosing. 
e An EOS visit is needed in Part A only if the patient does not continue into Part B. The EOS visit will occur 30 days (+ 10 days) after the last dose of study 
drugs or before the start of subsequent therapy for their indication, if that occurs sooner. 
f
MLN4924 will be administered via a 1-hour (5 minutes) IV infusion. If during Part A there is a need to interrupt or slow the IV infusion, refer to 
Section 6.1.1. 
g On Day 8, when the CYP3A inhibitor (fluconazole or itraconazole) and MLN4924 are given together, the CYP3A inhibitor (fluconazole or itraconazole) is to 
be given first, followed by the 1-hour (5 minutes) IV infusion of MLN4924 approximately 20 minutes (±10 min) after ingestion of the fluconazole tablet or 
itraconazole oral solution.
h Fluconazole and itraconazole are the CYP3A inhibitors used in Part A of the study. All doses of study drug(s) will be administered on an empty stomach. 
The first dose of fluconazole (400 mg as two 200-mg tablets) or itraconazole (200 mg as oral solution) will be administered in the clinic by a qualified study 
team member on the morning of Day 4 after collection of the 72-hour PK sample. A qualified study team member will also administer the oral dose of 
fluconazole (one 200-mg tablet) or itraconazole (200 mg as oral solution) on Day 8 just before the start of the 1-hour (5 minutes) IV infusion with 
MLN4924, and on the morning of Days 9 and 10 after the 24- and 48-hour PK sample collections.
i
Patients will self-administer fluconazole (200-mg tablet) or itraconazole (200 mg oral solution) at home. Patients are required to take the CYP3A inhibitor 
once daily on Days 5, 6, 7 at approximately the same time each day (2 hours from time of first dose). If any dose is missed, the subject will not be 
considered PK evaluable.
j
Thorough instructions regarding the fluconazole or itraconazole dosing schedule, study drug handling, use of the patient diary, follow-up visit expectations,
and return of study drug containers and unused study drug will be provided on Day 4 before dosing with fluconazole or itraconazole. Study staff are to review 
all entries in the patient diary on Day 8 before dosing. Study staff will assess patient compliance with at-home dosing on study Day 8 to confirm that the 
patient will be PK evaluable (see Section 8.1.4).
k Procedures conducted during screening that are performed within 3 days of Day 1 can also be used as the Day 1 predose evaluation and do not need to be 
repeated.
l
Vital signs are to be measured predose (20 minutes [± 10 min]) before the infusion of MLN4924; 30 minutes (± 10 min) after the start of MLN4924 dosing;
and 1 hour (± 10 min) and 3 hours (± 30 min) after the completion of MLN4924 dosing. All vital signs are measured with the patient in the sitting position. In 
addition, at predose and 1 hour postdose of MLN4924 administration on Day 1 and Day 8, orthostatic blood pressure and heart rate measurements will be 
taken with the patient in a supine position and then standing, after waiting approximately 3-4 minutes. When the timing of vital signs assessment coincides 
with the timing of a blood draw, vital signs will be measured before blood sample collection. 


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Schedule of Events for Drug-Drug Interaction (Part A)
Baseline
Treatment Period
Washout
End of 
Studye
Screeninga
Week 1
Week 2
Week 3
Day 1 
Predose
Day 1
Day 2
Day 4
Days
5-7b
Day 8 
Predose
Day 8
Days
9-10c
Day 11
Day 24d
m A 12-lead ECG will be performed during screening and before administration (within 3 hours) of MLN4924 on Day 1 and Day 8 and immediately after the 
MLN4924 infusion is complete (± 20 min) on Day 1 and Day 8. When the timing of ECG measurements coincides with the timing of a blood draw, the ECG 
will be completed before the blood sample collection, with the exception of the end-of-infusion PK sample, which should be collected before the ECG is 
completed. 
n Hematology samples will be collected during screening and before dosing with study drug on Days 1 and Day 8. These samples may be drawn with 24 hours 
predose. If dosing falls on a Monday, the collection window may be extended to collect samples on the previous Friday. In addition, samples will be taken on 
Days 2, 4, 9, 10, 11, and 24 and at the EOS visit.
o Clinical chemistry samples will be collected during screening, before dosing with study drug, and 3 hours (30 min) after completion of the MLN4924 
infusion. These predose samples can be drawn within 24 hours predose. If dosing falls on a Monday, the collection window may be extended to collect 
samples on the previous Friday. In addition, samples will be taken on Days 2, 4, 9, 10, 11, and 24 and at the EOS visit.
p A coagulation panel at screening will include the following: PT (INR), aPTT, fibrinogen, and D-dimer.
q Urinalysis samples will be analyzed at the site’s local laboratory.
r
See the Serial Pharmacokinetic Sample Breakdown for all PK collection times. During Part A of the study, serial blood sampling will be collected from each 
patient for determination of plasma concentrations of MLN4924 following MLN4924 1-hour (5 minutes) IV infusion on Day 1 and Day 8. Additionally, 
limited blood sampling for determination of MLN4924 content in whole blood will be performed on Day 1.
s See the Serial Pharmacodynamic Sample Breakdown for all pharmacodynamic collection times. 


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Serial Pharmacokinetic Sample Breakdown: Drug-Drug Interaction Cycle (Part A)
Study Day/Time
Day 1
Day 2
Day 3
Day 4
Day 8a
Day 9a
Day 10a
Day 11
Predoseb
X
X
End of infusion (EOI) (5 to 1 min)c,d
Xe
X
0.5 hour postinfusion (± 5 min)f
X
X
1 hour postinfusion (15 min)d,f
X
X
2 hours postinfusion (15 min)f
Xe
X
3 hours postinfusion (30 min)d,f
X
X
4 hours postinfusion (45 min)f
X
X
8 hours postinfusion (1 hour)f
Xe
X
12 hours postinfusion (1 hour)
X
X
24 hours postdose (1 hour)g
Xe
X
48 hours postdose (2 hours)g
X
X
72 hours postdose (3 hours)g
X
X
Abbreviations: ECG=electrocardiogram; IV=intravenous; min=minutes; PK=pharmacokinetic(s).
a
Patients should be instructed to come to the clinic in the morning without taking their morning doses of study drug(s). All doses of study drug(s) will be 
administered on an empty stomach. 
b
The sample is to be collected within 1 hour before the start of MLN4924 infusion.
c
The window for collection of the EOI time point is between 5 minutes before completion of the infusion to 1 minute after completion of the infusion. If the 
IV infusion is interrupted, 2 additional PK samples (1 sample drawn when the infusion is stopped and 1 sample drawn when the infusion is restarted) 
should be collected so that the patient may be considered PK evaluable. Please refer to Section 6.1.1 if the IV infusion needs to be interrupted or slowed.
d
When the timing of a blood draw coincides with the timing of vital signs or ECG measurements, the vital signs or ECG will be completed before the blood 
sample collection, with the exception of the EOI sample, which should be collected before the ECG is completed. Full details of PK sample preparation 
will be provided in the Study Manual.
e
Sampling for determination of MLN4924 concentrations in whole blood. Full details of PK sample preparation will be provided in the Study Manual.
f
Samples are to be collected after the completion of MLN4924 IV infusion.
g
Samples are to be collected 24 (1 hour), 48 (2 hours), and 72 (3 hours) hours after initiation of the MLN4924 IV infusion on Day 1 (or Day 8). 


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Serial Pharmacodynamic Sample Breakdown: Drug-Drug Interaction Cycle (Part A)
Study Day/Time
Screening
Day 1
Day 2
Day 8a
Day 9a
Predoseb
X
X
X
1 hour postinfusion (15 min)c,d
X
X
4 hours postinfusion (45 min)d
X
X
8 hours postinfusion (1 hour)d
X
X
24 hours postdose (1 hour)e
X
X
Abbreviations: ECG=electrocardiogram; min=minutes.
At each time point, 2 blood samples will be taken to enable 2 independent sets of pharmacodynamics assays to be performed. Full details of sample 
preparation will be provided in the Study Manual.
a
Patients should be instructed to come to the clinic in the morning without taking their morning doses of study drug(s). The timing of the morning visits 
should occur at approximately the same time as the morning dosing times on previous days of the cycle. 
b
The sample is to be collected within 1 hour before the start of MLN4924 infusion.
c
When the timing of a blood draw coincides with the timing of ECG measurements, the ECG will be completed before the collection of the blood sample. 
d
Samples are to be collected after the completion of the MLN4924 IV infusion. 
e
Sample is to be collected 24 hours after initiation of the MLN4924 IV infusion on Day 1 (or Day 8). 


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Patients are assessed for eligibility to participate in Part B only after completion of Part A and anytime 
during the 2- to 8-week washout period.
Schedule of Events for Continued Treatment With MLN4924+Standard of Care (Part B): Cycle 1 Through Cycle 12
MLN4924+SoC Treatment
End of Study/
Early Terminationc
Day 1 Predosea
Day 1
Day 2b
Day 3
Day 5
Day 8
Study Drug Administration
SoC administrationd
X
MLN4924 administrationd
X
X
X
Study Procedures
Physical examination 
X
X
Symptom-directed physical 
examination
X
X
X
X
X
ECOG performance status
X
X
Weight
X
X
Vital signse
X
X
X
X
X
X
X
12-Lead ECGf
X
X
Tumor assessmentsg
To be completed before dosing in Part B, end of Cycle 2, end of Cycle 4,
and every other cycle thereafter 
X
Concomitant medications, 
therapies and procedures
Recorded from first dose of study drug in Part A through 30 days (+ 10 days) after the last dose of study drug in Part B
Adverse event reporting
Recorded from first dose of study drug in Part A through 30 days (+ 10 days) after the last dose of study drug in Part B
Serious adverse events will be reported from signing of the informed consent form through 30 days (+ 10 days) 
after the last dose of study drug
Laboratory Assessments
Hematologyh
X
X
X
X
X
X
Clinical chemistry paneli
X
Xj
X
X
X
X
X
Coagulationk
X


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Schedule of Events for Continued Treatment With MLN4924+Standard of Care (Part B): Cycle 1 Through Cycle 12
MLN4924+SoC Treatment
End of Study/
Early Terminationc
Day 1 Predosea
Day 1
Day 2b
Day 3
Day 5
Day 8
Urinalysis with microscopic 
analysisl
X
X
X
X
Abbreviations: aPTT=activated partial thromboplastin time; CT=computed tomography; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology 
Group; EOS=End of Study; INR=international normalized ratio; MRI=magnetic resonance imaging; PT=prothrombin time; SoC=standard of care.
Tests and procedures should be performed on schedule, but occasional changes are allowable (± 2 days) for holidays, vacations, and other administrative 
reasons. 
a For patients to be eligible for dosing with MLN4924+SoC (Part B), they must meet certain entry criteria (see Section 7.4.20). If, at the end of Part A, the 
patient is eligible for dosing in Part B, the Day 24 assessments in Part A could be used as the Part B predose Cycle 1, Day 1 assessments if Cycle 1, Day 1 
occurs within 5 days of Day 24 in Part A; however, the liver function tests will need to be repeated within 3 days of Cycle 1, Day 1. The washout period 
may be extended up to 6 additional weeks to allow more time for patients to recover and qualify for Part B. The patient should be assessed at least every 
2 weeks for eligibility for Part B during this extended washout period. The patient can be deemed eligible for Part B anytime during the 2- to 8-week 
washout period. If, after 8 weeks from the last dose in Part A (eg, up to 8 weeks after the Day 10 visit), the predose Cycle 1, Day 1 assessments for Part B 
have not returned to Part A baseline values (or ≤ Grade 1) or to a level considered acceptable by the investigator after discussion with the project clinician 
or designee, then the patient will not be eligible for dosing with MLN4924+SoC, and all assessments required for the EOS visit should be completed. 
b The assessments conducted on Day 2 are required only during Cycle 1.
c If the patient continues into Part B, the EOS visit will occur 30 days (+ 10 days) after the last dose of study drug(s) in Part B or before the start of 
subsequent therapy for their indication, if that occurs sooner.
d The investigator will select which SoC chemotherapy (docetaxel or carboplatin+paclitaxel) that each patient will receive in combination with MLN4924. 
On Day 1, when MLN4924 and chemotherapy agents are both administered, chemotherapy will be administered first, followed by MLN4924. The infusion 
of MLN4924 may be slowed or stopped and restarted for any associated infusion-related reactions. The dose of MLN4924 may be reduced because of
toxicities in accordance with Section 6.4. The chemotherapeutic agent may be dose reduced because of toxicities in accordance with Section 6.4. See 
Section 6.1 for the details of study drug administration. NOTE: a time-out of approximately 15 minutes is required between the end of infusion of the
chemotherapy regimen and the start of infusion of MLN4924.
e Vital signs are to be measured predose (20 minutes [± 10 min]) before the infusion of MLN4924; 30 minutes (± 10 min) after start of MLN4924 dosing;
and 1 hour (± 10 min) after completion of MLN4924 dosing. All vital signs are measured with the patient in the sitting position. In addition, at predose and 
1 hour postdose of MLN4924 administration on Cycle 1, Day 1, orthostatic blood pressure and heart rate measurements will be taken with the patient in a 
supine position and then standing, after waiting for approximately 3-4 minutes. When the timing of vital signs assessment coincides with the timing of a 
blood draw, vital signs will be measured before blood sample collection.
f
A 12-lead ECG will be performed on Day 1 before administration (within 3 hours) of the chemotherapy regimen and immediately after the infusion of 
MLN4924 is complete (± 10 min). When the timing of ECG measurements coincides with the timing of a blood draw, the ECG will be completed before 
the collection of the blood sample, with the exception of the end of infusion PK sample which should be taken before the ECG is completed.
g Radiological evaluations (CT scan or MRI) of the chest, abdomen, and pelvis will be required as entry criteria for Part B to assess the status of the patient’s 


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Schedule of Events for Continued Treatment With MLN4924+Standard of Care (Part B): Cycle 1 Through Cycle 12
MLN4924+SoC Treatment
End of Study/
Early Terminationc
Day 1 Predosea
Day 1
Day 2b
Day 3
Day 5
Day 8
underlying disease. If the patient has had appropriate imaging scans performed within 28 days of Cycle 1, Day 1 of Part B, then the results of those scans 
may be used. During the study, CTs or MRIs encompassing the known sites of disease will be performed at the end of Cycle 2, end of Cycle 4, and at the 
end of every other cycle thereafter. An end of study/early termination CT scan does not need to be completed/repeated if a scan was performed within the 
previous 28 days.
h Hematology samples will be collected as part of the entry criteria for Part B and before dosing with study drug on Days 1, 3, and 5. On dosing days, 
samples can be drawn 24 hours predose. If dosing falls on a Monday, the collection window may be extended to collect samples on the previous Friday. In 
addition, samples will be taken on Day 2 (Cycle 1 only), Day 8, and at the EOS visit.
i
Clinical chemistry samples will be collected as part of the entry criteria for Part B and before dosing with study drug on Days 1, 3, and 5. On Days 1, 3, and 
5, samples may be drawn within 24 hours predose. If dosing falls on a Monday, the collection window may be extended to collect samples on the previous 
Friday. On Cycle 1, Day 1 an additional sample will be taken 3 hours (± 30mins) after completion of the MLN4924 infusion. In addition, samples will be 
taken on Day 2 (Cycle 1only), Day 8, and at the EOS visit.
j
The Day 1 postdose clinical chemistry assessment is required only during Cycle 1.
k A coagulation panel at screening for Part A will include the following: PT (INR), aPTT, fibrinogen, and D-dimer. If the initial coagulation screen in Part A 
is positive (ie, results are outside of the laboratory’s normal range), subsequent coagulation studies in Part B should include all of these parameters. If the 
initial coagulation screen in Part A is negative (ie, results are within the laboratory’s normal range), no further coagulation studies need to be done.
l Urinalysis samples will be analyzed at the site’s local laboratory.


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Schedule of Events for Continued Treatment With MLN4924+Standard of Care (Part B): Cycle 13 and Beyond (as of 
Amendment 2)
MLN4924+SoC Treatment
End of Study/
Early Terminationb
Day 1 Predosea
Day 1
Day 3
Day 5
Study Drug Administration
SoC administrationc
X
MLN4924 administrationc
X
X
X
Study Procedures
Symptom-directed physical 
examination
X
X
ECOG performance status
X
X
Weight
X
X
Vital signsd
X
X
X
X
X
12-Lead ECGe
X
Tumor assessmentsf
To be performed after completion of every sixth cycle after the patient’s 
previous scan
X
Concomitant medications, 
therapies and procedures
Recorded from first dose of study drug in Part A through 30 days (+ 10 days) after the last dose of study drug in Part B
Adverse event reporting
Recorded from first dose of study drug in Part A through 30 days (+ 10 days) after the last dose of study drug in Part B
Serious adverse events will be reported from signing of the informed consent form through 30 days (+ 10 days) 
after the last dose of study drug
Laboratory Assessments
Hematologyg
X
X
X
X
Clinical chemistry panelh
X
X
X
X
Coagulationi
X
Urinalysis with microscopic 
analysisj
X
X
X
X
Abbreviations: aPTT=activated partial thromboplastin time; CT=computed tomography; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology 


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Schedule of Events for Continued Treatment With MLN4924+Standard of Care (Part B): Cycle 13 and Beyond (as of 
Amendment 2)
MLN4924+SoC Treatment
End of Study/
Early Terminationb
Day 1 Predosea
Day 1
Day 3
Day 5
Group; EOS=End of Study; INR=international normalized ratio; MRI=magnetic resonance imaging; PK=pharmacokinetic; PT=prothrombin time; 
SoC=standard of care.
Tests and procedures should be performed on schedule, but occasional changes are allowable (± 2 days) for holidays, vacations, and other administrative 
reasons. After implementation of Amendment 2 and completion of Cycle 12, modifications of up to 2 weeks (up to 4 weeks after consulting with the 
sponsor) are permitted, at the investigator’s discretion; treatment breaks may not be taken consecutively.
a For patients who take treatment breaks at the investigator’s discretion, patient eligibility for continued treatment, including all Day 1 predose assessments, 
will be confirmed by the investigator before resumption of treatment. 
b If the patient continues into Part B, the EOS visit will occur 30 days (+ 10 days) after the last dose of study drug(s) in Part B or before the start of 
subsequent therapy for their indication, if that occurs sooner.
c The investigator will select which SoC chemotherapy (docetaxel or carboplatin+paclitaxel) that each patient will receive in combination with MLN4924. 
On Day 1, when MLN4924 and chemotherapy agents are both administered, chemotherapy will be administered first, followed by MLN4924. The infusion 
of MLN4924 may be slowed or stopped and restarted for any associated infusion-related reactions. The dose of MLN4924 may be reduced because of 
toxicities in accordance with Section 6.4. The chemotherapeutic agent may be dose reduced because of toxicities in accordance with Section 6.4. See 
Section 6.1 for the details of study drug administration. NOTE: a time-out of approximately 15 minutes is required between the end of infusion of the 
chemotherapy regimen and the start of infusion of MLN4924.
d Vital signs are to be measured predose (20 minutes [± 10 min]) before the infusion of MLN4924; 30 minutes (± 10 min) after start of MLN4924 dosing; 
and 1 hour (± 10 min) after completion of MLN4924 dosing. All vital signs are measured with the patient in either the sitting or supine position. When the 
timing of vital signs assessment coincides with the timing of a blood draw, vital signs will be measured before blood sample collection.
e A 12-lead ECG will be performed on Day 1 before administration (within 3 hours) of the chemotherapy regimen and immediately after the infusion of 
MLN4924 is complete (± 10 min). When the timing of ECG measurements coincides with the timing of a blood draw, the ECG will be completed before 
the collection of the blood sample, with the exception of the end of infusion PK sample which should be taken before the ECG is completed.
f
Radiological evaluations (CT scan or MRI) of the chest, abdomen, and pelvis will be required as entry criteria for Part B to assess the status of the patient’s 
underlying disease. CTs or MRIs encompassing the known sites of disease will be performed after completion of every sixth cycle after the patient’s 
previous scan (after completion of Cycle 12 and implementation of Amendment 2). Additional CT scans may be performed, per investigator's discretion, if 
clinically indicated. An end of study/early termination CT scan does not need to be completed/repeated if a scan was performed within the previous 
28 days.
g Hematology samples will be collected as part of the entry criteria for Part B and before dosing with study drug on Days 1, 3, and 5. On dosing days, 
samples can be drawn within 24 hours predose. If dosing falls on a Monday, the collection window may be extended to collect samples on the previous 
Friday. In addition, samples will be taken at the EOS visit.
h Clinical chemistry samples will be collected as part of the entry criteria for Part B and before dosing with study drug on Days 1, 3, and 5. On Days 1, 3, and 


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Schedule of Events for Continued Treatment With MLN4924+Standard of Care (Part B): Cycle 13 and Beyond (as of 
Amendment 2)
MLN4924+SoC Treatment
End of Study/
Early Terminationb
Day 1 Predosea
Day 1
Day 3
Day 5
5, samples may be drawn within 24 hours predose. If dosing falls on a Monday, the collection window may be extended to collect samples on the previous 
Friday. In addition, samples will be taken at the EOS visit.
i
A coagulation panel at screening for Part A will include the following: PT (INR), aPTT, fibrinogen, and D-dimer. If the initial coagulation screen in Part A 
is positive (ie, results are outside of the laboratory’s normal range), subsequent coagulation studies in Part B should include all of these parameters. If the 
initial coagulation screen in Part A is negative (ie, results are within the laboratory’s normal range), no further coagulation studies need to be done.
j Urinalysis samples will be analyzed at the site’s local laboratory.


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TABLE OF CONTENTS
LIST OF TABLES.............................................................................................................25
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ..........................................26
1. BACKGROUND AND STUDY RATIONALE..............................................................29
1.1 Scientific Background of Study Drug .......................................................................29
1.2 Nonclinical Experience of Single-agent MLN4924...................................................29
1.3 MLN4924 Pharmacokinetics ....................................................................................30
1.3.1 Nonclinical Pharmacokinetics and Risk Assessment for Drug-Drug 
Interactions .................................................................................................30
1.3.2 Clinical Pharmacokinetics..................................................................................30
1.4 MLN4924 Clinical Experience .................................................................................31
1.5 Study Rationale ........................................................................................................36
1.5.1 Rationale for Drug-drug Interaction Assessment (Part A)...................................36
1.5.2 Rationale for Continued Treatment With MLN4924 in Combination With 
Standard of Care (Part B)............................................................................39
1.6 Potential Risks and Benefits .....................................................................................41
1.6.1 Risks of MLN4924 Therapy...............................................................................41
1.6.2 Risks of Fluconazole Treatment.........................................................................45
1.6.3 Risks of Itraconazole Treatment.........................................................................46
1.6.4 Risks of Docetaxel Treatment ............................................................................48
1.6.5 Risks of Carboplatin and Paclitaxel Therapy......................................................49
1.6.6 Summary of Risks of Fluconazole, Itraconazole, or Standard of Care 
Therapies in Combination With MLN4924 .................................................50
2. STUDY OBJECTIVES ..................................................................................................51
2.1 Primary Objectives ...................................................................................................51
2.2 Secondary Objectives ...............................................................................................51
2.3 Exploratory Objective...............................................................................................52
3. STUDY ENDPOINTS....................................................................................................52
3.1 Primary Endpoints....................................................................................................52
3.2 Secondary Endpoints................................................................................................53
3.3 Exploratory Endpoints..............................................................................................53
4. STUDY DESIGN...........................................................................................................53
4.1 Overview of Study Design........................................................................................53
4.2 Number of Patients...................................................................................................57
4.3 Duration of Study.....................................................................................................57
5. STUDY POPULATION.................................................................................................58
5.1 Inclusion Criteria......................................................................................................58
5.2 Exclusion Criteria.....................................................................................................60
6. STUDY DRUG..............................................................................................................63
6.1 Study Drug Administration.......................................................................................63
6.1.1 MLN4924 and Fluconazole or Itraconazole Administration (Part A)..................63
6.1.2 Continued Treatment With MLN4924 in Combination With Standard of 
Care (Part B)...............................................................................................65
6.2 Reference/Control Therapy.......................................................................................67
6.3 Definitions of Dose-Limiting Toxicity Equivalents (Part B) .....................................67


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6.4 Dose Modification Guidelines (Dose Delays, Dose Reductions, and Dose 
Interruptions) (Part B).......................................................................................69
6.4.1 Dose Modification Guidelines for Specific Toxicities ........................................69
6.4.2 Dose Modification Guidelines for MLN4924.....................................................72
6.5 Excluded Concomitant Medications and Procedures.................................................73
6.5.1 Excluded Concomitant Medications and Procedures (Part A).............................73
6.5.2 Excluded Concomitant Medications and Procedures (Part B).............................73
6.6 Permitted Concomitant Medications and Procedures.................................................74
6.6.1 Permitted Concomitant Medications and Procedures (Part A) ............................74
6.6.2 Permitted Concomitant Medications and Procedures (Part B).............................74
6.7 Precautions and Restrictions .....................................................................................75
6.7.1 MLN4924..........................................................................................................76
6.7.2 Fluconazole .......................................................................................................77
6.7.3 Itraconazole .......................................................................................................78
6.7.4 Docetaxel...........................................................................................................78
6.7.5 Carboplatin........................................................................................................79
6.7.6 Paclitaxel...........................................................................................................80
6.8 Guidance for Clinical Assessment and Management of Hemodynamic 
Compromise (Part A and Part B).......................................................................81
6.9 Management of Clinical Events................................................................................82
6.9.1 Guidance for Use of Granulocyte-Colony Stimulating Factor.............................82
6.9.2 Guidance for Clinical Assessment and Management of Anemia.........................82
6.10 Blinding and Unblinding ........................................................................................82
6.11 Description of Investigational Agents .....................................................................83
6.11.1 MLN4924 ........................................................................................................83
6.11.2 Fluconazole......................................................................................................83
6.11.3 Itraconazole .....................................................................................................83
6.11.4 Docetaxel.........................................................................................................84
6.11.5 Carboplatin ......................................................................................................84
6.11.6 Paclitaxel .........................................................................................................84
6.12 Preparation, Reconstitution, and Dispensation ........................................................84
6.12.1 MLN4924 ........................................................................................................84
6.12.2 Docetaxel, Carboplatin, and Paclitaxel.............................................................85
6.13 Packaging and Labeling..........................................................................................85
6.13.1 MLN4924 ........................................................................................................85
6.13.2 Fluconazole......................................................................................................85
6.13.3 Itraconazole .....................................................................................................85
6.13.4 Docetaxel, Carboplatin, and Paclitaxel.............................................................85
6.14 Storage, Handling, and Accountability....................................................................86
6.14.1 MLN4924 ........................................................................................................86
6.14.2 Fluconazole......................................................................................................86
6.14.3 Itraconazole .....................................................................................................86
7. STUDY CONDUCT ......................................................................................................86
7.1 Study Personnel and Organizations...........................................................................87
7.2 Arrangements for Recruitment of Patients ................................................................87
7.3 Treatment Group Assignments .................................................................................87


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7.3.1 Drug-Drug Interaction Assessment (Part A).......................................................87
7.3.2 Continued Treatment With MLN4924 in Combination With Standard of 
Care (Part B)...............................................................................................88
7.4 Study Procedures......................................................................................................88
7.4.1 Informed Consent ..............................................................................................88
7.4.2 Patient Demographics ........................................................................................89
7.4.3 Medical History (Part A)....................................................................................89
7.4.4 Physical Examination.........................................................................................89
7.4.5 Patient Height ....................................................................................................89
7.4.6 Patient Weight ...................................................................................................89
7.4.7 Eastern Cooperative Oncology Group Performance Status.................................89
7.4.8 Echocardiogram or Radionuclide Angiography (Part A).....................................89
7.4.9 Vital Signs .........................................................................................................89
7.4.10 Pregnancy Test (Part A)...................................................................................90
7.4.11 Concomitant Medications and Procedures........................................................90
7.4.12 Adverse Events................................................................................................90
7.4.13 Enrollment .......................................................................................................90
7.4.14 Electrocardiogram............................................................................................90
7.4.15 Clinical Laboratory Evaluations.......................................................................91
7.4.16 Disease Assessment (Part B)............................................................................92
7.4.17 Pharmacokinetic Measurements.......................................................................92
7.4.18 Pharmacodynamic Measurements ....................................................................93
7.4.19 Patient Diary....................................................................................................94
7.4.20 Entry Criteria for Continuation Into Part B.......................................................94
7.5 Completion of Study.................................................................................................95
7.6 Discontinuation of Treatment with Study Drug, and Patient Replacement.................96
7.7 Withdrawal of Patients from Study...........................................................................96
7.8 Study Compliance ....................................................................................................97
8. STATISTICAL AND QUANTITATIVE ANALYSES ..................................................97
8.1 Statistical Methods ...................................................................................................97
8.1.1 Drug-Drug Interaction Assessment ....................................................................98
8.1.2 Determination of Sample Size............................................................................98
8.1.3 Randomization and Stratification .......................................................................99
8.1.4 Populations for Analysis ....................................................................................99
8.1.5 Procedures for Handling Missing, Unused, and Spurious Data...........................99
8.1.6 Demographic and Baseline Characteristics.......................................................100
8.1.7 Efficacy Analysis.............................................................................................100
8.1.8 Pharmacokinetic Analysis ................................................................................100
8.1.9 Pharmacodynamic Analysis .............................................................................101
8.1.10 Pharmacokinetic-Pharmacodynamic Analysis ................................................101
8.1.11 Safety Analysis ..............................................................................................101
8.1.12 Interim Analyses (Preliminary Drug-Drug Interaction Assessment, Part A)....103
9. STUDY COMMITTEES..............................................................................................104
9.1 Millennium Safety Assessments .............................................................................104
10. ADVERSE EVENTS .................................................................................................104
10.1 Definitions............................................................................................................104


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10.1.1 Pretreatment Event Definition........................................................................104
10.1.2 Adverse Event Definition...............................................................................105
10.1.3 Serious Adverse Event Definition ..................................................................105
10.2 Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events...............................................................................................106
10.3 Monitoring of Adverse Events and Period of Observation.....................................107
10.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events......108
11. ADMINISTRATIVE REQUIREMENTS ...................................................................108
11.1 Good Clinical Practice..........................................................................................108
11.2 Data Quality Assurance ........................................................................................109
11.3 Electronic Case Report Form Completion.............................................................109
11.4 Study Monitoring .................................................................................................109
11.5 Ethical Considerations..........................................................................................110
11.6 Patient Information and Informed Consent............................................................110
11.7 Patient Confidentiality..........................................................................................110
11.8 Investigator Compliance.......................................................................................110
11.9 On-site Audits ......................................................................................................111
11.10 Investigator and Site Responsibility for Drug Accountability..............................111
11.11 Product Complaints ............................................................................................111
11.12 Closure of the Study ...........................................................................................112
11.13 Record Retention................................................................................................112
12. USE OF INFORMATION..........................................................................................113
13. INVESTIGATOR AGREEMENT..............................................................................114
14. REFERENCES...........................................................................................................115
15. APPENDICES ...........................................................................................................117
15.1 Hematologic Toxicity of Carboplatin Alone and in Combination With Paclitaxel .117
15.2 Drugs Associated With Nephrotoxicity.................................................................120
15.3 Response Criteria .................................................................................................121
15.4 Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status.......122
15.5 Formula for Absolute Neutrophil Count Calculation.............................................122
15.6 Cockcroft-Gault Equation.....................................................................................122
15.7 Excluded CYP3A Inducers ...................................................................................123
15.8 New York Heart Association Classification of Cardiac Disease ............................123
15.9 Classification of Chronic Obstructive Pulmonary Disease by Spirometry..............124
15.10 Methods of Contraception Considered to be Effective.........................................124
15.11 Amendment 1 Rationale and Purpose..................................................................125
15.12 Amendment 2 Detailed Description of Amendments to Text...............................128


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LIST OF TABLES
Table 1-1
Potential Overlapping Toxicities With MLN4924 in Combination With 
Fluconazole, Itraconazole, or Standard of Care Therapies ...........................51
Table 6-1
Dose Modification Guidelines for Specific Toxicities..................................70
Table 6-2
Excluded Concomitant Medications and Procedures During Part A.............73
Table 6-3
Excluded Concomitant Medications and Procedures During Part B.............74
Table 6-4
Permitted Concomitant Medications and Procedures During Part A ............74
Table 6-5
Permitted Concomitant Medications and Procedures During Part B.............75
Table 15-1
Hematologic Adverse Experiences of in Patients With Ovarian Cancer 
Treated With Carboplatin in Combination With Cyclophosphamide..........117
Table 15-2
Hematologic Toxicities and Associated Supportive Care in Patients With 
Advanced Ovarian Cancer Stratified by Treatment Arm and Toxicity 
Grade........................................................................................................118
Table 15-3
Drugs Associated with Nephrotoxicity ......................................................120
Table 15-4
In Vivo Inducers of CYP3A......................................................................123
Table 15-5
Classification of Chronic Obstructive Pulmonary Disease by Spirometry..124


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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
ACS
acute coronary syndrome
AE
adverse event
ALL
acute lymphoblastic leukemia
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myelogenous leukemia
ANC
absolute neutrophil count
ANOVA
analysis of variance 
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the plasma concentration versus time curve
AUC0-24 hr
AUC from time zero to 24 hours
AUC0-inf
AUC from time zero to infinity
AUC0-tlast
AUC from time zero to the time of the last quantifiable concentration
BCRP
breast cancer resistance protein
B/P
blood to plasma ratio
BSA
body surface area
BUN
blood urea nitrogen
CD
compact disk
CDL
cullin-dependent ubiquitin E3 ligases
Cdt-1
chromatin-licensing and DNA-replication factor-1
CHF
congestive heart failure
CI
confidence intervals
CL
clearance
Cmax
single-dose maximum (peak) concentration
CO2
carbon dioxide
COPD
chronic obstructive pulmonary disease
CR
complete response
CSR
clinical study report
CT
computed tomography
CV
coefficient of variation
CYP
cytochrome P450


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Abbreviation
Term
DCSI
Development Core Safety Information
DDI
drug-drug interaction
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EOS
End of Study (visit)
FDA
Food and Drug Administration
GCP
Good Clinical Practice
G-CSF
granulocyte-colony stimulating factor
GFR
glomerular filtration rate
GGT
gamma glutamyl transferase
GI
gastrointestinal
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
IC50
concentration producing 50% inhibition
ICF
informed consent form
ICH
International Conference on Harmonisation
IDMC
independent data monitoring committee
IEC
independent ethics committee
IIV
interindividual variability 
IRB
institutional review board
IV
intravenous; intravenously
LDH
lactate dehydrogenase
LFT
liver function test(s)
MDS
myelodysplastic syndromes
MI
myocardial infarction
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
MRP2
multidrug resistance associated protein 2
MTD
maximum tolerated dose


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Abbreviation
Term
NAE
NEDD8-activating enzyme
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NEDD8
neural precursor cell expressed developmentally down-regulated protein 8
Nrf2
NFE2-related factor 2
NSCLC
nonsmall cell lung cancer
OATP
organic anion-transporting polypeptides
PBMC
peripheral blood mononuclear cell
PD
progressive disease (disease progression)
P-gp
P-glycoprotein
PK
pharmacokinetic(s)
PR
partial response
PS
performance status
PT
prothrombin time
QD
once daily
QTc
rate-corrected QT interval (millisec) of electrocardiograph
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SCLC
small cell lung cancer
SD
stable disease
SoC
standard of care
SWOG
Southwest Oncology Group
t1/2
terminal elimination half-life 
Tmax
first time to achieve maximum observed plasma concentration
ULN
upper limit of the normal range
US
United States
USP
United States Pharmacopeia
USPI
United States Package Insert
Vss
volume distribution 


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1.
BACKGROUND AND STUDY RATIONALE
1.1
Scientific Background of Study Drug
MLN4924 is a first-in-class small molecule inhibitor of the NEDD8 (neural precursor cell 
expressed developmentally down-regulated protein 8)-activating enzyme (NAE) that is 
being developed for the treatment of malignancies. NEDD8-activating enzyme is an 
E1-activating enzyme and is an essential component of the NEDD8 conjugation pathway, 
which controls the activity of a subset of ubiquitin E3 ligases, multiprotein complexes that 
transfer ubiquitin molecules to protein substrates that are then targeted to the proteasome for 
degradation. Cullin-dependent ubiquitin E3 ligases (CDLs) require conjugation to NEDD8 
to be activated. Cullin-dependent ubiquitin E3 ligases control the timely ubiquitination and 
consequent proteasomal degradation of proteins with important roles in cell cycle 
progression and signal transduction, cellular processes that are integral to tumor cell growth, 
proliferation, and survival. Inhibitors of NAE activity may be of therapeutic value in the 
treatment of various cancers by disrupting proteasomal degradation of a variety of critical 
regulatory proteins.
1.2
Nonclinical Experience of Single-agent MLN4924
MLN4924 is a potent and selective inhibitor of NAE activity. 
MLN4924 treatment of cultured tumor cells resulted in growth inhibition of a wide variety 
of cell lines. Changes in protein levels observed in cultured cells treated with MLN4924 
were consistent with the inhibition of NAE, in particular a decrease in NEDD8-cullin levels 
and a reciprocal increase in the levels of known CDL substrates, including NFE2-related 
factor 2 (Nrf2) and chromatin-licensing and DNA-replication factor-1 (Cdt-1). In most cell 
lines evaluated, NAE inhibition by MLN4924 led to DNA re-replication and accumulation 
of cells in the S phase of the cell cycle; this resulted in DNA damage and subsequent cell 
death through apoptosis.(1, 2, 3)  
MLN4924 demonstrated pharmacodynamic and antitumor activity in solid tumor, 
lymphoma, and acute myelogenous leukemia (AML) xenograft models when administered 
to immunocompromised mice by the subcutaneous (SC) route. 
Detailed information regarding the nonclinical pharmacology and toxicology of MLN4924
may be found in the Investigator’s Brochure (IB).


