Conditions: Solid Tumors
Keywords: MLN4924 Solid Tumors
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 64
Healthy volunteers: no

Brief summary:
The purpose of this study is to establish the maximum tolerated dose (MTD) and assess the safety and tolerability of MLN4924 (pevonedistat) in combination with docetaxel, paclitaxel and carboplatin, and gemcitabine in participants with solid tumors.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None

Interventions: intervention 1: MLN4924 intervention 2: Paclitaxel intervention 3: Gemcitabine intervention 4: Docetaxel intervention 5: Carboplatin
Intervention descriptions: intervention 1: MLN4924 (intravenously \[IV\]) in participants in a 21-day cycle:

* MLN4924 on Days 1,3,5 of each cycle intervention 2: Paclitaxel (IV) in a 21-day cycle:

* Paclitaxel on Day 1 of each cycle intervention 3: Gemcitabine (IV) in participants in a 28-day cycle:

-Gemcitabine on Days 1,8,15 of each cycle intervention 4: Docetaxel (IV) in participants in a 21-day cycle:

\- Docetaxel on Day 1 of each cycle intervention 5: Carboplatin (IV) in participants in a 21-day cycle:

\- Carboplatin on Day 1 of each cycle

Protocol document:
Prot_001.pdf: 



Title: A Phase 1b, Open-Label, Dose Escalation, Multi-arm Study of MLN4924 Plus Docetaxel, 
Gemcitabine, or Combination of Carboplatin and Paclitaxel in Patients With Solid Tumors
NCT Number: NCT01862328
Protocol Approve Date: 17 October 2017
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


MLN4924
Clinical Study Protocol C15010 Amendment 1
1
CLINICAL STUDY PROTOCOL C15010 AMENDMENT 1
MLN4924
A Phase 1b, Open-Label, Dose Escalation, Multi-arm Study of MLN4924 Plus Docetaxel, 
Gemcitabine, or Combination of Carboplatin and Paclitaxel in Patients With Solid 
Tumors
Protocol Number:
C15010
Indication:
Solid tumors
Phase:
1b
Sponsor:
Millennium Pharmaceuticals, Inc.
Therapeutic Area:
Oncology
Protocol History
Original
08 March 2013
Amendment 1
17 October 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.
PPD


MLN4924
Clinical Study Protocol C15010 Amendment 1
2
Rationale for Amendment 1
The original protocol was written in 2013 and was designed with procedures and 
assessments requiring many visits. As of 09 June 2017, 2 patients with solid tumors remain 
on study after completing at least 12 cycles of MLN4924 single-agent treatment in Arm 2. 
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. The primary reason for Amendment 1 is to 
add flexibility to relieve treatment fatigue for the 2 patients remaining in this study beyond 
the initially planned 12 cycles of treatment, and a new Schedule of Events table has been 
generated to reflect these changes. Clarifications regarding the duration of gemcitabine 
administration and the timing of urine safety assessments previously specified in 
administrative letters to the United States Food and Drug Administration have also been 
included to reflect study conduct.
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 15.10.
Changes in Amendment 1
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 and clinical chemistry assessments and 
physical examinations.
4.
Remove ketones, bilirubin, urobilinogen, and glucose from the Urinalysis With 
Microscopic Analysis 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 
Council for Harmonisation guidelines.
10.
Update the description of the dose-limiting toxicity observed in Study C15003 to be 
consistent with final data.
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MLN4924
Clinical Study Protocol C15010 Amendment 1
3
11.
Update vital signs assessments to allow measurements to be taken with the patient in 
the supine or sitting position.
12.
Clarify that if needed, a red blood cell transfusion must occur at least 1 day before 
study drug administration.
13.
Updated clinical laboratory evaluations.
14.
Remove statins, 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.
18.
Update contact information for serious adverse event reporting.
19.
Update the risks of MLN4924 therapy to be consistent with the current version of the 
Investigator’s Brochure (IB).
20.
Clarify the duration of gemcitabine administration per the prescribing information 
guidelines, as stated in Administrative Letter 1.
21.
Clarify the collection time points for the urine safety assessment at screening and 
Cycle 1 Day 1 (predose), as stated in Administrative Letter 2.
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MLN4924
Clinical Study Protocol C15010 Amendment 1
4
PROTOCOL SUMMARY  
Study Title: A Phase 1b, Open-Label, Dose Escalation, Multi-arm Study of MLN4924 Plus 
Docetaxel, Gemcitabine, or Combination of Carboplatin and Paclitaxel in Patients With Solid 
Tumors
Number of Patients: Approximately 69 patients
Study Objectives
Primary Objectives
! To establish the maximum tolerated dose (MTD) and assess the safety and tolerability of
MLN4924 in combination with docetaxel in patients with solid tumors
! To establish the MTD and assess the safety and tolerability of MLN4924 in combination with
paclitaxel and carboplatin in patients with solid tumors
! To establish the MTD and assess the safety and tolerability of MLN4924 in combination with
gemcitabine in patients with solid tumors
Secondary Objectives
! To evaluate disease response that may be observed with the combination of MLN4924 and
docetaxel
! To evaluate disease response that may be observed with the combination of MLN4924,
paclitaxel, and carboplatin
! To evaluate disease response that may be observed with the combination of MLN4924 and
gemcitabine
! To measure plasma MLN4924 concentrations to contribute to a population pharmacokinetic
(PK) analysis of MLN4924 co-administered with docetaxel, or paclitaxel + carboplatin, or
gemcitabine in patients with solid tumors
Exploratory Objectives
Overview of Study Design: This is an open-label, multicenter, phase 1b, dose escalation study of 
MLN4924 in combination with docetaxel, paclitaxel + carboplatin, or gemcitabine in adult patients 
with solid tumors (patients in the carboplatin lead-in cohort will receive MLN4924 + carboplatin 
only). The patient population will consist of patients 18 years of age or older with nonhematologic 
malignancies who, according to the investigator’s medical judgment, could potentially benefit from 
treatment with any of the 3 standard of care (SoC) therapies being studied.
It is expected that approximately 69 patients will be enrolled in this study. During the dose escalation 
portion of this study, the following dose levels of intravenous (IV) MLN4924 are planned to be 
studied in combination with docetaxel (Arm 1), paclitaxel + carboplatin (Arm 2), or gemcitabine 
CCI
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MLN4924
Clinical Study Protocol C15010 Amendment 1
5
(Arm 3).