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1.3
MLN4924 Pharmacokinetics
1.3.1
Nonclinical Pharmacokinetics and Risk Assessment for Drug-Drug 
Interactions
The absorption, distribution, metabolism, and excretion properties of MLN4924 have been 
studied in Sprague-Dawley rats, beagle dogs, cynomolgus monkeys, and chimpanzees. 
Hepatic metabolism appears to be the major route of elimination for MLN4924 in animal 
species. Urinary excretion of unchanged MLN4924 was found to be low (< 5%) in rats and 
primates. 
MLN4924 is metabolized in vitro via hydroxylation oxidation, predominantly by 
cytochrome P450 (CYP) 3A4 with a small (3%) contribution from CYP2D6. In vitro studies 
with efflux pump inhibitors demonstrated that MLN4924 is a substrate for P-glycoprotein 
(P-gp), breast cancer resistance protein (BCRP), and multidrug resistance associated protein 
2 (MRP2). However, MLN4924 is a weak inhibitor of P-gp (concentration producing 
50% inhibition [IC50] [paclitaxel and digoxin] of 41.2-56.0 M) and BCRP (IC50 [estrone-
3-sulfate] of 6.3 M) but is not likely to inhibit MRP2 (IC50 200 M). Additional studies 
with organic anion-transporting polypeptides (OATP) in sandwich-cultured human 
hepatocytes showed that MLN4924 can inhibit the hepatic uptake of estrone-3-sulfate (IC50
of 29.1 M) and of simvastatin (IC50 of 0.4-4.9 M) and lovastatin (IC50 of 0.9 M) from 
some, but not all, donors. Taking these data together and based on observed single-dose 
maximum (peak) concentration (Cmax) values at doses ≤110 mg/m2, MLN4924 is unlikely to 
interact with P-gp substrates, but the potential exists, albeit low, for drug interactions with 
BCRP and OATP substrates at clinical concentrations.
1.3.2
Clinical Pharmacokinetics
The pharmacokinetics (PK) of MLN4924 administered as an 1-hour intravenous (IV)
infusion have been evaluated following single and multiple doses in adult patients with 
nonhematologic malignancies (Study C15001); adult patients with lymphoma or multiple 
myeloma (Study C15002); adult patients with AML, high-grade myelodysplastic syndromes 
(MDS), or acute lymphoblastic leukemia (ALL) (Study C15003); and adult patients with 
melanoma (Study C15005). 
Pharmacokinetic results showed that MLN4924 PK is linear over the dose range studied as 
evidenced by area under the plasma concentration versus time curve from time zero to 
24 hours (AUC0-24hr) increasing proportionately with doses from 25 to 261 mg/m2. The peak 
concentration (theoretically end-of-infusion concentration) generally appeared to increase in 


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proportion with dose, although moderate to large interindividual variability (IIV) was 
apparent. MLN4924 plasma concentrations declined in a bi-exponential manner at the end of 
infusion, with little or no notable drug accumulation following once-daily dosing for 
5 consecutive days or more intermittent dosing (ie, Days 1, 3, and 5; Days 1, 2, 8, and 9; 
Days 1, 8, and 15; Days 1 and 8; or Days 1, 4, 8, and 11). This is consistent with a mean 
terminal elimination half-life (t1/2) of approximately 10 to 11 hours estimated across doses 
and schedules. Additionally, a preliminary population PK analysis indicated that MLN4924 
systemic clearance (CL) (IIV in CL ~ 27% coefficient of variation [CV]) and volume of 
distribution (Vss) (IIV central volume ~ 43% CV; IIV peripheral volume ~ 28% CV) appear 
to increase with increasing body size (body surface area [BSA] range 1.48-2.72 m2) 
supporting BSA-normalized dosing in minimizing variability in exposure.
Additional information on the nonclinical and clinical PK of MLN4924 is provided in the 
IB.
1.4
MLN4924 Clinical Experience
Single-agent MLN4924 has been studied in 4 phase 1 clinical trials in patients with 
advanced nonhematologic malignancies (Study C15001); lymphoma and multiple myeloma 
(Study C15002); AML, MDS, or ALL (Study C15003); and melanoma (Study C15005). 
These were all single-agent, dose-escalation studies. Based on information available as of 
02 April 2013, 227 patients were enrolled into these studies, and safety data are available 
and summarized for 224 of these patients (ie, those included in the Safety population). 
MLN4924 was administered as a 1-hour IV infusion in these protocols. Six dosing schedules 
using a 21-day cycle were assessed across these studies (dosing on Days 1-5; Days 1, 3, and 
5; Days 1 and 8; Days 1, 2, 8, and 9; Days 1, 8, and 15; and Days 1, 4, 8, and 11) in a 
coordinated fashion. 
Study C15001 was conducted in 62 patients with solid tumors. The median age of the 
patients included in the Safety population was 59.5 years, with a range from 34 to 84 years. 
One patient (a 45-year-old man with metastatic melanoma and bone and lung involvement) 
had a partial response (PR) on Schedule A (Days 1-5) at a dose of 25 mg/m2. In addition, 
13 patients with the following solid tumors remained on treatment for at least 5 cycles, and 
all achieved a best response of stable disease (SD) that lasted for up to 9 cycles: colorectal 
carcinoma (6), melanoma (3), breast cancer (2), and small cell lung cancer (SCLC) and head 
and neck cancer (1 each) (C15001 Clinical Study Report [CSR]).


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Study C15002 began in June 2008, and 56 patients with multiple myeloma (21) or 
lymphoma (35) were enrolled. The median age of the patients included in the Safety 
population was 60.0 years, with a range from 26 to 90 years. As of 30 September 2013, 
3 PRs were observed in this study at doses of 110 to 196 mg/m2: 1 patient each with diffuse 
large B-cell lymphoma (DLBCL), Hodgkin lymphoma, and peripheral T-cell lymphoma. 
The patient with DLBCL achieved PR in Cycle 3, and the duration of this response was 
134 days. 
Study C15003 began in July 2009, and 72 patients were enrolled as of 28 October 2013 in 
this phase 1 study evaluating single-agent MLN4924 in several 21-day dosing schedules in 
patients with AML (patients with MDS and ALL were also evaluated in this study). For 
Schedule A (Days 1, 3, and 5), 4 dose levels were determined safe: 25, 33, 44, and 
59 mg/m2. The maximum tolerated dose (MTD) for Schedule A was established at 59 mg/m2
based on a dose-limiting toxicity (DLT) of increased transaminases observed at a dose level 
of 78 mg/m2. Dosing in Schedule B (Days 1, 4, 8, and 11) was de-escalated to 110 mg/m2
based on 2 serious adverse events (SAEs) for patients dosed at 147 mg/m2: 1 fatal (acute 
renal failure) and 1 life threatening (cardiac failure). The dose was subsequently reduced to 
83 mg/m2 to further enhance the safety margin. Schedule C (Days 1, 8, and 15) was tested in 
2 patients (both received only 1 cycle of treatment), and Schedule D (Days 1, 4, 8, and 11 in 
combination with azacitidine) was tested in only 1 patient (although the patient received 
only MLN4924). Sixteen patients were enrolled in an additional expansion cohort, Schedule 
E, which was added to this protocol to further evaluate the dosing schedule of MLN4924 on 
Days 1, 3, and 5 at a fixed dose of 50 mg/m2. 
Both Schedules A and E (Days 1, 3, and 5) and Schedule B (Days 1, 4, 8, and 11) of 
MLN4924 administration appeared to be generally well tolerated. NEDD8-activating 
enzyme inhibition with MLN4924 demonstrated clinical activity in highly 
refractory/multiply relapsed AML patients. As an example, a 29-year-old woman with 
relapsed (French-American-British subtype M4) acute AML (with isolated trisomy 8) 
following allogeneic stem cell transplantation achieved complete remission after Cycle 1 
treatment on Schedule A (Days 1, 3, and 5) with 25-mg/m2 MLN4924. Her cytogenetic 
complete remission continued before she experienced extramedullary disease progression in 
Cycle 8. Prior treatments included “7 and 3” induction therapy followed by high-dose 
cytarabine and then allogeneic bone marrow transplantation.
Study C15005 was conducted in patients with melanoma. Thirty-seven patients were 
enrolled, and the median age of the patients in the Safety population was 61.8 years, ranging 


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from 33 to 79 years. Six patients stayed on the study for at least 6 cycles and achieved a best 
response of SD, and 1 patient achieved a PR (C15005 CSR).
In addition to single-agent studies, MLN4924 is currently being studied in combination with 
azacitidine in patients with AML. Study C15009 is a dose-escalation study that began in 
April 2013, and 15 patients 60 years of age or older with newly diagnosed AML have been 
enrolled as of 08 January 2014. The MTD of MLN4924 has been established at 20 mg/m2 on 
Days 1, 3, and 5 in combination with azacitidine 75 mg/m2 on Days 1 through 5, 8, and 9 in 
28-day cycles. This study is ongoing.
Overall, the intermittent schedule of drug administration was better tolerated than the daily 
schedule. The identified risks of MLN4924 treatment are increased heart rate, diarrhea, 
nausea, vomiting, pyrexia, liver function test (LFT) abnormal, musculoskeletal pain, and 
myalgia (see Section 1.6.1; additional information is available in the Development Core 
Safety Information [DCSI]).
A comprehensive review of the clinical trial safety data has shown that toxicity involving 
multi-organ failure on Cycle 1, Day 1, including SAEs of renal, hepatic, and cardiac failure, 
some with a fatal outcome, has been observed in MLN4924 studies. Based on the 
observation that these events are associated with higher MLN4924 doses, the sponsor has 
determined that newly enrolling patients will receive MLN4924 at doses equal to or below 
100 mg/m2. Our current understanding of the renal toxicity observed with MLN4924 
suggests that it is not a primary event; it is likely secondary to hemodynamic changes 
occurring in the setting of a type of acute phase response. Patients will be monitored closely 
for events of multi-organ failure after MLN4924 dosing. 
In October 2012, a revised risk mitigation strategy including dose reduction was 
implemented across the MLN4924 program. As of January 2014, approximately 
60 additional patients have been treated in single-agent and combination studies, and no 
Cycle 1, Day 1 SAEs have been observed. The majority of patients in these studies received 
MLN4924 at a dose of 50 mg/m2 or lower.
Hepatotoxicity has been noted following administration of MLN4924 in patients with 
advanced malignancy, including elevations of liver transaminases, alkaline phosphatase 
(ALP), and bilirubin. Grade 1, 2, and 3 increases in alanine aminotransferase (ALT) and 
aspartate aminotransferase (AST) have been observed in patients receiving the 50-mg/m2
dose on Days 1, 3, and 5 in Schedule E of Study C15003. The patients experiencing these 
changes in laboratory values have been asymptomatic. This type of elevation in 


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transaminases had been observed previously in patients treated with MLN4924. The 
elevations in laboratory values have been reversible with dose modification including dose 
delay and reduction. Patients with elevated transaminases have been successfully 
rechallenged at lower doses. 
Preliminary pharmacodynamic analyses in both hematologic and nonhematologic 
indications demonstrate target and downstream pathway inhibition following MLN4924 
dosing at all doses tested in tumor and surrogate tissues. MLN4924-NEDD8 adduct is a 
unique molecular species formed as a consequence of the intracellular interaction of NAE 
with MLN4924 and NEDD8, and is indicative of MLN4924 inhibition of NAE.(4)  
MLN4924-NEDD8 adduct was detected by immunohistochemistry in postdose but not 
predose solid tumor biopsies in 11/11 patients demonstrating target inhibition 3 to 6 hours 
following MLN4924 dosing in all cases (dose range 50-83 mg/m2). In addition, changes in 
CDL substrates Cdt-1 and Nrf2 were investigated in predose and postdose skin and tumor 
biopsies, with the majority of patients demonstrating postdose increases (1.5- to 25-fold) in 
Cdt-1 and/or Nrf2 in skin (27/34 patients) or tumor (9/11 patients). In addition, 
pharmacodynamic assessments of MLN4924 adduct and Cdt-1 in predose and postdose bone 
marrow aspirates obtained from patients with AML or high-grade MDS indicate target and 
pathway inhibition throughout the dose range tested (25-78 mg/m2). 
Additional information on safety and pharmacodynamics is provided in the IB.
The risks of MLN4924 treatment, based on preliminary findings from the clinical studies 
and the toxicities noted in the toxicology studies done in rats and dogs, are presented in 
Section 1.6.1.
Antitumor Activity of MLN4924 in Solid Tumors
MLN4924 has been investigated as a single agent in solid tumors in 2 phase 1 studies: 
C15001 was conducted in patients with any solid tumors for whom prior therapies had 
failed, and Study C15005 was conducted in patients with melanoma that was
relapsed/refractory to prior therapies. These studies were designed to determine safe and 
tolerable doses of MLN4924 in various solid tumors and establish a safety database for the 
molecule. The antitumor activity of MLN4924 as a single agent was also investigated in 
these studies. Overall, a total of 99 patients with various solid tumors have been treated in 
these 2 phase 1 studies. 


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In Study C15001, 13 patients with the following solid tumors stayed on the study for at least 
5 cycles: colorectal carcinoma (6); melanoma (3); breast cancer (2); and SCLC and head and 
neck cancer (1 each). 
Among 20 evaluable patients with melanoma in Study C15005, the disease control rate, 
defined as the proportion of patients achieving SD or better at first restaging, was 
50% (10/20); 6 patients stayed on the study for at least 5 cycles. One 60-year-old woman 
with wild type-BRAF disease who progressed through multiple (> 6) prior therapies 
achieved a PR at Cycle 4. She was treated at the 209-mg/m2 dose level of MLN4924. 
The results of these studies indicate potential antitumor activity of MLN4924 in a variety of 
solid tumors in patients who have been heavily treated with multiple lines of prior therapy 
and who are typically very difficult to treat. 
The use of combination therapy with standard of care (SoC) agents builds on nonclinical 
data demonstrating sensitivity to MLN4924 in certain types of malignancies such as colon
cancer, non-small cell lung cancer (NSCLC), SCLC, melanoma, breast cancer, and 
esophageal cancer and its augmentation by standard chemotherapy agents (see Section 1.2);
limited clinical data as described above; and the strength of published data with 
well-established chemotherapies used in various malignancies. 
Study C15010, a dose-escalation study of MLN4924 in combination with SoC, is being 
conducted in patients with solid tumors for whom prior therapies have failed. As of 
09 January 2014, 18 patients were treated with MLN4924 in combination with docetaxel, 
carboplatin, or carboplatin+paclitaxel. Based on preliminary data, these combinations have 
shown evidence of clinical benefit in the form of multiple PRs and extended durations of 
SD. The study is still in the dose-finding phase, and an MTD has not been established in any 
of these combinations. The current dose levels being investigated are:

Docetaxel Arm: MLN4924 25 mg/m2 on Days 1, 3, and 5 of a 21-day cycle in 
combination with docetaxel 75 mg/m2 on Day 1. 

Carboplatin+Paclitaxel Arm: MLN4924 25 mg/m2 on Days 1, 3, and 5 of a 21-day 
cycle in combination with carboplatin AUC5+paclitaxel 175 mg/m2 on Day 1.


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1.5
Study Rationale
1.5.1
Rationale for Drug-drug Interaction Assessment (Part A)
1.5.1.1
Study Rationale
Hepatic metabolism appears to be the major route of elimination for MLN4924. While no 
definitive information is currently available on the elimination pathways of MLN4924 in 
humans, urinary excretion of unchanged MLN4924 was found to be low (< 5%) in rats and 
primates. In vitro drug metabolism data indicate that MLN4924 is metabolized via 
hydroxylation and oxidation, predominantly by CYP3A4. The estimated contribution of 
CYP3A4 to MLN4924 biotransformation (97%) is largely above the 25% threshold of 
potential clinical relevance for drug-drug interactions (DDIs) based on United States (US)
Food and Drug Administration (FDA) and European Medicines Agency guidance 
documents.(5, 6)
MLN4924 is in fact considered to be a sensitive CYP3A substrate as physiologically based 
PK modeling and simulation predict an 8- to12-fold increase in area under the plasma 
concentration versus time curve (AUC) when co-administered with the strong CYP3A4 
inhibitor probe, ketoconazole. CYP3A is a major subclass of the CYP enzymes, accounting 
for more than 30% of total CYP proteins in the liver. Given the likelihood of a positive 
interaction between MLN4924 and a strong CYP3A inhibitor that may result in a clinically 
meaningful increase in MLN4924 exposure due to inhibition of CYP3A-mediated hepatic 
metabolism following IV administration, the impact of a less strong (or moderate) CYP3A 
inhibitor will also be evaluated. For drugs that distribute into red blood cells, the blood to 
plasma (B/P) ratio is important for estimation of in vivo hepatic metabolic clearance; 
however, the value is not always available. In vitro studies showed that MLN4924 
partitioned extensively into erythrocytes with a B/P ratio that is concentration-dependent and 
saturable. Limited blood sampling will be performed in this study for in vivo determination 
of B/P ratio and to inform estimation of human blood clearance. Until the magnitude of such 
potential interactions is characterized in a clinical DDI study, co-administration of moderate 
and strong CYP3A inhibitors is not currently permitted in the ongoing clinical studies of 
MLN4924. 
Fluconazole and itraconazole, 2 antifungal agents, are among choices of moderate and 
strong inhibitors of CYP3A4, respectively, that are recommended in regulatory 
guidelines.(5, 6) Fluconazole is an inhibitor of CYP3A4, CYP2C9, and CYP2C19 enzymes 
but not an inhibitor of transporters. Acute (400 mg) and steady-state (200 mg once daily 


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[QD]) administration of fluconazole has been shown to increase the AUC of orally 
administered midazolam up to 3.9-fold, which meets the criterion for a moderate CYP3A4 
inhibitor.(7)  There is no effect of food on the oral bioavailability of fluconazole tablets.(8)  
Itraconazole (200 mg QD), another validated inhibitor probe, was in fact chosen in place of 
ketoconazole based on recent FDA communications advising against its use for drug 
interaction studies due serious side effects (fda.gov/Drugs/DrugSafety/ucm371017.htm, 
FDA advises against using oral ketoconazole in drug interaction studies due to serious 
potential side effects, Accessed 13 January 2014).(9)  Itraconazole is commercially available 
as an oral solution or as capsules.(10)  Results from a cross-study comparison of solution and 
capsules indicated that when these 2 oral formulations are administered under optimal 
conditions for absorption, the bioavailability of the oral solution relative to the capsules is 
higher. Consequently, and in accordance with the FDA DDI Guidance for Industry, the oral 
solution of itraconazole administered on an empty stomach is selected for this study.(5)  Use 
of these CYP3A4 inhibitor probes belonging to the class of azole antifungal agents in this 
study is most appropriate as they are relevant to the target (AML) patient population.
Results from this study will inform strategies for managing potential DDIs with moderate
and strong CYP3A inhibitors in future clinical studies of MLN4924 and additionally 
contribute to the long-term clinical pharmacology objectives of the MLN4924 development 
program. 
1.5.1.2
MLN4924 Dose Rationale for Part A
In phase 1 clinical studies, patients have been receiving MLN4924 administered IV at doses 
ranging from 25 to 278 mg/m2 on multiple schedules for up to 19 cycles. Single-agent 
MLN4924 was specifically investigated in patients with solid tumors in 2 phase 1 studies: 
Study C15001 was conducted in patients with any solid tumors for whom prior therapies had 
failed, and Study C15005 was conducted in patients with melanoma that was 
relapsed/refractory to prior therapies. A total of 99 patients with various solid tumors have 
been treated in these studies designed to determine safe and tolerable doses of MLN4924. 
In Study C15001, sequential cohorts of patients received MLN4924 as a 1-hour infusion on 
4 different schedules. Of these schedules, the 2 in which MLN4924 was administered on 
Days 1, 3, and 5 on a 21-day cycle were generally better tolerated than those with once-daily 
dosing on 5 consecutive days at lower doses, or higher doses administered once weekly with 
a longer infusion. Common toxicities were diarrhea, nausea, vomiting, and increased LFTs. 


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After cross-program review, patients in ongoing and future studies will receive MLN4924 at 
doses equal to or below 100 mg/m2. 
The IV dose of MLN4924 (8 mg/m2) selected for the study is approximately 14-fold lower 
than starting doses of MLN4924 equal to or above 110 mg/m2, which were associated with 
an increased frequency of severe Cycle 1, Day 1 adverse events (AEs) in phase 1 studies of 
MLN4924. Only a single dose of MLN4924 will be administered in the presence of the 
CYP3A inhibitor. This low dose is anticipated to provide an adequate safety margin for 
conduct of this DDI assessment, based on the predicted 8- to 12-fold increase in MLN4924 
systemic exposure (AUC) upon strong CYP3A inhibition by the inhibitor probe 
ketoconazole. The expectation is based on model-based simulations of DDI potential 
(SimCYP®) using in vitro data on relative contribution of CYP3A to overall metabolism, in 
vivo preclinical information on drug disposition, and clinical PK data available to date on 
MLN4924. 
On the basis of emerging data from this study, the primary purpose of Amendment 1 is 
to further evaluate the effect of the strong CYP3A inhibitor itraconazole on MLN4924 PK at 
the clinically relevant dose of 20 mg/m2. The information from this additional Itraconazole 
Arm will provide further understanding of the contribution of CYP3A metabolism to the 
disposition of MLN4924 in humans within the clinically relevant dose range in support of 
adequate labeling. 
The proposed single IV dose of MLN4924, 20 mg/m2, is approximately 5-fold lower than 
doses of MLN4924 equal to or above 110 mg/m2, which were associated with more severe 
Cycle 1 Day 1 adverse events in phase 1 studies of MLN4924. Also, based on the 
dose-linear PK of MLN4924 and observed 23% increase in MLN4924 plasma systemic 
exposure by itraconazole at a single 8-mg/m2 dose, it can be inferred that exposures of 
MLN4924 when administered at a single 20-mg/m2 dose with itraconazole can be expected 
to be well below exposures seen at doses ≥ 110 mg/m2. Conservatively, enrollment into the 
Itraconazole Arm, 20-mg/m2 MLN4924 Cohort will begin once Part A PK and safety data 
from 3 PK-evaluable patients treated with 15-mg/m2 MLN4924+itraconazole, as an 
intermediate safety lead-in step, have confirmed that the anticipated safety margin is 
adequate for the proposed evaluation of the drug interaction with itraconazole at the 
20-mg/m2 dose of MLN4924. 


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1.5.1.3
Rationale for Inclusion of Blood Pharmacodynamic Assessment
This study will also include assessment of blood-based pharmacodynamic markers. 
Investigations of pharmacodynamic biomarker modulation of NAE pathway inhibition were 
performed in both tumor and surrogate tissues in previous phase 1 studies of MLN4924. 
Changes in pharmacodynamic biomarkers following MLN4924 treatment as a single agent 
indicative of target and pathway inhibition were detected at all doses tested (25-278 mg/m2). 
Therefore, the lower limit of target and pathway inhibition has not been determined to date. 
The use of a dose approximately one-third of the lowest dose tested to date in humans will 
enable further exploration of PK-pharmacodynamic relationships at systemic exposures of 
MLN4924 below those previously explored. 
1.5.2
Rationale for Continued Treatment With MLN4924 in Combination With 
Standard of Care (Part B)
1.5.2.1
Study Rationale
After completing Part A, patients are given the opportunity to participate in Part B where 
they will receive combination treatment with MLN4924 and SoC chemotherapy. 
Two chemotherapy regimens, docetaxel and carboplatin+paclitaxel, will be used in this 
study as combination partners with MLN4924. These regimens have been approved and are 
considered SoC therapies for various malignancies in front-line or relapsed/refractory 
settings.
Docetaxel is indicated as a single agent for locally advanced or metastatic breast cancer and 
for locally advanced or metastatic NSCLC after platinum therapy failure. 
Paclitaxel is indicated for the treatment of breast cancer after failure of combination 
chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. 
In addition, paclitaxel in combination with cisplatin is indicated for the first-line treatment 
of NSCLC in patients who are not candidates for potentially curative surgery or radiation 
therapy.
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Carboplatin is indicated for the initial treatment of advanced ovarian carcinoma in 
combination with other approved chemotherapeutic agents (one established combination 
regimen consists of carboplatin and cyclophosphamide). Carboplatin is also indicated for the 
palliative treatment of patients with ovarian carcinoma recurrent after prior chemotherapy, 
including patients who have been previously treated with cisplatin.
Docetaxel, paclitaxel, and carboplatin are also approved in combination with other 
chemotherapeutic agents to treat other indications; refer to package inserts for additional 
information. 
In addition to the approved indications outlined above, these agents are widely used in a 
variety of malignancies in patients for whom prior therapies have failed. Carboplatin/
paclitaxel is also widely used for treatment of newly diagnosed NSCLC.
For a detailed description of each of these medications, please see Section 6.11. The choice 
of the above chemotherapy agents in combination with MLN4924 in this study is based on 
the following considerations:

These agents have been well recognized as SoC in a number of malignancies in 
front-line (carboplatin+paclitaxel) or in various relapse settings (both regimens). 

Their safety profiles, risks, and benefits have been widely studied and reported.

Additive/synergistic effect of these agents in combination with MLN4924 has been 
studied in a number of in vitro and in vivo models in house.
Therefore, it is thought that the above SoCs will serve as reasonable partners in combination 
with MLN4924 for investigations in patients with various solid tumors in this study. 
As discussed in Section 1.4, MLN4924 in combination with SoC is currently being 
investigated in Study C15010, a multi-arm, phase 1b, dose-escalation study of MLN4924 in 
combination with docetaxel or carboplatin+paclitaxel in patients with solid tumors for whom
prior therapies have failed. This study is ongoing, and no MTD has been established yet. 
The current dose levels that are being investigated are: 

Docetaxel Arm: MLN4925 25 mg/m2 on Days 1, 3, and 5 of a 21-day cycle in 
combination with docetaxel 75 mg/m2 on Day 1


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
Carboplatin+Paclitaxel Arm: MLN4924 25 mg/m2 on Days 1, 3, and 5 of a 21-day 
cycle in combination with carboplatin AUC5+paclitaxel 175 mg/m2 on Day 1
1.5.2.2
MLN4924 Dose Rationale in Combination With Standard of Care
Patients will receive MLN4924 in combination with either docetaxel or 
carboplatin+paclitaxel at a dose regimen informed from Study C15010 that has been deemed 
tolerable (eg, no DLTs in 3 patients or no more than 1 DLT in 6 patients). The selected dose 
may be adjusted accordingly based on information obtained from the ongoing review of 
safety data. The information learned from Study C15010, including the tolerable dose levels, 
will be provided to the sites in writing and per the Study Manual.
1.6
Potential Risks and Benefits
Given limited existing clinical experience, it is not known whether patients will benefit from 
participation in this study. However, a number of patients treated with MLN4924 as a single 
agent did demonstrate clinical benefit based primarily on prolonged SD (see Section 1.4). In 
addition, it is anticipated that the SoC therapies used in Part B of this study may provide 
additional clinical benefit to patients. Study C15010 is an open-label, dose-finding study to 
assess MLN4924+SoC and is ongoing. Eighteen patients have been treated with MLN4924 
in combination with docetaxel, carboplatin, or carboplatin+paclitaxel. Based on preliminary 
data, these combinations have shown evidence of clinical benefit in the form of multiple PRs
and extended durations of SD. 
1.6.1
Risks of MLN4924 Therapy
Safety information gained from single-agent clinical studies of MLN4924 and from 
toxicology studies in rats and dogs has been used to guide the safety evaluation of 
MLN4924. Additional information on risks is provided in the IB and the DCSI.
Based on preliminary findings from the single-agent clinical studies and the toxicities noted 
in the toxicology studies done in rats and dogs, the risks of MLN4924 treatment are 
presented below. 


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Identified Risks

Increased heart rate

Diarrhea

Nausea

Vomiting

Pyrexia

Liver function test abnormal

Musculoskeletal pain/myalgia
Potential Risks
There are potential risks in the MLN4924 program that require further monitoring. While 
the potential toxicities listed below may be severe or life threatening, it is anticipated that 
they can be managed by clinical monitoring and intervention.
Potential Risks From Phase 1 Studies (at Higher Doses)
There are events that have been reported in phase 1 studies, which have been closed, 
including at doses and schedules substantially higher than those being used in current 
clinical trials. These events are being considered potential risks for the doses and schedules 
currently being studied:

Multi-organ failure that could result in death

Renal failure 
o
The events of multi-organ failure (hepatic, renal, and cardiac) with a fatal 
outcome, and renal failure alone, have been reported at doses of MLN4924 
ranging from 110 to 278 mg/m2. Please refer to Section 1.4 for additional 
information about multi-organ failure and dosing.


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
Cardiac arrhythmias
o
All events were supraventricular arrhythmias; all except 1 were unrelated. The 
case of atrial fibrillation assessed by the investigator as related occurred in a 
patient with cardiovascular risk factors.

Myelosuppression with increased susceptibility to infection, bleeding, and anemia

Acute phase response

Gastrointestinal (GI) toxicity including or resulting in dehydration, and electrolyte 
imbalance

Hypophosphatemia
Potential Risks Confounded by Underlying Disease or Malignancy
Events have been reported from clinical trials that are confounded by the patient’s 
underlying medical condition, including malignancy. These events are noted in the absence 
of randomized, controlled data:

Fatigue

Chills

Decreased appetite

Neutropenia

Febrile neutropenia

GI bleeding
o
All events were assessed by the investigator as unrelated; the majority occurred 
in the setting of thrombocytopenia.


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Potential Risks Primarily Based on Findings from Animal Studies
Potential risks that are derived from findings in animal studies in rats and dogs include:

Cardiovascular changes that could result in tachycardia, decreased or increased 
systolic blood pressure, and increased diastolic blood pressure.

Myocardial degeneration and thrombosis.

Pulmonary hypertension.

Effects on the testes and ovaries that represent a reproductive hazard, including 
sterility.

Increased developmental risk to the fetus or embryo.

Decreased trabecular bone (graded minimal to moderate) was noted in the femur and 
in the sternum in rats at all dose groups (low, medium, and high). This finding was 
considered adverse in the high-dose group; however, no bone fractures were noted at 
any of the doses.

Prolongation of the activated partial thromboplastin time (aPTT).

Local tissue injury when administered SC.
Hepatotoxicity has been noted following administration of MLN4924 in patients with 
advanced malignancy, including elevations of liver transaminases, ALP, and bilirubin
(see Section 1.4). Liver enzymes and liver function are frequently monitored during clinical 
studies of MLN4924. Acetaminophen and acetaminophen-containing compounds may not 
be used in Part A; however, they may be used judiciously in Part B and should not exceed a 
dose of 2 g of acetaminophen in a 24-hour period (see Section 6.5).
Patients must be carefully evaluated at screening and before each MLN4924 dose for early 
symptoms and signs of hemodynamic compromise or active infection. Particular attention 
should be paid to unexplained fever, tachycardia, hypotension, orthostasis, tachypnea, recent 
nausea and vomiting, and clinical evidence of dehydration. Guidance on rehydration is 
provided in Section 6.8. 
These potential toxicities will be managed by careful, frequent monitoring and intervention, 
as needed, with supportive care. It is possible that MLN4924 will have toxicities that were 


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not observed in or predicted from the studies completed in rats and dogs, or have not yet 
been identified in patients.
Patients will be monitored closely when they are receiving this agent and for at least 30 days 
after their last dose for these anticipated and potential toxicities and for unanticipated 
toxicities. Monitoring will include the following: laboratory assessments, physical 
examinations, SAE and AE reporting, and safety review (see Section 9.1). 
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
and the applicable regulatory requirements (including International Conference on 
Harmonisation [ICH] guidelines).
1.6.2
Risks of Fluconazole Treatment 
Anaphylaxis
In rare cases, anaphylaxis has been reported in patients who received fluconazole (brand 
name DIFLUCAN®). Patients have rarely developed exfoliative skin disorders during 
treatment with fluconazole. In patients with serious underlying diseases (predominantly 
acquired immunodeficiency syndrome and malignancy), these have rarely resulted in a fatal 
outcome. 
Cardiac Dysrhythmias
Some azoles, including fluconazole, have been associated with prolongation of the 
QT interval on the electrocardiogram. During post-marketing surveillance, there 
have been rare cases of QT prolongation and torsade de pointes in patients taking 
fluconazole. Most of these reports involved seriously ill patients with multiple 
confounding risk factors, such as structural heart disease, electrolyte abnormalities, 
and concomitant medications that may have been contributory.(8)
Hepatotoxicity Warning
DIFLUCAN should be administered with caution to patients with liver dysfunction. 
DIFLUCAN has been associated with rare cases of serious hepatic toxicity, 
including fatalities primarily in patients with serious underlying medical conditions. 
In cases of DIFLUCAN-associated hepatotoxicity, no obvious relationship to total 
daily dose, duration of therapy, sex, or age of the patient has been observed. 
DIFLUCAN hepatotoxicity has usually, but not always, been reversible on 
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during DIFLUCAN therapy should be monitored for the development of more severe 
hepatic injury. Fluconazole should be discontinued if clinical signs and symptoms 
consistent with liver disease develop that may be attributable to DIFLUCAN.(8)
For more details, refer to the fluconazole oral solution US Package Insert (USPI).(8)
Drug Interaction Precautions
See the DIFLUCAN USPI Sections on CLINICAL PHARMACOLOGY: Drug Interaction 
Studies and CONTRAINDICATIONS for additional information.

Fluconazole is a potent inhibitor of CYP isoenzyme 2C9 and a moderate inhibitor of 
CYP3A4; therefore, there is a risk of increased plasma concentration of other 
compounds metabolized by CYP2C9 and CYP3A4 co-administered with fluconazole
(see Section 6.5). 
Risks of MLN4924 and Fluconazole as Combination Therapy
Based on the known individual safety profiles of MLN4924 and fluconazole, the following 
potential risks of combination therapy may apply: headache, abdominal pain, nausea, 
diarrhea, and serum transaminase elevations. 
1.6.3
Risks of Itraconazole Treatment
Congestive Heart Failure and Cardiac Effects 
When itraconazole (SPORANOX®) was administered intravenously to dogs and healthy 
human volunteers, negative inotropic effects were seen. 
SPORANOX® (itraconazole) oral solution should not be administered to patients 
with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a 
history of CHF except for the treatment of life-threatening or other serious 
infections.(10)  
If signs or symptoms of congestive heart failure occur during administration of itraconazole 
oral solution, continued use should be reassessed.
Cardiac Dysrhythmias and Drug Interaction Warning
Co-administration of cisapride, oral midazolam, nisoldipine, felodipine, pimozide, 
quinidine, dofetilide, triazolam, levacetylmethadol (levomethadyl), lovastatin, 


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simvastatin, ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), 
ergotamine and methylergometrine (methylergonovine) or methadone with 
SPORANOX® (itraconazole) Capsules or Oral Solution is contraindicated. 
SPORANOX®, a potent cytochrome P450 3A4 isoenzyme system (CYP3A4) inhibitor, 
may increase plasma concentrations of drugs metabolized by this pathway. Serious 
cardiovascular events, including QT prolongation, torsades de pointes, ventricular 
tachycardia, cardiac arrest, and/or sudden death have occurred in patients using 
cisapride, pimozide, methadone, levacetylmethadol (levomethadyl), or quinidine 
concomitantly with SPORANOX® and/or other CYP3A4 inhibitors.
These medications are excluded from this study (see Section 6.5).
Other Cardiac Effects
Please see the SPORANOX® USPI WARNINGS section under the heading CARDIAC 
DISEASE for ischemic valvular disease, chronic obstructive pulmonary disease (COPD), 
renal and edematous disorders (including postmarketing reports of peripheral edema and 
pulmonary edema), and additional information on the negative inotropic effects of 
itraconazole when co-administered with calcium channel blockers.
Hepatotoxicity Warning
SPORANOX® has been associated with rare cases of serious hepatotoxicity, 
including liver failure and death. Some of these cases had neither pre-existing liver 
disease nor a serious underlying medical condition and some of these cases 
developed within the first week of treatment. If clinical signs or symptoms develop 
that are consistent with liver disease, treatment should be discontinued and liver 
function testing performed. Continued itraconazole oral solution use is strongly 
discouraged unless there is a serious or life-threatening situation where the expected 
benefit exceeds the risk.(10)
For additional information on the safety profile of SPORANOX®, please refer to the 
USPI.(10)
Drug Interaction Precautions
Please consult the PRECAUTIONS/DRUG INTERACTIONS section of the SPORANOX®
USPI for additional information.


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Itraconazole and its major metabolite, hydroxyitraconazole, are inhibitors of CYP3A4. 
SPORANOX® may decrease the elimination of drugs metabolized by CYP3A4, resulting in 
increased plasma concentrations of these drugs when they are administered with 
SPORANOX® (see Section 6.5).
Risks of MLN4924 and Itraconazole as Combination Therapy
Based on the known individual safety profiles of MLN4924 and itraconazole, the following 
potential risks of combination therapy may apply: fever, nausea, vomiting, diarrhea, and 
hepatotoxicity.
1.6.4
Risks of Docetaxel Treatment
Treatment-related mortality increases with abnormal liver function, at higher doses, and in 
patients with NSCLC and prior platinum-based therapy receiving docetaxel at 100 mg/m2.
Severe hypersensitivity, including very rare, fatal anaphylaxis, has been reported in patients 
who received dexamethasone premedication. Severe reactions require immediate 
discontinuation of docetaxel and administration of appropriate therapy. 
Docetaxel is contraindicated if the patient has a history of severe hypersensitivity reactions 
to docetaxel or to drugs formulated with polysorbate 80.
Severe fluid retention may occur despite dexamethasone.
For more details, refer to the Taxotere® (docetaxel) USPI.(11)
1.6.4.1
Hepatotoxicity Warning
Docetaxel should not be given if total bilirubin is greater than the upper limit of the normal 
range (ULN) or if AST or ALT is greater than 1.5 times the ULN. Liver function test
elevations increase the risk of severe or life threatening complications. Liver function tests
should be obtained before each treatment cycle.
1.6.4.2
Hematologic Warning
Docetaxel should not be given if the absolute neutrophil count (ANC) is less than 
1500 cells/mm3.


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1.6.4.3
Risks of MLN4924 and Docetaxel as Combination Therapy
Based on the known individual safety profiles of MLN4924 and docetaxel, the following 
potential risks of combination therapy may apply: death, hypersensitivity, hepatoxicity, 
neutropenia, and fluid retention (cardiac/pulmonary). With regard to docetaxel, 
treatment-related mortality increases with abnormal liver function, at higher doses, and in 
patients with NSCLC and prior platinum-based therapy receiving docetaxel at 100 mg/m2.
1.6.5
Risks of Carboplatin and Paclitaxel Therapy
See Section 15.1 for information on the hematologic toxicity of carboplatin alone and in 
combination with paclitaxel.
1.6.5.1
Carboplatin
Anaphylaxis-like reactions to carboplatin have been reported and may occur within minutes 
of carboplatin administration. Epinephrine, corticosteroids, and antihistamines have been 
employed to alleviate symptoms.
Vomiting is another frequent drug-related side effect.
Carboplatin Injection is contraindicated in patients with a history of severe allergic reactions 
to cisplatin or other platinum-containing compounds.
Carboplatin Injection should not be employed in patients with severe bone marrow 
depression or significant bleeding.
For more details, please refer to the Paraplatin® (carboplatin) USPI.(12)
Nephrotoxicity Warning
The renal effects of nephrotoxic compounds may be potentiated by carboplatin.
Hematologic Warning
Bone marrow suppression is dose related and may be severe, resulting in infection or 
bleeding. Peripheral blood counts should be frequently monitored during carboplatin 
treatment and, when appropriate, until recovery is achieved.
Anemia may be cumulative and may require transfusion support.


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1.6.5.2
Paclitaxel
Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and 
hypotension requiring treatment, angioedema, and generalized urticaria have occurred in 
2% to 4% of patients receiving paclitaxel in clinical trials. Fatal reactions have occurred in 
patients despite premedication. All patients should be pretreated with corticosteroids, 
diphenhydramine, and H2 antagonists. Patients who experience severe hypersensitivity 
reactions to paclitaxel should not be rechallenged with the drug.
Severe conduction abnormalities have been documented in less than 1% of patients during 
paclitaxel therapy and, in some cases, require pacemaker placement. If patients develop 
significant conduction abnormalities during paclitaxel infusion, appropriate therapy should 
be administered, and continuous cardiac monitoring should be performed during subsequent 
therapy with paclitaxel.
Paclitaxel is contraindicated in patients who have a history of hypersensitivity reactions to 
paclitaxel or other drugs formulated in Cremophor® EL (polyoxyethylated castor oil).
For more details, please refer to the Taxol® (paclitaxel) USPI.(13)
Hematologic Warning
Paclitaxel Injection, US Pharmacopeia (USP) therapy should not be given to patients with 
solid tumors who have baseline neutrophil counts of less than 1500 cells/mm3. To monitor 
for the occurrence of bone marrow suppression, primarily neutropenia, which may be severe 
and result in infection, it is recommended that frequent peripheral blood cell counts be 
performed on all patients receiving Paclitaxel Injection, USP.
1.6.5.3
Risks of MLN4924 and Carboplatin+Paclitaxel as Combination Therapy
Based on the known individual safety profiles of MLN4924 and carboplatin+paclitaxel, the 
following potential risks of combination therapy may apply: bone marrow suppression, 
hypersensitivity/anaphylaxis reactions, and hepatotoxicity. Renal effects of nephrotoxic 
compounds (see Section 15.2) may be potentiated by carboplatin.
1.6.6
Summary of Risks of Fluconazole, Itraconazole, or Standard of Care 
Therapies in Combination With MLN4924
Potential overlapping toxicities of CYP3A-mediated inhibitors and SoCs in combination 
with MLN4924 that are described in more detail above are summarized in Table 1-1.


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Table 1-1
Potential Overlapping Toxicities With MLN4924 in Combination With 
Fluconazole, Itraconazole, or Standard of Care Therapies
Agent
Potential Overlapping Toxicities With MLN4924
Fluconazole
Abdominal pain
Nausea
Diarrhea
Hepatotoxicity
Headache
Itraconazole
Fever
Nausea
Vomiting
Diarrhea
Hepatoxicity
Cardiac dysrhythmias (with concomitant CYP3A4 inhibitors)
Docetaxel
Deatha
Hypersensitivity
Hepatoxicity
Neutropenia
Fluid retention (cardiac/pulmonary)
Carboplatin+paclitaxel
Bone marrow suppression
Hypersensitivity/anaphylaxis reactions
Hepatotoxicity
Renal effects of nephrotoxic compounds may be potentiated by carboplatin
Abbreviations: CYP=cytochrome P450.
a Docetaxel treatment-related mortality increases with abnormal liver function, occurs at higher doses, and in 
patients with nonsmall cell lung cancer who received prior platinum-based therapy and are receiving 
docetaxel at 100 mg/m2.
2.
STUDY OBJECTIVES
2.1
Primary Objectives

To assess the effect of multiple-dose administration of fluconazole, a moderate 
CYP3A inhibitor, on the single-dose IV PK of MLN4924

To assess the effect of multiple-dose administration of itraconazole, a strong CYP3A 
inhibitor, on the single-dose IV PK of MLN4924
2.2
Secondary Objectives
The secondary objectives for Part A are:

To further evaluate the safety and tolerability of MLN4924


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
To further describe the IV PK of MLN4924 before and after multiple oral dosing 
with fluconazole or itraconazole 
The secondary objectives for Part B are:

To further assess the safety and tolerability of MLN4924 in combination with 
docetaxel in patients with solid tumors

To further assess the safety and tolerability of MLN4924 in combination with 
carboplatin and paclitaxel in patients with solid tumors

To further evaluate disease response that may be observed with the combination of 
MLN4924 and docetaxel

To further evaluate disease response that may be observed with the combination of 
MLN4924, carboplatin, and paclitaxel
2.3
Exploratory Objective
The exploratory objective for Part A is:
3.
STUDY ENDPOINTS
3.1
Primary Endpoints

Ratio of geometric mean, Cmax, AUC from time zero to the time of the last 
quantifiable concentration (AUC0-tlast), and AUC from time zero to infinity 
(AUC0-inf) of MLN4924 administered with fluconazole versus MLN4924 
administered alone and 90% confidence intervals (CIs)

Ratio of geometric mean, Cmax, AUC0-tlast, and AUC0-inf of MLN4924 administered 
with itraconazole versus MLN4924 administered alone and 90% CI
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3.2
Secondary Endpoints
The secondary endpoints for Part A are:

Adverse events, SAEs, assessments of clinical and laboratory values, weight, and 
vital sign measurements

Pharmacokinetic parameters including but not limited to CL, first time to achieve 
maximum observed plasma concentration (Tmax), Vss, t1/2, and B/P ratio of MLN4924
The secondary endpoints for Part B are:

Adverse events, SAEs, assessments of clinical and laboratory values, weight, and
vital sign measurements

Measures of disease response including objective response rate and duration of 
response based on investigator’s assessment using the Response Evaluation Criteria 
in Solid Tumors (RECIST) guideline (Version 1.1)(14)
3.3
Exploratory Endpoints
The exploratory endpoint for Part A is:
4.
STUDY DESIGN 
4.1
Overview of Study Design
This study is an open-label, multicenter, parallel group, 2-arm, phase 1 study of MLN4924 
designed to assess DDIs with the moderate and strong CYP3A inhibitors fluconazole and
itraconazole, respectively. The patient population will consist of patients 18 years of age or 
older who have a histologically or cytologically confirmed metastatic or locally advanced 
solid tumor that is deemed appropriate for treatment with 1 of the 2 combination therapies in 
Part B of this study, or who have progressed despite standard therapy, or for whom 
conventional therapy is not considered effective. 
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It is expected that approximately 52 patients will be enrolled in this study to reach the 
intended total number of PK-evaluable patients in each arm/cohort. In the Fluconazole Arm, 
approximately 12 PK-evaluable patients will be enrolled. In the Itraconazole Arm, 
approximately 12 PK-evaluable patients will be enrolled in the 8-mg/m2 and 20-mg/m2
MLN4924 cohorts, and 3 additional PK-evaluable patients will be needed in the safety 
lead-in cohort. Once enrolled into the study, patients will begin treatment in Part A of the 
study. In Part A, patients will be administered MLN4924 via a 1-hour (5 minutes) IV 
infusion in combination with either fluconazole or itraconazole as indicated below. Once 
patients complete Part A (including the washout period), they can begin treatment in Part B 
of the study. In Part B, patients will be administered MLN4924 via a 1-hour (10 minutes
as of Amendment 2) IV infusion in combination with either docetaxel or 
carboplatin+paclitaxel. 
Part A: Drug-Drug Interaction Assessment
MLN4924+Fluconazole: Patients will receive a single 8-mg/m2 dose of MLN4924 given as 
a 1-hour (5 minutes) IV infusion on Day 1 and Day 8. This low dose of MLN4924 is 
anticipated to provide an adequate safety margin for DDI assessment (see Section 1.5.1.2). 
Patients will receive concomitant oral fluconazole at a starting dose of 400 mg on Day 4 and 
then 200 mg QD on Days 5 through 10. Pharmacokinetic samples will be taken after the 
MLN4924 dose on Day 1 and after the Day 8 dose of MLN4924 with fluconazole at 
predetermined time points (up to 72 hours after dosing) to assess the effect of fluconazole on 
the PK of MLN4924. Additional samples for determination of MLN4924 concentrations in 
whole blood will be collected on Day 1 only.
MLN4924+Itraconazole: Patients will receive a single dose of MLN4924 given as a 1-hour
(5 minutes) IV infusion on Day 1 and Day 8 (see dose cohorts below). Patients will 
receive concomitant oral itraconazole at a dose of 200 mg QD on Days 4 through 10. 
Pharmacokinetic samples will be taken after the MLN4924 dose on Day 1 and after the 
Day 8 dose of MLN4924 with itraconazole at predetermined time points (up to 72 hours 
after dosing) to assess the effect of itraconazole on the PK of MLN4924. Additional samples 
for determination of MLN4924 concentrations in whole blood will be collected on Day 1 
only. The following dose cohorts will be enrolled sequentially within the Itraconazole Arm:

Itraconazole Arm, 8-mg/m2 MLN4924 Cohort: Patients will receive a single 
8-mg/m2 dose of MLN4924 given as a 1-hour (5 minutes) IV infusion on Day 1 


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and Day 8. This low dose of MLN4924 is anticipated to provide an adequate safety 
margin for DDI assessment. 

Itraconazole Arm, Safety Lead-in 15-mg/m2 MLN4924 Cohort: Patients will receive 
a single 15-mg/m2 dose of MLN4924 given as a 1-hour (5 minutes) IV infusion on 
Day 1 and Day 8. This safety lead-in cohort will confirm the safety margin is 
adequate before any patients are enrolled in the 20-mg/m2 MLN4924 Cohort. 

Itraconazole Arm, 20-mg/m2 MLN4924 Cohort: Patients will receive a single 
20-mg/m2 dose of MLN4924 given as a 1-hour (5 minutes) IV infusion on Day 1 
and Day 8. This dose of MLN4924 falls within the clinically relevant dose range 
currently evaluated in Phase 1b combination studies of MLN4924 plus standard of 
care.
A preliminary PK analysis will be conducted after the first 4 to 8 patients have completed 
the Fluconazole Arm of Part A. After review of the emerging data from the Fluconazole
Arm, patient assignment to the Itraconazole Arm will be initiated. Dose modifications of 
MLN4924 in the Itraconazole Arm may be reconsidered based on the magnitude of the 
interaction with the moderate CYP3A inhibitor fluconazole and the ability to accurately 
estimate PK parameters for DDI evaluation.
Following completion of the first 3 patients in the Itraconazole Arm, 8-mg/m2 MLN4924 
Cohort, preliminary PK data will be reviewed to guide expansion of the Itraconazole Arm to 
the total intended number of 12 PK-evaluable patients. If these emerging preliminary PK 
data indicate that the magnitude of the interaction with the strong CYP3A inhibitor 
itraconazole reaches the anticipated approximately 10-fold change, and individual drug 
exposures do not exceed those seen at doses of MLN4924 110 mg/m2, then up to 
3 additional patients to provide 4 to 6 PK-evaluable patients will be enrolled. If the 
magnitude of the interaction with the strong CYP3A inhibitor itraconazole is much greater 
than anticipated (greater than the predefined safety margin of 14-fold), with individual 
MLN4924 exposures exceeding those seen at doses of MLN4924 110 mg/m2, then no 
additional patients will be enrolled in the Itraconazole Arm of Part A.
As of the implementation of Amendment 1, following completion of Part A by 
3 PK-evaluable patients in the Safety Lead-in 15-mg/m2 MLN4924 Cohort, safety and PK 
data will be reviewed to inform expansion of the Itraconazole Arm to the total intended 
number of 12 PK-evaluable patients in the 20-mg/m2 MLN4924 Cohort. If the preliminary 


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PK data from the safety lead-in cohort indicate that the magnitude of the interaction between 
the proposed 20-mg/m2 MLN4924 dose and the strong CYP3A inhibitor itraconazole would 
be greater than the predefined safety margin (5-fold, with individual MLN4924 exposures 
potentially exceeding those seen at doses of MLN4924 110 mg/m2), then no patients will 
be enrolled in the 20-mg/m2 MLN4924 Cohort. Dosing with intermediate doses of 
MLN4924 and/or evaluation of the drug interaction with the moderate CYP3A inhibitor,
fluconazole, may then be reconsidered if it is deemed necessary to further enhance our 
understanding of the effect of CYP3A inhibition on the PK of MLN4924.
Patients will be required to visit the clinic on Day 4 for their first dose of fluconazole or 
itraconazole. For both the Fluconazole and Itraconazole Arms, all doses of fluconazole and 
itraconazole will be administered on an empty stomach with the patient fasting from food 
and fluids, except water and prescribed medications, for 2 hours before and 1 hour after each 
dose. Patients are encouraged to take fluconazole or itraconazole doses at approximately the 
same time each morning and approximately 24 hours apart. On Day 8, patients will take 
fluconazole or itraconazole together with MLN4924 in the morning at the clinic.
In addition to blood sampling for PK, blood samples in the 24-hour postdose window of 
each arm following dosing on Day 1 and Day 8 will be collected to measure 
pharmacodynamic effects of MLN4924. These data will be pooled with data from other 
MLN4924 clinical studies to contribute to an integrated PK-pharmacodynamic analysis 
across the program.
Part B: Continued Treatment With MLN4924 in Combination With Standard of Care
After patients complete Part A, they will have the opportunity to continue in the study by 
participating in Part B. In Part B, patients will receive MLN4924 in combination with either 
docetaxel or carboplatin+paclitaxel at a dose regimen informed from Study C15010 that has 
been deemed tolerable (eg, no DLTs in 3 patients or no more than 1 DLT in 6 patients). The 
selected dose of MLN4924 may be adjusted based on information obtained from the 
ongoing review of safety data. Safety and disease assessments will be conducted in Part B of 
the study.
Study drug will be discontinued if a patient experiences study drug-related toxicities. 
Patients may discontinue therapy at any time. After completion of at least 12 cycles of 
treatment, patients will be permitted to take treatment breaks, at the investigator’s discretion, 
that are no longer than 2 weeks in duration (up to 4 weeks after consulting with the sponsor); 
treatment breaks may not be taken consecutively. The investigator will confirm patient 


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eligibility for continued treatment (Section 6.4.2) upon return from a treatment break, before
treatment. Patients will attend the End-of-Study (EOS) visit 30 days after receiving their last 
dose of study drug.
Throughout the study, Eastern Cooperative Oncology Group (ECOG) performance status 
(PS) and AEs will be assessed, and laboratory values, vital signs, and electrocardiograms 
(ECGs) will be obtained and assessed.
Computed tomography (CT) scans with IV contrast of the chest, abdomen, and pelvis will 
be performed as entry criteria for Part B (after completing of Part A). In addition, in Part B, 
CT scans with IV contrast encompassing the known sites of disease will be performed at 
every other cycle (Cycles 1 through 12), or after completion of every sixth cycle after the 
patient’s previous scan (after completion of Cycle 12 and implementation of Amendment 2), 
and at the EOS visit. Additional CT scans may be performed, per investigator's discretion, if 
clinically indicated. If CT scan does not provide adequate imaging, magnetic resonance 
imaging (MRI) may be used to evaluate sites of disease. Tumor response will be assessed by 
the investigator at these times using the RECIST criteria, version 1.1.(14)
4.2
Number of Patients
Approximately 52 patients will be enrolled in this study from approximately 3 study centers 
in the US, to reach the intended total number of PK-evaluable patients in each arm/cohort. 
Patients are considered to be enrolled when they receive their first dose of any drug. Patients 
who are not PK evaluable (see Section 8.1.4) will be replaced.
4.3
Duration of Study
Patients participating in Part B will be treated (after at least a 2-week [and up to 8-week] 
washout period after receiving their last dose of fluconazole or itraconazole in Part A) until 
they experience symptomatic deterioration or progressive disease (PD) (see definition in 
Section 15.3), or until their treatment is discontinued for another reason (see Section 7.6), or 
until the study is stopped. After completion of at least 12 cycles of treatment, patients will 
be permitted to take treatment breaks, at the investigator’s discretion, that are no longer than 
2 weeks in duration (up to 4 weeks after consulting with the sponsor); treatment breaks may 
not be taken consecutively. The investigator will confirm patient eligibility for continued 
treatment (Section 6.4.2) upon return from a treatment break, before treatment. The analyses 
for the CSR will be conducted after all patients enrolled in the study have provided PK 
assessments in Part A to meet the primary (DDI) objectives of the protocol or have 


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discontinued treatment. Patients still on therapy at this point will continue in the study 
through their EOS visit. 
5.
STUDY POPULATION
Confirmation of eligibility must be obtained before the patient can enter the study. After 
completion of Part A, patients who are to continue into Part B must meet the entry criteria 
listed in Section 7.4.20.
5.1
Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1. Male or female patients 18 years of age or older.
2. Patients must have a histologically or cytologically confirmed metastatic or locally 
advanced and incurable solid tumor that is deemed appropriate for treatment with 
1 of the 2 chemotherapy regimens in Part B of this study, or have progressed despite 
standard therapy, or for whom conventional therapy is not considered effective. The 
tumor must be radiographically or clinically evaluable or measurable.
3. Recovered (ie, Grade 1 toxicity) from the effects of prior antineoplastic therapy.
4. Suitable venous access for the study-required blood sampling for MLN4924 PK and 
pharmacodynamic assessments.
5. Eastern Cooperative Oncology Group PS of 0 or 1 (refer to Section 15.4). 
6. Clinical laboratory values as specified below within 3 days before the first dose of 
study drug:

Hemoglobin 9 g/dL

Absolute neutrophil count ≥ 1,500/mm3 (refer to Section 15.5), not supported by 
growth factor

Platelet count ≥ 100,000/mm3

Total bilirubin ≤ ULN

Prothrombin time (PT) and aPTT ≤ 1.5 ULN


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
Alanine aminotransferase, AST, and ALP  ≤ 2.5 ULN
o
For patients to be treated with MLN4924+docetaxel in Part B, AST and ALT 
must be ≤ 1.5 ULN, and total bilirubin should be within the normal range.

Serum creatinine ≤ 1.2 mg/dL or calculated/measured creatinine clearance 
≥50 mL/minute (see Section 15.6)
7. Female patients who:

Are postmenopausal for at least 1 year before the screening visit, OR

Are surgically sterile, OR

As of Amendment 2, if they are of childbearing potential, agree to practice 
1 highly effective method and 1 additional effective (barrier) method of 
contraception (see Section 15.10), at the same time, from the time of signing the 
informed consent form (ICF) through 4 months after the last dose of study drug, 
OR

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, and postovulation methods], withdrawal, spermicides only [as of 
Amendment 2], and lactational amenorrhea [as of Amendment 2] are not 
acceptable methods of contraception. Female and male condoms should not be 
used together.) 
Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study treatment 
period and through 4 months after the last dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, and postovulation methods for the female partner], withdrawal, 
spermicides only [as of Amendment 2], and lactational amenorrhea [as of 
Amendment 2] are not acceptable methods of contraception. Female and male 
condoms should not be used together.)


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8. Voluntary written consent must be given before performance of any study-related 
procedure not part of standard medical care, with the understanding that consent may 
be withdrawn by the patient at any time without prejudice to future medical care.
9. Patients who are willing to refrain from donating blood for at least 90 days after their 
final dose of MLN4924 and (for male patients) willing to refrain from donating 
semen for at least 4 months after their final dose of MLN4924.
5.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Prior treatment with MLN4924; however, prior treatment with docetaxel, paclitaxel, 
and carboplatin is allowed.
2. Treatment with any systemic antineoplastic therapy or investigational products 
within 21 days before the first dose of study treatment.
3. Radiotherapy within 14 days before the first dose of study treatment.
4. Prior treatment with radiation therapy involving ≥ 25% of the hematopoietically 
active bone marrow.
5. Known hypersensitivity or history of severe intolerance or toxicity to study-assigned 
chemotherapy.
Note: History of severe hypersensitivity reactions to docetaxel (polysorbate 80-based 
formulations) for patients to be treated with MLN4924+docetaxel; history of 
hypersensitivity to carboplatin for patients to be treated with 
MLN4924+carboplatin+paclitaxel; or history of severe hypersensitivity to paclitaxel 
(Cremophor-based formulations) for patients to be treated with 
MLN4924+carboplatin+paclitaxel in Part B  
6. Known hypersensitivity/allergy to fluconazole or itraconazole or their respective 
excipients.
7. Systemic treatment with moderate and strong CYP3A inhibitors or inducers must be 
discontinued at least 14 days before the first dose of MLN4924. Moderate and strong 
CYP3A inhibitors and clinically significant CYP3A inducers were not permitted 
during Part A of the study or during Part B of the study until implementation of 


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Amendment 2; following implementation of Amendment 2 and completion of at 
least 12 cycles of treatment, concomitant use of moderate and strong CYP3A 
inhibitors is permitted in Part B (see Table 6-2 and Section 15.7). Patients must have 
no history of amiodarone use in the 6 months before the first dose of MLN4924.
8. Any life-threatening or serious medical or psychiatric illness unrelated to cancer that 
could, in the investigator’s opinion, potentially interfere with the completion of 
treatment according to this protocol.
9. Major surgery within 14 days before the first dose of study treatment.
10. Active uncontrolled infection or severe infectious disease, such as pneumonia, 
meningitis, septicemia, or methicillin-resistant Staphylococcus aureus infection.
11. Clinically significant central nervous system disease defined as untreated, 
progressive, or requiring steroids for control of symptoms.
12. Known GI disease or GI procedure that could interfere with the oral absorption or 
tolerance of fluconazole or itraconazole including difficulty swallowing capsules. 
13. Persistent diarrhea (Grade 2) lasting > 3 days within 2 weeks before the first dose 
of study treatment.
14. Known hepatic cirrhosis, hepatitis B surface antigen-positive status, or suspected 
active hepatitis C infection.
Note: Patients who have isolated positive hepatitis B core antibody (ie, in the setting 
of negative hepatitis B surface antigen and negative hepatitis B surface antibody) 
must have an undetectable hepatitis B viral load.
15. Known human immunodeficiency virus (HIV) positive status.
16. Female patients who are lactating and breastfeeding or have a positive serum 
pregnancy test during the Screening period or a positive urine pregnancy test on 
Day 1 before first dose of study drug.
17. Uncontrolled high blood pressure (ie, systolic blood pressure > 180 mm Hg, diastolic 
blood pressure > 95 mm Hg).


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18. Left ventricular ejection fraction < 50% as assessed by echocardiogram or 
radionuclide angiography.
19. Congestive heart failure New York Heart Association Class III or IV, or Class II 
with a recent decompensation requiring hospitalization within 4 weeks before 
screening (Section 15.7).
20. Cardiomyopathy or history of ischemic heart disease.

Patients with ischemic heart disease who have had acute coronary syndrome 
(ACS), myocardial infarction (MI), or revascularization (eg, coronary artery 
bypass graft, stent) in the past 6 months are excluded. However, patients with 
ischemic heart disease who have had ACS, MI, or revascularization greater than 
6 months before screening and who are without cardiac symptoms may enroll.
21. Arrhythmia (eg, history of polymorphic ventricular fibrillation or torsade de pointes). 
However, patients with < Grade 3 atrial fibrillation for a period of at least 6 months 
may enroll. Grade 3 atrial fibrillation is defined as symptomatic and incompletely 
controlled medically, or controlled with device (eg, pacemaker) or ablation, and is
excluded. Patients with paroxysmal atrial fibrillation are permitted to enroll.
22. Prolonged rate corrected QT interval (QTc) 500 msec, calculated according to 
institutional guidelines.
23. Implantable cardioverter defibrillator.
24. Patients with a cardiac pacer whose heart rate is set at a fixed rate and patients on 
concomitant medication that may limit increase in heart rate in response to 
hypotension (eg, high-dose beta blocker).
25. Moderate to severe aortic or mitral stenosis or other valvulopathy (ongoing).
26. Known moderate to severe COPD (Section 15.9), interstitial lung disease, pulmonary 
fibrosis, and pulmonary arterial hypotension.


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6.
STUDY DRUG
6.1
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented 
before drug administration. Study drug will be administered only to eligible patients under 
the supervision of the investigator or identified subinvestigator(s).
6.1.1
MLN4924 and Fluconazole or Itraconazole Administration (Part A)
Patients will receive a single dose of MLN4924 given as an IV infusion on Day 1 and Day 8. 
Patients will receive either concomitant oral fluconazole or itraconazole on Days 4 through 
10. 
MLN4924+Fluconazole
Patients will receive a single 8-mg/m2 dose of MLN4924 given as a 1-hour 
(5 minutes) IV infusion on Day 1 and Day 8. Patients will receive concomitant oral 
fluconazole at a starting dose of 400 mg on Day 4 and then 200 mg QD on Days 5 
through 10.
MLN4924, 8 mg/m2+Itraconazole
Patients will receive a single 8-mg/m2 dose of MLN4924 given as a 1-hour 
(5 minutes) IV infusion on Day 1 and Day 8. Patients will receive concomitant oral 
itraconazole at a dose of 200 mg QD on Days 4 through 10.
MLN4924, 15 mg/m2+Itraconazole (Safety Lead-in Cohort added per 
Amendment 1)
Patients will receive a single 15-mg/m2 dose of MLN4924 given as a 1-hour 
(5 minutes) IV infusion on Day 1 and Day 8. Patients will receive concomitant oral 
itraconazole at a dose of 200 mg QD on Days 4 through 10.
MLN4924, 20 mg/m2+Itraconazole (added per Amendment 1)
Patients will receive a single 20-mg/m2 dose of MLN4924 given as a 1-hour 
(5 minutes) IV infusion on Day 1 and Day 8. Patients will receive concomitant oral 
itraconazole at a dose of 200 mg QD on Days 4 through 10. 


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Patients will receive MLN4924 diluted with 5% dextrose in a 250-mL bag via a 
1-hour (5 minutes) IV infusion. MLN4924 should be administered through central or 
peripheral venous access. 
The entire content of the MLN4924 IV bag will be infused at a constant rate over 1 hour
(5 minutes). The start and end time of the IV infusion should be recorded accurately. To 
ensure that all the MLN4924 is administered, the infusion line will be flushed with saline or 
5% dextrose immediately after administration or per similar institutional standards. The 
volume used for line flushing is not considered part of the volume of the MLN4924 IV bag 
to be documented. All infusion times must be recorded. The total time from drug 
reconstitution to end of infusion must not exceed 6 hours. 
In Part B (see Section 6.1.2), the infusion may be slowed or stopped and restarted for any 
associated infusion-related reactions; however, this should be avoided in Part A. If during 
Part A there is a need to interrupt or slow the IV infusion, contact the project clinician 
or designee as soon as possible for consideration of patient replacement as appropriate. 
If the IV infusion is interrupted, 2 additional PK samples (1 sample drawn when the infusion 
is stopped and 1 sample drawn when the infusion is restarted) should be collected so that the 
patient may be considered evaluable. The exact date and time of each additional sample 
collection and the actual start and stop times of the infusion should be recorded accurately. 
During Part A, all doses must be taken as outlined in the Schedules of Events. No doses 
should be missed or delayed due to patient scheduling. For both the Fluconazole and 
Itraconazole Arms, all doses of fluconazole and itraconazole will be administered on an 
empty stomach with the patient fasting from food and fluids, except water and 
prescribed medications, for 2 hours before and 1 hour after each dose. Patients will be 
required to visit the clinic on the morning of Day 4 for their first oral dose of fluconazole or
itraconazole. On Days 5 through 7, patients will take their second, third, and fourth oral dose 
of fluconazole or itraconazole at home. While at home, patients are encouraged to take 
fluconazole or itraconazole oral doses at approximately the same time each morning and 
approximately 24 hours apart. On Day 8, patients will be instructed to come to the clinic in 
the morning without taking their morning dose of fluconazole or itraconazole; patients will 
be administered oral fluconazole or itraconazole first, followed by the 1-hour (5 minutes) 
IV infusion of MLN4924 approximately 20 minutes (± 10 minutes) after ingestion of the 
fluconazole tablet or itraconazole oral solution. On the morning of Days 9 and 10, patients 
will be asked to return to the clinic without taking their morning dose of fluconazole or 
itraconazole for PK, pharmacodynamic, and safety follow-up assessments.


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If a patient fails to take the fluconazole or itraconazole dose within the time frame specified 
(ie, within ± 2 hours of first dosing time), that dose should be omitted and considered a 
missed dose. Patients should record any missed doses in their dosing diaries (see the 
Study Manual). If emesis occurs after study medication (fluconazole) ingestion, and if whole 
tablet(s) are visible in the vomitus, replacement tablet(s) should be taken; otherwise, the 
dose will not be re-administered, and the patient should simply adhere to the dosing 
schedule and resume dosing at the next scheduled time with the prescribed dosage. In the 
event of emesis occurring after dosing with the itraconazole solution, the patient should 
simply adhere to the dosing schedule and resume dosing at the next scheduled time with the 
prescribed dosage. Patients should record the time of the emesis in their dosing diaries (see 
the Study Manual). Under no circumstance should a patient repeat a dose or double-up 
doses. In the case of missed dose or emesis for either fluconazole or itraconazole during Part 
A, patients may be considered unevaluable and may be replaced to ensure an adequate 
number of PK-evaluable patients. A patient who is considered unevaluable during Part A 
will have the opportunity to participate in Part B of the study.
6.1.2
Continued Treatment With MLN4924 in Combination With Standard of 
Care (Part B)
MLN4924 Administration
Patients will receive MLN4924 given as a 1-hour (10 minutes as of Amendment 2) IV 
infusion in combination with either docetaxel or with carboplatin+paclitaxel at a dose 
regimen informed from Study C15010 that has been deemed tolerable (eg, no DLTs in 
3 patients or no more than 1 DLT in 6 patients). The selected dose may be adjusted based on 
information obtained from the ongoing review of safety data. In Part B, the infusion may be 
slowed or stopped and restarted for any associated infusion-related reactions; however, this 
should be avoided in Part A. 
In Part B only, Day 1 dosing may be delayed by up to 2 days (Cycles 1 through 12) or up to 
2 weeks (after completion of Cycle 12; up to 4 weeks after consulting with the sponsor) to 
accommodate inclement weather, holidays, vacations, or other administrative reasons. See 
Section 7.4 for information about corresponding study procedures if dosing is delayed for 
reasons noted above. After completion of at least 12 cycles of treatment, patients will be 
permitted to take treatment breaks, at the investigator’s discretion, that are no longer than 
2 weeks in duration (up to 4 weeks after consulting with the sponsor); treatment breaks may 
not be taken consecutively. The investigator will confirm patient eligibility for continued 


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treatment (Section 6.4.2) upon return from a treatment break, before treatment. Refer to the 
Study Manual for additional instructions regarding study drug administration.
Docetaxel Administration
Docetaxel will be administered per institutional guidelines as a 1-hour IV infusion at a dose 
of 75 mg/m2 on Day 1 combined with the recommended IV dose of MLN4924 on Days 1, 3, 
and 5. Refer to the most recent prescribing information for further details regarding 
docetaxel administration.(11)
Premedication for Docetaxel-Associated Hypersensitivity or Other Acute Reactions 
Guidelines
Premedication to prevent docetaxel-associated (hypersensitivity or other) reactions is 
recommended according to institutional guidelines or local practices. For example, patients 
may be treated with dexamethasone (Decadron, 4 mg twice daily for 3 days), which should 
start 24 hours before docetaxel administration.
Carboplatin Administration
Carboplatin will be administered per institutional guidelines as a 30-minute IV infusion at a 
dose of AUC5 on Day 1 combined with the recommended IV dose of MLN4924 on Days 1, 
3, and 5. Refer to the most recent prescribing information for further details regarding 
carboplatin administration.(12)
If a patient’s glomerular filtration rate (GFR) is estimated based on serum 
creatinine measurements by the standardized Isotope Dilution Mass Spectrometry 
method, FDA recommends that physicians consider capping the dose of carboplatin 
for desired exposure (AUC) to avoid potential toxicity due to overdosing. Based on 
the Calvert formula described in the carboplatin label, the maximum doses can be 
calculated as:
Total Carboplatin Dose (mg)=(target AUC) (GFR+25) [Calvert formula]
Maximum Carboplatin Dose (mg)=target AUC (mg min/mL) (150 mL/min)
The maximum dose is based on a GFR estimate that is capped at 125 mL/min for 
patients with normal renal function. No higher estimated GFR values should be 
used.


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For a target AUC=5, the maximum dose is 5 150=750 mg
For a target AUC=4, the maximum dose is 4 150=600 mg
Source: fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/ 
CDER/ucm228974.htm, Carboplatin dosing, Accessed 19 February 2013.
Paclitaxel Administration
Paclitaxel will be administered per institutional guidelines as a 3-hour IV infusion at a dose 
of 175 mg/m2 on Day 1 combined with the recommended IV dose of MLN4924 on Days 1, 
3, and 5. Refer to the most recent prescribing information for further details regarding 
paclitaxel administration.(13)  
Premedication for Paclitaxel-Associated Hypersensitivity or Other Acute Reactions
Premedication to prevent paclitaxel-associated (hypersensitivity or other) reactions is 
recommended according to institutional guidelines or local practices. For example, patients 
may be treated with either dexamethasone (10 mg) 24 hours before and on the day of 
paclitaxel dosing or methylprednisone (solu-Medrol) immediately before paclitaxel dosing. 
6.2
Reference/Control Therapy
No reference or placebo treatment will be used in this study. All eligible patients will 
receive treatment with MLN4924 in the absence or presence of fluconazole or itraconazole 
in Part A. Participation in Part B of the study is optional. 
6.3
Definitions of Dose-Limiting Toxicity Equivalents (Part B)
Toxicity will be evaluated according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), Version 4.03, effective 14 June 2010.(15)  These 
criteria are provided in the Study Manual. Although this is not a dose escalation study, DLT 
equivalents will be collected. Dose-limiting toxicity equivalents will be defined as any of the 
following events that are considered by the investigator to be at least possibly related to 
therapy with MLN4924, docetaxel, or carboplatin+paclitaxel. When a dose modification is 
warranted for safety, and the toxicity is thought to be attributable to the chemotherapeutic 
agent(s), consider dose reductions for chemotherapy first, if appropriate. Dose modification 
of MLN4924 may also be considered for events judged by the investigator to be directly 
related to MLN4924 (see Section 6.4.2) or chemotherapy-related toxicities that may have 
been exacerbated by MLN4924 in a combination setting.


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Hematologic Dose-Limiting Toxicity Equivalents

Any Grade 4 hematologic toxicity using NCI CTCAE, Version 4.03, with the 
exception of Grade 4 neutropenia lasting < 7 days in duration

Grade 3 or greater neutropenia with fever > 38.5C sustained for longer than 1 hour

For patients in Part B, a delay in the initiation of Cycle 2 by 4 weeks due to a lack 
of adequate recovery from treatment-related toxicity (recovery to Grade 1 or to the 
patient’s baseline values or to a level considered acceptable by the investigator after 
discussion with the project clinician or designee) due to hematologic toxicity 
believed not related to tumor infiltration (bone marrow evaluation may be required)
Nonhematologic Dose-Limiting Toxicity Equivalents

Grade 3 or greater diarrhea that is uncontrolled despite maximal supportive therapy.

Grade 3 or greater nausea or emesis that is uncontrolled despite the use of optimal 
antiemetic prophylaxis. Optimal antiemetic prophylaxis is defined as an antiemetic 
regimen that employs both a 5-hydroxytryptamine 3 serotonin receptor antagonist 
and a corticosteroid given in standard doses and according to standard schedules.

Grade 3 or greater arthralgia/myalgia lasting longer than 48 hours that is 
uncontrolled despite the use of optimal analgesia.

Grade 3 or greater electrolyte disturbance that is uncontrolled despite appropriate 
medical management.