MLN4924 + Docetaxel (Arm 1): A total of 4 dose levels of IV MLN4924 (15, 25, 37, and 50 mg/m2) 
are planned to be studied in combination with 75 mg/m2 of docetaxel. On Day 1 of each cycle when 
both drugs are administered, docetaxel will be administered first at a dose of 75 mg/m2 IV over 
1 hour. After a mandatory approximately 15-minute time out (MLN4924-free period), MLN4924 
will be administered IV. On Days 3 and 5, only MLN4924 will be given. The duration of each cycle 
will be 21 days. No dose reduction of MLN4924 below 15 mg/m2 is allowed. 
MLN4924 + Carboplatin Lead-in Cohort (before Arm 2): Before patients are enrolled in Arm 2 with 
paclitaxel + carboplatin, a cohort of approximately 3 to 6 patients will be treated with AUC6 dose of 
carboplatin in combination with MLN4924 at a dose of 15 mg/m2. On Day 1 of each cycle, both 
compounds will be given. On Days 3 and 5, only MLN4924 will be given. The duration of each 
cycle will be 21 days. If 1 dose-limiting toxicity (DLT) is seen in this cohort, 3 additional patients 
will be treated with the same combination regimen. The carboplatin dose may be reduced to AUC5 
for safety as needed. No dose reduction of MLN4924 below 15 mg/m2 is allowed. No dose 
escalation of MLN4924 is planned in this cohort. The only chemotherapy agent that patients in this 
lead-in cohort will receive is carboplatin; these patients will not enroll in the MLN4924 + paclitaxel 
+ carboplatin phase (Arm 2).
Observing no more than 1 DLT in this lead-in cohort will trigger enrollment in Arm 2 at AUC6 
(MLN4924 [15 mg/m2] + paclitaxel [200 mg/m2] + carboplatin [AUC6]), and patients will be treated 
as described below for Arm 2.
If a total of 2 or more DLTs are observed in this cohort, enrollment in Arm 2 will open at reduced 
paclitaxel and carboplatin doses (MLN4924 [15 mg/m2] + paclitaxel [175 mg/m2] + carboplatin 
[AUC5]), and patients will be treated as described below in Arm 2.
MLN4924 + Paclitaxel + Carboplatin (Arm 2): During the dose escalation phase, a total of 4 dose 
levels of IV MLN4924 (15, 25, 37, and 50 mg/m2) are planned to be studied in combination with 
paclitaxel and carboplatin. On Day 1 of each cycle when all 3 drugs are administered, paclitaxel is 
given first at a dose of 200 mg/m2 (or 175 mg/m2, if the dose was reduced in the carboplatin lead-in 
cohort) IV over 3 hours followed by carboplatin AUC6 (or AUC5 if the dose was reduced in 
carboplatin lead-in cohort) over 30 minutes. After a mandatory approximately 15-minute time out 
(MLN4924-free period) 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. 
MLN4924 + Gemcitabine (Arm 3): A total of 4 dose levels of IV MLN4924 (25, 50, 75, and 
100 mg/m2) are planned to be studied in combination with 1000 mg/m2 of gemcitabine. Gemcitabine 
will be administered IV at a dose of 1000 mg/m2 over 30 to 60 minutes or per current prescribing 
guidelines.  After a 15-minute time out, MLN4924 will be administered. Patients will receive both 
agents on Days 1, 8, and 15, and the duration of each cycle will be 28 days.
After the determination of the MTD of MLN4924 with docetaxel (Arm 1), paclitaxel + carboplatin 
(Arm 2), and gemcitabine (Arm 3), approximately 6 additional patients will be enrolled to each arm, 
for a total of approximately 12 patients treated in each arm at the MTD to more fully characterize the 
safety, tolerability, and PK of MLN4924 in combination with each SoC regimen and to evaluate 
disease response. 
An adaptive approach using a continual reassessment method (CRM) will be used for dose escalation 
(see Section 6.4). The dose toxicity relationship and the predicted maximum tolerated dose (PMTD) 
level will be updated as new data become available. The recommendation to escalate, de-escalate, or 
expand at the same dose level will be determined by comparing the PMTD level from the dose 
toxicity model to the prespecified dose levels. From the starting dose, subsequent increases will be 
made according to the dose levels indicated for each arm; however, for safety reasons, no dose level 
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MLN4924
Clinical Study Protocol C15010 Amendment 1
6
will be skipped, and a minimum of 3 patients is required before escalating to the next dose level. 
Once at least 6 patients are treated at any dose level and the algorithm does not recommend 
escalation or de-escalation, this dose level may be considered the MTD. 
Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE), Version 4.03, effective date 14 June 2010.(1)  
Throughout the study, 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 to evaluate the safety and tolerability of MLN4924 in 
combination with docetaxel, paclitaxel + carboplatin, and gemcitabine (patients in the carboplatin 
lead-in cohort will receive MLN4924 + carboplatin only).
Blood samples (sparse sampling) for the determination of MLN4924 plasma concentrations and, if 
appropriate, its metabolites will be collected from each patient during Cycle 1 of treatment to 
contribute to a population PK analysis of MLN4924 co-administered with docetaxel, or 
paclitaxel + carboplatin, or gemcitabine. During the dose escalation portion of the study (excluding 
the Arm 2 carboplatin lead-in cohort), blood samples will be collected from each patient for the 
determination of MLN4924 plasma concentrations during the first cycle of treatment at the time 
points indicated in the Schedules of Events. During the MTD expansion portion of the study, serial 
blood samples will be collected from all patients at the time points indicated in the Schedules of 
Events before and after the start of MLN4924 infusion. 
Computed tomography (CT) scans with IV contrast of the chest, abdomen, and pelvis will be 
performed during screening. CT scans with IV contrast encompassing the known sites of disease will 
be performed at the end of Cycle 2 and then every other cycle thereafter (Cycles 4-12) or after 
completion of every sixth cycle after the patient’s previous scan (after completion of Cycle 12 and 
implementation of Amendment 1), and at the End of Study (EOS) visit. Additional CT scans may be 
performed, per the investigator’s discretion, if clinically indicated. 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 Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. 
Paraffin-embedded tumor tissue or unstained slides of the tumor tissue will be collected at screening 
to enable genetic characterization of the patient’s tumor and to evaluate expression levels of 
candidate response biomarkers 
 
 
 
Study Population: Patients 18 years of age or older who have a histologically or cytologically 
confirmed metastatic or locally advanced and incurable solid tumor that is felt to be appropriate for 
treatment with 1 of the 3 chemotherapy regimens in this study, or have progressed despite standard 
therapy, or for whom conventional therapy is not considered effective. 
Duration of Study: The maximum duration of treatment will be 12 cycles; however, if it is 
determined after discussion between the investigator and the sponsor that a patient would derive 
benefit from continued treatment, the patient may remain on the current combination therapy or 
receive MLN4924 as a single agent beyond 12 cycles.
CCI
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MLN4924
Clinical Study Protocol C15010 Amendment 1
7
STUDY OVERVIEW DIAGRAM
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MLN4924
Clinical Study Protocol C15010 Amendment 1
8
SCHEDULES OF EVENTS
Cycle 1:  Arm 1 and Arm 2
Arm 1 (MLN4924 + Docetaxel)
Arm 2 (Carboplatin Lead-in [MLN4924 + Carboplatin] and MLN4924 + Paclitaxel + Carboplatin)
Screeninga
Treatment Cycle (21 Days)
End of Studyb
Week 1
Week 2
Week 3
Day 1 
Predose
Day 1 
Postdose
Day 2
Day 3
Day 5
Day 8 
(1 day)
Day 15 
(1 day)
Study Drug Administration
MLN4924 Infusionc
X
X
X
Docetaxel Administration 
(Arm 1)c
X
Carboplatin Administration 
(Arm 2 Lead-In)c
X
Paclitaxel + Carboplatin 
Administration (Arm 2)c
X
Procedures
Informed Consent
X
Inclusion/Exclusion
X
Demographics
X
Complete Medical History
X
Full Physical Examination
X
X
Symptom-directed Physical 
Examination
X
X
X
X
X
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MLN4924
Clinical Study Protocol C15010 Amendment 1
9
Cycle 1:  Arm 1 and Arm 2
Arm 1 (MLN4924 + Docetaxel)
Arm 2 (Carboplatin Lead-in [MLN4924 + Carboplatin] and MLN4924 + Paclitaxel + Carboplatin)
Screeninga
Treatment Cycle (21 Days)
End of Studyb
Week 1
Week 2
Week 3
Day 1 
Predose
Day 1 
Postdose
Day 2
Day 3
Day 5
Day 8 
(1 day)
Day 15 
(1 day)
Pregnancy Test (Females of 
Child-bearing Potential Only)
X
Height
X
Weightd
X
Xe
X
ECOG Performance Status
X
Xe
X
Vital Signsf
X
Xe
X
X
X
X
X
12-Lead ECGg
X
Xe
X
X
X
Concomitant 
Medications/Therapy
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)
Hematologyh
X
Xe
X
X
X
X
X
X
Coagulationi
X
Xe
Clinical Chemistry Panelj
X
Xe
X
X
X
X
X
X
X
Urinalysis With Microscopic 
Analysisk
X
Xe
X
X
Urine Safety Assessmentl
X
X
X
X
X
Echocardiogram
X
Serious Pretreatment Events 
and SAE Collectionm
Serious pretreatment events and SAEs will be reported from the time informed consent is signed through 30 days 
(+ 10 days) after the last dose of study drug(s)
AE Collectionm
Recorded from the first dose of any study drug through 30 days (+ 10 days) after the last dose of study 
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MLN4924
Clinical Study Protocol C15010 Amendment 1
10
Cycle 1:  Arm 1 and Arm 2
Arm 1 (MLN4924 + Docetaxel)
Arm 2 (Carboplatin Lead-in [MLN4924 + Carboplatin] and MLN4924 + Paclitaxel + Carboplatin)
Screeninga
Treatment Cycle (21 Days)
End of Studyb
Week 1
Week 2
Week 3
Day 1 
Predose
Day 1 
Postdose
Day 2
Day 3
Day 5
Day 8 
(1 day)
Day 15 
(1 day)
drug(s)
Blood Samples for PKn
X
X
X
X
X
Biomarker Blood Sampleso
X
Banked Tumor Tissuep
X
Tumor Assessment by 
RECIST (CT/MRI)q
X
Abbreviations:  AE=adverse event; aPTT=activated partial thromboplastin time; CT=computed tomography; DNA=deoxyribonucleic acid; 
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; eCRF=electronic case report form; EOS=End of Study (visit); hr=hour(s); 
INR=international normalized ratio; IV=intravenous(ly); min=minute(s); MRI=magnetic resonance imaging; MTD=maximum tolerated dose; PE=physical 
examination; PK=pharmacokinetic; PT=prothrombin time; RECIST=Response Evaluation Criteria in Solid Tumors; SAE=serious adverse event.
a Screening assessments will be performed within 28 days before the Day 1 dose of study drugs.
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.
c On Day 1, when MLN4924 and chemotherapy agents are 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 due to toxicities in 
accordance with Section 6.5. The chemotherapeutic agent may be dose-reduced due to toxicities in accordance with Section 6.5. See Section 6.1 for details 
of study drug administration. NOTE:  a time-out of approximately 15 minutes is required between end of infusion of chemotherapy regimen and 
start of infusion of MLN4924.
d Weight should be measured predose.
e 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.
f
Vital signs are taken immediately before each infusion of docetaxel, paclitaxel, carboplatin, and MLN4924. In addition, vital signs are taken 30 min 
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MLN4924
Clinical Study Protocol C15010 Amendment 1
11
Cycle 1:  Arm 1 and Arm 2
Arm 1 (MLN4924 + Docetaxel)
Arm 2 (Carboplatin Lead-in [MLN4924 + Carboplatin] and MLN4924 + Paclitaxel + Carboplatin)
Screeninga
Treatment Cycle (21 Days)
End of Studyb
Week 1
Week 2
Week 3
Day 1 
Predose
Day 1 
Postdose
Day 2
Day 3
Day 5
Day 8 
(# 1 day)
Day 15 
(# 1 day)
(± 10 min) after start of MLN4924 dosing, and 1 hr (± 10 min) after completion of MLN4924 dosing. On Cycle 1 Day 1, additional vital signs should be 
obtained 3 hours (± 30 min) after completion of MLN4924 dosing. All of these vital signs are taken 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 to 4 minutes. 
g A 12-lead ECG will be performed during screening and on Day 1 before administration (within 3 hours) of chemotherapy regimen, immediately after the 
infusion of MLN4924 is complete (± 10 min). On Days 3 and 5, 12-lead ECGs will be performed before MLN4924 dosing and 90 min (± 10 min) after the 
start of MLN4924 infusion.
h Hematology samples will be collected during screening; before dosing with study drug(s) on Days 1, 3, and 5; Day 2; Day 8; Day 15; and at the EOS visit. 