Any other Grade 3 or greater nonhematologic toxicity with the following exceptions: 
o
Brief (< 1 week) fatigue
o
Hypophosphatemia that can be controlled with appropriate medical management

For patients in Part B, a delay in the initiation of Cycle 2 of more than 2 weeks due 
to a lack of adequate recovery from nonhematologic toxicity (recovery to Grade ≤ 1 
or to patient’s baseline values or to a level considered acceptable by the investigator 
after discussion with the project clinician or designee). 


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
Other study drug-related, nonhematologic toxicities Grade 2 or greater that, in the 
opinion of the investigator, require a dose modification or discontinuation of therapy 
with MLN4924 (see Section 6.4.2).
Other Dose-Limiting Toxicity Equivalents
In addition, the following will be considered DLT equivalents if they occur within the first 
cycle:

Any AE at least possibly related to the study drugs, regardless of NCI CTCAE grade, 
leading to dose modification of MLN4924 or other study treatments (docetaxel, 
carboplatin, or paclitaxel) in the next cycle.

Patients will be monitored through all cycles of therapy for treatment-related 
toxicities.
6.4
Dose Modification Guidelines (Dose Delays, Dose Reductions, and Dose 
Interruptions) (Part B) 
6.4.1
Dose Modification Guidelines for Specific Toxicities
The following apply to DLT equivalents occurring during any cycle of Part B of the study. 
For individual patients experiencing a DLT equivalent, treatment for each new cycle will be 
delayed until toxicity is reduced to ≤ Grade 1 or patient’s baseline or to a level considered 
acceptable by the investigator after discussion with the project clinician or designee. 

Alopecia of any duration will not lead to dose modification or treatment delay. 

Patients receiving MLN4924+docetaxel may have a maximum of 2 dose 
modifications (if applicable) of chemotherapy agents as outlined below or 
modification of MLN4924 (see Section 6.4.2). Patients who require more than 2 dose 
modifications will be discontinued from the study.

Patients receiving MLN4924+carboplatin+paclitaxel may have no more than 1 dose 
modification (if applicable) of chemotherapy agents as outlined below or 
modification of MLN4924 (see Section 6.4.2). Patients who require additional dose 
modifications will be discontinued from the study.
o
Paclitaxel is initially dosed at 175 mg/m2. One dose reduction to 135 mg/m2 may 
be considered.


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o
Docetaxel is initially dosed at 75 mg/m2. Up to 2 dose modifications to 60 and 45 
mg/m2 may be considered.
o
Carboplatin is initially dosed at AUC5. One dose reduction to AUC4 may be 
considered.

In the event of a DLT equivalent, hold treatment and provide supportive care until 
the patient recovers to Grade 1 toxicity or baseline level before considering a dose 
modification as specified above. Patients with unresolved toxicities Grade 1 lasting 
3 weeks or longer from the date of the next scheduled treatment will be discontinued 
from the study.

The decision to treat at a reduced dose level of SoC therapy is at the discretion of the 
investigator. Discussions with the project clinician or designee are encouraged.
Table 6-1 outlines the dose modification guidelines for specific toxicities.
Table 6-1
Dose Modification Guidelines for Specific Toxicities 
NCI CTCAE Category
Severity
Action on Study Drug
Hematologic
ANC
Febrile neutropenia
Hold dosing on Day 1 of Cycles ≥ 2 up to 3 weeks until 
febrile neutropenia is resolved, then resume dosing as 
appropriate. Consider use of growth factor or reduce 
chemotherapy by 1 dose level as appropriate.
ANC < 1500 cells/L 
on Day 1 of Cycles ≥ 2
Initiation (Day 1) of Cycles ≥ 2 should be delayed for up 
to 3 weeks until the ANC is ≥1500 cells/L. Consider use 
of growth factor or reduce chemotherapy by 1 dose level 
as appropriate.
Grade ≥ 3 neutropenia 
lasting more than 
7 days
Initiation (Day 1) of Cycles ≥ 2 should be delayed until 
the ANC is ≥1500 cells/L. Consider use of growth 
factor or reduce chemotherapy by 1 dose level as 
appropriate.
Hematologic
Platelets
Platelet count 
< 100,000/L on any 
dosing day of Cycles 
≥2
Dosing in Cycles ≥ 2 should be delayed for up to 3 weeks 
until the platelet count is ≥100,000 cells/L. Dose of 
chemotherapy may be reduced by 1 dose level as 
appropriate.
Grade 4 
thrombocytopenia 
lasting more than 
7 days or  platelet 
count  
< 25,000 cells/L at 
any time
Dosing in Cycles ≥ 2 should be delayed until the platelet 
count is ≥100,000 cells/L. Dose of chemotherapy may 
be reduced by 1 dose level as appropriate.


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Table 6-1
Dose Modification Guidelines for Specific Toxicities 
NCI CTCAE Category
Severity
Action on Study Drug
Hematologic
Anemia
≥ Grade 1 
No dose modification is allowed for anemia. Transfusion 
and/or erythropoietin may be given as clinically indicated 
for the treatment of anemia (see Section 6.9.2).
Nausea, emesis, or 
diarrhea despite maximal 
prophylaxis
Grade 3
On days that both chemotherapy and MLN4924 are 
administered, hold all dosing for up to 3 weeks or until the 
toxicity returns to Grade 1, and restart at the next lower 
dose of chemotherapy. On days when MLN4924 is given 
as a single agent, hold dosing of MLN4924 for up to 
3 weeks or until the toxicity returns to Grade 1 before 
dosing is resumed. If treatment is delayed by more than 
3 weeks, all treatments must be discontinued, and the 
patient comes off of the study. NOTE: Please ensure that 
optimal prophylaxis has been employed before dose 
reduction. Supportive care with moderate or strong 
CYP3A inhibitor/inducer should be avoided.
Stomatitis
Grade 3
Hold treatment for up to 3 weeks until the stomatitis is 
Grade 1. If the stomatitis is not Grade 1 in 3 weeks, 
discontinue treatment. If acute Grade 3 stomatitis occurs 
at any time, the dose of chemotherapy should be reduced 
1 level. This is a permanent dose reduction.
Hepatic toxicity
ALT/AST Grade 3 at 
any time 
If ALT or AST is Grade 3 at any time, withhold 
MLN4924 dosing until patient has recovered to Grade 1
(see Section 6.4.2 for further details on dose modification 
of MLN4924).
In addition, if toxicity is felt to be attributable to the 
chemotherapy agent(s), consider dose reduction for 
chemotherapy also by 1 dose level.
Hepatic toxicity
Total bilirubin 
> 1.5 ULN, 
regardless of AST/AST
Hold all dosing for up to 3 weeks until bilirubin returns to 
within normal range and/or dose reduce chemotherapy by 
1 level and/or modify MLN4924 dose (see Section 6.4.2).
Cardiac toxicity
Symptomatic 
arrhythmia during 
infusion
Stop infusion and manage arrhythmia according to 
institutional guidelines. Report as AE and discontinue 
further dosing.
Cardiac toxicity
Chest pain and/or 
symptomatic
hypotension 
(< 90/60 mmHg)
Stop infusion. Perform an ECG. Give IV
diphenhydramine and dexamethasone if hypersensitivity 
is thought to be the etiology. Also, consider epinephrine 
or bronchodilators if chest pain is not thought to be 
cardiac. If Grade 3, the patient comes off the study.
Neurotoxicity
(paclitaxel or 
docetaxel only)
Grade 2
Hold treatment until patient recovers to Grade 1 toxicity 
then resume treatment at the next lower dose level. This 
will be a permanent dose reduction. Carboplatin or
MLN4924 are not to be dose modified.


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Table 6-1
Dose Modification Guidelines for Specific Toxicities 
NCI CTCAE Category
Severity
Action on Study Drug
Allergic reaction
(paclitaxel or docetaxel 
only
Moderate symptoms
Stop infusion. Give IV diphenhydramine 25-50 mg and IV
dexamethasone 10 mg and/or treatment per institutional 
guidelines. Resume infusion after recovery of symptoms 
at a low infusion rate. If no further symptoms, resume full 
dose rate until infusion is complete. If symptoms recur, 
stop infusion and discontinue patient.
Allergic reaction
(paclitaxel or docetaxel 
only)
Severe symptoms
Stop infusion. Give IV diphenhydramine and 
dexamethasone and/or treatment per institutional 
guidelines as above. Add epinephrine or bronchodilators 
if indicated. Report as an AE and discontinue patient.
Abbreviations: AE=adverse event; ALT=alanine aminotransferase; ANC=absolute neutrophil count; 
AST=aspartate aminotransferase; CYP=cytochrome P450; ECG=electrocardiogram; IV=intravenous; NCI 
CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; ULN=upper limit 
of the normal range. 
6.4.2
Dose Modification Guidelines for MLN4924

Patients will receive MLN4924 in combination with SoC at a dose regimen informed 
from Study C15010. If dosing with MLN4924 is held for toxicity during any given 
cycle, dosing may resume within that same cycle when toxicity is resolved 
(ALT/AST to ≤ Grade 1 or bilirubin within normal range). Alternatively, dosing may 
be held until the next cycle (in combination with SoC). Start of the next cycle may 
also be delayed for up to 2 weeks to allow patients to recover from any safety 
concerns, so that MLN4924 may be administered in combination with SoC. For 
patients who take treatment breaks at the investigator’s discretion, patient eligibility 
for continued treatment, including all Day 1 predose assessments specified in the 
Schedules of Events, will be confirmed by the investigator before resumption of 
treatment. Treatment breaks must be no longer than 2 weeks in duration (4 weeks 
after consulting with the sponsor); treatment breaks may not be taken consecutively.

In general, no dose reduction of MLN4924 is permitted. However, if toxicity is not 
resolved by the dose delays described in the bullet point above, and the patient is 
judged by the investigator to derive clinical benefit (SD or better) from continued 
treatment, the dose of MLN4924 may be reduced after discussion with and 
permission from the project clinician or designee.


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6.5
Excluded Concomitant Medications and Procedures
6.5.1
Excluded Concomitant Medications and Procedures (Part A)
Medications that are prohibited in Part A are listed in Table 6-2.
Table 6-2
Excluded Concomitant Medications and Procedures During Part A
Drug Class/Therapy
Drug Name
Antiarrhythmics
Digoxin, dofetilide, quinidine, disopyramide
Anticoagulants
Warfarin
Antihistamines
Astemizole, terfenadine
Antipsychotics
Pimozide
Benzodiazepines
Alprazolam, diazepam, midazolam,  triazolam, clobazam
Calcium channel blockers
Dihydropyridines (including felodipine and nisoldipine),verapamil
Gastrointestinal motility agents
Cisapride
HMG CoA-reductase inhibitors
Atorvastatin, cerivastatin, lovastatin, simvastatin
Immunosuppressants
Cyclosporine, tacrolimus, sirolimus
Oral hypoglycemics
Tolbutamide, glyburide, glipizide, repaglinide
Proton pump inhibitors
Lansoprazole (Prevacid®), omeprazole (Prilosec®)
Others
Methadone, levacetylmethadol (levomethadyl), ergotalkaloids, 
halofantrine, alfentanil, buspirone,
methylprednisolone, budesonide, dexamethasone, fluticasone, 
trimetrexate,  cilostazol, eletriptan, fentanyl,
losartan, celecoxib, S-mephenytoin
Acetaminophen and acetaminophen-
containing products
Any investigational agent other than 
MLN4924
Known BCRP substrates 
ie, methotrexate and sulfasalazine
Known BCRP inhibitors
ie, cyclosporine and eltrombopag (Promacta)
Moderate and strong CYP3A4 
inhibitors and clinically significant 
CYP3A4 inducers 
See Section 15.7
Known P-gp inhibitors 
ie, azithromycin (Zithromax), captopril, carvedilol, felodipine, 
quercetin, quinidine, ranolazine, ticagrelor
Abbreviations: BCRP=breast cancer-resistance protein; CYP=cytochrome P450; P-gp=P-glycoprotein.
This list is not all-inclusive; please consult the fluconazole or itraconazole prescribing information for 
additional information regarding precautions, warnings, and contraindications. 
6.5.2
Excluded Concomitant Medications and Procedures (Part B) 
Medications and procedures that are prohibited in Part B are listed in Table 6-3.


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Table 6-3
Excluded Concomitant Medications and Procedures During Part B
Therapy
Comment
Acetaminophen and acetaminophen-containing products May be used judiciously in Part B and should not 
exceed a dose of 2 g in 24 hours 
Amiodarone
Excluded within 6 months before the first dose of 
MLN4924 and during the study
Azole antifungal agents 
Generally excluded during the study but 
voriconazole and fluconazole may be used as 
specified in Table 6-5
Any investigational agent other than MLN4924
Excluded during the study
Known BCRP inhibitors (ie, cyclosporine and 
eltrombopag [Promacta])
Generally excluded during the study but may be 
used as specified in Table 6-5
Clinically significant CYP3A4 inducers
Excluded within 14 days before dosing with 
MLN4924 and during the study (Section 15.7)
Abbreviations: BCRP=breast cancer-resistance protein; CYP=cytochrome P450. 
6.6
Permitted Concomitant Medications and Procedures
6.6.1
Permitted Concomitant Medications and Procedures (Part A)
Medications and procedures that are specifically permitted during Part A are listed in 
Table 6-4.
Table 6-4
Permitted Concomitant Medications and Procedures During Part A
Therapy
Comment
Nephrotoxic medications, 
including nonsteroidal 
anti-inflammatory drugs
Whenever possible, caution should be used with nephrotoxic concomitant 
medications (Section 15.2). Alternative concomitant non-nephrotoxic 
medications should be used whenever possible.
Red blood cell transfusion
For all patients with anemia, and especially for patients with hemoglobin 
values < 9 g/dL during the conduct of the study, consideration should be 
given for red blood cell transfusions based on the patient’s risk of inadequate 
oxygenation, underlying cardiopulmonary status, clinical judgment, and 
hospital guidelines.
Red blood cell transfusions must be administered before administration of 
study drug. Each transfusion episode, including the type of transfusion (red 
blood cell), should be recorded.
6.6.2
Permitted Concomitant Medications and Procedures (Part B)
Medications and procedures that are specifically permitted during Part B are listed in 
Table 6-5.


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Table 6-5
Permitted Concomitant Medications and Procedures During Part B
Therapy
Comment
Azole antifungal agents
Permitted only if the patient’s clinical condition requires the use of an azole 
antifungal agent. The patient may receive voriconazole and fluconazole from 
24 hours after the last MLN4924 dose to 72 hours before the next MLN4924 
dose. For example, if a patient receives MLN4924 on a Monday (Day 1), 
Wednesday (Day 3), Friday (Day 5) schedule, then an azole may be 
administered (if clinically necessary and no suitable alternative) from the 
Saturday after the Day 5 dose (Day 6) up to the Friday (Day 19) before the 
Monday dose of the next cycle.
Known BCRP substrates (ie, 
methotrexate and 
sulfasalazine) and known 
BCRP inhibitors (ie, 
cyclosporine and 
eltrombopag [Promacta])
Permitted only if the patient’s clinical condition requires the use of a known 
BCRP substrate/inhibitor. The patient may receive it from 24 hours after the 
last MLN4924 dose to 72 hours before the next MLN4924 dose. For 
example, if a patient receives MLN4924 on a Monday (Day 1), Wednesday 
(Day 3), Friday (Day 5) schedule, then the BCRP substrate/inhibitor may be 
administered (if clinically necessary and no suitable alternative) from the 
Saturday after the Day 5 dose (Day 6) up to the Friday (Day 19) before the 
Monday dose of the next cycle.
Nephrotoxic medications, 
including nonsteroidal anti-
inflammatory drugs
Whenever possible, caution should be used with nephrotoxic concomitant 
medications (Section 15.2). Alternative concomitant non-nephrotoxic 
medications should be used whenever possible.
Known P-gp inhibitors (ie, 
azithromycin [Zithromax],
captopril, carvedilol, 
felodipine, quercetin, 
quinidine, ranolazine, 
ticagrelor)
Permitted only if the patient’s clinical condition requires the use of a known 
P-gp inhibitor. The patient may receive it from 24 hours after the last 
MLN4924 dose to 72 hours before the next MLN4924 dose. For example, if 
a patient receives MLN4924 on a Monday (Day 1), Wednesday (Day 3), 
Friday (Day 5) schedule, then the P-gp inhibitor may be administered (if 
clinically necessary and no suitable alternative) from the Saturday after the 
Day 5 dose (Day 6) up to the Friday (Day 19) before the Monday dose of the 
next cycle.
Red blood cell transfusion
For all patients with anemia, and especially for patients with hemoglobin 
values < 9 g/dL during the conduct of the study, consideration should be 
given for red blood cell transfusions based on the patient’s risk of inadequate 
oxygenation, underlying cardiopulmonary status, clinical judgment, and 
hospital guidelines.
Red blood cell transfusions must be administered before administration of 
study drug (ie, at least 1 day before dosing). Each transfusion episode, 
including the type of transfusion (red blood cell), should be recorded.
Abbreviation: BCRP=breast cancer-resistance protein; P-gp=P-glycoprotein.
6.7
Precautions and Restrictions 
Concomitant medications and procedures that are excluded or must be used with caution are 
described in Section 6.5 and Section 6.6, respectively.
Certain situations may warrant further caution, such as modifying the dose of study drug(s). 
Dose modification guidelines are provided in Section 6.4. 


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6.7.1
MLN4924
It is not known what effects MLN4924 has on human pregnancy or development of the 
embryo or fetus. Therefore, female patients participating in this study should avoid 
becoming pregnant, and male patients should avoid impregnating a female partner. 
Nonsterilized female patients of reproductive age group and male patients should use 
effective methods of contraception through defined periods during and after study treatment 
as specified below and in Section 15.10.
Female patients must meet 1 of the following: 

Postmenopausal for at least 1 year before the screening visit, OR

Surgically sterile, OR

As of Amendment 2, if they are of childbearing potential, agree to practice 1 highly 
effective method and 1 additional effective (barrier) method of contraception, at the 
same time, from the time of signing of the ICF through 4 months after the last dose 
of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods], withdrawal, spermicides only [as of Amendment 2], and 
lactational amenorrhea [as of Amendment 2] are not acceptable methods of 
contraception. Female and male condoms should not be used together.)
As of Amendment 2, female patients must agree to not donate eggs (ova) during the course 
of this study or 4 months after receiving their last dose of study drug(s). 
Male patients, even if surgically sterilized (ie, status postvasectomy), must agree to 1 of the 
following:

Practice effective barrier contraception during the entire study treatment period and 
through 4 months after the last dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods for the female partner], withdrawal, spermicides only [as of 


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Amendment 2], and lactational amenorrhea [as of Amendment 2] are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
As of Amendment 2, male patients must agree to not donate sperm during the course of this 
study or 4 months after receiving their last dose of study drug(s).
6.7.2
Fluconazole
Pregnancy
Fluconazole single 150-mg tablet when used for candidiasis is classified as Pregnancy 
Category C. For all other indications, fluconazole is classified as Pregnancy Category D. 
Use in Pregnancy: There are no adequate and well-controlled studies of DIFLUCAN
in pregnant women. Available human data do not suggest an increased risk of 
congenital anomalies following a single maternal dose of 150 mg. A few published 
case reports describe a rare pattern of distinct congenital anomalies in infants 
exposed in utero to high dose maternal fluconazole (400–800 mg/day) during most 
or all of the first trimester. The features seen in these infants include: brachycephaly, 
abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin 
ribs and long bones, arthrogryposis, and congenital heart disease. These effects are 
similar to those seen in animal studies. If this drug is used during pregnancy or if the 
patient becomes pregnant while taking the drug, the patient should be informed of 
the potential hazard to the fetus (See PRECAUTIONS, Pregnancy).(8)
Geriatric Use 
Of the most frequently reported (> 1%) side effects, rash, vomiting, and diarrhea 
occurred in greater proportions of older patients.
Controlled clinical trials of fluconazole did not include sufficient numbers of patients 
aged 65 and older to evaluate whether they respond differently from younger 
patients in each indication. Other reported clinical experience has not identified 
differences in responses between the elderly and younger patients.(8)
Please refer to the DIFLUCAN USPI for more information.


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6.7.3
Itraconazole 
Pregnancy
Itraconazole is a pregnancy Category C drug. Please refer to the itraconazole USPI(10) for 
more information.
Itraconazole was found to cause a dose-related increase in maternal toxicity, 
embryotoxicity, and teratogenicity in rats at dosage levels of approximately 
40-160 mg/kg/day (5–20x MRHD), and in mice at dosage levels of approximately 
80 mg/kg/day (10x MRHD). In rats, the teratogenicity consisted of major skeletal 
defects; in mice, it consisted of encephaloceles and/or macroglossia. 
There are no studies in pregnant women. SPORANOX should be used in pregnancy 
only if the benefit outweighs the potential risk. 
During post-marketing experience, cases of congenital abnormalities have been 
reported. (See ADVERSE REACTIONS: Post-marketing Experience.)(10)
Geriatric Use 
Transient or permanent hearing loss has been reported in elderly patients receiving 
treatment with itraconazole. Several of these reports included concurrent 
administration of quinidine which is contraindicated (see BOX WARNING: Drug 
Interactions, CONTRAINDICATIONS: Drug Interactions and PRECAUTIONS: 
Drug Interactions). Itraconazole should be used with care in elderly patients (see 
PRECAUTIONS).(10)
6.7.4
Docetaxel
Pregnancy
TAXOTERE is a pregnancy Category D drug. Please refer to the TAXOTERE USPI for 
more information.
TAXOTERE can cause fetal harm when administered to a pregnant woman. 
Docetaxel caused embryofetal toxicities including intrauterine mortality when 
administered to pregnant rats and rabbits during the period of organogenesis. 
Embryofetal effects in animals occurred at doses as low as 1/50 and 1/300 the 
recommended human dose on a body surface area basis.


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There are no adequate and well-controlled studies in pregnant women using 
TAXOTERE. If TAXOTERE is used during pregnancy, or if the patient becomes 
pregnant while receiving this drug, the patient should be apprised of the potential 
hazard to the fetus. Women of childbearing potential should be advised to avoid 
becoming pregnant during therapy with TAXOTERE.(11)  
Geriatric Use
In general, dose selection for an elderly patient should be cautious, reflecting the 
greater frequency of decreased hepatic, renal, or cardiac function and of 
concomitant disease or other drug therapy in elderly patients.
Please see the Docetaxel USPI(11) for additional information on geriatric use in different 
types of cancer.
6.7.5
Carboplatin
Pregnancy
Carboplatin is a pregnancy Category D drug. Please refer to the Carboplatin Injection USPI 
for more information.
Carboplatin Injection may cause fetal harm when administered to a pregnant 
woman. Carboplatin has been shown to be embryotoxic and teratogenic in rats. 
There are no adequate and well-controlled studies in pregnant women. If this drug is 
used during pregnancy, or if the patient becomes pregnant while receiving this drug, 
the patient should be apprised of the potential hazard to the fetus. Women of 
childbearing potential should be advised to avoid becoming pregnant.(12)  
Geriatric Use
Of the 789 patients in initial treatment combination therapy studies (NCIC and 
SWOG), 395 patients were treated with carboplatin in combination with 
cyclophosphamide. Of these, 141 were over 65 years of age and 22 were 75 years or 
older. In these trials, age was not a prognostic factor for survival. In terms of safety, 
elderly patients treated with carboplatin were more likely to develop severe 
thrombocytopenia than younger patients. In a combined database of 1,942 patients 
(414 were 65 years of age) that received single-agent carboplatin for different 
tumor types, a similar incidence of adverse events was seen in patients 65 years and 
older and in patients less than 65. Other reported clinical experience has not 


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identified differences in responses between elderly and younger patients, but greater 
sensitivity of some older individuals cannot be ruled out. Because renal function is 
often decreased in the elderly, renal function should be considered in the selection of 
carboplatin dosage (see DOSAGE AND ADMINISTRATION).
Please see the Carboplatin USPI(12) for additional information.
6.7.6
Paclitaxel
Pregnancy
Paclitaxel is a pregnancy Category D drug. Please refer to the Paclitaxel Injection USPI for 
more information.
Paclitaxel Injection, USP can cause fetal harm when administered to a pregnant 
woman. Administration of paclitaxel during the period of organogenesis to rabbits at 
doses of 3 mg/kg/day (about 0.2 the daily maximum recommended human dose on a 
mg/m2 basis) caused embryo- and fetotoxicity, as indicated by intrauterine mortality, 
increased resorptions and increased fetal deaths.
Maternal toxicity was also observed at this dose. No teratogenic effects were 
observed at 1 mg/kg/day (about 1/15 the daily maximum recommended human dose 
on a mg/m2 basis); teratogenic potential could not be assessed at higher doses due to 
extensive fetal mortality.
There are no adequate and well-controlled studies in pregnant women. If Paclitaxel 
Injection, USP, is used during pregnancy, or if the patient becomes pregnant while 
receiving this drug, the patient should be apprised of the potential hazard to the 
fetus. Women of childbearing potential should be advised to avoid becoming 
pregnant.(13)  
Geriatric Use 
Of 2228 patients who received paclitaxel in eight clinical studies evaluating its 
safety and effectiveness in the treatment of advanced ovarian cancer, breast 
carcinoma, or NSCLC, and 1570 patients who were randomized to receive paclitaxel 
in the adjuvant breast cancer study, 649 patients (17%) were 65 years or older and 
49 patients (1%) were 75 years or older. In most studies, severe myelosuppression 
was more frequent in elderly patients; in some studies, severe neuropathy was more 
common in elderly patients. In two clinical studies in NSCLC, the elderly patients 


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treated with paclitaxel had a higher incidence of cardiovascular events. Estimates of 
efficacy appeared similar in elderly patients and in younger patients; however, 
comparative efficacy cannot be determined with confidence due to the small number 
of elderly patients studied. In a study of first-line treatment of ovarian cancer, 
elderly patients had a lower median survival than younger patients, but no other 
efficacy parameters favored the younger group.
Please see the Paclitaxel USPI(13) for additional information.
6.8
Guidance for Clinical Assessment and Management of Hemodynamic 
Compromise (Part A and Part B)
It is essential that the patient is carefully evaluated at screening and before each 
MLN4924 dose for early symptoms and signs of hemodynamic compromise and active 
infection. Particular attention should be paid to unexplained fever, tachycardia, 
hypotension, orthostasis, tachypnea, recent nausea and vomiting, and clinical evidence 
of dehydration. 
For those patients for whom there is a concern of dehydration, the following guidance 
for rehydration before MLN4924 dosing may be considered: 500 mL/hour of 0.5 N 
saline given over 2 to 4 hours for a total of 1 to 2 L of fluid as clinically appropriate; 
each infusion of IV fluids should be recorded in the electronic case report forms 
(eCRFs).
For all patients with anemia, and especially for patients with hemoglobin values 
< 9 g/dL at screening or during the conduct of the study, red blood cell transfusions 
should be considered before MLN4924 dosing based on the patient’s risk of inadequate 
oxygenation, underlying cardiopulmonary status, clinical judgment, and hospital 
guidelines; each red blood cell transfusion should be recorded in the eCRFs.
Patients who experience signs and symptoms of hemodynamic compromise after 
MLN4924 dosing (eg, tachycardia, hypotension, orthostasis, changes in mental status, 
syncope, and dizziness) should be followed closely and managed with supportive care,
including hospitalization as clinically indicated. 
Patients who experience an untoward reaction with MLN4924 should be followed 
closely on subsequent dosing.


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6.9
Management of Clinical Events
Specific recommendations for the management of MLN4924 clinical events that were 
identified from toxicology studies in dogs and rats and from early experience in ongoing 
clinical studies are outlined in the MLN4924 IB and DCSI.
The most common adverse drug reactions for docetaxel and carboplatin+paclitaxel are 
described in Section 1.6. Refer to the applicable USPIs for additional details regarding the 
management of clinical events attributed to these agents. 
Patients who experience an AE with MLN4924 should be followed closely for a recurrence 
of similar or other AEs upon subsequent dosing of MLN4924.
6.9.1
Guidance for Use of Granulocyte-Colony Stimulating Factor
Use of growth factors such as granulocyte-colony stimulating factor (G-CSF) are permitted 
at the investigator’s discretion. If G-CSF is used, it should be used in accordance with the 
Revised American Society of Clinical Oncology guidelines.(16)
6.9.2
Guidance for Clinical Assessment and Management of Anemia
Transfusion and/or erythropoietin may be given as clinically indicated for the treatment of 
anemia. These should be recorded in the eCRFs.
For all patients with anemia, and especially for patients with hemoglobin values < 9 g/dL at 
screening or during the conduct of the study, red blood cell transfusions should be 
considered before MLN4924 dosing based on the patient’s risk of inadequate oxygenation, 
underlying cardiopulmonary status, clinical judgment, and hospital guidelines; each red 
blood cell transfusion should be recorded in the eCRFs. Transfusions should be conducted 
before study drug administration (ie, at least 1 day before dosing).
Use of Erythropoietin
Use of erythropoietin may be considered per the investigator’s discretion and per 
institutional guidelines.
6.10
Blinding and Unblinding
This is an open-label study. 


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6.11
Description of Investigational Agents  
6.11.1
MLN4924
The drug product is labeled MLN4924 (MLN4924-003 concentrate for solution for 
infusion).
The formulation consists of 10 mg/mL MLN4924-003 (as free base) in a solution containing 
citric acid, sulfobutylether-beta-cyclodextrin, and sodium hydroxide. Each USP Type I glass 
vial nominally contains 5 mL of compounded sterile solution, sealed with a coated butyl 
rubber stopper, and oversealed with an aluminum seal with a plastic cap.
MLN4924-003 concentrate for solution for infusion Drug Product is formulated with the 
following excipients: citric acid, sulfobutylether-beta-cyclodextrin, sodium hydroxide, and 
water for injection.
Details are available in the MLN4924 IB.
6.11.2
Fluconazole
Fluconazole is a synthetic triazole antifungal agent available as tablets for oral 
administration. Fluconazole Tablets USP contain 200 mg of fluconazole USP and are 
commercially available in 100 count bottles. Please refer to the fluconazole USPI.
The precautions, warnings, contraindications, and AEs associated with fluconazole therapy 
are included in the fluconazole USPI.
6.11.3
Itraconazole
SPORANOX® (itraconazole) Oral Solution is a synthetic triazole antifungal agent. 
SPORANOX® contains 10 mg of itraconazole per mL, solubilized by 
hydroxypropyl-β-cyclodextrin (400 mg/mL) as a molecular inclusion complex. 
SPORANOX® Oral Solution is commercially available in bottles containing 150 mL. Please 
refer to the SPORANOX® USPI.
The precautions, warnings, contraindications, and AEs associated with itraconazole therapy 
are included in the itraconazole USPI.


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6.11.4
Docetaxel
Docetaxel is obtained from commercial sources according to local practice standards, and it 
is provided as a commercially available dosage formulation. Please refer to the docetaxel 
USPI.
6.11.5
Carboplatin
Carboplatin is obtained from commercial sources according to local practice standards, and 
it is provided as a commercially available dosage formulation. Please refer to the carboplatin 
USPI.
6.11.6
Paclitaxel
Paclitaxel is obtained from commercial sources according to local practice standards, and it 
is provided as a commercially available dosage formulation. Please refer to the paclitaxel 
USPI.
6.12
Preparation, Reconstitution, and Dispensation
Parenteral drug products should be inspected visually for particulate matter and 
discoloration before administration, whenever solution and container permit. 
MLN4924, docetaxel, carboplatin, and paclitaxel are anticancer drugs, and as with other 
potentially toxic compounds, caution should be exercised when handling MLN4924 and 
chemotherapy agents.
6.12.1
MLN4924
The specified number of MLN4924-003 concentrate for solution for infusion Drug Product 
vials should be removed and allowed to equilibrate to room temperature before dilution. 
Using aseptic technique, the specified amount of drug product solution should be removed 
and administered using a 250-mL 5% dextrose solution. For detailed instructions for the
preparation of the infusion, refer to the Pharmacy Manual. The MLN4924 (MLN4924-003 
concentrate for solution for infusion) prepared IV bag must be used within 6 hours. The vial 
must not be shaken at any time during dose preparation. The bag, needle, and syringe must 
be disposed of in a proper biohazard container.
Detailed reconstitution and dosage preparation instructions are provided in the Pharmacy 
Manual.


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6.12.2
Docetaxel, Carboplatin, and Paclitaxel
Please refer to the USPIs for the SoCs (docetaxel, carboplatin, and paclitaxel) for 
instructions and precautions regarding preparation.
6.13
Packaging and Labeling
6.13.1
MLN4924
MLN4924 (MLN4924-003 concentrate for solution for infusion) will be provided in 10-mL 
USP Type I glass vials nominally containing 5 mL of compounded sterile solution at a 
concentration of 10 mg/mL (as free base), sealed with a coated butyl rubber stopper, and 
oversealed with an aluminum seal with a plastic cap.
6.13.2
Fluconazole
Fluconazole will be provided by Millennium Pharmaceuticals, Inc. (Millennium) as generic,
200-mg fluconazole tablets USP that are commercially available in 100-count bottles. As 
required by local regulations, any modifications to the plan for drug supply or storage will 
be communicated to the investigator and detailed in the Study Manual.
6.13.3
Itraconazole
Itraconazole will be provided by Millennium as SPORANOX® Oral Solution, which is 
commercially available in bottles containing 150 mL. As required by local regulations, any 
modifications to the plan for drug supply or storage will be communicated to the 
investigator and detailed in the Study Manual.
6.13.4
Docetaxel, Carboplatin, and Paclitaxel
Docetaxel, carboplatin, and paclitaxel may be sourced locally by the clinical sites when 
arrangements have been made and agreed to by Millennium and the clinical site and when 
regulations allow for clinical site sourcing, appropriate labeling, and compliance with local 
and regional regulations. As required by local regulations, any modifications to the plan for 
drug supply or storage will be communicated to the investigator and detailed in the 
Study Manual.


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6.14
Storage, Handling, and Accountability
6.14.1
MLN4924
Vials of MLN4924 (MLN4924-003 concentrate for solution for infusion) are to be stored at 
2°C to 8°C.
All investigational supplies are to be kept in a secure area with controlled access.
A drug dispensing log, including records of drug received from the sponsor and drug 
dispensed to the patients, will be provided and kept at the study site. Disposal instructions 
are provided in the Pharmacy Manual.
6.14.2
Fluconazole
Fluconazole 200-mg Tablets USP must be kept in the original bottle and stored at 20°C to 
25°C (68°F-77°F). All investigational supplies are to be kept in a secure area with controlled 
access.
A drug dispensing log, including records of drug received from the sponsor and drug 
dispensed to the patients, will be provided and kept at the study site. Disposal instructions 
are provided in the Pharmacy Manual.
6.14.3
Itraconazole
SPORANOX® Oral Solution must be kept in the original bottle until it is time to take it.
Keep the SPORANOX® Oral Solution in a cool, dry place where the temperature is at or 
below 25°C (77°F). Do not freeze. All investigational supplies are to be kept in a secure area 
with controlled access.
A drug dispensing log, including records of drug received from the sponsor and drug 
dispensed to the patients, will be provided and kept at the study site. Disposal instructions 
are provided in the Pharmacy Manual.
7.
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
applicable regulatory requirements, and ICH guidelines.


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7.1
Study Personnel and Organizations
The contact information for the project clinician for this study, clinical pharmacologist, the 
central laboratory and any additional clinical laboratories, contract research organization 
team, and other vendors can be found in the Study Manual. A full list of investigators is 
available in the sponsor’s investigator database.
7.2
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. If advertisements become 
part of the recruitment strategy, they will be reviewed by the institutional review board 
(IRB)/independent ethics committee (IEC). It is not envisioned that prisoners (or other 
populations that might be subject to coercion or exploitation) will be enrolled into this study.
7.3
Treatment Group Assignments 
7.3.1
Drug-Drug Interaction Assessment (Part A)
The first 4 to 8 patients will be assigned to the Fluconazole Arm (moderate CYP3A 
inhibitor). After review of the emerging data (see Section 8.1.12 for details of interim 
analyses), the investigator will recommend each patient to the Fluconazole Arm
(MLN4924+fluconazole) or the first cohort in the Itraconazole Arm (8-mg/m2
MLN4924+itraconazole), and the patient will be assigned to the appropriate arm by the 
sponsor based on slot availability until enrollment in each arm is filled.
Enrollment into the Itraconazole Arm, Safety Lead-in 15-mg/m2 MLN4924 Cohort, added 
per Amendment 1, may begin once the amendment is approved at the clinical site. 
Enrollment into the Itraconazole Arm, 20-mg/m2 MLN4924 Cohort, also added per 
Amendment 1, may begin once the Part A PK and safety data from 3 PK-evaluable patients 
in the safety lead-in cohort have been reviewed and the sponsor has confirmed that the 
anticipated safety margin for the 20-mg/m2 dose is adequate.
In Part A, Day 8 dosing of MLN4924 should not be delayed or missed. If the Day 8 dosing 
is delayed or missed, then the patient will not be considered PK evaluable and will be 
replaced.
All doses of fluconazole or itraconazole must be taken per the Schedules of Events. If any 
dose is missed, the patient will not be considered PK evaluable and will be replaced.