On Days 1 and 5, samples can be drawn within 24 hours predose. For Day 1 dosing only:  if dosing falls on a Monday, the collection window may be 
extended to collect samples on the previous Friday. 
i
A coagulation panel at screening will include the following:  PT (INR), aPTT, fibrinogen, and D-dimer. If the initial coagulation screen is positive, 
subsequent coagulation studies should include all of these parameters. If the initial coagulation screen is negative, subsequent coagulation studies should 
include only PT (INR) and aPTT.
j
Clinical chemistry samples will be collected during screening and before dosing with study drugs on Days 1, 3, and 5. On Days 1 and 5, samples can be 
drawn within 24 hours predose. In addition, samples will be taken on Day 1 at 3 hours (# 30 min) postinfusion with MLN4924; on Day 2, Day 8, and 
Day 15; and at the EOS visit. For Day 1 dosing only:  if dosing falls on a Monday, the collection window may be extended to collect samples on the 
previous Friday.
k Urinalysis samples will be analyzed at the site’s local laboratory.
l
Urine samples for safety assessments will be collected at screening; before any study drug dosing on Days 1, 3, and 5; and on Day 2. These samples will be 
analyzed at a central laboratory.
m Serious pretreatment events (occurring before the first dose of any study drug) will only be reported to 
 and will not be entered on 
the eCRF. All 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). Refer to Section 10 for details regarding definitions, documentation, and reporting of pretreatment events, AEs, and SAEs.   
n See the PK Schedules of Events for all PK collection times:  refer to Cycle 1:  Arm 1 Dose Escalation Pharmacokinetics Schedule and Cycle 1:  Arm 2 
CCI
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MLN4924
Clinical Study Protocol C15010 Amendment 1
12
Cycle 1:  Arm 1 and Arm 2
Arm 1 (MLN4924 + Docetaxel)
Arm 2 (Carboplatin Lead-in [MLN4924 + Carboplatin] and MLN4924 + Paclitaxel + Carboplatin)
Screeninga
Treatment Cycle (21 Days)
End of Studyb
Week 1
Week 2
Week 3
Day 1 
Predose
Day 1 
Postdose
Day 2
Day 3
Day 5
Day 8 
(1 day)
Day 15 
(1 day)
Dose Escalation Pharmacokinetics Schedule during the dose escalation phase of the study, and refer to Cycle 1:  Arm 1 Maximum Tolerated Dose 
Expansion Pharmacokinetics Schedule and Cycle 1:  Arm 2 MTD Expansion Pharmacokinetics Schedule during the MTD expansion phase of the study. 
Note that the Day 5 PK collection applies only to the MTD Expansion Phase.
o Two blood samples will be collected:  one to generate a plasma sample and the other to generate genomic DNA for assessment of biomarkers of response.
p A specimen of fixed tumor sample will be collected for genetic characterization of the patient’s tumor and for assessment of candidate biomarkers of 
response to MLN4924-containing therapy. Suitable specimens are either a tumor block or 10 to 20 unstained slides.
q CT scans with IV contrast of the chest, abdomen, and pelvis will be performed during screening. If the sites of disease are not adequately imaged by CT, 
MRI may also 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 screening assessment.
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erty of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN4924
Clinical Study Protocol C15010 Amendment 1
13
Cycle 1:  Arm 1 Dose Escalation Pharmacokinetics Schedule
Arm 1 (MLN4924 + Docetaxel) Dose Escalation Phase:  Cycle 1 Timing of Pharmacokinetic Measurements
Cycle 1
Pre-infusion
End of MLN4924 Infusion 
After End of MLN4924 Infusion
1.5 hour ± 15 min
3 hour ± 30 min
20 hour ± 2 hour
Day 1
Xa
Xb
X
X
Day 2
Xc
Day 3
Xd
a The sample is to be collected within 1 hour before the start of MLN4924 infusion.
b The sample is to be collected at the end of MLN4924 infusion (immediately before switching off the infusion pump). 
c Note that the 20-hour time point after completion of the infusion on Day 1 will actually fall on Day 2.
d The sample is to be collected within 10 minutes before the start of MLN4924 infusion.
Pr
erty of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN4924
Clinical Study Protocol C15010 Amendment 1
14
Cycle 1:  Arm 2 Dose Escalation Pharmacokinetics Schedule
Arm 2 (MLN4924 + Paclitaxel + Carboplatin) Dose Escalation Phase:  Cycle 1 Timing of Pharmacokinetic Measurements
Cycle 1
Pre-infusion
End of MLN4924 Infusion 
After End of MLN4924 Infusion
1.5 hour ± 15 min
3 hour ± 30 min
20 hour ± 2 hour
Day 1
Xa
Xb
X
X
Day 2
Xc
Day 3
Xd
a The sample is to be collected within 1 hour before the start of MLN4924 infusion.
b The sample is to be collected at the end of MLN4924 infusion (immediately before switching off the infusion pump). 
c Note that the 20-hour time point after completion of the infusion on Day 1 will actually fall on Day 2.
d The sample is to be collected within 10 minutes before the start of MLN4924 infusion.
Pr
erty of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN4924
Clinical Study Protocol C15010 Amendment 1
15
Cycle 1:  Arm 1 Maximum Tolerated Dose Expansion Pharmacokinetics Schedule
Arm 1 (MLN4924 + Docetaxel) Maximum Tolerated Dose Expansion Phase:  Cycle 1 Timing of Pharmacokinetic 
Measurements
Cycle 1
Pre-infusion
End of MLN4924 Infusion 
After End of MLN4924 Infusion
1.5 hour ± 15 min
3 hour ± 30 min
7 hour ± 45 min
20 hour ± 2 hour
Day 1
Xa
Xb
X
X
X
Day 2
Xc
Day 3
Xd
Day 5
Xd
Xb
X
X
X
Day 6
Xe
a The sample is to be collected within 1 hour before the start of MLN4924 infusion.
b The sample is to be collected at the end of MLN4924 infusion (immediately before switching off the infusion pump).
c Note that the 20-hour time point after completion of the infusion on Day 1 will actually fall on Day 2.
d The sample is to be collected within 10 minutes before the start of MLN4924 infusion.
e Note that the 20-hour time point after completion of the infusion on Day 5 will actually fall on Day 6.