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7.3.2
Continued Treatment With MLN4924 in Combination With Standard of 
Care (Part B)
Investigators may assign each patient to 1 of the 2 combination regimens
(MLN4924+docetaxel or MLN4924+carboplatin+paclitaxel) in Part B based on their
medical judgment after a washout period of at least 2 weeks (and up to 8 weeks) from the 
last dose of fluconazole or itraconazole to allow patients to recover from any safety concerns
and to confirm that the patient is eligible to participate in Part B. Participation in Part B of 
the study is optional. Any patient who continues on to Part B will need to be re-evaluated for 
entry criteria (see Section 7.4.20) before treatment in Part B can begin.
7.4
Study Procedures
The timing of the study procedures outlined in the following subsections is provided in the 
Schedules of Events. When applicable, specific visit windows for assessments are provided 
in the footnotes to the study schedules. 
In Part B, dosing of MLN4924 on Days 1, 3, or 5 (of any cycle) may be delayed by up to 
2 days (Cycles 1 through 12) or up to 2 weeks (after completion of Cycle 12; up to 4 weeks 
after consulting with the sponsor) to accommodate inclement weather, holidays, vacations, 
or other administrative reasons; treatment breaks may not be taken consecutively. 
Refer to the Schedules of Events for timing of assessments. 

Schedule of Events for Drug-Drug Interaction (Part A)

Serial Pharmacokinetic Sample Breakdown

Schedule of Events for Continued Treatment With MLN4924+Standard of Care 
(Part B): Cycle 1 Through Cycle 12

Schedule of Events for Continued Treatment With MLN4924+Standard of Care 
(Part B): Cycle 13 and Beyond (as of Amendment 2)
Additional details are provided as necessary in the sections that follow.
7.4.1
Informed Consent
Each patient must provide written informed consent before any study-required procedures 
are conducted, unless those procedures are performed as part of the patient’s standard care. 


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7.4.2
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during screening.
7.4.3
Medical History (Part A)
During screening, a complete medical history will be compiled for each patient in Part A. 
The history will emphasize the background and progress of the patient’s malignancy and 
include a description of prior therapies for it (see inclusion criterion 2, Section 5.1). 
Concomitant medications will be recorded as specified in Section 7.4.11.
7.4.4
Physical Examination
A physical examination will be completed per standard of care at the times specified in the 
Schedules of Events. 
7.4.5
Patient Height
Height will be measured during screening only.
7.4.6
Patient Weight
Weight will be measured as indicated in the Schedules of Events. On dosing days, weight 
will be measured before dosing of MLN4924.
7.4.7
Eastern Cooperative Oncology Group Performance Status
Eastern Cooperative Oncology Group PS (Section 15.4) will be assessed as indicated in the 
Schedules of Events (see inclusion criterion 5, Section 5.1).
7.4.8
Echocardiogram or Radionuclide Angiography (Part A)
Left ventricular ejection fraction should be assessed by echocardiogram or radionuclide 
angiography at screening in Part A only. 
7.4.9
Vital Signs 
Vital signs, including diastolic and systolic blood pressure, heart rate, and body temperature,
will be collected as indicated in the Schedules of Events and as clinically indicated. All vital 
signs will be measured in the sitting position (and/or supine after completion of Cycle 12) as 
noted in the Schedules of Events.


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In addition, during Part A at predose and 1 hour postdose of MLN4924 administration on 
Day 1 and Day 8, orthostatic blood pressure and heart rate measurements will be measured 
with the patient in a supine position and then standing, after waiting for approximately 3 to 
4 minutes. In Part B, orthostatic blood pressure and heart rate measurements will be taken on 
Cycle 1, Day 1 only, per the Schedules of Events.
When the timing of vital signs assessment coincides with the timing of a blood draw, vital 
signs will be measured before blood sample collection unless otherwise noted in the 
Schedules of Events. 
7.4.10
Pregnancy Test (Part A)
A serum pregnancy test will be performed for women of childbearing potential at screening
in Part A only. The results from this test must be available and negative before the first dose 
of study drug.
7.4.11
Concomitant Medications and Procedures
Concomitant medications and procedures will be recorded from the time of the first dose of 
any study drug through 30 days (+ 10 days) after the last dose of study drug(s). See 
Section 6.5 and Section 6.6 for additional details regarding excluded and permitted 
concomitant medications and procedures.
7.4.12
Adverse Events
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as 
specified in the Schedules of Events. Refer to Section 10 for details regarding definitions, 
documentation, and reporting of pretreatment events, AEs, and SAEs. 
7.4.13
Enrollment
Enrollment is achieved when the first dose of any study drug has been administered.
Procedures for completion of the enrollment information are described in the Pharmacy and 
Study Manuals.
7.4.14
Electrocardiogram
A 12-lead ECG will be performed as indicated in the Schedules of Events. When the timing 
ECG assessment coincides with the timing of a blood draw, ECG assessments will be 


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completed before blood sample collection unless otherwise noted in the Schedules of 
Events.
The ECGs performed after infusion should be reviewed by the investigator or designee
before the patient leaves the clinic.
7.4.15
Clinical Laboratory Evaluations
Clinical Chemistry, Hematology, and Urinalysis
Blood samples for analysis of the following clinical chemistry and hematological parameters 
and urine samples for urinalysis will be obtained as specified in the Schedules of Events.
Hematology

Hemoglobin

Hematocrit

Platelet (count)

Leukocytes with differential

Neutrophils (absolute neutrophil count [ANC])
Serum Chemistry

Blood urea nitrogen 
(BUN)

Creatinine

Bilirubin (total)

Direct bilirubin

Urate

Lactate dehydrogenase 
(LDH)

Gamma glutamyl 
transferase (GGT)a

Phosphate

Albumin

Alkaline phosphatase 
(ALP)

Aspartate 
aminotransferase (AST)

Alanine 
aminotransferase (ALT)

Glucose 

Sodium

Potassium

Calcium

Chloride

Carbon 
dioxide (CO2)

Magnesium
a
No longer required after completion of Cycle 12 (as of Amendment 2).
Coagulation
Part A Screening

Prothrombin time international normalized ratio

Activated partial thromboplastin time

Fibrinogen 

D-dimer
Part B
If the initial coagulation screen is positive (ie, results are outside of the laboratory’s 


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Coagulation
normal range) in Part A, coagulation studies in Part B should include a full coagulation 
panel. If the initial coagulation screen is negative (ie, results are within the laboratory’s 
normal range) in Part A, then no further coagulation studies need to be done.
Urinalysis With Microscopic Analysis

Turbidity and color

pH

Specific gravity

Protein

Phosphatea

Ketones

Bilirubin

Occult blood

Nitrite

Urobilinogen

Glucose

Leukocytes

Microscopic assessment
a
Included after completion of Cycle 12 (as of Amendment 2).
7.4.16
Disease Assessment (Part B)
Computed tomography scans with IV contrast (unless medically contraindicated) or MRI of 
the chest, abdomen, and pelvis will be performed as entry criteria for Part B. 
Computed tomography scans with IV contrast encompassing the known sites of disease will 
also be performed at the end of Cycle 2, end of Cycle 4, and at the end of every other cycle
(Cycles 1-12), or after completion of every sixth cycle after the patient’s previous scan (after 
completion of Cycle 12 and implementation of Amendment 2) thereafter. Additional CT 
scans may be performed, per investigator's discretion, if clinically indicated. A scan should 
be taken at the EOS visit if a scan has not been completed within the past 28 days. 
If CT scan does not provide adequate imaging, MRI may be used to evaluate sites of 
disease. If the patient has had appropriate imaging scans performed within 28 days of 
Cycle 1, Day 1, then the results of those scans may be used for the entry criteria for Part B. 
For each site of disease, the imaging modality (CT or MRI) used at entry criteria for Part B
must be used throughout the study. Tumor response will be assessed by the investigator at 
these times using RECIST, version 1.1.(14)
7.4.17
Pharmacokinetic Measurements
During Part A of the study, for both the Fluconazole and Itraconazole Arms, serial blood 
samples (approximately 3 mL each) will be collected from each patient for the determination 
of MLN4924 plasma concentrations before and after the start of MLN4924 infusion on 
Day 1 (when administered alone) and Day 8 (when co-administered with fluconazole or 
itraconazole) at the time points indicated in the Serial Pharmacokinetic Sample Breakdown. 


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Four additional blood samples for the determination of MLN4924 concentrations in whole 
blood will be drawn following MLN4924 infusion on Day 1 only.
The timing, but not the number, of PK blood samples may be changed if emerging data 
indicate that an alteration in the sampling scheme is needed to better characterize the PK of 
MLN4924. To ensure that the measurements are representative of plasma exposure, blood 
draws will be conducted in the arm opposite to a patient’s IV infusion. If only a single arm is 
available, blood should be drawn as distal to the site of the IV infusion as feasible, and the 
site of the blood draw should be documented. 
The exact date and time of each sample collection and the actual start and stop times of the 
infusion should be recorded accurately, and particular care should be given to recording 
blood sampling times that occur close to the infusion.
Details regarding the preparation, handling, and shipping of samples are provided in the 
Study and Laboratory Manuals.
For patients who experience hypersensitivity or a hepatic, cardiac, or renal SAE considered 
by the investigator to be at least possibly related to study drug, an additional blood sample 
should be collected, if clinically feasible, for the determination of MLN4924 plasma 
concentration as close to the onset of the event as possible.
If deemed appropriate, the blood samples collected in this study may be analyzed to 
determine plasma concentrations of MLN4924 major metabolites in humans. Also, if 
considered necessary to verify treatment assignments, a subset of the samples may be used 
for measurement of concentration of the co-administered drugs (fluconazole or 
itraconazole).
7.4.18
Pharmacodynamic Measurements 
CCI


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Blood samples will be collected during screening and at the time points indicated in the 
Serial Pharmacodynamic Sample Breakdown following MLN4924 dosing on Days 1 and 8.
The timing, but not the number, of blood samples may be changed if emerging data indicate 
that an alteration in the sampling scheme is needed to better characterize the 
pharmacodynamic effects of MLN4924. 
Details regarding the preparation, handling, and shipping of samples are provided in the 
Study Manual.
7.4.19
Patient Diary  
Patient instructions regarding the CYP3A inhibitor dosing schedule, study drug handling, 
use of the patient diary, visit expectations, diary review and return of study drug containers 
and unused study drug will be provided on Day 4 of Part A before dosing with the CYP3A 
inhibitor. 
Patients are to be instructed to bring their diaries and study drug to the clinic on the Day 8 
visit of Part A, and all entries are to be reviewed by study staff with the patient. If the patient 
misses any dose of the CYP3A inhibitor, they will not be considered PK evaluable and will 
be replaced (see Section 8.1.4). Understanding of and compliance with instructions should 
be continually evaluated and addressed as needed throughout trial participation. 
7.4.20
Entry Criteria for Continuation Into Part B
For patients to be eligible for dosing with MLN4924+SoC (Part B), they must meet the 
following entry criteria:

Eastern Cooperative Oncology Group PS of 0 to 1 

Laboratory values for hemoglobin, ANC, platelet, total bilirubin, ALT, AST, ALP, 
and serum creatinine or calculated/measured creatinine clearance as specified in 
Section 5.1

Diarrhea symptoms resolved to Grade 1 or better

Rate-corrected QT interval of electrocardiograph 500 msec

Computed tomography scan or MRI of the chest, abdomen, and pelvis within 
28 days of Cycle 1 Day 1


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In addition, patients will require at least a 2-week (may be extended up to 8 weeks) washout 
period after their last dose of fluconazole or itraconazole. For patients to begin dosing in 
Part B, their predose Cycle 1, Day 1 assessments in Part B must return to the baseline values 
of Part A (or ≤ Grade 1) or to a level considered acceptable by the investigator after 
discussion with the project clinician or designee. If, after a maximum of 8 weeks from the 
last dose in Part A (eg, up to 8 weeks after the Day 10 visit), the predose Cycle 1, Day 1 
assessments in Part B have not returned to Part A baseline values (or ≤ Grade 1), the patient 
will not be eligible for dosing with MLN4924+SoC, and all assessments required for the 
EOS visit should be completed. The predose Cycle 1, Day 1 assessments for Part B do not 
need to be repeated if the Day 24 Part A results confirm that the patient is eligible for dosing 
in Part B AND Cycle 1, Day 1 occurs within 5 days from Part A Day 24; however, the LFTs
will need to be repeated within 3 days of Cycle 1, Day 1. 
7.5
Completion of Study
Part A
Patients will be considered to have completed Part A of the study if they have completed the 
protocol-specified assessments within Part A (ie, MLN4924+fluconazole or 
MLN4924+itraconazole) of the protocol.
An EOS visit is needed in Part A only if the patient does not continue into Part B for any 
reason. The EOS visit will include physical examination (including ECOG PS and vital
signs), laboratory assessments (hematology, chemistry, and urinalysis), and 12-lead ECG. 
The EOS visit will be conducted 30 (+ 10) days after the last dose of study drug in Part A. If 
the EOS visit occurs before 30 days after the last dose of MLN4924, patients should be 
contacted via telephone on Day 30 to assess for any new or ongoing AEs or SAEs that may 
have occurred since the previous visit.
Part B
Patients will be considered to have completed Part B of the study if they discontinue 
treatment for any of the reasons outlined in Section 7.6. The EOS visit will be conducted 
30 (+ 10) days after the last dose of study drug in Part B. If the EOS visit occurs before 
30 days after the last dose of MLN4924, patients should be contacted via telephone on 
Day 30 to assess for any new or ongoing AEs or SAEs that may have occurred since the 
previous visit. 


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7.6
Discontinuation of Treatment with Study Drug, and Patient Replacement
Treatment with study drug may be discontinued for any of the following reasons:

Adverse event

Protocol violation

Progressive disease 

Symptomatic deterioration 

Unsatisfactory therapeutic response 

Study terminated by sponsor

Withdrawal by subject

Lost to follow-up

Other
Once study drug has been discontinued, all study procedures outlined for the EOS visit will 
be completed as specified in the Schedules of Events. The primary reason for study drug 
discontinuation will be recorded on the eCRF. In both arms of Part A of the study, patients 
who are not PK evaluable (see Section 8.1.4) will be replaced.
Note: In Part B of the study, patients may receive MLN4924 until they experience PD or 
unacceptable MLN4924-related toxicities or discontinue treatment for any reason. 
Patients who have achieved objective clinical benefit from combination therapy (SoC plus 
MLN4924) AND who have developed intolerance that is reasonably attributable to the SoC 
after 4 or more cycles may continue on single-agent MLN4924 at the same dose and 
schedule upon request by the investigator and agreement by the sponsor.
7.7
Withdrawal of Patients from Study  
A patient may be withdrawn from the study for any of the following reasons:

Lost to follow-up


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
Study terminated by sponsor

Withdrawal by subject

Completed study 

Death 

Other

Progressive disease 
The consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database.
7.8
Study Compliance  
Study drug will be administered or dispensed only to eligible patients under the supervision 
of the investigator or identified subinvestigator(s). The appropriate study personnel will 
maintain records of study drug receipt and dispensing.
The clinical team and the clinical research associate will review treatment compliance 
during investigational visits and at the completion of the study. Tests and procedures should 
be performed on schedule, but unless otherwise specified, occasional changes are allowable 
within a 2-day (Cycles 1 through 12) to a 4-week (after completion of Cycle 12) window for 
holidays, vacations, and other administrative reasons (see Section 6.4.2); treatment breaks 
may not be taken consecutively. If the study schedule is shifted, both assessments and 
dosing must be shifted to ensure that collection of assessments is completed before dosing. 
These 2-day to 4-week windows are allowed for Part B and do not apply for Part A.
8.
STATISTICAL AND QUANTITATIVE ANALYSES
8.1
Statistical Methods
Statistical analyses will be primarily descriptive and graphical in nature. No formal 
statistical hypothesis testing will be performed. Analysis of variance (ANOVA) analysis will 
be conducted on log-transformed PK parameters, Cmax and AUC, to estimate the magnitude 
of the DDI interaction. Summary tabulations will be presented that display the number of 
observations, mean, standard deviation, median, minimum, and maximum for continuous 


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variables, and the number and percentage per category for categorical data. A formal 
statistical analysis plan (SAP) will be developed and finalized before database lock.
8.1.1
Drug-Drug Interaction Assessment
Assessments for the DDI portion of the study (Part A) will include the following:

For the MLN4924-fluconazole DDI assessment, the ratios of geometric mean Cmax, 
AUC0-last, and AUC0-inf of MLN4924 (in the presence of fluconazole on Day 8 vs in 
the absence of fluconazole on Day 1) and associated 2-sided 90% CIs will be 
calculated based on the within-patient variance calculated by ANOVA.

For the MLN4924-itraconazole DDI assessment, the ratios of geometric mean Cmax, 
AUC0-last, and AUC0-inf of MLN4924 (in the presence of itraconazole on Day 8 vs in 
the absence of itraconazole on Day 1) and associated 2-sided 90% CIs will be 
calculated based on the within-patient variance calculated by ANOVA. 

Individual values and descriptive statistics of MLN4924 plasma concentrationtime 
data and PK parameters will be listed and tabulated (see Section 8.1.8) by study day, 
in the presence and absence of the inhibitor (fluconazole or itraconazole).
8.1.2
Determination of Sample Size
It is anticipated that as many as approximately 52 patients will be enrolled in this study.
The sample size calculation is based on the expected 2-sided 90% CI for the difference in 
the paired, log transformed AUC (or Cmax) means of MLN4924 on Day 1 (MLN4924 alone) 
and Day 8 (MLN4924 co-administered with CYP3A inhibitor). Based on the PK 
information obtained from Schedules B and C of Study C15001, the within-subject CV was 
estimated to be 0.12 for AUC and 0.17 for Cmax, respectively. Assuming that the AUC (or 
Cmax) ratio in the presence of fluconazole versus in the absence of fluconazole or in the 
presence of itraconazole versus in the absence of itraconazole is 2.0, with a sample size of 
12 evaluable patients per arm, the 90% CI of the ratio of geometric means is expected to be 
(1.833, 2.182) for AUC and (1.759, 2.274) for Cmax based on the above discussed variance 
assumptions. If the geometric mean AUC (or Cmax) ratio is X, the corresponding 90% CI is 
expected to be (1.833X/2, 2.182X/2) (or [1.759X/2, 2.274X/2]).
In the Fluconazole Arm, approximately 12 PK-evaluable patients will be enrolled. In the 
Itraconazole Arm, approximately 12 PK-evaluable patients will be enrolled in the 8-mg/m2


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and 20-mg/m2 MLN4924 cohorts, and 3 additional PK-evaluable patients will be needed in 
the safety lead-in cohort. A patient is PK-evaluable if he or she completes the protocol-
specified dosing and PK assessments without dose reductions in Part A. Patients who are not 
PK evaluable (see Section 8.1.4) will be replaced. Assuming that 25% of the enrolled 
patients will not be PK evaluable, approximately 52 patients will be enrolled to provide the 
total intended number of PK-evaluable patients in each arm of Part A.
8.1.3
Randomization and Stratification  
No randomization or stratification will be performed in this study.
8.1.4
Populations for Analysis
Safety population for Part A: All enrolled patients who receive at least 1 dose of MLN4924 
during Part A. All safety and pharmacodynamic analyses in Part A will be performed using 
the safety population for Part A.
Safety population for Part B: All patients who continue to Part B and receive at least 1 dose 
of study drug during Part B. All safety analyses in Part B will be performed using the safety 
population for Part B. 
Pharmacokinetic-Evaluable population: Patients who receive all protocol-specified dose 
regimens, did not receive any excluded medications throughout the completion of PK 
sampling, and have MLN4924 plasma concentrationtime data to reliably estimate PK 
parameters based on noncompartmental analysis methods. 
Response-Evaluable population: Patients who receive at least 1 dose of study drug in Part B, 
have measurable disease as entry criteria for Part B, and have at least 1 postbaseline disease 
assessment. 
8.1.5
Procedures for Handling Missing, Unused, and Spurious Data
All available data will be included in data listings. In general, no imputation of values for 
missing data will be performed. The relevance of missing sample data will be assessed. Data 
that are potentially spurious or erroneous will be examined according to standard data 
management operating procedures.


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8.1.6
Demographic and Baseline Characteristics
The demographic and baseline characteristics will be summarized descriptively, including 
age, sex, race, ethnicity, weight, height, body mass index, baseline disease characteristics, 
primary diagnosis, and other parameters as appropriate. Baseline characteristics will be 
defined separately for Part A and Part B.
8.1.7
Efficacy Analysis
Analysis of all efficacy measures collected from Part B will be descriptive. Disease response 
to MLN4924 in combination with SoC will be based on the best overall response as 
determined by the investigator using RECIST version 1.1 guidelines (Section 15.3). The 
duration of response will be defined in patients with disease response (complete response 
[CR] or PR) as the time between the first documentation of response and PD. Responders 
without PD will be censored at the last clinical assessment of response.
8.1.8
Pharmacokinetic Analysis
Individual values and descriptive statistics of MLN4924 plasma concentrationtime data 
and PK parameters will be listed and tabulated by treatment arm and study day on Day 1 of 
Part A (MLN4924 alone) and Day 8 of Part A (MLN4924 co-administered with either 
fluconazole or itraconazole). Pharmacokinetic parameters of MLN4924 with and without the 
inhibitor (fluconazole or itraconazole) in individual patients will be calculated using 
noncompartmental methods. Pharmacokinetic parameters include, but are not limited to,
Cmax, Tmax, AUC0-last, t1/2 (as permitted by the data), CL, Vss, and AUC0-inf (as permitted by 
the data). The B/P ratio of MLN4924 will also be derived from plasma and whole blood 
concentration data.
Descriptive statistics of MLN4924 plasma concentrationtime data and PK parameters will 
be tabulated by treatment arm and study day (ie, Day 1 or Day 8 with or without the 
inhibitor [fluconazole or itraconazole]). For each of the treatment arms, individual and mean 
MLN4924 plasma concentration data during Part A will be plotted over time on Day 1 and 
Day 8.
See Section 8.1.12 for information on the preliminary PK analysis.


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8.1.9
Pharmacodynamic Analysis
8.1.10
Pharmacokinetic-Pharmacodynamic Analysis
8.1.11
Safety Analysis
A safety analysis will be conducted separately for Part A and Part B to respectively 
characterize the safety profiles of MLN4924 co-administered with CYP3A inhibitors and 
MLN4924 in combination with SoC. The Safety population will be used for the safety 
analysis. Safety will be evaluated based on the incidence of AEs, severity and type of AEs, 
and by changes from baseline in the patient’s vital signs, weight, and clinical laboratory 
values using the Safety population. Exposure to study drug and reasons for discontinuation 
will be tabulated.
A treatment-emergent AE in Part A is defined as any AE that occurs after administration of 
the first dose of study treatment during Part A and up through 30 days after the last dose of 
study drug during Part A for patients who do not continue into Part B, or up through Part B 
Cycle 1 Day 1 (predose) for patients who continue into Part B, any event that is considered 
drug-related regardless of the start date of the event for patients who do not continue into 
part B, or any event that is present at baseline but worsens in severity during Part A. 
A treatment-emergent AE in Part B is defined as any AE that occurs after administration of 
the first dose of study treatment during Part B and up through 30 days after the last dose of 
CCI
CCI


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study drug during Part B, or any event that is present at Part B baseline but worsens in 
severity during Part B.
Adverse events will be tabulated according to the Medical Dictionary for Regulatory 
Activities by System Organ Class, High-Level Term, and Preferred Terms and will include 
the following categories: 

Treatment-emergent AEs

Drug-related treatment-emergent AEs

Grade 3 or higher treatment-emergent AEs

Grade 3 or higher drug-related treatment-emergent AEs

The most commonly reported treatment-emergent AEs (ie, those events reported by 
10% of all patients)

Serious adverse events

Drug-related SAEs
A listing of treatment-emergent AEs resulting in study drug discontinuation will be 
provided.
The most commonly reported treatment-emergent AEs (ie, those events reported by 
10% of all patients) will be tabulated by System Organ Class and Preferred Term. 
Tabulation also will be provided that enumerates AEs by maximum intensity. Deaths, SAEs, 
and AEs resulting in study drug discontinuation will be tabulated.
Descriptive statistics for the actual values of clinical laboratory parameters (and change 
from baseline in clinical laboratory parameters) will be presented for all scheduled 
measurements over time. Mean laboratory values over time will be plotted for key 
laboratory parameters.
Shift tables for laboratory parameters will be generated based on changes in NCI CTCAE 
grade from baseline to the worst postbaseline value. Graphical displays of key safety 
parameters, such as scatter plots of baseline versus worst postbaseline values, may be used 
to understand the MLN4924 safety profile.


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The number and percent of patients experiencing abnormal ECG results will be summarized 
over each time point, separately for Part A by DDI cohort, and for Part B by treatment arm.
Graphical displays will be used to show vital sign parameters over time, separately for 
Part A by DDI cohort, and for Part B by treatment arm. In addition, descriptive statistics will 
be tabulated for orthostatic hypotension and orthostatic heart rate. 
All concomitant medications collected from screening throughout the study period will be 
classified to Preferred Terms according to the World Health Organization drug dictionary.
Additional safety analyses may be performed to enumerate rates of toxicities and to further 
define the safety profile of MLN4924.
8.1.12
Interim Analyses (Preliminary Drug-Drug Interaction Assessment, Part A)
No formal interim analysis is planned. There will be an ongoing review of safety data with 
the medical monitor and study investigators. 
A preliminary PK analysis will be conducted after the first 4 to 8 patients have completed 
the Fluconazole Arm (MLN4924+fluconazole) of Part A. After review of the emerging data
from the Fluconazole Arm, patient assignment to the first cohort in the Itraconazole Arm 
(8-mg/m2 MLN4924+itraconazole) will be initiated. Dose modifications of MLN4924 in the 
Itraconazole Arm may be reconsidered based on the magnitude of the interaction with the 
moderate CYP3A inhibitor fluconazole and the ability to accurately estimate PK parameters 
for DDI evaluation.
Following completion of the first 3 patients in the Itraconazole Arm, 8-mg/m2 MLN4924 
Cohort, preliminary PK data will be reviewed to guide expansion of the Itraconazole Arm to 
the total intended number of 12 PK-evaluable patients. If these emerging preliminary PK 
data indicate that the magnitude of the interaction with the strong CYP3A inhibitor 
itraconazole reaches the anticipated approximately 10-fold change, and individual drug 
exposures do not exceed those seen at doses of MLN4924 110 mg/m2, then up to 
3 additional patients to provide at least 4 to 6 PK-evaluable patients will be enrolled. If the 
magnitude of the interaction with the strong CYP3A inhibitor itraconazole is much greater 
than anticipated (greater than the predefined safety margin of 14-fold), with individual 
MLN4924 exposures exceeding those seen at doses of MLN4924 110 mg/m2, then no 
additional patients will be enrolled in the Itraconazole Arm of Part A.


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As of the implementation of Amendment 1, following completion of Part A by 
3 PK-evaluable patients in the Safety Lead-in 15-mg/m2 MLN4924 Cohort, safety and PK 
data will be reviewed to inform expansion of the Itraconazole Arm to the total intended 
number of 12 PK-evaluable patients in the 20-mg/m2 MLN4924 Cohort. If the preliminary 
PK data from the safety lead-in cohort indicate that the magnitude of the interaction between 
the proposed 20-mg/m2 MLN4924 dose and the strong CYP3A inhibitor itraconazole would 
be greater than the predefined safety margin (5-fold, with individual MLN4924 exposures
potentially exceeding those seen at doses of MLN4924 110 mg/m2), then no patients will 
be enrolled in the 20-mg/m2 MLN4924 Cohort. Dosing with intermediate doses of 
MLN4924 and/or evaluation of the drug interaction with the moderate CYP3A inhibitor,
fluconazole, may then be reconsidered if it is deemed necessary to further enhance our 
understanding of the effect of CYP3A inhibition on the PK of MLN4924. 
9.
STUDY COMMITTEES 
9.1
Millennium Safety Assessments
Safety data will be reviewed and assessed periodically by a Global Pharmacovigilance team 
and a cross-functional Safety Management Team throughout the conduct of the study. These 
cross-functional reviews will include a Global Safety Lead from the study team, as well as 
other representation from other departments at Millennium such as Clinical Research, 
Pharmacovigilance, Biostatistics, Clinical Pharmacology, and Clinical Operations. 
10.
ADVERSE EVENTS
10.1
Definitions
10.1.1
Pretreatment Event Definition
A pretreatment event is any untoward medical occurrence in a patient or subject who has 
signed informed consent to participate in a study but before administration of any study 
medication; it does not necessarily have to have a causal relationship with study 
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10.1.2
Adverse Event Definition
Adverse event (AE) means any untoward medical occurrence in a patient or subject 
administered a pharmaceutical product; the untoward medical occurrence does not 
necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product whether 
or not it is related to the medicinal product. This includes any newly occurring event, or a 
previous condition that has increased in severity or frequency since the administration of 
study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline. 
10.1.3
Serious Adverse Event Definition
Serious AE (SAE) means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the 
time of the event. It does not refer to an event which hypothetically might have 
caused death if it were more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization
(see clarification in the paragraph below on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined 
as a substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered 
serious when, based on appropriate medical judgment, may jeopardize the patient, 
require medical or surgical intervention to prevent 1 of the outcomes listed above, or 
involves suspected transmission via a medicinal product of an infectious agent. 
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; any organism, virus, or infectious particle (eg, prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or nonpathogenic, is 
considered an infectious agent. 
In this study, intensity for each AE, including any lab abnormality, will be determined using 
the NCI CTCAE, Version 4.03, effective date 14 June 2010.(15)  Clarification should be 
made between a serious AE (SAE) and an AE that is considered severe in intensity (Grade 3 
or 4), because the terms serious and severe are NOT synonymous. The general term severe
is often used to describe the intensity (severity) of a specific event; the event itself, however, 
may be of relatively minor medical significance (such as a Grade 3 headache). This is NOT 
the same as serious, which is based on patient/event outcome or action criteria described 
above, and is usually associated with events that pose a threat to a patient’s life or ability to 
function. A severe AE (Grade 3 or 4) does not necessarily need to be considered serious. For 
example, a white blood cell count of 1000/mm3 to less than 2000 is considered Grade 3 
(severe) but may not be considered serious. Seriousness (not intensity) serves as a guide for 
defining regulatory reporting obligations.
10.2
Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events
All AEs spontaneously reported by the patient and/or in response to an open question from 
study personnel or revealed by observation, physical examination, or other diagnostic 
procedures will be recorded on the appropriate page of the eCRF (see Section 10.3 for the 
period of observation). Any clinically relevant deterioration in laboratory assessments or 
other clinical finding is considered an AE. When possible, signs and symptoms indicating a 
common underlying pathology should be noted as 1 comprehensive event.
Regardless of causality, SAEs and serious pretreatment events (as defined in Section 10.1) 
must be reported (see Section 10.3 for the period of observation) by the investigator to the 
Millennium Department of Pharmacovigilance or designee (contact information provided 
below). This should be done by faxing the SAE Form within 24 hours after becoming aware 
of the event. The SAE Form, created specifically by Millennium, will be provided to each 
clinical study site. A sample of the SAE Form may be found in the Study Manual. 
Follow-up information on the SAE or serious pretreatment event may be requested by 
Millennium. SAE report information must be consistent with the data provided on the eCRF.


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SAE Reporting Contact Information
Planned hospital admissions or surgical procedures for an illness or disease that existed
before the patient was enrolled in the trial are not to be considered AEs unless the condition 
deteriorated in an unexpected manner during the trial (eg, surgery was performed earlier or 
later than planned).
For both serious and nonserious AEs, the investigator must determine both the intensity of 
the event and the relationship of the event to study drug administration. For serious 
pretreatment events, the investigator must determine both the intensity of the event and the 
relationship of the event to study procedures.
Intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, Version 4.03, effective date 14 June 2010.(15)  The criteria are provided in the 
Study Manual.
Relationship to study drug administration will be determined by the investigator responding 
yes or no to this question: Is there a reasonable possibility that the AE is associated with the 
study drug?
10.3
Monitoring of Adverse Events and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows: 

AEs will be reported from the first dose of study drug through 30 days (+ 10 days)
after administration of the last dose of study drug and recorded in the eCRFs. 

Serious pretreatment events will be reported to the Millennium Department of 
Pharmacovigilance or designee from the time of the signing of the informed consent 
form (ICF) up to first dose of study drug, but will not be recorded in the eCRF.

Related and unrelated SAEs will be reported to the Millennium Department of 
Pharmacovigilance or designee from the first dose of study drug through 30 days 
(+ 10 days) days after administration of the last dose of study drug and recorded in 
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the eCRF. After this period, only related SAEs must be reported to the Millennium 
Department of Pharmacovigilance or designee. SAEs should be monitored until they 
are resolved or are clearly determined to be due to a patient’s stable or chronic 
condition or intercurrent illness(es). 
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this 
study, she must inform the investigator immediately and permanently discontinue study 
drug. The sponsor must also be contacted immediately by faxing a completed Pregnancy 
Form to the Millennium Department of Pharmacovigilance or designee (see Section 10.2). 
The pregnancy must be followed for the final pregnancy outcome.
If a female partner of a male patient becomes pregnant during the male patient’s 
participation in this study, the sponsor must also be contacted immediately by faxing a 
completed Pregnancy Form to the Millennium Department of Pharmacovigilance or 
designee (see Section 10.2). Every effort should be made to follow the pregnancy for the 
final pregnancy outcome.
11.
ADMINISTRATIVE REQUIREMENTS
11.1   
Good Clinical Practice
The study will be conducted in accordance with the ICH-GCP and the appropriate regulatory 
requirement(s). The investigator will be thoroughly familiar with the appropriate use of the 
study drug as described in the protocol and the IB.
The investigator is responsible for supervising any individual or party to whom the 
investigator delegates trial-related duties and functions conducted at the trial site. If the 
investigator/institution retains the services of any individual or party to perform trial-related 
duties and functions, the investigator/institution should ensure that this individual or party is 
qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
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11.2
Data Quality Assurance
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
patient. Study data will be entered into an eCRF by site personnel using a secure, validated, 
web-based electronic data capture (EDC) application. Millennium will have access to all 
data upon entry in the EDC application. 
Study monitors will discuss instances of missing or uninterpretable data with the 
investigator for resolution. Any changes to study data will be made to the eCRF and 
documented via an electronic audit trail associated with the affected eCRF.
11.3
Electronic Case Report Form Completion 
Millennium or designee will provide the study sites with secure access to and training on the 
EDC application, sufficient to permit site personnel to enter or correct information in the 
eCRFs for the patients for whom they are responsible.
eCRFs will be completed for each study patient. It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the 
patient’s eCRF.
The investigator, or designated representative, should complete the eCRF as soon as 
possible after information is collected.
The investigator must provide through the EDC application formal approval of all the 
information in the eCRFs and changes to the eCRFs to endorse the final submitted data for 
the patients for which he or she is responsible. The audit trail entry will show the user’s 
identification information and the date and time of the correction.
Millennium, or a designee, will retain the eCRF data and corresponding audit trails. A copy 
of the final archival eCRF in the form of a compact disk (CD) or other electronic media will 
be placed in the investigator’s study file.
11.4
Study Monitoring
Monitoring and auditing procedures developed or approved by Millennium will be followed 
to comply with GCP guidelines.


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All information recorded on the eCRFs for this study must be consistent with the patient’s 
source documentation. During the course of the study, the study monitor will make study 
site visits to review protocol compliance, verify eCRFs against source documentation, assess 
drug accountability, and ensure that the study is being conducted according to pertinent 
regulatory requirements. The review of medical records will be performed in a manner that 
ensures that patient confidentiality is maintained. 
11.5
Ethical Considerations
The study will be conducted in accordance with applicable regulatory requirement(s) and 
will adhere to GCP standards. The IRB/IEC will review all appropriate study documentation 
to safeguard the rights, safety, and well-being of the patients. The study will be conducted 
only at sites where IRB/IEC approval has been obtained. The protocol, IB, ICF, 
advertisements (if applicable), written information given to the patients (including diary 
cards), safety updates, annual progress reports, and any revisions to these documents will be 
provided to the IRB/IEC by the investigator or the sponsor, as allowed by local regulations.
11.6
Patient Information and Informed Consent
After the study has been fully explained, written informed consent will be obtained from 
either the patient or his/her guardian or legal representative before study participation. The 
method of obtaining and documenting the informed consent and the contents of the consent 
must comply with the ICH-GCP and all applicable regulatory requirements.
11.7
Patient Confidentiality
To maintain patient privacy, all eCRFs, study drug accountability records, study reports, and 
communications will identify the patient by initials where permitted and/or by the assigned 
patient number. The patient’s confidentiality will be maintained and will not be made 
publicly available to the extent permitted by the applicable laws and regulations.
11.8
Investigator Compliance
The investigator will conduct the trial in compliance with the protocol provided by 
Millennium and given approval/favorable opinion by the IRB/IEC and the appropriate 
regulatory authority(ies). Modifications to the protocol are not to be made without 
agreement of both the investigator and Millennium. Changes to the protocol will require 
written IRB/IEC approval/favorable opinion before implementation, except when the 
modification is needed to eliminate an immediate hazard or hazards to patients. Millennium, 


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or a designee, will submit all protocol modifications to the appropriate regulatory 
authority(ies) in accordance with the governing regulations.
When immediate deviation from the protocol is required to eliminate an immediate hazard 
or hazards to patients, the investigator will contact Millennium, or a designee, if 
circumstances permit, to discuss the planned course of action. Any departures from the 
protocol must be documented.
11.9
On-site Audits
Regulatory authorities, the IEC/IRB, and/or Millennium may request access to all source 
documents, eCRFs, and other study documentation for on-site audit or inspection. Direct 
access to these documents must be guaranteed by the investigator, who must provide support 
at all times for these activities.
11.10
Investigator and Site Responsibility for Drug Accountability
Accountability for the study drug at the trial site is the responsibility of the investigator. 
Drug accountability records indicating the drug’s delivery date to the site, inventory at the 
site, use by each patient, and amount returned to Millennium, or a designee (or disposal of 
the drug, if approved by Millennium) will be maintained by the clinical site. Millennium or 
its designee will review drug accountability at the site on an ongoing basis.
All material containing study drug will be treated and disposed of in accordance with 
governing regulations.
11.11
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 report this via the 
phone numbers or email address provided below. Whenever possible, the associated product 
should be maintained in accordance with the label instructions pending further guidance 
from a Millennium Quality representative.
Call Center
Phone Number
Email
Fax
PPD


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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
(refer to Section 10.2).
11.12
Closure of the Study
Study participation by individual sites or the entire study may be prematurely terminated if, 
in the opinion of the investigator or Millennium, there is sufficient reasonable cause. Written 
notification documenting the reason for study termination will be provided to the 
investigator or Millennium by the terminating party.
Circumstances that may warrant termination include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to patients

Failure to enter patients at an acceptable rate

Insufficient adherence to protocol requirements

Insufficient, incomplete, and/or unevaluable data

Determination of efficacy based on interim analysis

Plans to modify, suspend or discontinue the development of the study drug
Should the study be closed prematurely, the site will no longer be able to access the EDC 
application, will not have a right to use the EDC application, and will cease using the 
password or access materials once their participation in the study has concluded. In the event 
that any access devices for the EDC application have been provided, these will be returned 
to Millennium once the site’s participation in the study has concluded.
11.13
Record Retention
The investigator will maintain all study records according to the ICH-GCP and applicable 
regulatory requirement(s). Records will be retained for at least 2 years after the last 
marketing application approval or 2 years after formal discontinuation of the clinical 
development of the investigational product or according to applicable regulatory 
requirement(s). If the investigator withdraws from the responsibility of keeping the study 
records, custody must be transferred to a person willing to accept the responsibility and 
Millennium notified. 
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12.
USE OF INFORMATION
All information regarding MLN4924 supplied by Millennium to the investigator is 
privileged and confidential information. The investigator agrees to use this information to 
accomplish the study and will not use it for other purposes without consent from 
Millennium. It is understood that there is an obligation to provide Millennium with complete 
data obtained during the study. The information obtained from the clinical study will be used 
toward the development of MLN4924 and may be disclosed to regulatory authority(ies), 
other investigators, corporate partners, or consultants as required.
Upon completion of the clinical study and evaluation of results by Millennium, the hospital 
or institution and/or investigator may publish or disclose the clinical trial results pursuant to 
the terms contained in the applicable Clinical Trial Agreement.


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13.
INVESTIGATOR AGREEMENT
I have read Protocol C15011 Amendment 2: A Phase 1 Study to Evaluate the Effects of 
Fluconazole and Itraconazole CYP3A-Mediated Inhibition on the Pharmacokinetics, Safety,
and Tolerability of MLN4924 in Patients With Advanced Solid Tumors 
I agree to conduct the study as detailed herein and in compliance with International 
Conference on Harmonisation Guidelines for Good Clinical Practice and applicable 
regulatory requirements and to inform all who assist me in the conduct of this study of their 
responsibilities and obligations.
Principal investigator printed name
Principal investigator signature
Date
Investigational site or name of institution and 
location (printed)


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Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, et al. 
2006 update of recommendations for the use of white blood cell growth factors: an 
evidence-based clinical practice guideline. Journal of Clinical Oncology 
2006;24(19):3187-205.
17.
du Bois A, Luck HJ, Meier W, Adams HP, Mobus V, Costa S, et al. A randomized 
clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line 
treatment of ovarian cancer. J Natl Cancer Inst 2003;95(17):1320-9.
18.
Naughton CA. Drug-induced nephrotoxicity. American Family Physician 
2008;78(6):743-50.
19.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. 
American Journal of Clinical Oncology 1982;5(6):649-55.
20.
The Criteria Committee of New York Heart Association. Nomenclature and Criteria 
for Diagnosis of Diseases of the Heart and Great Vessels. 9 ed. Boston, MA: Little, 
Brown & Co; 1994.


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15.
APPENDICES
15.1
Hematologic Toxicity of Carboplatin Alone and in Combination With
Paclitaxel
In 2 prospectively randomized, controlled studies conducted by the National Cancer Institute 
of Canada Clinical Trials Group and the SWOG, 789 chemotherapy-naïve patients with 
advanced ovarian cancer were treated with carboplatin or cisplatin in combination with 
cyclophosphamide every 28 days for 6 courses before surgical re-evaluation. See 
Table 15-1 for the hematologic adverse experiences of patients treated with carboplatin in 
combination with cyclophosphamide.
Table 15-1
Hematologic Adverse Experiences of in Patients With Ovarian Cancer 
Treated With Carboplatin in Combination With Cyclophosphamide
Adverse Experience
Laboratory Value
NCIC CTG Study
% Patients
(N=447)
SWOG Study
% Patients
(N=342)
Bone Marrow
   Thrombocytopenia
< 100,000/mm3
70
59
< 50,000/mm3
41
22
   Neutropenia
< 2000 cells/mm3
97
95
< 1000 cells/mm3
81
84
   Leukopenia
< 4000 cells/mm3
98
97
  
< 2000 cells/mm3
68
76
   Anemia
< 11 g/dL
91
88
< 8 g/dL
18
8
Infections
14
18
Bleeding
10
6
Transfusions
42
25
Source: Carboplatin US Package Insert.(12)
Abbreviations: NCIC CTG=National Cancer Institute of Canada Clinical Trials Group; SWOG=Southwest 
Oncology Group. 
In a randomized clinical trial, 798 patients with ovarian cancer were treated with either 
cisplatin/paclitaxel or paclitaxel/carboplatin therapy at 3-week intervals for 6 courses. See 
Table 15-2 for the hematologic adverse experiences of patients treated with 
paclitaxel/carboplatin.


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Table 15-2
Hematologic Toxicities and Associated Supportive Care in Patients With Advanced Ovarian Cancer Stratified by 
Treatment Arm and Toxicity Grade
NCI CTC Grade, %
Differencea in the Proportions of 
Patients With Grades 3/4 Toxicity, %
Paclitaxel/Carboplatin Arm
Cisplatin/Paclitaxel Arm
Toxicity
Set
N
0
1
2
3
4
N
0
1
2
3
4
E
95% CI
Hemoglobin
C
2209
29.1
49.4
20.1
1.3
0.1
2095
33.6
49.5
16.1
0.8
0.0
-0.6
-1.3 to 0.0
P
388
9.0
40.7
44.3
5.4
0.5
382
14.7
44.2
37.2
3.9
0.0
-2.0
-5.1 to 1.1
Platelets
C
2193
71.9
19.9
5.2
2.5
0.5
2082
93.4
6.2
0.2
0.2
0.0
-2.9
-3.6 to -2.1
P
388
43.3
31.2
12.6
10.1
2.8
382
78.3
19.4
1.3
1.0
0.0
-11.8
-15.3 to -8.4
Transfusions 
pRBCsa
C
1868
94.3
--
--
5.7
--
1766
97.2
--
--
2.8
--
-2.9
-4.2 to -1.6
P
383
81.7
--
--
18.3
--
370
89.5
--
--
10.5
--
-7.7
-12.7 to -2.8
Leukocytes
C
2200
37.0
22.6
29.3
10.8
0.3
2073
56.4
23.3
17.3
2.9
0.0
-8.1
-9.6 to -6.6
P
388
13.4
16.0
38.7
30.4
1.5
382
31.4
35.1
32.7
10.5
0.3
-21.2
-26.8 to -15.6
Neutrophils
C
1842
56.9
12.9
12.8
12.4
5.0
1864
70.9
10.6
9.8
6.4
2.3
-8.7
-10.8 to -6.5
P
371
31.3
12.9
18.9
21.6
15.4
373
48.0
13.1
16.9
15.0
7.0
-14.9
-21.4 to -8.5
Febrile 
neutropenia
C
2228
98.3
--
--
1.7
0.0
2110
99.3
--
--
0.7
0.0
-0.9
-1.6 to -0.3
P
388
92.0
--
--
8.0
0.0
384
96.4
--
--
3.6
0.0
-4.3
-7.6 to -1.1
Supportive 
care: 
antibioticsb
C
1868
98.3
--
--
1.7
--
1768
97.9
--
--
2.1
--
0.4
-0.5 to 1.3
P
383
93.2
--
--
6.8
--
370
90.5
--
--
9.5
--
2.7
-1.2 to 6.6
Supportive 
care: G-CSFb
C
1868
94.0
--
--
6.0
--
1767
98.2
--
--
1.8
--
-4.2
-5.5 to -3.0
P
383
85.6
--
--
14.4
--
370
95.4
--
--
4.6
--
-9.8
-13.9 to -5.7
Source: du Bois et al, 2003.(17)
Abbreviations: --=not defined; C=maximum grade over all courses; CI=confidence interval; G-CSF=granulocyte colony-stimulating factor; E=estimate; 
N=number of courses in set C and number of patients in set P; NCI CTC=National Cancer Institute Common Toxicity Criteria;


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Table 15-2
Hematologic Toxicities and Associated Supportive Care in Patients With Advanced Ovarian Cancer Stratified by 
Treatment Arm and Toxicity Grade
NCI CTC Grade, %
Differencea in the Proportions of 
Patients With Grades 3/4 Toxicity, %
Paclitaxel/Carboplatin Arm
Cisplatin/Paclitaxel Arm
Toxicity
Set
N
0
1
2
3
4
N
0
1
2
3
4
E
95% CI
P=maximum grade over all courses within a patient; pRBCs=packed red blood cells.
a Differences are calculated by subtracting the paclitaxel/carboplatin arm proportion from the cisplatin/paclitaxel arm proportion; statistically significant 
differences in proportions between the 2 treatment arms are in bold font. All percentages are rounded; therefore, the estimates may differ by 1 from the 
difference of the percentages of the treatment arm columns.
b Transfusion of pRBCs, use of antibiotics, and G-CSF were not assessed for the last treatment cycle within a patient. Use of antibiotics and G-CSF is graded in 
the same fashion as transfusion of pRBCs. Use of antibiotics/application of G-CSF is coded as a toxicity of Grade 3; a Grade 0 is applied otherwise.


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15.2
Drugs Associated With Nephrotoxicity
The drugs listed in Table 15-3 are permitted to be used during the conduct of this study but 
should be used with caution.
Table 15-3
Drugs Associated with Nephrotoxicity
Analgesics
Cardiovascular agents
Nonsteroidal anti-inflammatory drugs
Angiotensin-converting enzyme inhibitors, 
angiotensin receptor blockers
Antidepressants/mood stabilizers
Clopidogrel (Plavix), ticlopidine (Ticlid)
Lithium
Contrast dye
Antimicrobials
Diuretics
Acyclovir (Zovirax)
Loops, thiazides
Aminoglycosides
Triamterene (Dyrenium)
Amphotericin B (Fungizone; deoxycholic acid 
formulation more so than the lipid formulation)
Herbals
Beta lactams (penicillins, cephalosporins)
Chinese herbals with aristocholic acid
Foscarnet (Foscavir)
Others
Ganciclovir (Cytovene)
Allopurinol (Zyloprim)
Pentamidine (Pentam)
Gold therapy
Quinolones
Haloperidol (Haldol)
Rifampin (Rifadin)
Pamidronate (Aredia)
Sulfonamides
Phenytoin (Dilantin)
Vancomycin (Vancocin)
Quinine (Qualaquin)
Antiretrovirals
Zoledronate (Zometa)
Adefovir (Hepsera), cidofovir (Vistide), tenofovir 
(Viread)
Indinavir (Crixivan)
Calcineurin inhibitors
Cyclosporine (Neoral)
Tacrolimus (Prograf)
Source: Modified from Naughton et al, 2008.(18)


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15.3
Response Criteria
Disease Response Criteria for Target and Nontarget Lesions
Evaluation of Target Lesions
Complete response 
(CR)
Disappearance of all target lesions. Any pathological lymph nodes (whether target or 
nontarget) must have reduction in short axis to < 10 mm.
Partial response (PR)
At least a 30% decrease in the sum of diameters of target lesions, taking as reference 
the baseline sum of diameters.
Progressive disease 
(PD)
At least a 20% increase in the sum of diameters of target lesions, taking as reference 
the smallest sum on study (this includes the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. The appearance of 1 or more new lesions is also 
considered progression.
Stable disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum of diameters while on study.
Evaluation of Nontarget Lesions
CR
Disappearance of all nontarget lesions and normalization of tumor marker level. All 
lymph nodes must be nonpathological in size (< 10 mm short axis). 
Non-CR/non-PD 
Persistence of one or more nontarget lesion(s) or/and maintenance of tumor marker 
level above the normal limits.
PD
Appearance of one or more new lesions and/or unequivocal progression of existing 
nontarget lesions.
Source: Eisenhauer et al, 2009.(14)
Overall Disease Response Criteria
Target Lesions
Nontarget Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
Inevaluable
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Source: Eisenhauer et al, 2009.(14)
Abbreviations: CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease.


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15.4
Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction
1
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (eg, light housework, office 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.
3
In bed > 50% of the time. Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair
5
Dead
Source: Oken et al, 1982.(19)
15.5
Formula for Absolute Neutrophil Count Calculation
ANC=total leukocyte count × total percentage of neutrophils (segmented neutrophils+band 
neutrophils)
Example
If: total leukocyte count=4.3; segmented neutrophils=48%; band neutrophils=2% 
Then: 4300 × (0.48+0.02)=4300 × 0.5=ANC of 2150
15.6
Cockcroft-Gault Equation
For males: 
Creatinine Clearance=(140-age [years] weight [kg])  OR (140–age [years] weight [kg])
72 (serum creatinine [mg/dL])
0.81 (serum creatinine [mol/L])
For females:
Creatinine Clearance=0.85 (140-age[years] weight [kg]) OR  0.85 (140–age[years] weight [kg])
72 (serum creatinine [mg/dL])         0.81 (serum creatinine[mol/L])


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15.7
Excluded CYP3A Inducers
Note that HIV medications that are strong CYP3A inducers are not included in this list 
because HIV-positive patients are excluded from study participation.
Use of the clinically significant CYP3A inducers listed in Table 15-4 should be avoided 
during MLN4924 therapy.
Table 15-4
In Vivo Inducers of CYP3A
Strong Inducers
≥ 80% Decrease in AUC
Moderate Inducers
50%-80% Decrease in AUC
Carbamazepine
Bosentan
Phenytoin
Efavirenz
Phenobarbital
Modafinil
Primidone
Nafcillin
Rifabutin
Rifampin
Rifapentine
St. John’s Wort
Abbreviations: AUC=area under the plasma concentration versus time curve; CYP=cytochrome P450.
This is not an exhaustive list; please refer to the following sources: medicine.iupui.edu/flockhart/table.htm 
and fda.gov/CDER/drug/drugInteractions/tableSubstrates.htm for additional information.
15.8
New York Heart Association Classification of Cardiac Disease
The following table presents the New York Heart Association classification of cardiac 
disease.(20)
Class
Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting limitations of 
physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain.
No objective evidence 
of cardiovascular 
disease
II
Patients with cardiac disease resulting in slight limitation of physical 
activity. They are comfortable at rest. Ordinary physical activity results 
in fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of 
minimal cardiovascular 
disease
III
Patients with cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary activity causes 
fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of 
moderately severe 
cardiovascular disease
IV
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of heart failure or the 
anginal syndrome may be present even at rest. If any physical activity is 
undertaken, discomfort is increased.
Objective evidence of 
severe cardiovascular 
disease


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15.9
Classification of Chronic Obstructive Pulmonary Disease by Spirometry
Table 15-5
Classification of Chronic Obstructive Pulmonary Disease by 
Spirometry
Stage
Severity
FEV1/FVC
FEV1
Stage I
Mild
< 0.70
FEV1 80% predicted
Stage II
Moderate
< 0.70
50% FEV1 < 80% predicted
Stage III
Severe
< 0.70
30% FEV1 < 50% predicted
Stage IV
Very severe
< 0.70
FEV1 < 30% predicted or 
FEV1 < 50% predicted plus chronic 
respiratory failure
Abbreviations: FEV1=forced expiratory volume in 1 second; FVC=forced vital capacity.
15.10
Methods of Contraception Considered to be Effective
Acceptable Contraception Methods Considered Highly Effective
Birth control methods that can achieve a failure rate of less than 1% per year when used 
consistently and correctly are considered to be highly effective. Such methods include:

Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulationa:
–
Oral.
–
Intravaginal.
–
Transdermal.

Progestogen-only hormonal contraception associated with inhibition of ovulationa:
–
Oral.
–
Injectable.
–
Implantable.b

Intrauterine device.b

Intrauterine hormone-releasing system.b


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
Bilateral tubal occlusion.b

Vasectomised partner.b,c

Sexual abstinence.d
Contraception Methods Considered Less Highly Effective
Acceptable birth control methods that result in a failure rate of more than 1% per year 
include:

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not 
the primary mode of action.

Male or female condom with or without spermicide.e

Cap, diaphragm, or sponge with spermicide.e
Source: European Heads of Medicines Agencies (HMA) Clinical Trial Facilitation Group (CTFG); see 
hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09_HMA_ 
CTFG_Contraception.pdf
a Hormonal contraception may be susceptible to interaction with the investigational medicinal product, which 
may reduce the efficacy of the contraception method.
b Contraception methods that in the context of this guidance are considered to have low user dependency.
c Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual 
partner of the woman of childbearing potential participant of the study and that the vasectomised partner has 
received medical assessment of the surgical success.
d In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the subject.
e A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-barrier 
methods) are also considered acceptable, but not highly effective birth control methods.
15.11
Amendment 1 Rationale and Purpose
Rationale for Amendment 1
The primary purpose of this amendment is to enroll additional patients in this study to 
further evaluate the effect of the strong cytochrome P450 (CYP) 3A inhibitor, itraconazole, 
on MLN4924 pharmacokinetics (PK) at the clinically relevant dose of MLN4924, 20 mg/m2. 
On the basis of preliminary assessments from 26 patients (13 fluconazole, 13 itraconazole) 
who have completed Part A to date, steady-state exposures of fluconazole (classified as a 
moderate CYP3A inhibitor) had minimal effect (average 13% increase in area under the 
plasma concentration versus time curve from time zero to infinity) on the single-dose 


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intravenous (IV) PK of MLN4924, while MLN4924 systemic exposure increased by 23% on 
average in the presence of itraconazole (classified as a strong CYP3A inhibitor). These 
modest drug interaction effects observed with 2 validated moderate and strong CYP3A 
inhibitor probes, respectively, appear inconsistent with the currently available in vitro 
metabolism data indicating a major role of CYP3A in MLN4924 metabolism. The 
information from these additional patients will provide further understanding of the 
contribution of CYP3A metabolism to the disposition of MLN4924 in humans within the 
clinically relevant dose range in support of adequate labeling.
On the basis of the emerging safety information in the 26 patients, co-administration of 
MLN4924 with fluconazole or itraconazole was generally well tolerated. The proposed 
single IV dose of MLN4924, 20 mg/m2, is approximately 5-fold lower than doses of 
MLN4924 equal to or above 110 mg/m2, which were associated with more severe Cycle 1 
Day 1 adverse events in phase 1 studies of MLN4924. Also, on the basis of the dose-linear 
PK of MLN4924 and observed 23% increase in MLN4924 systemic exposure by 
itraconazole at a single 8-mg/m2 dose, it can be inferred that plasma exposures of MLN4924 
when administered at a single 20-mg/m2 dose with itraconazole can be expected to be well 
below exposures seen at doses ≥110 mg/m2. 
Before enrolling patients at the target dose of 20 mg/m2 MLN4924, an intermediate dose of 
15 mg/m2 MLN4924+itraconazole will be evaluated as a safety lead-in cohort. If the review 
of safety and PK data from 3 PK-evaluable patients in this safety lead-in cohort confirms 
that the anticipated safety margin is adequate, enrollment into the 20-mg/m2 MLN4924 arm 
will begin. Thus, this amendment is adding a total of approximately 20 patients to the 
Itraconazole Arm: approximately 4 patients (for 3 PK evaluable) in the safety lead-in cohort 
and approximately 16 patients (for 12 PK evaluable) in the 20-mg/m2 MLN4924 cohort.
The 3-hours postdose vital sign assessment will no longer be required in Part B. This change 
is based on the available safety data from the MLN4924 program; at the doses to be 
explored in this study, there have been no significant alterations of vital signs reported at 
3 hours postdose. Furthermore, the change is aligned with the current Study C15010 on 
which Part B of this study is based. Study C15010 does not require 3-hours postdose vital 
signs for the same safety considerations. 
Dose modifications related to platelet counts have been clarified to ensure that MLN4924 
dosing is delayed if the platelet count is < 100,000/µL during Cycle 2 and beyond. 
Purposes for Amendment 1
The purposes of this amendment are as follows:

Add 12 PK-evaluable patients to evaluate the CYP3A inhibition-mediated drug 
interaction effect of itraconazole on MLN4924 PK at the clinically relevant dose of 
20 mg/m2 MLN4924.

Add 3 PK-evaluable patients treated with 15 mg/m2 MLN4924 in the Itraconazole Arm 
as an intermediate safety lead-in step before dosing any patients with 20 mg/m2
MLN4924. 

Update the stopping rules for the additional patients enrolled in the new Itraconazole 
Arm, 20-mg/m2 MLN4924 Cohort, on the basis of review of the Part A safety and PK 
data obtained from the Safety Lead-in 15-mg/m2 MLN4924 Cohort.


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
Include the possibility that a subset of the PK samples may be used for measurement of 
concentration of the co-administered drugs (fluconazole or itraconazole), if considered 
necessary to verify treatment assignments.

Remove vital signs measurement at 3 hours postdose in Part B (ie, Days 1, 3, and 5 of 
all cycles in Part B) for all patients.

Clarify in Table 6-1 that the platelet count must be > 100,000/µL on any dosing day in 
Cycles ≥ 2, or MLN4924 dosing will be delayed and chemotherapy dose may be 
modified. 

Correct a typographical error in Inclusion Criterion 6 (the unit for creatinine clearance 
is now mL/minute, instead of L/minute as incorrectly stated in the original protocol).

Revise text within Section 8.1, Statistical Methods: safety populations and treatment-
emergent adverse events are defined separately for Part A and Part B, and details have 
been added for electrocardiogram and vital sign assessments.

Correct typographical errors, punctuation, grammar, and formatting.


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15.12
Amendment 2 Detailed Description of Amendments to Text 
The primary sections of the protocol affected by the changes in Amendment 2 are indicated. 
The corresponding text has been revised throughout the protocol. All changes are applicable 
after completion of Cycle 12.
Change 1: Extend the 2-day window for scheduling issues (eg, inclement weather, holidays, 
vacations, or other administrative reasons) to 2 weeks; treatment breaks of up to 4 weeks 
may be permitted after discussion between the investigator and the project clinician or 
designee, and the investigator will confirm patient eligibility for continued treatment upon 
return, before treatment.
The primary change occurs in: Section 6.4.2 Dose Modification Guidelines for 
MLN4924:
Added 
text:
For patients who take treatment breaks at the investigator’s discretion, 
patient eligibility for continued treatment, including all Day 1 predose 
assessments specified in the Schedules of Events, will be confirmed by the 
investigator before resumption of treatment. Treatment breaks must be no 
longer than 2 weeks in duration (4 weeks after consulting with the sponsor); 
treatment breaks may not be taken consecutively.
Rationale for Change:
The visit window for assessments was extended to 2 weeks to accommodate scheduling 
issues, and an option for treatment breaks (up to 4 weeks after consulting with the sponsor) 
was added to allow flexibility for patients continuing beyond 12 cycles of treatment.
The following sections also contain this change:

Protocol Summary.

Section 4.1 Overview of Study Design.

Section 4.3 Duration of Study.

Section 6.1.2 Continued Treatment With MLN4924 in Combination With Standard of 
Care (Part B).

Section 7.4 Study Procedures.

Section 7.8 Study Compliance.


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Change 2: Reduce the frequency of disease response assessments from every 3 cycles to 
every 6 cycles.
The primary change occurs in Section 7.4.16 Disease Assessment (Part B):
Added 
text:
Computed tomography scans with IV contrast encompassing the known sites of 
disease will also be performed at the end of Cycle 2, end of Cycle 4, and at the 
end of every other cycle (Cycles 1-12), or after completion of every sixth cycle 
after the patient’s previous scan (after completion of Cycle 12 and 
implementation of Amendment 2) thereafter. Additional CT scans may be 
performed, per investigator's discretion, if clinically indicated. 
Rationale for Change:
The reduction in frequency of disease response assessments was made to lessen the burden 
for patients continuing beyond 12 cycles of treatment.
The following sections also contain this change:

Schedule of Events for Continued Treatment With MLN4924+Standard of Care 
(Part B): Cycle 13 and Beyond (as of Amendment 2).

Section 4.1 Overview of Study Design.
Change 3: Reduce the frequency of hematology, vital sign, clinical chemistry, and 
electrocardiogram assessments and physical examinations.
The primary change is reflected in the new Schedule of Events for Continued Treatment 
With MLN4924+Standard of Care (Part B): Cycle 13 and Beyond (as of Amendment 2):
Description 
of change:
Day 8 hematology, vital signs, clinical chemistry, and symptom-directed 
physical examination are not present in the new Schedule of Events for Cycle 13 
and Beyond. As these were the only activities on Day 8, the clinic visit on this 
day is not present in the new Schedule of Events. The complete physical 
examination on Day 1 was replaced with a symptom-directed physical 
examination.
Rationale for Change:
The Day 8 hematology assessment, vital signs assessment, clinical chemistry panel, and 
symptom-directed physical examination and the Day 1 complete physical examination are 
not present in the new Schedule of Events for Cycle 13 and beyond because these 
assessments are no longer considered necessary for patients continuing beyond 12 cycles of 
treatment; on Day 1, a symptom-directed physical examination was considered sufficient. 


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Change 4: Add phosphate to the urinalysis parameters.
The primary change is reflected in Section 7.4.15 Clinical Laboratory Evaluations:
Description 
of change:
Phosphate has been added to the urinalysis parameters after completion of 
Cycle 12.
Rationale for Change:
Phosphate has been added to the urinalysis parameters to be consistent with program-wide 
recommendations.
Change 5: Add a ±10-minute window to the MLN4924 infusion duration.
The primary change occurs in Section 6.1.2 Continued Treatment With MLN4924 in 
Combination With Standard of Care (Part B):
Added 
text:
Patients will receive MLN4924 given as a 1-hour (±10 minutes as of 
Amendment 2) IV infusion in combination with either docetaxel or with 
carboplatin+paclitaxel at a dose regimen informed from Study C15010 that has 
been deemed tolerable (eg, no DLTs in 3 patients or no more than 1 DLT in 6 
patients).
Rationale for Change:
The addition of the ±10-minute window to the MLN4924 infusion duration was made to 
allow flexibility in MLN4924 infusion duration.
The following sections also contain this change:

Study Flow Diagram 2.

Section 4.1 Overview of Study Design.


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Change 6: Remove the requirement for independent data monitoring committee monitoring.
The primary change occurs in deleted Section 9.2 Independent Data Monitoring Committee:
Deleted 
text:
9.2   Independent Data Monitoring Committee
An IDMC has been formed to periodically monitor the overall conduct of studies 
within the MLN4924 program, including review of accumulating clinical study 
data and safety data (both clinical and nonclinical) and to make 
recommendations to Millennium to safeguard the interests of study participants. 
Additionally, the IDMC may make recommendations relating to the 
selection/recruitment/ retention of study participants, patient management, 
improving adherence to protocol-specified regimens, and the procedures for data 
management and quality control. Further details regarding the IDMC are located
in the IDMC charter.
Rationale for Change:
No new safety issues were identified from Study C15011 data analyzed during IDMC 
meetings, and only 3 patients remain active in the study; therefore, as of Amendment 2
implementation, the IDMC will no longer be required to monitor Study C15011.
Section 1.6.1 Risks of MLN4924 Therapy also contains this change.


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Change 7: Adjust contraception requirements to be consistent with Clinical Trial 
Facilitation Group recommendations.
The primary change occurs in Section 6.7.1 MLN4924:
Initial 
wording:
6.7.1
MLN4924
…

If they are of childbearing potential, agree to practice 2 effective methods
of contraception, at the same time, from the time of signing the informed 
consent form (ICF) through 4 months after the last dose of study drug, or 

Agree to practice true abstinence, when this is in line with the preferred and 
usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, and postovulation methods] and withdrawal are not 
acceptable methods of contraception.) 
Male patients, even if surgically sterilized (ie, status postvasectomy), must agree 
to 1 of the following:
…
Agree to practice true abstinence, when this is in line with the preferred and 
usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, and postovulation methods for the female partner] and 
withdrawal are not acceptable methods of contraception.)
Amended 
or new 
wording:
6.7.1
MLN4924
…

As of Amendment 2, Iif they are of childbearing potential, agree to 
practice 2 1 highly effective methods and 1 additional effective (barrier) 
method of contraception, at the same time, from the time of signing the 
ICF through 4 months after the last dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and 
usual lifestyle of the subject patient. (Periodic abstinence [eg, calendar, 
ovulation, symptothermal, and postovulation methods], and withdrawal, 
spermicides only [as of Amendment 2], and lactational amenorrhea [as 
of Amendment 2] are not acceptable methods of contraception. Female 
and male condoms should not be used together.) 
As of Amendment 2, female patients must agree to not donate eggs (ova) 
during the course of this study or 4 months after receiving their last dose of 
study drug(s).
Male patients, even if surgically sterilized (ie, status postvasectomy), must agree 
to 1 of the following:
…


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
Agree to practice true abstinence, when this is in line with the preferred and 
usual lifestyle of the subject patient. (Periodic abstinence [eg, calendar, 
ovulation, symptothermal, and postovulation methods for the female 
partner], and withdrawal, spermicides only [as of Amendment 2], and 
lactational amenorrhea [as of Amendment 2] are not acceptable methods 
of contraception. Female and male condoms should not be used 
together.) 
As of Amendment 2, male patients must agree to not donate sperm during 
the course of this study or 4 months after receiving their last dose of study 
drug(s).
Rationale for Change:
The update in contraception requirements was included for consistency with program-wide 
updates.
The following sections also contain this change:

Section 5.1.Inclusion Criteria.

Section 15.10 Methods of Contraception Considered to be Effective.
Change 8: Update the description of the drug product.
The primary change occurs in Section 6.11.1 MLN4924:
Initial 
wording:
The drug product is labeled MLN4924 (MLN4924-003 Injection).
Amended 
or new 
wording:
The drug product is labeled MLN4924 (MLN4924-003 Injection concentrate 
for solution for infusion).
Rationale for Change:
The update of drug product description was an administrative change in response to the new, 
program-wide description for the drug product.
The following sections also contain this change:

Section 6.12.1 MLN4924.

Section 6.13.1 MLN4924.

Section 6.14.1 MLN4924.


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Change 9: Update the investigator responsibilities for compliance with updated
International Conference on Harmonisation guidelines.
The primary change occurs in Section 11.1 Good Clinical Practice:
Added 
Text:
The investigator is responsible for supervising any individual or party to 
whom the investigator delegates trial-related duties and functions 
conducted at the trial site. If the investigator/institution retains the services 
of any individual or party to perform trial related duties and functions, the 
investigator/institution should ensure that this individual or party is 
qualified to perform those trial-related duties and functions and should 
implement procedures to ensure the integrity of the trial-related duties and 
functions performed and any data generated.
Rationale for Change:
Investigator responsibilities were updated to comply with updated changes in ICH 
guidelines. 
Change 10: Update the description of dose-limiting toxicities observed in Study C15003 to 
be consistent with final data.
The primary change occurs in Section 1.4 MLN4924 Clinical Experience:
Initial 
wording:
The maximum tolerated dose (MTD) for Schedule A was established at 
59 mg/m2 based on dose-limiting toxicities (DLTs) of increased transaminases 
and shock observed at a dose level of 79 mg/m2.
Amended 
or new 
wording:
The maximum tolerated dose (MTD) for Schedule A was established at 
59 mg/m2 based on a dose-limiting toxicityies (DLTs) of increased 
transaminases and shock observed at a dose level of 79 78 mg/m2.
Rationale for Change:
The description of DLTs observed in Study C15003 were updated to be consistent with the 
final data presented in the Investigator’s Brochure and clinical study report.


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Change 11: Update vital signs assessments to allow measurements to be taken with the 
patient in the supine or sitting position.
The primary change occurs in Section 7.4.9 Vital Signs:
Added text: Vital signs, including diastolic and systolic blood pressure, heart rate, and body 
temperature will be collected as indicated in the Schedules of Events and as 
clinically indicated. All vital signs will be measured in the sitting position 
(and/or supine after completion of Cycle 12) as noted in the Schedules of 
Events.
Rationale for Change:
Supine vital signs assessments are permitted after completion of Cycle 12, consistent with 
program-wide recommendations.
The Schedule of Events for Continued Treatment With MLN4924+Standard of Care 
(Part B): Cycle 13 and Beyond (as of Amendment 2) also contains this change.
Change 12: Clarify the timing of transfusion for red blood cells to at least 1 day before
study drug administration.
The primary change occurs in Section 6.6.2 Permitted Concomitant Medications and 
Procedures (Part B):
Added 
text:
Red blood cell transfusions must be administered before administration of study 
drug (ie, day before dosing). Each transfusion episode, including the type of 
transfusion (red blood cell), should be recorded.
Rationale for Change:
The timing of transfusions was revised to occur at least 1 day before study drug 
administration.
Section 6.9.2 Guidance for Clinical Assessment and Management of Anemia also contains 
this change.
Change 13: Remove gamma glutamyl transferase from the serum chemistry parameters.
The primary change occurs in Section 7.4.15 Clinical Laboratory Evaluations:
Description 
of Change:
Assessment of gamma glutamyl transferase as part of serum chemistry is no 
longer required after completion of Cycle 12.


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Rationale for Change:
Assessment of gamma glutamyl transferase is no longer considered necessary for patients 
continuing beyond 12 cycles of treatment. 
Change 14: Remove known breast cancer resistance protein substrates, moderate and strong
inhibitors of cytochrome P450 3A4, and inhibitors of P-glycoprotein from the list of 
excluded concomitant medications.
The primary change occurs in Section 6.5.2 Excluded Concomitant Medications and 
Procedures (Part B):
Description 
of Change
Known BCRP substrates, moderate and strong inhibitors of CYP3A4, and 
inhibitors of P-gp were removed from the list of excluded concomitant 
medications. 
Rationale for Change:
Known BCRP substrates, moderate and strong inhibitors of CYP3A4, and inhibitors of P-gp
are no longer prohibited for MLN4924 therapy. Preliminary data from 11 patients who 
completed protocol-specified dosing and PK evaluations to assess the effect of itraconazole, 
a strong CYP3A inhibitor and P-gp inhibitor, on pevonedistat PK indicated that systemic 
exposures of pevonedistat following IV administration at 20 mg/m2 in the presence of 
itraconazole were similar to those in the absence of itraconazole. The data support removing 
strong CYP3A inhibitors and P-gp inhibitors from the list of prohibited concomitant 
medications in ongoing and planned pevonedistat clinical studies. The rationale for 
removing substrates of BCRP from excluded concomitant medications is based on an 
assessment of the DDI potential of MLN4924. When viewed in the context of the MLN4924 
mean Cmax value observed at the established MTD of 20 mg/m2 for the combination of 
MLN4924 plus azacitidine in Study C15009, MLN4924 is unlikely to inhibit the drug efflux 
transporter, and hence affect the PK of other drugs that are known BCRP substrates.
The following sections also contain this change:

Section 5.2 Exclusion Criteria.

Section 15.7 Excluded CYP3A Inducers.
Change 15: Replace references to the Safety Management Attachment with references to 
the Development Core Safety Information.
The primary change occurs in Section 1.6.1 Risks of MLN4924 Therapy:
Initial 
wording:
Additional information on risks is provided in the IB and the SMA.


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Amended 
or new 
wording:
Additional information on risks is provided in the IB and the SMADCSI.
Rationale for Change:
The content of the Safety Management Attachment has been incorporated into the DCSI 
which renders the Safety Management Attachment obsolete.
The following sections also contain this change:

Section 1.4 MLN4924 Clinical Experience.

Section 6.9 Management of Clinical Events.
Change 16: Update the description of the Safety Management Team to be consistent with 
current preferred language and to reflect its cross-functional nature.
The primary change occurs in Section 9.1 Millennium Safety Assessments:
Initial 
wording:
Safety data will be reviewed and assessed periodically by an internal safety 
working group throughout the conduct of the study. These reviews will include 
a safety physician, a clinical physician from the study team, and other 
representation from the Clinical Research, Pharmacovigilance, Biostatistics, 
Clinical Pharmacology, Regulatory Affairs, Drug Safety 
Evaluation/Toxicology, and Clinical Operations departments at Millennium. 
Escalation of safety issues to a senior management cross-functional safety board 
will be performed on an ad hoc basis.
Amended 
or new 
wording:
Safety data will be reviewed and assessed periodically by an internal safety 
working group a Global Pharmacovigilance team and a cross-functional 
Safety Management Team throughout the conduct of the study. These 
cross-functional reviews will include a safety physician, a clinical physician
Global Safety Lead from the study team, and as well as other representation 
from the Clinical Research, Pharmacovigilance, Biostatistics, Clinical 
Pharmacology, Regulatory Affairs, Drug Safety Evaluation/Toxicology, and 
Clinical Operations other departments at Millennium such as Clinical 
Research, Pharmacovigilance, Biostatistics, Clinical Pharmacology, and 
Clinical Operations. Escalation of safety issues to a senior management cross-
functional safety board will be performed on an ad hoc basis.
Rationale for Change:
This language was updated to be consistent with preferred terminology across the program 
and to reflect the cross-functional nature of the teams reviewing safety data.