Pr
erty of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN4924
Clinical Study Protocol C15010 Amendment 1
16
Cycle 1:  Arm 2 MTD Expansion Pharmacokinetics Schedule
Arm 2 (MLN4924 + Paclitaxel + Carboplatin) Maximum Tolerated Dose Expansion Phase:  Cycle 1 Timing of 
Pharmacokinetic Measurements
Cycle 1
Pre-infusion
End of MLN4924 Infusion 
After End of MLN4924 Infusion
1.5 hour ± 15 min
3 hour ± 30 min
6 hour ± 45 min
20 hour ± 2 hour
Day 1
Xa
Xb
X
X
X
Day 2
Xc
Day 3
Xd
Day 5
Xd
Xb
X
X
X
Day 6
Xe
a The sample is to be collected within 1 hour before the start of MLN4924 infusion.
b The sample is to be collected at the end of MLN4924 infusion (immediately before switching off the infusion pump).
c Note that the 20-hour time point after completion of the infusion on Day 1 will actually fall on Day 2.
d The sample is to be collected within 10 minutes before the start of MLN4924 infusion.
e Note that the 20-hour time point after completion of the infusion on Day 5 will actually fall on Day 6.
Pr
rty of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN4924
Clinical Study Protocol C15010 Amendment 1
17
Cycle 2 and Beyond:  Arm 1, and Cycle 2 through Cycle 12:  Arm 2
Arm 1 (MLN4924 + Docetaxel) 
Arm 2 (Carboplatin Lead-in [MLN4924 + Carboplatin] and MLN4924 + Paclitaxel + Carboplatin)
Treatment Cycle (21 Days)a 
End of Studyb
Week 1
Week 2
Week 3 
Day 1
Predose
Day 1
Postdose
Day 3
Day 5
Day 8 (1 day)
Day 15 (1 day)
Study Drug Administration
MLN4924 Infusion (Arm 1 and Arm 2)c
X
X
X
Docetaxel Administration (Arm 1)c
X
Carboplatin Administration (Arm 2 
Lead-in)c
X
Paclitaxel + Carboplatin  Administration 
(Arm 2)c
X
Procedures
Full Physical Examination
X
X
Symptom-directed Physical Examination
X
X
Weight
X
X
ECOG Performance Status
X
X
Vital Signsd
X
X
X
X
X
12-Lead ECGe
X
X
Concomitant Med/Therapy
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)
Hematologyf
X
X
X
X
X
X
Coagulationg
X
Clinical Chemistry Panelh
X
X
X
X
X
X
Pr
erty of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN4924
Clinical Study Protocol C15010 Amendment 1
18
Cycle 2 and Beyond:  Arm 1, and Cycle 2 through Cycle 12:  Arm 2
Arm 1 (MLN4924 + Docetaxel) 
Arm 2 (Carboplatin Lead-in [MLN4924 + Carboplatin] and MLN4924 + Paclitaxel + Carboplatin)
Treatment Cycle (21 Days)a 
End of Studyb
Week 1
Week 2
Week 3 
Day 1
Predose
Day 1
Postdose
Day 3
Day 5
Day 8 (1 day)
Day 15 (1 day)
Urinalysis with Microscopic Analysisi
X
X
X
Urine Safety Assessmentsj
X
SAE Collectionk
SAEs will be reported from the time informed consent is signed through 30 days (+ 10 days) after the last dose of 
study drug(s)
AE Collectionk
Recorded from the first dose of any study drug through 30 days (+ 10 days) after the last dose of study drug(s)
Tumor Assessment by RECIST 
(CT/MRI)l
X
X
Abbreviations:  AE=adverse event; aPTT=activated partial thromboplastin time; CT=computed tomography; ECG=electrocardiogram; ECOG=Eastern 
Cooperative Oncology Group; eCRF=electronic case report form; EOS=End of Study (visit); INR=international normalized ratio; IV=intravenous(ly); 
Med=medication; MRI=magnetic resonance imaging; PE=physical examination; PT=prothrombin time; RESIST=Response Evaluation Criteria in Solid 
Tumors; SAE=serious adverse event.
a For a new cycle of treatment with study drugs to begin, toxicities considered to be related to treatment with study drugs must have resolved to ≤Grade 1, to 
the patient’s baseline values, or to a level considered acceptable by the investigator after discussion with the project clinician (Section 6.5). 
b The EOS visit will occur 30 days (+ 10 days) after the last dose of study drug(s) or before the start of subsequent therapy for their indication, if that occurs 
sooner. 
c On Day 1, when chemotherapy agents are 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 due to toxicities in accordance with 
Section 6.5. The chemotherapeutic agent may be reduced due to toxicities in accordance with Section 6.5. See Section 6.1 for details of study drug 
administration. NOTE:  a time-out of approximately 15 minutes is required between end of infusion of chemotherapy regimen and start of infusion of 
MLN4924.
d Vital signs are taken immediately before each infusion of docetaxel, paclitaxel, carboplatin, and MLN4924. In addition, vital signs are taken 30 min 
(± 10 min) after the start of MLN4924 dosing and 1 hr (± 10 min) after completion of MLN4924 dosing. Vital sign measurements will be taken with the 
Pr
erty of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN4924
Clinical Study Protocol C15010 Amendment 1
19
Cycle 2 and Beyond:  Arm 1, and Cycle 2 through Cycle 12:  Arm 2
Arm 1 (MLN4924 + Docetaxel) 
Arm 2 (Carboplatin Lead-in [MLN4924 + Carboplatin] and MLN4924 + Paclitaxel + Carboplatin)
Treatment Cycle (21 Days)a 
End of Studyb
Week 1
Week 2
Week 3 
Day 1
Predose
Day 1
Postdose
Day 3
Day 5
Day 8 (1 day)
Day 15 (1 day)
patient in a sitting position.
e A 12-lead ECG will be performed on Day 1 before (within 3 hours) chemotherapy dosing and immediately after the infusion of MLN4924 is complete 
(± 10 min). 
f
Hematology samples will be collected before dosing with study drug(s) during Cycle 2 and subsequent cycles on Days 1, 3, and 5; Day 8; Day 15; and at the 
EOS visit. On Days 1, 3, and 5, samples can be drawn within 24 hours predose. For Day 1 dosing only:  if dosing falls on a Monday, the collection window 
may be extended to collect samples on the previous Friday.
g A coagulation panel at screening (see Schedules of Events:  Cycle 1:  Arm 1 and Arm 2) will include the following:  PT (INR), aPTT, fibrinogen, and 
D-dimer. If the initial coagulation screen is positive, subsequent coagulation studies should include all of these parameters. If the initial coagulation screen is 
negative, subsequent coagulation studies should include only PT (INR) and aPTT.
h Clinical chemistry samples will be collected before dosing with study drugs on Days 1, 3, and 5; Day 8; Day 15; and at the EOS visit. On Days 1, 3, and 5, 
samples can be drawn within 24 hours predose. For Day 1 dosing only:  if dosing falls on a Monday, the collection window may be extended to collect 
samples on the previous Friday. 
i
Urinalysis samples will be analyzed at the site’s local laboratory.
j
Urine samples for safety assessments will be collected before any study drug dosing on Day 1 of each new cycle. These samples will be analyzed at a central 
laboratory.
k All 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). 