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Change 17: Update contact information for product complaints.
The primary change occurs in Section 11.11 Product Complaints:
Initial 
wording:
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
(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,
Amended 
or new 
wording:
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
(see below) and report the 
event report this via the phone numbers or email address provided below. 
Whenever possible, the associated product should be maintained in accordance 
with the label instructions pending further guidance from a Millennium Quality 
representative.
Call Center
Phone Number
Email
Fax
Rationale for Change:
This contact information was updated to reflect an administrative change.
PPD
PPD
PPD
PPD
PPD


 
  
 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d6805c1bc8
Amendment 2 to A Phase 1 Study to Evaluate the Effects of Fluconazole and Itraconazole CYP3A-mediated
Inhibition on the Pharmacokinetics, Safety and Tolerability of MLN4924 in Patients With Advanced Solid Tumors
Biostatistics Approval
19-Apr-2017 02:03 UTC
Clinical Approval
19-Apr-2017 02:55 UTC
Clinical Pharmacology Approval
19-Apr-2017 05:32 UTC
PPD

SAP_001.pdf: 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

•
Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 1 Study to Evaluate the Effects of Fluconazole and Itraconazole
CYP3A-Mediated Inhibition on the Pharmacokinetics, Safety, and Tolerability of
MLN4924 in Patients With Advanced Solid Tumors
NCT Number: NCT02122770 
SAP Approve Date: 31 August 2017
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content 
is masked irreversibly from view with a black bar) to protect either personally identifiable 
information or company confidential information. 
Proprietary information, such as scales or coding systems, which are considered confidential
information under prior agreements with license holder.


1.0
MEDDRTITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: C15011
A Phase 1 Study to Evaluate the Effects of Fluconazole and Itraconazole
CYP3A-Mediated Inhibition on the Pharmacokinetics, Safety, and Tolerability of
MLN4924 in Patients With Advanced Solid Tumors
PHASE 1
Version: Final
Date: 31 August 2017
Prepared by:
Based on:
Protocol Version: Protocol Amendment No. 02
Protocol Date: 12 April 2017
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda.
PPD


C15011
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Statistical Analysis Plan
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CONFIDENTIAL
1.1
APPROVAL SIGNATURES
Study Title:
A Phase 1 Study to Evaluate the Effects of Fluconazole and Itraconazole
CYP3A-Mediated Inhibition on the Pharmacokinetics, Safety, and 
Tolerability of MLN4924 in Patients With Advanced Solid Tumors
Approvals:
Date
Date
Date
Date
Date
PPD
PPD
PPD
PPD
PPD


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CONFIDENTIAL
2.0
TABLE OF CONTENTS
1.0
MEDDRTITLE PAGE ....................................................................................................1
1.1
APPROVAL SIGNATURES.....................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................7
4.1
Primary Objectives ....................................................................................................7
4.2
Secondary Objectives.................................................................................................7
4.3
Exploratory Objectives ..............................................................................................7
4.4
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS.............................................................................................11
5.1
Primary Endpoint.....................................................................................................11
5.2
Secondary Endpoints ...............................................................................................11
5.3
Exploratory Endpoints .............................................................................................11
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................12
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................13
7.1
General Principles....................................................................................................13
7.1.1
Randomization and Stratification .......................................................................13
7.1.2
Methods for Handling Missing Data...................................................................13
7.1.3
Definitions of Baseline Values...........................................................................14
7.2
Analysis Sets ...........................................................................................................15
7.2.1
Safety Population...............................................................................................15
7.2.2
Pharmacokinetic-Evaluable Population ..............................................................15
7.2.3
Response-Evaluable Population .........................................................................16
7.3
Disposition of Subjects ............................................................................................16
7.4
Demographic and Other Baseline Characteristics.....................................................17
7.4.1
Inclusion/Exclusion Criteria...............................................................................17
7.4.2
Baseline Disease Status......................................................................................17
7.5
Medical History and Concurrent Medical Conditions...............................................18
7.6
Medication History and Concomitant Medications...................................................18
7.6.1
PriorTherapies....................................................................................................18
7.7
Study Drug Exposure and Compliance.....................................................................22
7.7.1
Study Treatments ...............................................................................................22
7.7.2
Treatment Compliance and Modifications..........................................................24
7.8
Efficacy Analysis (Part B) .......................................................................................24


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7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................25
7.9.1
Pharmacokinetic Analysis (Part A).....................................................................25
7.9.2
Pharmacodynamic Analysis (Part A)..................................................................28
7.10
Other Outcomes.......................................................................................................29
7.11
Safety Analysis........................................................................................................29
7.11.1 Adverse Events ..................................................................................................29
7.11.2 Clinical Laboratory Evaluations .........................................................................35
7.11.3 Vital Signs .........................................................................................................38
7.11.4 Electrocardiograms ............................................................................................39
7.11.5 Disseminated Intravascular Coagulation (DIC) and PT/PTT...............................39
7.11.6 Echocardiograms ...............................................................................................39
7.12
Interim Analysis ......................................................................................................40
7.13
Changes in the Statistical Analysis Plan...................................................................41
8.0
REFERENCES..............................................................................................................42


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Statistical Analysis Plan
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3.0
LIST OF ABBREVIATIONS
AE(s)
adverse event (or events)
ALT
alanine aminotransferase (SGPT)
ANC
absolute neutrophil count
ANOVA
Analysis of Variance
AST
aspartate aminotransferase (SGOT)
AUC
area under the plasma concentration-time curve
AUEC
area under the effect-time curve
AUEC_Above_24
area of the effect-time curve above baseline (positive value) from 0 to 24 hours 
post-dose
AUEC_Net_24
sum of the area of the effect-time curve above baseline (positive value) and the 
area of the effect-time curve below baseline (negative value) from 0 to 24 hours 
post-dose
AUMC
area under the first moment curve
BSA
body surface area
CKD-epi
chronic kidney disease epidemiology collaboration
CLp
Systemic clearance
Cmax
maximum plasma concentration
CPK
creatine phosphokinase
Cr
creatinine
CR
complete response
CRF
Case Report Form
CRP
C-reactive protein
CV
coefficient of variation
DBP
diastolic blood pressure
DDI
drug-drug interaction
DIC
disseminated intravascular coagulation
DLT
dose limiting toxicity
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EMax
observed maximum effect
EOS
End of Study
GFR
glomerular filtration rate
HLT
high level term
IV
intravenous
lambdaz
terminal disposition phase rate constant
LLQ
limit of quantification
LFT
liver function test
LVEF
left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities


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Statistical Analysis Plan
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CONFIDENTIAL
MRT
mean residence time
MTD
maximum tolerated dose
NAE
Nedd8-activating enzyme
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
PD
progressive disease
PK
pharmacokinetic
PR
partial response
PT
preferred term
PT
prothrombin time
QTcB
QT interval corrected for heart rate using Bazett’s formula
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RBC
red blood cell
SAE
serious adverse event
SBP
systolic blood pressure
SD
stable disease
SOC 
system organ class
t1/2
terminal disposition phase half-life   
TAD
time after dosing
TEmax
time to Emax
Tmax
first time at which Cmax occurs
TPR
Ratio of Day 8 pre-dose concentration to Day 8 Cmax
Vss
volume of distribution at steady state   
WBC
white blood cell   
WHO
World Health Organization


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CONFIDENTIAL
4.0
OBJECTIVES
4.1
Primary Objectives
The primary objective of the study is:
!
To assess the effect of multiple-dose administration of fluconazole, a moderate CYP3A 
inhibitor, on the single-dose IV PK of MLN4924
!
To assess the effect of multiple-dose administration of itraconazole, a strong CYP3A 
inhibitor, on the single-dose IV PK of MLN4924
4.2
Secondary Objectives
The secondary objectives for Part A are:
!
To further evaluate the safety and tolerability of MLN4924
!
To further describe the IV PK of MLN4924 before and after multiple oral dosing with 
fluconazole or itraconazole
The secondary objectives for Part B are:
!
To further assess the safety and tolerability of MLN4924 in combination with docetaxel in 
patients with solid tumors
!
To further assess the safety and tolerability of MLN4924 in combination with carboplatin 
and paclitaxel in patients with solid tumors
!
To further evaluate disease response that may be observed with the combination of
MLN4924 and docetaxel
!
To further evaluate disease response that may be observed with the combination of
MLN4924, carboplatin, and paclitaxel
4.3
Exploratory Objectives
The exploratory objective for Part A is:
4.4
Study Design
This study is an open-label, multicenter, parallel group, 2-arm, phase 1 study of MLN4924 
designed to assess DDIs with the moderate and strong CYP3A inhibitors fluconazole and 
itraconazole, respectively. The patient population will consist of patients 18 years of age or older 
who have a histologically or cytologically confirmed metastatic or locally advanced solid tumor 
that is deemed appropriate for treatment with 1 of the 2 combination therapies in Part B of this 
study, or who have progressed despite standard therapy, or for whom conventional therapy is not 
considered effective.
CCI


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Statistical Analysis Plan
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CONFIDENTIAL
It is expected that approximately 52 patients will be enrolled in this study to reach the intended 
total number of PK-evaluable patients in each arm/cohort. In the Fluconazole Arm, 
approximately 12 PK-evaluable patients will be enrolled. In the Itraconazole Arms, 
approximately 12 PK-evaluable patients will be enrolled in the 8-mg/m2 and 20-mg/m2
MLN4924 cohorts, and 3 additional PK-evaluable patients will be needed in the safety lead-in 
cohort (15-mg/m2). Once enrolled into the study, patients will begin treatment in Part A of the 
study. In Part A, patients will be administered MLN4924 via a 1-hour (± 5 minutes) IV infusion 
in combination with either fluconazole or itraconazole as indicated below. Once patients 
complete Part A (including the washout period), they can begin treatment in Part B of the study. 
In Part B, patients will be administered MLN4924 via a 1-hour (± 5 minutes) IV infusion in 
combination with either docetaxel or carboplatin + paclitaxel.
Part A: Drug-drug Interaction Assessment
MLN4924 + Fluconazole: Patients will receive a single 8-mg/m2 dose of MLN4924 given as a 
1-hour (± 5 minutes) IV infusion on Day 1 and Day 8. This low dose of MLN4924 is anticipated 
to provide an adequate safety margin for DDI assessment. Patients will receive concomitant oral 
fluconazole at a starting dose of 400 mg on Day 4 and then 200 mg QD on Days 5 through 10. 
Pharmacokinetic samples will be taken after the MLN4924 dose on Day 1 and after the Day 8 
dose of MLN4924 with fluconazole at predetermined time points (up to 72 hours after dosing) to 
assess the effect of fluconazole on the PK of MLN4924. Additional samples for determination of 
MLN4924 concentrations in whole blood will be collected on Day 1 only.
MLN4924 + Itraconazole:  Patients will receive a single dose of MLN4924 given as a 1-hour 
(5 minutes) IV infusion on Day 1 and Day 8 (see dose cohorts below).  Patients will receive 
concomitant oral itraconazole at a dose of 200 mg QD on Days 4 through 10.  Pharmacokinetic 
samples will be taken after the MLN4924 dose on Day 1 and after the Day 8 dose of MLN4924 
with itraconazole at predetermined time points (up to 72 hours after dosing) to assess the effect 
of itraconazole on the PK of MLN4924.  Additional samples for determination of MLN4924 
concentrations in whole blood will be collected on Day 1 only.  The following dose cohorts will 
be enrolled sequentially within the Itraconazole Arm:

Itraconazole Arm, 8-mg/m2 MLN4924 Cohort:  Patients will receive a single 8-mg/m2 dose 
of MLN4924 given as a 1-hour (5 minutes) IV infusion on Day 1 and Day 8.  This low 
dose of MLN4924 is anticipated to provide an adequate safety margin for DDI assessment.  

Itraconazole Arm, Safety Lead-in 15-mg/m2 MLN4924 Cohort:  Patients will receive a single 
15-mg/m2 dose of MLN4924 given as a 1-hour (5 minutes) IV infusion on Day 1 and Day 
8.  This safety lead-in cohort will confirm the safety margin is adequate before any patients 
are enrolled in the 20-mg/m2 MLN4924 Cohort.  

Itraconazole Arm, 20-mg/m2 MLN4924 Cohort:  Patients will receive a single 20-mg/m2
dose of MLN4924 given as a 1-hour (5 minutes) IV infusion on Day 1 and Day 8.  This 
dose of MLN4924 falls within the clinically relevant dose range currently evaluated in Phase 
1b combination studies of MLN4924 plus standard of care.


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Statistical Analysis Plan
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CONFIDENTIAL
A preliminary PK analysis will be conducted after the first 4 to 8 patients have completed the 
Fluconazole Arm of Part A. After review of the emerging data from the Fluconazole Arm, 
patient assignment to the Itraconazole Arm will be initiated. Dose modifications of MLN4924 in 
the Itraconazole Arm may be reconsidered based on the magnitude of the interaction with the 
moderate CYP3A inhibitor fluconazole and the ability to accurately estimate PK parameters for 
DDI evaluation.
Following completion of the first 3 patients in the Itraconazole Arm 8-mg/m2 MLN4924 Cohort, 
preliminary PK data will be reviewed to guide expansion of the Itraconazole Arm to the total 
intended number of 12 PK-evaluable patients. If these emerging preliminary PK data indicate 
that the magnitude of the interaction with the strong CYP3A inhibitor itraconazole reaches the 
anticipated approximately 10-fold change, and individual drug exposures do not exceed those 
seen at doses of MLN4924 ≥ 110 mg/m2, then up to 3 additional patients to provide 4 to 6 
PK-evaluable patients will be enrolled. If the magnitude of the interaction with the strong 
CYP3A inhibitor itraconazole is much greater than anticipated (greater than the predefined safety 
margin of 14-fold), with individual MLN4924 exposures exceeding those seen at doses of 
MLN4924 ≥ 110 mg/m2, then no additional patients will be enrolled in the Itraconazole Arm of 
Part A.
As of the implementation of Protocol Amendment 1, following completion of Part A by 3 
PK-evaluable patients in the Safety Lead-in 15-mg/m2 MLN4924 Cohort, safety and PK data 
will be reviewed to inform expansion of the Itraconazole Arm to the total intended number of 
12 PK-evaluable patients in the 20-mg/m2 MLN4924 Cohort. If the preliminary PK data from the 
safety lead-in cohort indicate that the magnitude of the interaction between the proposed 
20-mg/m2 MLN4924 dose and the strong CYP3A inhibitor itraconazole would be greater than 
the predefined safety margin (5-fold, with individual MLN4924 exposures potentially exceeding 
those seen at doses of MLN4924 ≥110 mg/m2), then no patients will be enrolled in the 20-mg/m2
MLN4924 Cohort. Dosing with intermediate doses of MLN4924 and/or evaluation of the drug 
interaction with the moderate CYP3A inhibitor, fluconazole, may then be reconsidered if it is 
deemed necessary to further enhance our understanding of the effect of CYP3A inhibition on the 
PK of MLN4924. 
Patients will be required to visit the clinic on Day 4 for their first dose of fluconazole or 
itraconazole. For both the Fluconazole and Itraconazole Arms, all doses of fluconazole and 
itraconazole will be administered on an empty stomach with the patient fasting from food and 
fluids, except water and prescribed medications, for 2 hours before and 1 hour after each dose. 
Patients are encouraged to take fluconazole or itraconazole doses at approximately the same time 
each morning and approximately 24 hours apart. On Day 8, patients will take fluconazole or 
itraconazole together with MLN4924 in the morning at the clinic.
In addition to blood sampling for PK, blood samples in the 24-hour postdose window of each 
arm following dosing on Day 1 and Day 8 will be collected to measure pharmacodynamic effects 
of MLN4924. These data will be pooled with data from other MLN4924 clinical studies to 
contribute to an integrated PK-pharmacodynamic analysis across the program.


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Part B: Continued Treatment With MLN4924 in Combination With Standard of Care
After patients complete Part A, they will have the opportunity to continue in the study by 
participating in Part B. In Part B, patients will receive MLN4924 in combination with either 
docetaxel or carboplatin + paclitaxel at a dose regimen informed from Study C15010 that has 
been deemed tolerable (eg, no DLTs in 3 patients or no more than 1 DLT in 6 patients). The 
selected dose of MLN4924 may be adjusted based on information obtained from the ongoing 
review of safety data. Safety and disease assessments will be conducted in Part B of the study.
Study drug will be discontinued if a patient experiences study drug-related toxicities. Patients 
may discontinue therapy at any time. Patients will attend the End-of-Study (EOS) visit 30 days 
after receiving their last dose of study drug. 
Throughout the study in Parts A and B, Eastern Cooperative Oncology Group (ECOG) 
performance status (PS) and adverse events (AEs) will be assessed, and laboratory values, vital 
signs, and electrocardiograms (ECGs) will be obtained and assessed. 
Computed tomography (CT) scans with IV contrast of the chest, abdomen, and pelvis will be 
performed as entry criteria for Part B (after completing of Part A), along with a clinical 
reassessment. In addition, in Part B, CT scans with IV contrast encompassing the known sites of 
disease will be performed at every other cycle and at the EOS visit. If CT scan does not provide 
adequate imaging, magnetic resonance imaging (MRI) may be used to evaluate sites of disease. 
Tumor response will be assessed by the investigator at these times using the RECIST criteria, 
version 1.1.


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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoint
!
Ratio of geometric mean, Cmax, AUC from time zero to the time of the last quantifiable 
concentration (AUC0-tlast), and AUC from time zero to infinity (AUC0-inf) of MLN4924 
administered with fluconazole versus MLN4924 administered alone and 90% confidence 
intervals (CIs)
!
Ratio of geometric mean, Cmax, AUC0-tlast, and AUC0-inf of MLN4924 administered with 
itraconazole versus MLN4924 administered alone and 90% CI
5.2
Secondary Endpoints
The secondary endpoints for Part A are:
!
AEs, serious adverse events (SAEs), assessments of clinical and laboratory values, weight 
and vital signs measurements
!
Pharmacokinetic parameters including but not limited to CL, first time to achieve maximum 
observed plasma concentration (Tmax), Vss, t1/2, and B/P ratio of MLN4924
The secondary endpoints for Part B are:
!
AEs, SAEs, assessments of clinical and laboratory values, weight and vital signs
measurements
!
Measures of disease response including objective response rate and duration of response 
based on investigator’s assessment using the Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (Version 1.1)
5.3
Exploratory Endpoints
The exploratory endpoint for Part A is:
CCI


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6.0
DETERMINATION OF SAMPLE SIZE
It is anticipated that as many as approximately 52 patients will be enrolled in this study.
The sample size calculation is based on the expected 2-sided 90% CI for the difference in the 
paired, log transformed AUC (or Cmax) means of MLN4924 on Day 1 (MLN4924 alone) and Day 
8 (MLN4924 co-administered with CYP3A inhibitor). Based on the PK information obtained 
from Schedules B and C of Study C15001, the within-subject CV was estimated to be 0.12 for 
AUC and 0.17 for Cmax, respectively. Assuming that the AUC (or Cmax) ratio in the presence of 
fluconazole versus in the absence of fluconazole or in the presence of itraconazole versus in the 
absence of itraconazole is 2.0, with a sample size of 12 evaluable patients per arm, the 90% CI of 
the ratio of geometric means is expected to be (1.833, 2.182) for AUC and (1.759, 2.274) for 
Cmax based on the above discussed variance assumptions. If the geometric mean AUC (or Cmax) 
ratio is X, the corresponding 90% CI is expected to be (1.833X/2, 2.182X/2) (or [1.759X/2, 
2.274X/2]).
In the Fluconazole Arm, approximately 12 PK-evaluable patients will be enrolled.  In the 
Itraconazole Arm, approximately 12 PK-evaluable patients will be enrolled in the 8-mg/m2 and 
20-mg/m2 MLN4924 cohorts, and 3 additional PK-evaluable patients will be needed in the safety 
lead-in cohort.  A patient is PK-evaluable if he or she completes the protocol-specified dosing 
and PK assessments without dose reductions in Part A.  Patients who are not PK-evaluable (see 
Section 7.2.2) will be replaced.  Assuming 25% of the enrolled patients will not be PK-
evaluable, approximately 52 patients will be enrolled to provide the total intended number of 
PK-evaluable patients in each arm of Part A.


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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles
All statistical analyses will be conducted using SAS® Version 9.2.
In general, summary tabulations will include the number of observations, (arithmetic) mean, 
standard deviation (SD), geometric mean  and coefficient of variation (%CV) for PK related 
parameters, median, minimum, and maximum for continuous variables, and the number and 
percent (of non-missing) per category for categorical data, unless specified otherwise.  
Descriptive statistics will be presented with the same precision as the original data. The PK 
parameters will be summarized with a precision of 3 significant digits, while tmax is presented
with the number of relevant decimal places to specify the sampling time. Percent CV and 
frequency percentages will be presented as integers.
Summary statistics will be calculated by time point, if applicable.
7.1.1
Randomization and Stratification
There is no randomization in this study. Patient assignment in Part A and Part B will proceed as 
below:
Part A: The first 4 to 8 patients will be assigned to the Fluconazole Arm (moderate CYP3A 
inhibitor). After review of the emerging data (see interim analyses section), the investigator will 
recommend each patient to the Fluconazole Arm (MLN4924 + fluconazole) or the Itraconazole 
Arm (MLN4924 + itraconazole), and the patient will be assigned to the appropriate arm by the 
sponsor based on slot availability until enrollment in each arm is filled.
Part B: Investigators may assign each patient to 1 of the 2 combination regimens (MLN4924 + 
docetaxel or MLN4924 + carboplatin + paclitaxel) in Part B based on their medical judgment 
after a washout period of at least 2 weeks (and up to 8 weeks) from the last dose of fluconazole 
or itraconazole to allow patients to recover from any safety concerns and to confirm that the 
patient is eligible to participate in Part B.
7.1.2
Methods for Handling Missing Data
All available data will be presented.  Data that are potentially spurious or erroneous will be 
examined under the auspices of standard data management operating procedures. Every effort 
will be made to avoid missing/partial date in on-study data.
In general, missing data will be treated as missing and no data imputation will be applied. 
MLN4924 concentration values missing the corresponding sampling date and time records will 
be excluded from PK analysis.


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7.1.2.1
Missing/Partial Dates in Screening Visit
The following rules apply to dates recorded in the screening visits. 

If only the day-component is missing, the first day of the month will be used if the year and 
the month are the same as those for the first dose of study drug. Otherwise, the 15th will be 
used.

If only a year is present, and it is the same as the year of the first dose of study drug, the 15th
of January will be used unless it is later than the first dose, in which case the date of the first 
of January will be used, unless other data indicate that the date is earlier. 

If only a year is present, and it is not the same as the year of the first dose of study drug, the 
15th of June will be used, unless other data indicates that the date is earlier. 
7.1.2.2
Missing/Partial Dates in Subsequent Therapies
Subsequent therapies with start dates that are completely or partially missing will be analyzed as 
follows:
1. When month and year are present and the day is missing, 
a.
If the onset month and year are the same as the month and year of last dose with study
drug, the day of last dose + 1 will be imputed.  
b. If the onset month and year are not the same as the month and year of last dose with 
study drug, the first day of the month will be imputed. 
2. When only a year is present, 
a.
If the onset year is the same as the year of last dose with study drug, the date of last 
dose + 1 will be imputed.  
b. If the onset year is not the same as the year of last dose with study drug, the first day 
of the year will be imputed. 
3. If no components of the onset date are present, the date of last dose + 1 will be imputed.
7.1.3
Definitions of Baseline Values
Part A
Unless otherwise specified, the baseline value is defined as the value collected at the time closest 
to, but prior to, the start of study drug administration during Part A.  For analysis of ECG data, 
the baseline value is the average of the screening and Part A Day 1 predose value if ECG is 


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collected at both screening and Part A Day 1 predose. If ECG is collected at only one of these 
two time points, the baseline value takes the value of the one that is collected.
Part B
Similarly, the baseline value is defined as the value collected at the time closest to, but prior to, 
the start of study drug administration during Part B. Since there is no screening visit for Part B, 
the baseline value for ECG is also the one collected at the time closest to, but prior to, the start of 
study drug administration during Part B.
Windowing of Visits
All data will be categorized based on the scheduled visit at which they were collected.  The
analysis of PK data and determination of PK parameters will be based on the actual elapsed time 
postdose relative to the start of first dosing.
Definition of Study Start Date
Study start date is defined as the date of the signing of the informed consent. 
Justification of Pooling
All data from all sites will be pooled.  Study center or treatment-by-center interaction will not be 
included in any statistical analysis.
Withdrawals, Dropouts, Loss to Follow-up
Patients who are not PK-evaluable will be replaced. Generally no additional patients will be 
enrolled due to withdrawals, dropouts, or loss to follow-up.
7.2
Analysis Sets
7.2.1
Safety Population
The safety population for Part A is defined as all enrolled patients who receive at least 1 dose of 
MLN4924 during Part A. 
All safety and pharmacodynamic analyses in Part A will be performed using the safety 
population for Part A.
The safety population for Part B is defined as all patients who continue to Part B and receive at 
least 1 dose of study drugs during Part B.
All safety analyses in Part B will be performed using the safety population for Part B.
7.2.2
Pharmacokinetic-Evaluable Population
The PK-evaluable
population is defined as all enrolled patients who receive all 
protocol-specified dose regimens within each period during Part A, did not receive any excluded 
medications throughout the completion of PK sampling, and have sufficient MLN4924 plasma 
concentration-time data to reliably estimate PK parameters based on noncompartmental analysis 


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methods. The patients to be included in the PK-evaluable population will be determined by the 
Takeda Clinical Pharmacologist upon review of the final data.
PK analyses during Part A will be performed using the PK-evaluable population.
7.2.3
Response-Evaluable Population
The response-evaluable population is defined as all patients who receive at least 1 dose of study 
drug in Part B, have measurable disease as entry criteria for Part B, and have at least 1 
postbaseline disease assessment.
Response analyses for Part B will be performed using the response-evaluable population.
7.3
Disposition of Subjects
Separate tabulations of patient disposition data will be generated for Part A and Part B. 
A tabulation of patient disposition data by the DDI cohort (fluconazole and itraconazole 
treatment arms) and the Part A total for Part A will include the number of patients for the 
following categories: patients treated (safety population for Part A) during Part A, patients in the 
PK-evaluable population, patients completing Part A, patients who discontinued study treatment 
during Part A (including the washout period), the primary reason off study treatment during Part 
A (including the washout period). Patients will be considered to have completed Part A if they 
have completed the protocol-specified assessments within Part A of the protocol. Percentages 
will be based on the number of patients in the safety populations for Part A.
A tabulation of patient disposition data by treatment arm and the Part B total for Part B will also 
be generated to include the following categories: patients treated (safety population for Part B) in 
Part B, patients in the response-evaluable population for Part B, patients completing Part B, 
patients who discontinue study treatment from Part B, and the primary reason off study treatment 
during Part B. Patients will be considered to have completed Part B of the study if they 
discontinue treatment during Part B for any of the following reasons:

Adverse event

Lost to follow-up

Progressive disease

Protocol violation

Study terminated by sponsor

Symptomatic deterioration

Unsatisfactory therapeutic response

Withdrawal by subject

Other


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Percentages in the table of disposition data for Part B will be based on the number of patients in 
the safety populations for Part B
Data concerning patient disposition (eg, primary reason off study treatment, patient population) 
will be presented in by-patient listings.
7.4
Demographic and Other Baseline Characteristics
7.4.1
Demographics
Demographics will be summarized by DDI cohort and total for the safety population in Part A, 
and by treatment arm and total for the safety population in Part B. Demographic data to be 
evaluated will include age at date of informed consent, sex, ethnicity, race, height, weight and 
body surface area (BSA).   
BSA is calculated for each patient using the following formula: 
BSA = 
Both Part A and Part B use Height collected at screening. Part A uses weight collected at 
screening.  If a weight at screening is not available, the Part A Day 1 predose weight can be used. 
Part B uses weight collected at the visit closest, but prior to the Part B Cycle 1 Day 1 study drug 
administration.
No inferential statistics will be generated.
Demographic data will also be presented in a by-patient listing.
7.4.1
Inclusion/Exclusion Criteria 
All inclusion/exclusion information on enrolled patients will be included in a by-patient listing 
for Part A.  Eligibility criteria for dosing during Part B for patients who continue into Part B will 
be presented in a separate listing. These listings will include whether all criteria were satisfied.  
For patients who did not satisfy the criteria, the criteria number will be listed with the deviation. 
In addition, all protocol deviations will be reviewed, and major protocol deviations will be 
identified and summarized by Part A and Part B in a table.  Any enrolled patients who did not 
meet inclusion or exclusion criteria will be summarized under the category “Not meeting study 
inclusion/exclusion criteria”.
Patient pregnancy test results will be included in a separate by-patient listing.
7.4.2
Baseline Disease Status
Baseline disease characteristics (disease type, disease stage, sites of involvement, time since 
initial diagnosis) will be summarized by DDI cohort and total for the safety population in Part A, 
and by treatment arm and total for the safety population in Part B, if applicable.  ECOG 
performance status will be summarized similarly in the same table.  Separate by-patient listings 
3600
)
(
)
(
kg
Weight
cm
Height



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will also be presented by Part A and Part B for baseline disease characteristics and ECOG 
performance status.  
Dates of initial diagnosis which are partially missing will be imputed as follows:   

If the date of initial diagnosis has a month and year but the day is missing, the 15th will 
be inserted as the day.

If the date of initial diagnosis has a year but the month and the day are missing, June 30th 
will be inserted.
7.5
Medical History and Concurrent Medical Conditions
Patients with a medical (and/or surgical) history will be presented in a by-patient listing, 
including the medical and surgical history, date of onset and the outcome status (whether it is 
resolved or ongoing). 
7.6
Medication History and Concomitant Medications
No summary for medication history.
All concomitant medications will be mapped to generic terms according to the World Health 
Organization (WHO) drug dictionary.  The number and percentage of patients taking 
concomitant medications will be tabulated by WHO drug generic term, presented by DDI cohort 
and total for the safety population in Part A, and by treatment arm and total for the safety 
population in Part B. Patients are counted once for each WHO drug generic term. Concomitant 
procedures will not be coded.
Concomitant medication for Part A is defined as any medication that occurs after administration 
of the first dose of study treatment during Part A and up through 30 days after the last dose of 
study drug during Part A for patients who do not continue into Part B or up through Part B C1D1 
(predose) for patients who continue into Part B. 
Concomitant medication for Part B is defined as any medication that occurs after administration 
of the first dose of study treatment during Part B and up through 30 days after the last dose of 
study drug during Part B.
Concomitant therapies with start or end dates that are completely or partially missing will be 
analyzed using the same imputation rules as adverse events.
Concomitant medications and procedures will be presented in separate by-patient listings.
7.6.1
PriorTherapies
Information on prior therapies will be summarized by DDI cohort and total for the safety 
population in Part A, and by treatment arm and total for the safety population in Part B. 
Summarized information on prior therapies will include:

Number of patients with prior chemotherapy

Months from last dose of prior chemotherapy to first study dose


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
Number of patients with prior radiation

Months from last prior radiation to first study dose

Number of patients with prior surgery or non-radiation procedures

Number of patient with prior transplant
If a day of the month is not provided for the date of prior therapy, prior radiation, or prior 
surgery, then the 15th will be inserted as the day.  If neither a day nor month is provided, then 
June 30th will be inserted.
In addition, prior chemotherapy regimens will be tabulated by treatment arm and total in Part B.   
A second tabulation will summarize the following:

Percentage of patients in Arm 1 (MLN4924+Docetaxel) receiving any taxane-containing 
regimen prior to dosing in C15011

Percentage of patients in Arm 2 (MLN4924+ Paclitaxel+Carboplatin) receiving any regimen 
containing a taxane but not a platinum prior to dosing in C15011

Percentage of patients in Arm 2 (MLN4924+ Paclitaxel+Carboplatin) receiving any regimen 
containing a platinum but not a taxane prior to dosing in C15011

Percentage of patients in Arm 2 (MLN4924+ Paclitaxel+Carboplatin) receiving any regimen 
containing both a platinum and a taxane prior to dosing in C15011
The categories of regimens described above are defined in the following table.
Taxane-containing regimens
BEVACIZUMAB+CARBOPLATIN+PACLITAXEL
BEVACIZUMAB+CISPLATIN+DOCETAXEL
BEVACIZUMAB+CISPLATIN+PACLITAXEL
BEVACIZUMAB+PACLITAXEL
CAPECITABINE+DOCETAXEL
CAPECITABINE+PACLITAXEL 
CARBOPLATIN+PACLITAXEL 
CARBOPLATIN+PACLITAXEL+TRASTUZUMAB 
CISPLATIN+DOCETAXEL 
CISPLATIN+DOCETAXEL+FLUOROURACIL 
CISPLATIN+PACLITAXEL 
CYCLOPHOSPHAMIDE+DOCETAXEL 
CYCLOPHOSPHAMIDE+DOCETAXEL+DOXORUBICIN 
CYCLOPHOSPHAMIDE+DOXORUBICIN+PACLITAXEL 


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DOCETAXEL (TAXOTERE) 
DOCETAXEL+DOXORUBICIN 
DOCETAXEL+FLUOROURACIL 
DOXORUBICIN+PACLITAXEL 
FLUOROURACIL+PACLITAXEL 
GEMCITABINE+PACLITAXEL 
PACLITAXEL (ABRAXANE FOR INJECTABLE 
SUSPENSION; APO-PACLITAXEL; ONXOL; TAXOL)
PACLITAXEL+TRASTUZUMAB
Regimens containing a 
taxane but not a platinum
BEVACIZUMAB+PACLITAXEL 
CAPECITABINE+DOCETAXEL 
CAPECITABINE+PACLITAXEL 
CYCLOPHOSPHAMIDE+DOCETAXEL
CYCLOPHOSPHAMIDE+DOCETAXEL+DOXORUBICIN
CYCLOPHOSPHAMIDE+DOXORUBICIN+PACLITAXEL
DOCETAXEL (TAXOTERE)
DOCETAXEL+DOXORUBICIN 
DOCETAXEL+FLUOROURACIL
DOXORUBICIN+PACLITAXEL 
FLUOROURACIL+PACLITAXEL
GEMCITABINE+PACLITAXEL
PACLITAXEL (ABRAXANE FOR INJECTABLE 
SUSPENSION; APO-PACLITAXEL; ONXOL; TAXOL)
PACLITAXEL+TRASTUZUMAB
Regimens containing a 
platinum but not a taxane
CAPECITABINE+CISPLATIN 
CAPECITABINE+CISPLATIN+EPIRUBICIN 
CAPECITABINE+EPIRUBICIN+OXALIPLATIN 
CAPECITABINE+OXALIPLATIN 
CARBOPLATIN (PARAPLATIN-AQ) 
CARBOPLATIN+ETOPOSIDE 


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CARBOPLATIN+FLUOROURACIL 
CETUXIMAB+CISPLATIN+VINBLASTINE 
CETUXIMAB+CISPLATIN+VINORELBINE 
CISPLATIN (PLATINOL)
CISPLATIN+EPIRUBICIN+FLUOROURACIL 
CISPLATIN+ETOPOSIDE 
CISPLATIN+FLUOROURACIL 
CISPLATIN+FLUOROURACIL+LEUCOVORIN 
CALCIUM 
CISPLATIN+GEMCITABINE 
CISPLATIN+IRINOTECAN 
CISPLATIN+PEMETREXED 
CISPLATIN+VINBLASTINE 
FLUOROURACIL+LEUCOVORIN 
CALCIUM+OXALIPLATIN 
FLUOROURACIL+OXALIPLATIN
OXALIPLATIN (ELOXATIN)
Regimens containing both a 
platinum and a taxane
BEVACIZUMAB+CARBOPLATIN+PACLITAXEL 
BEVACIZUMAB+CISPLATIN+DOCETAXEL 
BEVACIZUMAB+CISPLATIN+PACLITAXEL 
CARBOPLATIN+PACLITAXEL 
CARBOPLATIN+PACLITAXEL+TRASTUZUMAB 
CISPLATIN+DOCETAXEL 
CISPLATIN+DOCETAXEL+FLUOROURACIL 
CISPLATIN+PACLITAXEL


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7.7
Study Drug Exposure and Compliance
7.7.1
Study Treatments
Part A
During Part A, patients will receive a single dose of MLN4924 given as an IV infusion on Day 1 
and Day 8. Patients will receive either concomitant oral fluconazole or itraconazole on Days 4
through 10.
Part B
During Part B, for Arm 1 (MLN4924 + Docetaxel), patients will be administered docetaxel at a 
dose of 75 mg/m2 IV over 1 hour on Day 1 of each cycle. After a mandatory approximately
15-minute time out, MLN4924 will be administered IV.  On Days 3 and 5, only MLN4924 will 
be given.  The duration of each cycle will be 21 days.  
For Arm 2 (MLN4924 + Paclitaxel + Carboplatin), patients will be administered all three drugs 
on Day 1 of each cycle.  Paclitaxel is given first at a dose of 175 mg/m2 IV over 3 hours followed 
by carboplatin AUC5 over 30 minutes.  After a mandatory approximately 15-minute time out 
after carboplatin administration, MLN4924 will be administered IV.  On Days 3 and 5, only 
MLN4924 will be given.  The duration of each cycle will be 21 days.  
All dosing information for each visit will be presented by Part A and Part B in a by-patient 
listing.
7.7.2
Extent of Exposure
Extent of exposure will be reported separately for Part A by DDI cohort and for Part B by 
treatment arm.
Part A
The exposure to MLN4924 during Part A will be characterized by the number of doses received, 
Total Dose Received, Total Dose Expected, and Percent Dosing Intensity. 
Percent Dosing Intensity will be calculated using the following equations for Daily Expected 
Dose (mg), Daily Prepared Dose (mg), and Daily Dose Received (mg):  
The scheduled dose level will be collected on the electronic case report form (eCRF) for each 
dosing day.  Body surface area (BSA) will be calculated on Day 1.  
Total Dose Received, Total Dose Expected, and Percent Dosing Intensity for MLN4924 will be 
based on the following formulas: 








Volume
Prepared
(mL)
infused
actually 
bag
IV
of
Volume
*
Dose
Prepared
Daily 
Received
Dose
Daily 
)
(m
Area
Surface
Body 
*
)
(mg/m
Level
Dose
Scheduled
Dose
Prepared
Daily 
)
(m
Area
Surface
Body 
*
)
(mg/m
Entry 
Study 
at 
Assigned
Level
Dose
=
Dose
Expected
Daily 
2
2
2
2


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100
*
Expected
Dose
Total
Received
Dose
Total
Intensity 
Dosing
Percent 
2
*
Dose
Expected
Daily 
Expected
Dose
Total
A
Part 
during
tion 
administra
MLN4924
 with 
days
all
over 
Received
Dose
Daily 
of
Sum
Received
Dose
Total



The extent of exposure to MLN4924 during Part A will be summarized by DDI cohort.
The extent of exposure to fluconazole or itraconazole will be summarized for the number of 
doses received and Total Dose Received (mg) by DDI cohort.
Part B
The extent of exposure to MLN4924 will be based on the number of cycles received and the 
mean number of doses administered per cycle.  The distribution of the number of cycles received 
will be presented by treatment arm for all patients treated in Part B. Patients will be considered to 
have been treated for a cycle if they receive at least one dose of MLN4924 during the 21 days of 
that cycle.  Percentages will be calculated by treatment arm, and total for Part B.  
The mean number of doses per cycle will be calculated for each patient and summarized by
treatment arm, and total for Part B.
For MLN4924, calculation of Percent Dosing Intensity will use similar equations as specified in 
Part A for Daily Expected Dose (mg), Daily Prepared Dose (mg), and Daily Dose Received 
(mg). Daily Expected Dose and Daily Prepared Dose may differ if there are dose decreases.
Body surface area (BSA) will be calculated on Cycle 1, Day 1, and at subsequent visits if the 
patient experiences a >5% change in body weight from the weight used for the most recent BSA 
calculation. 
Total Dose Received, Total Dose Expected, and Percent Dosing Intensity for MLN4924 during 
Part B will be based on the following formulas: 
100
*
Expected
Dose
Total
Received
Dose
Total
Intensity 
Dosing
Percent 
cycles
 treated
of
number 
*
cycle
per 
doses
  
3
*
Dose
Expected
Daily 
Expected
Dose
Total
B
Part 
in 
tion 
administra
MLN4924
 with 
days
all
on 
Received
Dose
Daily 
of
Sum
Received
Dose
Total



Total dose expected will be calculated based on the BSA measured at baseline for Part B.  If
there are dose increases, the Dosing Intensity may exceed 100%.  The number of patients with 
100% intensity, 80% - <100%, 50 - <80, and <50% intensity will be summarized by treatment 
arm, and total for Part B.
For each of the standard of care drugs, the extent of exposure will be summarized in a similar 
manner as MLN4924. The number of cycles of standard of care drug administered will also be 
summarized. 
The mean number of doses per cycle will be calculated for each patient and summarized by 
treatment arm, and total for Part B.


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Daily Expected Dose, Total Dose Received, Total Dose Expected, and Dosing Intensity for each 
standard of care drug will be based on the following formulas:  











Volume
Prepared
(mL)
infused
actually 
bag
IV
of
Volume
*
Dose
Prepared
Daily 
Received
Dose
Daily 
25)
rate
filtration
r 
(Glomerula
*
)
(AUC
Level
Dose
Scheduled
          
(mg)
in)
(Carboplat
Dose
Prepared
Daily 
)
(m
Area
Surface
Body 
*
)
(mg/m
Level
Dose
Scheduled
          
)
Paclitaxel
and
(Docetaxel
Dose
Prepared
Daily 
25)
(mL/min)
rate
filtration
r 
(Glomerula
*
min/mL)
 x 
(mg
Entry 
Study 
at 
AUC
Assigned
Level
Dose
          
=
in)
(Carboplat
Dose
Expected
Daily 
)
(m
Area
Surface
Body 
*
)
(mg/m
Entry 
Study 
at 
Assigned
Level
Dose
          
=
)
Paclitaxel
and
(Docetaxel
Dose
Expected
Daily 
2
2
2
2
AUC is the area under the free carboplatin plasma concentration versus time curve.
Dosing intensity for each standard of care drug will be summarized by treatment arm, and total
for Part B, in a similar manner to MLN4924 dosing intensity.
Dosing administration data for both Part A (including CYP3A inhibitors) and Part B (including 
SoC) will also be presented in separate by-patient listings.
7.7.2
Treatment Compliance and Modifications
The actions on study drugs (Dose Held, Dose Reduced, Dose Interrupted, Dose Delayed, Dose 
Missed, Dose Increased, or Discontinued) will be summarized by DDI cohort for the safety 
population in Part A, and by treatment arm and total in Part B. For Part B, data will be
summarized for Cycle 1 only as well as all cycles.  A patient will count only once for each type 
of action.
7.8
Efficacy Analysis (Part B)
Efficacy analysis is only conducted for Part B, where efficacy is not a primary endpoint.  A
summary of the best overall response as determined by the investigator using the RECIST 
version 1.1 guidelines will be presented as a measure of antitumor activity of MLN4924 in 
combination with standard of care drugs.  The number and percentage of patients in each disease 
response category (e.g., complete response [CR], partial response [PR], stable disease [SD], 
progressive disease [PD], overall response rate (CR + PR) and CR+PR+SD) will be presented by 
treatment arm.  Percentages will also be calculated for the total in Part B. All evaluations of 
response will be conducted using the response-evaluable population.
For each patient, the best percent change (ie, largest reduction) from baseline in the sum of the 
longest diameter will be calculated and displayed in a waterfall plot to show the distribution of 
response in each arm.  Unscheduled visits will also be included in such displays.


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The duration of disease response (CR or PR) will be presented in a by-patient listing for all 
response-evaluable patients with CR or PR.  Duration of response is the time from the date of 
first documented response per the investigator response assessment to the date of first 
documentation of PD, or death , or the date of last disease assessment if the patient discontinues 
treatment before PD or still ongoing. In addition, the date of first response and the date of first 
documentation of PD after the first response will be shown. The duration of response (in
treatment cycle and months), will also be summarized descriptively by treatment arm for all 
response-evaluable patients.   
The duration of SD or better will be presented in a by-patient listing for all response-evaluable 
patients with SD or better.  Duration of SD or better is the time from the date of first documented 
SD or better to the date of first documentation of PD or death, or the date of last disease 
assessment if the patient discontinues treatment before PD. In addition, the date of first dose, the 
date of first SD or better, the date of first documentation of PD, and the number of cycles with 
SD or better will be shown. The duration of SD or better (in months) and the number of cycles 
with SD or better will also be summarized descriptively by treatment arm for all response-
evaluable patients.    
A separate listing will be generated for patients who are on treatment for at least 4 cycles during 
Part B. This listing should include disease type, number of cycles on treatment, duration of stable 
disease or better, and prior therapies.
Results from all disease response assessments and whether there was symptomatic deterioration 
will be presented in by-patient listings.
Any tumor assessments after the alternate antineoplastic therapies or after disease progression 
will be excluded in the analyses.
7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis (Part A)
During Part A of the study, for both the Fluconazole and Itraconazole Arms, serial blood samples 
(approximately 3 mL each) will be collected from each patient for the determination of 
MLN4924 plasma concentrations before and after the start of MLN4924 infusion on Day 1 
(when administered alone) and Day 8 (when co-administered with fluconazole or itraconazole) at 
the time points indicated below:


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Additionally, 4 samples for the determination of MLN4924 concentrations in whole blood will 
be drawn from each patient at pre-specified time points (EOI, 2, 8 and 24 hours) following 
MLN4924 infusion on Day 1 only.
Individual MLN4924 plasma concentration-time data obtained on Day 1 and Day 8 will be 
analyzed by noncompartmental methods using WinNonlin version 6.1 (or higher).
The PK analysis population will be used for the description of the concentration-time profiles 
and for the estimation of PK parameters.
Plasma concentration values below the lower limit of quantification (<LLQ) of the bioanalytical 
assay will be set to zero for analysis. Actual PK sampling times will be used in the derivation of 
PK parameters. The exact date and time of each sample collection, as well as the actual start and 
stop times of the infusion, should be recorded accurately, and particular care should be given to 
the recording of blood sampling times that occur close to the infusion. Actual time after dosing 
(TAD) will be set to zero for pre-infusion samples and calculated as the difference between the 
sample collection date/time and the start date/time of the IV infusion.
The following plasma PK parameters will be estimated, as permitted by the data:


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Parameters
Definition
Units
Cmax
Maximum observed concentration 
(theoretically end-of-infusion 
concentration)
ng/mL
Tmax
First time at which Cmax occurs
hr
AUClast
Area under the plasma concentration-time 
curve from time zero to the time of the 
last measurable concentration
hr*ng/mL
AUC0-72hr
Area under the plasma concentration-time 
curve from time zero to 72 hours post-
dose
hr*ng/mL
AUC0-inf
Area under the plasma concentration-time 
curve extrapolated to infinity
hr*ng/mL
lambdaz
Terminal disposition phase rate constant
1/hr
t1/2
Terminal disposition phase half-life
hr
CLp
Systemic clearance
L/hr
Vss
Volume of distribution at steady-state
L
TPR
Ratio of Day 8 pre-dose concentration to 
Day 8 Cmax
%
To report lambdaz, t1/2, AUC0-inf, CLp, and Vss, the terminal disposition phase data time span 
must be greater than or equal to 2, the number of data points included in the calculation must be 
at least 3, and R2 must be greater than or equal to 0.8.
If a subject’s predose MLN4924 concentration is ≤ 5% of Cmax on Day 8, the subject’s data 
without any adjustments will be included in the PK and statistical calculations. If the predose 
concentration is > 5% of Cmax on Day 8, the subject will be excluded from PK parameter 
calculations and summary statistics of concentrations for the given period, and from the 
statistical comparison of PK parameters.
For assessment of the effect of fluconazole on the single-dose IV PK of MLN4924, the ratios of 
geometric mean Cmax, AUC0-last, AUC0-72hr, and AUC0-inf of MLN4924 (in the presence of 
fluconazole on Day 8 vs in the absence of fluconazole on Day 1) and associated 2-sided 90% CIs 
will be calculated based on the within-patient variance calculated by ANOVA. Subject will be 
treated as a random effect in the model.  Point estimates and adjusted 90% confidence intervals 
for the difference in the log ratios will be constructed.  The point estimate and adjusted 90% 
confidence intervals will then be exponentially back transformed to provide point and confidence 


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interval estimates for the ratios of interest appropriately (eg, Cmax of MLN4924 with fluconazole 
vs. Cmax of MLN4924).
For assessment of the effect of itraconazole on the single-dose IV PK of MLN4924, the ratios of 
geometric mean Cmax, AUC0-last, AUC0-72hr, and AUC0-inf of MLN4924 (in the presence of 
itraconazole on Day 8 vs in the absence of itraconazole on Day 1) and associated 2-sided 90% 
CIs will be calculated based on the within-patient variance calculated by ANOVA. Subject will 
be treated as a random effect in the model.  Point estimates and adjusted 90% confidence 
intervals for the difference in the log ratios will be constructed.  The point estimate and adjusted 
90% confidence intervals will then be exponentially back transformed to provide point and 
confidence interval estimates for the ratios of interest appropriately (eg, Cmax of MLN4924 with 
itraconazole vs. Cmax of MLN4924).
Individual MLN4924 plasma concentration-time data (including nominal, actual and elapsed 
times relative to dosing; TAD) and individual plasma PK parameters will be listed and 
summarized descriptively on Day 1 and Day 8 by DDI cohort. 
Individual MLN4924 whole blood concentration-time data (including nominal, actual and 
elapsed times relative to dosing; TAD) and individual blood to plasma (B/P) concentration ratios
obtained on Day 1 will be listed and summarized descriptively by DDI cohort. The B/P 
concentration ratio will be calculated as [MLN4924] in blood divided by [MLN4924] in plasma
for each of the 4 pre-specified collection times.
Summary statistics (N, arithmetic mean, standard deviation, geometric mean, coefficient of 
variation [CV], median, minimum, and maximum) will be calculated if there is less than 50% of 
the values missing. The arithmetic mean and geometric mean will be reported on at least 2 non-
missing values; and the median, standard deviation and CV will be reported on at least 3 non-
missing values. For Tmax, only N, median, minimum, and maximum will be calculated.
Individual (multiple-subject/spaghetti plots; and single-subject plots with Day 1/Day 8 overlaid) 
and mean MLN4924 plasma concentration-time data will be plotted against time after the start of 
the infusion by study Day for each DDI cohort. Linear and logarithmic scales will be used.
7.9.2
Pharmacodynamic Analysis (Part A)
Whole blood RT-PCR assay of genes (Part A)
Serial whole blood samples will be collected to measure pharmacodynamic effects via reverse-
transcriptase polymerase chain reaction (RT-PCR) of NAE-regulated gene transcripts.
Eight genes of interest were identified as induced by NAE inhibition: ATF3, GCLM, GSR, 
MAG1, NQO1, SLC7A11, SRXN1, and TXNRD1.  The percent change from baseline in the 
relative expression of each of the eight genes of interest will be calculated as (2 -(Post Baseline Delta Ct –
Baseline Delta Ct)-1)*100.   The delta Ct is the mean Ct (over the replicates) for each gene of interest 
minus the mean Ct for the 4 housekeeping genes (18S, B2M, RPLP0, and UBC) calculated at 
each time point.  A positive percent change is equivalent to an increase in expression after dosing 
with MLM4924.


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Summary statistics of the percent change from baseline at each time point will be generated for 
each gene by DDI cohort. For each gene, the mean percent change from baseline over time will 
be plotted in a line plot with separate lines for each DDI cohort.
7.10
Other Outcomes
Not Applicable
7.11
Safety Analysis
Safety analyses will be conducted separately for Part A and Part B. 
Safety evaluations will be based on the incidence, severity, type of AEs, clinically significant 
changes or abnormalities in the patient’s physical examination, vital signs, ECG, and clinical 
laboratory results. 
These analyses for Part A will be performed by DDI cohort using the safety population for Part 
A. Safety analyses for Part B will be performed by treatment arm and DDI cohort using the 
safety population for Part B who continue from Part A into Part B with at least one dose 
administration of study drugs during Part B.
7.11.1 Adverse Events
AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA). 
A treatment-emergent AE for Part A is defined as any AE that occurs after administration of the 
first dose of study treatment during Part A and up through 30 days after the last dose of study 
drug during Part A for patients who do not continue into Part B or up through Part B C1D1 
(predose) for patients who continue into Part B. Any event that is considered drug-related,
regardless of the start date of the event for patients who do not continue into part B, or any event 
that is present at Part A Baseline but worsens in severity postbaseline is considered a TEAE.
A treatment-emergent AE for Part B is defined as any AE that occurs after administration of the 
first dose of study treatment during Part B and up through 30 days after the last dose of study 
drug during Part B, or any event that is present at Part B Baseline (C1D1 predose) but worsens in 
severity postbaseline.
AEs will be tabulated by system organ class (SOC), high level term (HLT), and preferred term 
(PT) for Part A by DDI cohort, and for Part B by treatment arm and DDI cohort.  Percentages 
will be calculated for the Part A total, arm totals for Part B and the Part B total. Summary 
tabulations include the following subsets:

Treatment-emergent AEs

Drug-related treatment-emergent AEs  

Grade 3 or higher treatment-emergent AEs 

Grade 3 or higher drug-related treatment-emergent AEs 


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
Treatment-emergent AEs resulting in study drug discontinuation

SAEs  

Treatment-emergent drug-related SAEs
Treatment-emergent AEs will be tabulated by SOC, HLT, PT, and highest intensity.  Most 
commonly reported (at least 10% of all patients) treatment-emergent AEs will be presented by 
preferred term. Most commonly reported (at least 10% of all patients) treatment-emergent AEs 
by preferred term will also be summarized by dosing windows (Day 1-3, Day 4-7, Day 8-10, 
Day 11+) for Part A, and by treatment cycles (Cycle 1, Cycle 2-3, Cycle 4+) for Part B. 
Additionally, tabulations of AE (by SOC, HLT, and PT) vs grade intensity will be made 
separately for Part A by DDI cohort, and for Part B by treatment arm and DDI cohort.  All 
adverse events will also be reported in by-patient listings separately for Part A, and Part B, which 
will include the variable AE onset window (i.e., "Part A" or "Part B").
During Part B, all adverse events for patients who have dose modification in the standard of care 
treatments will be included in a by-patient listing. This listing should additionally include 
reduced doses during AE occurrence and omitted doses during AE occurrence. Reduced doses 
during AE occurrence refer to any dose level, administered during the period of AE onset date to 
AE ending date, which is lower than the dose closest but prior to AE onset date. Omitted doses
during AE occurrence refer to any scheduled dose which is omitted during the period of AE 
onset date to AE ending date.
Adverse events with start dates that are completely or partially missing will be analyzed as 
follows:

If the start date has month and year but day is missing, the event will be considered
–
treatment emergent for Part A if both the month and year of the start date of the event are 
on or after the month and year of the date of the first dose of study drug in Part A, and on 
or before the month and year of the date of the last dose of study drugs in Part A plus 
30 days for patients who do not continue into Part B or the date of the first dose of study 
drugs in Part B for patients who continue into Part B. 
–
treatment emergent for Part B if both the month and year of the start date of the event are 
on or after the month and year of the date of the first dose of study drugs in Part B, and 
on or before the month and year of the date of the last dose of study drugs in Part B plus 
30 days.

If the start date has year, but day and month are missing, the event will be considered:
–
treatment emergent for Part A if the year of the start date of the event is on or after the 
year of the date of the first dose of MLN4924 in Part A, and on or before the year of the 
date of the last dose of study drugs in Part A plus 30 days for patients who do not 
continue into Part B or the date of the first dose of study drugs in Part B for patients who 
continue into Part B.


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–
treatment emergent for Part B if the year of the start date of the event is on or after the 
year of the date of the first dose of study drugs in Part B, and on or before the year of the 
date of the last dose of study drugs in Part B plus 30 days.

If the start date of an event is completely missing, the event will be considered:
–
treatment emergent for Part A for patients who do not continue into Part B.
–
treatment emergent for Part A for patients who continue into Part B if the ending date of 
the event is before the date of the first dose of study drugs in Part B.
–
treatment emergent for both Part A and Part B for patients who continue into Part B if 
the ending date does not reflect whether the AE ends prior to the first dose of study drug 
in Part B.
7.11.1.1 Serious Adverse Events
The number and percentage of patients experiencing at least one treatment emergent serious AE 
(SAE) will be summarized by MedDRA SOC, HLT, and PT, and separately for Part A by DDI 
cohort, and for Part B by treatment arm and DDI cohort. Similar summary will be generated for 
treatment emergent drug-related SAEs.
By-patient listings of the SAEs will be presented (the patient listing will contain all SAEs 
regardless of treatment-emergent AE status) separately for Part A by DDI cohort, and for Part B
by treatment arm and DDI cohort.
The drug-related SAEs will also be presented separately for Part A by DDI cohort, and for Part B
by treatment arm and DDI cohort in by-patient listings. 
Listings of treatment emergent SAEs on the first dose of MLN4924 will be generated for Part A.
7.11.1.2 Deaths
By-subject listings of the deaths will be presented separately for Part A by DDI cohort, and for 
Part B by treatment arm and DDI cohort.  All deaths occurring on-study will be displayed 
(regardless of treatment-emergent AE status). Deaths with start dates that are completely or 
partially missing will be imputed to the date of last contact. An on-study death is defined as a 
death that occurs between the first dose of study drug in Part A and 30 days after the last dose of 
study drug.
7.11.1.3 Adverse Events Resulting in Discontinuation of Study Drug
The number and percentage of patients experiencing at least one adverse event resulting in 
discontinuation of study drug will be summarized by MedDRA SOC, HLT, and PT and 
separately for Part A by DDI cohort, and for Part B by treatment arm and DDI cohort.
By-patient listing of AEs resulting in discontinuation of study drug will be presented separately
for Part A and Part B.  All AEs resulting in discontinuation of study drug occurring on-study will 
be displayed (regardless of treatment emergent AE status).


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7.11.1.4 Myalgia Events
Listings of patients who experience treatment emergent myalgia events will be presented
separately for Part A, and Part B. The corresponding preferred terms include myalgia, 
musculoskeletal pain, and musculoskeletal discomfort.
7.11.1.5 Acute Renal Failure Events
Listings of treatment-emergent acute renal failure events will be generated separately for Part A
and Part B. The corresponding preferred terms are listed as below:

Acute phosphate nephropathy

Acute prerenal failure

Anuria

Azotaemia

Continuous haemodiafiltration

Dialysis

Haemodialysis

Neonatal anuria

Nephropathy toxic

Oliguria

Peritoneal dialysis

Prerenal failure

Renal failure

Renal failure acute

Renal failure neonatal

Renal impairment

Renal impairment neonatal

Albuminuria

Blood creatinine abnormal

Blood creatinine increased

Blood urea abnormal

Blood urea increased

Blood urea nitrogen/creatinine ratio increased

Creatinine renal clearance abnormal

Creatinine renal clearance decreased

Creatinine urine abnormal

Creatinine urine decreased

Crystal nephropathy

Glomerular filtration rate abnormal

Glomerular filtration rate decreased

Hypercreatininaemia

Nephritis

Oedema due to renal disease

Protein urine present

Proteinuria

Renal function test abnormal

Renal transplant

Renal tubular disorder

Renal tubular necrosis

Tubulointerstitial nephritis

Urea renal clearance decreased

Urine output decreased


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7.11.1.6 Liver Function Test Elevations
Listing of treatment-emergent liver function test (LFT) elevations will be generated separately
for Part A and Part B. The corresponding preferred terms are listed as below:

Liver function test

Liver function test abnormal

Alanine aminotransferase

Alanine aminotransferase abnormal

Alanine aminotransferase increased

Aspartate aminotransferase

Aspartate aminotransferase increased

Mitochondrial aspartate 
aminotransferase increased

Aspartate aminotransferase abnormal

Blood alkaline phosphatase

Blood alkaline phosphatase abnormal

Blood alkaline phosphatase increased

Blood bilirubin

Bilirubin urine

Bilirubin conjugated

Blood bilirubin abnormal

Blood bilirubin increased

Urine bilirubin increased

Bilirubin conjugated increased

Blood bilirubin unconjugated 
increased

Gamma-glutamyltransferase

Gamma-glutamyltransferase 
abnormal

Gamma-glutamyltransferase 
increased
7.11.1.7 Tachycardia Events
Listings of treatment-emergent tachycardia events will be generated separately for Part A and 
Part B. The corresponding preferred terms are listed as below:

Extrasystoles

Heart rate increased

Heart rate irregular

Rebound tachycardia

Sinus tachycardia

Supraventricular extrasystoles

Supraventricular tachyarrhythmia

Tachyarrhythmia

Tachycardia

Tachycardia paroxysmal
7.11.1.8 Hypertension
Listings of treatment-emergent hypotension will be generated separately for Part A and Part B. 
The corresponding preferred terms are listed as below:


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
Blood pressure ambulatory decreased

Blood pressure decreased

Blood pressure diastolic decreased

Blood pressure orthostatic abnormal

Blood pressure orthostatic decreased

Blood pressure systolic decreased

Hypotension

Orthostatic hypotension
7.11.1.9 Anemia
The highest intensity of treatment emergent anemia will be summarized by administration of red 
blood cells as a concomitant medication, separately for Part A and Part B. 
Listings of treatment-emergent anemia will also be generated separately for Part A and Part B. 
The corresponding preferred terms are listed as below:

Anaemia of chronic disease

Anaemia of malignant disease

Anaemia

Red blood cell count decreased

Haemoglobin decreased

Mean cell haemoglobin decreased

Haematocrit decreased
7.11.1.10
Neutropenia
Listings of treatment emergent neutropenia will also be generated separately for Part A and 
Part B. The corresponding preferred terms are listed as below:

Agranulocytosis

Band neutrophil count decreased

Band neutrophil percentage decreased

Febrile neutropenia

Idiopathic neutropenia

Leukopenia

Neutropenia

Neutropenic infection

Neutropenic sepsis

Neutrophil count abnormal

Neutrophil count decreased

Neutrophil percentage abnormal

Neutrophil percentage decreased
7.11.1.11
Overall Summary
The number and percentage of patients who experience any of the following treatment-emergent 
adverse events will be summarized separately for Part A by DDI cohort, and for Part B by 
treatment arm and DDI cohort:

Any adverse event

Grade 3 or higher adverse event


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
Drug-related adverse event

Drug-related Grade 3 or higher adverse event

Serious adverse event

Drug related serious adverse event

Adverse events resulting in study drug discontinuation

On-study deaths
Percentages will be calculated for the Part A total, arm totals for Part B and the Part B total.
7.11.2 Clinical Laboratory Evaluations
For the purposes of summarization, all laboratory values will be converted to standardized units.  
If a lab value is reported using a non-numeric qualifier (eg, less than (<) a certain value, or 
greater than (>) a certain value), the given numeric value will be used in the summarization, 
ignoring the non-numeric qualifier.  
If a subject has repeated laboratory values for a given time point, the value from the last 
evaluation will be used.
Shift tables of the change in NCI CTC from baseline to the post baseline worst CTC grade will 
be generated for relevant measurements, separately for Part A and Part B.  Graphical displays 
will be used to show changes in laboratory measures over time, separately for Part A, and Part B: 
1. Box graphs of individual tests over time by DDI cohort for Part A, and by treatment arm for 
Part B.  
2. Spaghettis plot of selected lab tests over time by treatment arm and DDI cohort for Part B
3. Scatter plots of baseline versus worst postbaseline values by DDI cohort for Part A and by 
treatment arm for Part B.  Separate plotting characters will be used for each subgroup.  These 
will be generated for only selected labs (see table below).
Panel
Test
CTCAE Shift Table
MTD Box 
Plots
Spaghetti 
Plots
Scatter
Plots
Chemistry
Albumin
X
X
Alanine aminotransferase 
(SGPT)
X
X
X
Aspartate 
aminotransferase (SGOT)
X
X
X
Alkaline Phosphatase
X
X
X
Carbon Dioxide
X
X
Direct Bilirubin
X
X
X
Total Bilirubin
X
X
X
Blood urea nitrogen
X
X


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Statistical Analysis Plan
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Panel
Test
CTCAE Shift Table
MTD Box 
Plots
Spaghetti 
Plots
Scatter
Plots
Blood urea nitrogen 
(mg/dL)/Creatinine 
(mg/dL)
X
X
Calcium
X
X
Chloride
X
X
Creatinine
X
X
X
Creatinine clearance
X
X
Glomerular filtration rate 
(estimated)
X
X
Glucose
X
X
Gamma-glutamyl-
transpeptidase
X
X
X
Lactate dehydrogenase
X
X
Magnesium
X
X
Phosphate
X
X
X
Potassium
X
X
Sodium
X
X
Urate
X
X
Hematology
Platelets
X
X
X
Hematocrit
X
Hemoglobin
X
X
X
White Blood Cells
X
X
X
Lymphocyte Count
X
X
Neutrophils (ANC)
X
X
X
Monocytes
X
Eosinophils
X
Basophils
X
For patients with neutrophil lab results reported as segmented neutrophils and neutrophil bands, 
ANC will be calculated by the Sponsor (or designee) as:
ANC=total leukocyte count × total percentage of neutrophils (segmented neutrophils + band 
neutrophils)
Example: 
If total leukocyte count = 4.3 x 103;  segmented neutrophils = 48%;  band neutrophils = 2% 
Then:  4300 × (0.48 + 0.02) = 4300 × 0.5 = ANC of 2150


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Statistical Analysis Plan
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Creatinine clearance and estimated glomerular filtration rate (GFR) will be derived by the 
Sponsor (or designee) using the Cockcroft-Gault and chronic kidney disease epidemiology 
collaboration (CKD-epi) formulas as follows:
Cockcroft-Gault equation:
For males:


mol/L])
[
creatinine
(serum
*
0.81
weight[kg]
*
)
age[years]
-
(140
Clearance
Creatinine


For females:


mol/L])
[
creatinine
(serum
*
0.81
weight[kg]
*
)
age[years]
-
(140
*
85
.0
Clearance
Creatinine


A cap value of 125 will be set to creatinine clearance values (calculated from Cockcroft-Gault
equation) higher than 125.
CKD-epi equation:
For males:
black]
race
1.159[if
*
  
0.993
*
1)
  
/0.9,
creatinine
max(serum
*
1)
  
/0.9,
creatinine
min(serum
*
141
GFR
Age
-1.209
-0.411


For females:
black]
race
1.159[if
*
1.018
*
0.993
*
1)
  
/0.7,
creatinine
max(serum
*
1)
  
/0.7,
creatinine
min(serum
*
141
GFR
Age
-1.209
-0.329


For purposes of the scatterplots, the worst value will be the largest value observed after baseline 
for BUN and BUN/creatinine ratio. The worst value will be the smallest value observed after 
baseline for creatinine clearance and GFR.
All chemistry and hematology lab data will also be presented in by-patient listings separately for 
Part A and Part B.
In addition, by-patient listings of selected urinalysis parameters will be generated separately for 
Part A and Part B. The parameters to be displayed include the patient ID, visit and the results 
from protein, glucose, occult blood, leukocyte esterase, and erythrocytes, leukocytes, bacteria, 
casts, and crystals from microscopic evaluation.


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Statistical Analysis Plan
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7.11.3 Vital Signs
Graphical displays will be used to show vital sign parameters over time, separately for the Part A
by DDI cohort, and for Part B by treatment arm: 

Individual patient line graphs of temperature, diastolic blood pressure (DBP), systolic blood 
pressure (SBP), and heart rate over time for each dose level in each subgroup.  These will be 
summarized for measurements taken in the sitting position.

Box plots over time for temperature, DBP, SBP, and heart rate during Cycle 1 will be 
generated for each subgroup.  These will be summarized for measurements taken in the 
sitting position.
In addition, orthostatic hypotension will be defined as a decrease in systolic blood pressure of at 
least 20 mm Hg or in diastolic blood pressure of at least 10 mm Hg after the patient changes 
from a supine position to a standing position.  Orthostatic heart rate will be defined as increase in 
heart rate of at least 20 beats/min after the patient changes from a supine position to a standing 
position.
Tables will be generated to summarize the following at baseline and post-baseline, separately for 
Part A by DDI cohort, and for Part B by treatment arm:

Percentage of patients who experienced orthostatic hypotension at baseline

Percentage of patients who had orthostatic heart rate at baseline

Percentage of patients who had both orthostatic hypotension and orthostatic heart rate at 
baseline

Percentage of patients who experienced orthostatic hypotension postbaseline

Percentage of patients who had orthostatic heart rate postbaseline

Percentage of patients who had both orthostatic hypotension and orthostatic heart rate 
postbaseline
Moreover, the summary table should also include the following:

Percentage of patients who had orthostatic hypotension postbaseline and did not have 
orthostatic hypotension at baseline

Percentage of patients who had orthostatic heart rate postbaseline and did not have 
orthostatic heart rate at baseline

Percentage of patients who had both orthostatic hypotension and orthostatic heart rate 
postbaseline and had neither orthostatic hypotension nor orthostatic heart rate at baseline

Percentage of patients who had orthostatic hypotension at baseline and did not have 
orthostatic hypotension postbaseline

Percentage of patients who had orthostatic heart rate at baseline and did not have orthostatic 
heart rate postbaseline

Percentage of patients who had both orthostatic hypotension and orthostatic heart rate at 
baseline and had neither orthostatic hypotension nor orthostatic heart rate postbaseline


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Statistical Analysis Plan
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Additional listings of patients who had orthostatic hypotension or orthostatic heart rate 
postbaseline will be presented separately for Part A and Part B. The listings will include the 
baseline and postbaseline heart rate, SBP, and DBP in both the supine and standing positions.  
The listings will also include the patient’s age and whether they were taking a beta blocking 
agent as a concomitant medication.  Patients should be considered to be taking a beta blocking 
agent during Part A if they are taking any of the following at Day 1 of Part A, or considered to be 
one during Part B if taking any at Cycle 1 Day 1 of Part B:
Acebutolol, Atenolol, Atenolol, Betaxolol, Bisoprolol, Carteolol, Carteolol, Carvedilol, 
Celiprolol, Esmolol, Labetalol, Levobunolol, Metipranolol, Metoprolol, Nadolol, Nebivolol, 
Oxprenolol, Penbutolol, Pindolol, Propranolol, Sotalol, Timolol
Vital signs data will also be presented in by-patient listings, separately for Part A and Part B.
7.11.4 Electrocardiograms
The number and percentage of patients experiencing abnormal ECG results will be summarized 
over each time point, separately for Part A by DDI cohort, and for Part B by treatment arm.
Corrected QT intervals (QTcF and QTcB) will be derived by the Sponsor (or designee) using the 
following formulas.
3
/
1
d
uncorrecte
Rate
r 
Ventricula
60
QT
QTcF







                
Rate
r 
Ventricula
60
QT
QTcB
d
uncorrecte

ECG findings will also be presented in by-patient listings separately for Part A, and Part B.  
ECG Parameter
Abnormal values
QT, QTcF and QTcB
New absolute values >450, >480 and >500
Changes from baseline >30 and >60
HR
Decrease from baseline >25% and to a HR < 50
Increase from baseline >25% and to a HR > 100
PR
Increase from baseline >25% and to a value >200
QRS
Increase from baseline >25% and to a value >110
7.11.5 Disseminated Intravascular Coagulation (DIC) and PT/PTT
Data from the DIC panel at screening and prothrombin/partial thromboplastin times will be 
presented in separate by-patient listings, separately for Part A and Part B.
7.11.6 Echocardiograms
Echocardiogram results (e.g. LVEF) will be presented in by-patient listings separately for Part A 
and Part B.


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Statistical Analysis Plan
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7.12
Interim Analysis
As this is a phase 1 study there is no formal interim analysis.  There will be an ongoing review of 
safety data with the medical monitor and study investigators, as well as within an internal Safety 
Working Group and the Independent Data Monitoring Committee (IDMC).   
A preliminary PK analysis will be conducted after the first 4 to 8 patients have completed the 
Fluconazole Arm (MLN4924 + fluconazole) of Part A. After review of the emerging data from 
the Fluconazole Arm, patient assignment to the first cohort in the Itraconazole Arm (8 mg/m2
MLN4924 + itraconazole) will be initiated. Dose modifications of MLN4924 in the Itraconazole 
Arm may be reconsidered based on the magnitude of the interaction with the moderate CYP3A 
inhibitor fluconazole and the ability to accurately estimate PK parameters for DDI evaluation.
Following completion of the first 3 patients in the Itraconazole Arm 8 mg/m2 MLN4924 cohort,
preliminary PK data will be reviewed to guide expansion of the Itraconazole Arm to the total 
intended number of 12 PK-evaluable patients. If these emerging preliminary PK data indicate 
that the magnitude of the interaction with the strong CYP3A inhibitor itraconazole reaches the
anticipated approximately 10-fold change, and individual drug exposures do not exceed those 
seen at doses of MLN4924 ≥110 mg/m2, then up to 3 additional patients to provide at least 4 to 
6 PK-evaluable patients will be enrolled. If the magnitude of the interaction with the strong 
CYP3A inhibitor itraconazole is much greater than anticipated (greater than the predefined safety 
margin of 14-fold), with individual MLN4924 exposures exceeding those seen at doses of 
MLN4924 ≥110 mg/m2, then no additional patients will be enrolled in the Itraconazole Arm of 
Part A.
As of the implementation of Protocol Amendment 1, following completion of Part A by 
3 PK-evaluable patients in the Safety Lead-in 15-mg/m2 MLN4924 Cohort, safety and PK data 
will be reviewed to inform expansion of the Itraconazole Arm to the total intended number of 12 
PK-evaluable patients in the 20-mg/m2 MLN4924 Cohort. If the preliminary PK data from the 
safety lead-in cohort indicate that the magnitude of the interaction between the proposed 
20-mg/m2 MLN4924 dose and the strong CYP3A inhibitor itraconazole would be greater than 
the predefined safety margin (5-fold, with individual MLN4924 exposures potentially exceeding 
those seen at doses of MLN4924 110 mg/m2), then no patients will be enrolled in the 
20-mg/m2 MLN4924 Cohort.  Dosing with intermediate doses of MLN4924 and/or evaluation of 
the drug interaction with the moderate CYP3A inhibitor, fluconazole, may then be reconsidered 
if it is deemed necessary to further enhance our understanding of the effect of CYP3A inhibition 
on the PK of MLN4924.  


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Statistical Analysis Plan
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7.13
Changes in the Statistical Analysis Plan 
!
!
PK-PD analysis to study relationships between MLN4924 plasma exposure and 
pharmacodynamic effects in blood as stated in the protocol will be not performed in the SAP 
and TLFs for this analysis will not be generated
Reference materials for this statistical plan include Clinical Study Protocol C15011 Amendment 
2 (dated 12APRIL2017), and the accompanying data collection documents (Annotated Case 
Report Form [CRF], version 0.0 dated 21MAY2014).
CCI


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Statistical Analysis Plan
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8.0
REFERENCES
1. U.S. Department of Health and Human Services, National Institutes of Health National 
Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). Version 4.03. 
14 June 2010.
2. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer 2009;45(2):228-47.