Refer to Section 10 for details regarding definitions, documentation, and reporting of pretreatment events, AEs, and SAEs.     
l
CT scans with IV contrast encompassing the known sites of disease will be performed at the end of Cycle 2 and then every other cycle thereafter, and at the 
EOS visit. For each site of disease, the imaging modality (CT or CT and MRI) used at screening must be used throughout the study. CT scans (or MRI) can be 
taken up to 6 days after the Day 15 visit.
Pr
erty of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN4924
Clinical Study Protocol C15010 Amendment 1
20
Cycle 13 and Beyond:  Arm 2 (as of Amendment 1)
Arm 2 (Carboplatin Lead-in [MLN4924 + Carboplatin] and MLN4924 + Paclitaxel + Carboplatin)
Treatment Cycle (21 Days)a 
End of Studyb
Week 1
Day 1
Predose
Day 1
Postdose
Day 3
Day 5
Study Drug Administration
MLN4924 Infusionc
X
X
X
Paclitaxel + Carboplatin Administrationc
X
Procedures
Symptom-directed Physical Examination
X
X
Weight
X
X
ECOG Performance Status
X
X
Vital Signsd
X
X
X
X
X
12-Lead ECGe
X
X
Concomitant Med/Therapy
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)
Hematologyf
X
X
X
X
Coagulationg
X
Clinical Chemistry Panelh
X
X
X
X
Urinalysis with Microscopic Analysisi
X
X
X
SAE Collectionj
SAEs will be reported from the time informed consent is signed through 30 days (+ 10 days) after the last 
dose of study drug(s)
P
erty of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN4924
Clinical Study Protocol C15010 Amendment 1
21
Cycle 13 and Beyond:  Arm 2 (as of Amendment 1)
Arm 2 (Carboplatin Lead-in [MLN4924 + Carboplatin] and MLN4924 + Paclitaxel + Carboplatin)
Treatment Cycle (21 Days)a 
End of Studyb
Week 1
Day 1
Predose
Day 1
Postdose
Day 3
Day 5
AE Collectionj
Recorded from the first dose of any study drug through 30 days (+ 10 days) after the last dose of study 
drug(s)
Tumor Assessment by RECIST (CT/MRI)k
To be performed after completion of every sixth cycle after the patient’s 
previous scan
X
Abbreviations:  AE=adverse event; aPTT=activated partial thromboplastin time; CT=computed tomography; ECG=electrocardiogram; ECOG=Eastern 
Cooperative Oncology Group; eCRF=electronic case report form; EOS=End of Study (visit); INR=international normalized ratio; IV=intravenous(ly); 
Med=medication; MRI=magnetic resonance imaging; PE=physical examination; PT=prothrombin time; RESIST=Response Evaluation Criteria in Solid 
Tumors; SAE=serious adverse event.
a For a new cycle of treatment with study drugs to begin, toxicities considered to be related to treatment with study drugs must have resolved to ≤Grade 1, to 
the patient’s baseline values, or to a level considered acceptable by the investigator after discussion with the project clinician (Section 6.5). 
b The EOS visit will occur 30 days (+ 10 days) after the last dose of study drug(s) or before the start of subsequent therapy for their indication, if that occurs 
sooner. 
c On Day 1, when chemotherapy agents are 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 due to toxicities in accordance with 
Section 6.5. The chemotherapeutic agent may be reduced due to toxicities in accordance with Section 6.5. See Section 6.1 for details of study drug 
administration. NOTE:  a time-out of approximately 15 minutes is required between end of infusion of chemotherapy regimen and start of infusion of 
MLN4924.
d Vital signs are taken immediately before each infusion of drug(s). In addition, vital signs are taken 30 min (± 10 min) after the start of MLN4924 dosing and 
1 hr (± 10 min) after completion of MLN4924 dosing. Vital sign measurements will be taken with the patient in a sitting or supine position.
e A 12-lead ECG will be performed on Day 1 before (within 3 hours) chemotherapy dosing and immediately after the infusion of MLN4924 is complete 
(± 10 min). 
f
Hematology samples will be collected before dosing with study drug(s) during Cycle 13 and subsequent cycles on Days 1, 3, and 5; and at the EOS visit. On 
Days 1, 3, and 5, samples can be drawn within 24 hours predose. For Day 1 dosing only:  if dosing falls on a Monday, the collection window may be 
extended to collect samples on the previous Friday.
g A coagulation panel at screening (see Schedules of Events:  Cycle 1:  Arm 1 and Arm 2) will include the following:  PT (INR), aPTT, fibrinogen, and 
Pr
erty of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN4924
Clinical Study Protocol C15010 Amendment 1
22
Cycle 13 and Beyond:  Arm 2 (as of Amendment 1)
Arm 2 (Carboplatin Lead-in [MLN4924 + Carboplatin] and MLN4924 + Paclitaxel + Carboplatin)
Treatment Cycle (21 Days)a 
End of Studyb
Week 1
Day 1
Predose
Day 1
Postdose
Day 3
Day 5
D-dimer. If the initial coagulation screen is positive, subsequent coagulation studies should include all of these parameters. If the initial coagulation screen is 
negative, subsequent coagulation studies should include only PT (INR) and aPTT.
h Clinical chemistry samples will be collected before dosing with study drugs on Days 1, 3, and 5 and at the EOS visit. On Days 1, 3, and 5, samples can be 
drawn within 24 hours predose. For Day 1 dosing only:  if dosing falls on a Monday, the collection window may be extended to collect samples on the 
previous Friday. 
i
Urinalysis samples will be analyzed at the site’s local laboratory.
j
All 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). 
Refer to Section 10 for details regarding definitions, documentation, and reporting of pretreatment events, AEs, and SAEs.     
k CT scans with IV contrast encompassing the known sites of disease will be performed after completion of every sixth cycle after the patient's previous scan, 
and at the EOS visit. For each site of disease, the imaging modality (CT or CT and MRI) used at screening must be used throughout the study. CT scans (or 
MRI) can be taken up to 6 days after the Day 15 visit.
Pr
erty of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN4924
Clinical Study Protocol C15010 Amendment 1
23
Cycle 1: Arm 3
Arm 3 (MLN4924 + Gemcitabine)
Screeninga
Treatment Cycle (28 Days)
End of Studyb
Week 1
Week 2
Week 3
Week 4
Day 1 
Predose
Day 1 
Postdose
Day 2
Day 8 
(1 day)
Day 15
(1 day)
Day 22
(1 day)
Study Drug Administration
MLN4924 Infusionc
X
X
X
Gemcitabine Administrationc
X
X
X
Procedures
Informed Consent
X
Inclusion/Exclusion
X
Demographics
X
Complete Medical History
X
Full Physical Examination
X
X
Symptom-directed Physical 
Examination
X
X
X
X
Pregnancy Test (Females of 
Child-bearing Potential Only)
X
Height
X
Weightd
X
Xe
X
ECOG Performance Status
X
Xe
X
Vital Signsf
X
Xe
X
X
X
X
X
12-Lead ECGg
X
Xe
X
Concomitant 
Medications/Therapy
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)
Pr
erty of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN4924
Clinical Study Protocol C15010 Amendment 1
24
Cycle 1: Arm 3
Arm 3 (MLN4924 + Gemcitabine)
Screeninga
Treatment Cycle (28 Days)
End of Studyb
Week 1
Week 2
Week 3
Week 4
Day 1 
Predose
Day 1 
Postdose
Day 2
Day 8 
(1 day)
Day 15
(1 day)
Day 22
(1 day)
Hematologyh
X
Xe
X
X
X
X
X
Coagulationi
X
Xe
Clinical Chemistry Panelj
X
Xe
X
X
X
X
X
X
Urinalysis With Microscopic 
Analysisk
X
Xe
X
X
X
Urine Safety Assessmentl
X
X
X
X
X
Echocardiogram
X
Serious Pretreatment Events 
and SAE Collectionm
Serious pretreatment events and SAEs will be reported from the time informed consent is signed through 30 days (+ 10 days) 
after the last dose of study drug(s)
AE Collectionm
Recorded from the first dose of any study drug through 30 days (+ 10 days) after the last dose of study drug(s)
Blood Samples for PKn
X
X
X
Biomarker Blood Sampleso
X
Banked Tumor Tissuep
X
Tumor Assessment by 
RECIST (CT/MRI)q
X
Abbreviations:  AE=adverse event; aPTT=activated partial thromboplastin time; CT=computed tomography; DNA=deoxyribonucleic acid; 
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; eCRF=electronic case report form; EOS=End of Study (visit); hr=hour(s); 
INR=international normalized ratio; IV=intravenous(ly); min=minute(s); MRI=magnetic resonance imaging; PE=physical examination; PK=pharmacokinetic; 
PT=prothrombin time; RECIST=Response Evaluation Criteria in Solid Tumors; SAE=serious adverse event.
a Screening assessments will be performed within 28 days before the Day 1 dose of study drugs.
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 
P
erty of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN4924
Clinical Study Protocol C15010 Amendment 1
25
Cycle 1: Arm 3
Arm 3 (MLN4924 + Gemcitabine)
Screeninga
Treatment Cycle (28 Days)
End of Studyb
Week 1
Week 2
Week 3
Week 4
Day 1 
Predose
Day 1 
Postdose
Day 2
Day 8 
(1 day)
Day 15
(1 day)
Day 22
(1 day)
sooner.
c On Days 1, 8, and 15, gemcitabine will be administered first, followed by MLN4924. The infusion of ML4924 may be slowed or stopped and restarted for 
any associated infusion-related reactions. The dose of MLN4924 may be reduced due to toxicities in accordance with Section 6.5. The dose of gemcitabine 
may be reduced due to toxicities in accordance with Section 6.5. See Section 6.1 for details of study drug administration. Note: a time-out of approximately 
15 minutes is required after dosing with gemcitabine and before the start of MLN4924 infusion. 
d Weight should be measured predose.
e 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.
f
Vital signs are taken immediately before each infusion of gemcitabine and MLN4924. In addition, vital signs are taken 30 min (± 10 min) after the start of 
MLN4924 dosing, and 1 hour (± 10 min) after completion of MLN4924 dosing. On Cycle 1 Day 1, additional vital signs should be obtained 3 hours 
(± 30 min) after completion of MLN4924 dosing. All of these vital signs are taken with the patient in a 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 to 4 minutes. 
g A 12-lead ECG will be performed during screening and on Day 1 before (within 3 hours) gemcitabine dosing, immediately after the infusion of MLN4924 is 
complete (10 min). 
h Hematology samples will be collected during screening; before dosing with study drug(s) on Days 1, 8, and 15; Day 2; Day 22; and at the EOS visit. On 
Days 1, 8, and 15, samples can be drawn within 24 hours predose. For dosing Days only:  if dosing falls on a Monday, the collection window may be 
extended to collect samples on the previous Friday. 
i
A coagulation panel at screening will include the following:  PT (INR), aPTT, fibrinogen, and D-dimer. If the initial coagulation screen is positive, follow-up 
coagulation studies should include all of these parameters. If the initial coagulation screen is negative, follow-up coagulation studies should include only 
PT (INR) and aPTT.
j
Clinical chemistry samples will be collected during screening and before dosing with study drugs on Days 1, 8, and 15. On Days 1, 8, and 15, samples can be 
drawn within 24 hours predose. In addition, samples will be taken on Day 1 at 3 hours (30 min) postinfusion with MLN4924; Day 2; Day 22; and at the 
EOS visit. For Day 1 dosing only:  if dosing falls on a Monday, the collection window may be extended to collect samples on the previous Friday.
k Urinalysis samples will be analyzed by the site’s local laboratory.
P
erty of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN4924
Clinical Study Protocol C15010 Amendment 1
26
Cycle 1: Arm 3
Arm 3 (MLN4924 + Gemcitabine)
Screeninga
Treatment Cycle (28 Days)
End of Studyb
Week 1
Week 2
Week 3
Week 4
Day 1 
Predose
Day 1 
Postdose
Day 2
Day 8 
(# 1 day)
Day 15
(# 1 day)
Day 22
(# 1 day)
l
Urine samples for safety assessments will be collected at screening; before any study drug dosing on Days 1, 8, and 15; and on Day 2. These samples will be 
analyzed at a central laboratory.
m All serious pretreatment events (occurring before the first dose of any study drug) will only be reported to 
 and will not be entered on 
the eCRF. 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). Refer to Section 10 for details regarding definitions, documentation, and reporting of pretreatment events, AEs, and SAEs.    
n See the Schedules of Events:  refer to Cycle 1:  Arm 3 Dose Escalation Pharmacokinetics Schedule during the dose escalation phase of the study, and refer to 
Cycle 1:  Arm 3 MTD Expansion Pharmacokinetics Schedule during the MTD expansion phase of the study.
o Two blood samples will be collected:  one to generate a plasma sample and the other to generate genomic DNA for assessment of biomarkers of response.
p A specimen of fixed tumor sample will be collected for genetic characterization of the patient’s tumor and for assessment of candidate biomarkers of response 
to MLN4924-containing therapy. Suitable specimens are either a tumor block or 10 to 20 unstained slides.
q CT scans with IV contrast of the chest, abdomen, and pelvis will be performed during screening. If the sites of disease are not adequately imaged by CT, MRI 
may also 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 screening assessment.
CCI
Pr
erty of Takeda: For non-commercial use only and subjec
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osing on
only be r
only be
ned to be d
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and repor
d repo
ect to the applicable Terms of Use
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MLN4924
Clinical Study Protocol C15010 Amendment 1
27
Cycle 1:  Arm 3 Dose Escalation Pharmacokinetics Schedule
Arm 3 (MLN4924 + Gemcitabine) Dose Escalation Phase:  Cycle 1 Timing of Pharmacokinetic Measurements
Cycle 1
Pre-infusion
End of MLN4924 Infusion
After End of MLN4924 Infusion
1.5 hour ± 15 min
3 hour ± 30 min
20 hour ± 2 hour
Day 1
Xa
Xb
X
X
Day 2
Xc
a The sample is to be collected within 1 hour before the start of MLN4924 infusion.
b The sample is to be collected at the end of MLN4924 infusion (immediately before switching off the infusion pump). 
c Note that the 20-hour time point after completion of the infusion on Day 1 will actually fall on Day 2.
Pr
erty of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN4924
Clinical Study Protocol C15010 Amendment 1
28
Cycle 1:  Arm 3 MTD Expansion Pharmacokinetics Schedule
Arm 3 (MLN4924 + Gemcitabine) Maximum Tolerated Dose Expansion Phase:  Cycle 1 Timing of Pharmacokinetic 
Measurements
Cycle 1
Pre-infusion
End of MLN4924 Infusion 
After End of MLN4924 Infusion
1.5 hour ± 15 min
3 hour ± 30 min
7 hour ± 45 min
20 hour ± 2 hour
Day 1
Xa
Xb
X
X
X
Day 2
Xc
a The sample is to be collected within 1 hour before the start of MLN4924 infusion.
b The sample is to be collected at the end of MLN4924 infusion (immediately before switching off the infusion pump).
c Note that the 20-hour time point after completion of the infusion on Day 1 will actually fall on Day 2.
Pr
erty of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN4924
Clinical Study Protocol C15010 Amendment 1
29
Cycle 2 and Beyond:  Arm 3
Arm 3 (MLN4924 + Gemcitabine)
Treatment Cycle (28 Days)a 
End of Studyb
Week 1
Week 2
Week 3 
Week 4
Day 1
Predose
Day 1
Postdose
Day 8
(1 day)
Day 15
(1 day)
Day 22
(4 days)
Study Drug Administration
MLN4924 Infusionc
X
X
X
Gemcitabine Administrationc
X
X
X
Procedures
Full Physical Examination
X
X
Symptom-directed Physical 
Examination
X
X
Weight
X
X
ECOG Performance Status
X
X
Vital Signsd
X
X
X
X
X
12-Lead ECGe
X
X
Concomitant Med/Therapy
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)
Hematologyf
X
X
X
X
X
Coagulationg
X
Clinical Chemistry Panelh
X
X
X
X
X
Urinalysis with Microscopic 
Analysisi
X
Urine Safety Assessmentsj
X
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Cycle 2 and Beyond:  Arm 3
Arm 3 (MLN4924 + Gemcitabine)
Treatment Cycle (28 Days)a 
End of Studyb
Week 1
Week 2
Week 3 
Week 4
Day 1
Predose
Day 1
Postdose
Day 8
(1 day)
Day 15
(1 day)
Day 22
(4 days)
SAE Collectionk
SAEs will be reported from the time informed consent is signed through 30 days (+ 10 days) after the last dose of study 
drug(s)
AE Collectionk
Recorded from the first dose of any study drug through 30 days (+ 10 days) after the last dose of study drug(s)
Tumor Assessment by RECIST 
(CT/MRI)l
X
X
Abbreviations:  AE=adverse event; aPTT=activated partial thromboplastin time; CT=computed tomography; ECG=electrocardiogram; ECOG=Eastern 
Cooperative Oncology Group; eCRF=electronic case report form; EOS=End of Study (visit); INR=international normalized ratio; IV=intravenous(ly); 
Med=medication; MRI=magnetic resonance imaging; PE=physical examination; PT=prothrombin time; RECIST=Response Evaluation Criteria in Solid 
Tumors; SAE=serious adverse event.
a For a new cycle of treatment with study drugs to begin, toxicities considered to be related to treatment with study drugs must have resolved to ≤Grade 1, to 
the patient’s baseline values, or to a level considered acceptable by the investigator after discussion with the project clinician (Section 6.5). 
b The EOS visit will occur 30 days (+ 10 days) after the last dose of study drug(s) or before the start of subsequent therapy for their indication, if that occurs 
sooner. 
c The infusion of MLN4924 may be slowed or stopped and restarted for any associated infusion-related reactions. The dose of MLN4924 may be reduced 
due to toxicities in accordance with Section 6.5. The dose of gemcitabine may be reduced due to toxicities in accordance with Section 6.5. See Section 6.1
for details of study drug administration. Note:  a time-out of approximately 15 minutes is required after dosing with gemcitabine and before the start 
of MLN4924 infusion.
d Vital signs are taken immediately before infusion of gemcitabine and MLN4924. In addition, vital signs are taken 30 min (± 10 min) after the start of 
MLN4924 dosing and 1 hr (± 10 min) after completion of MLN4924 dosing. Vital sign measurements will be taken with the patient in a sitting position.
e A 12-lead ECG will be performed on Day 1 before (within 3 hours) gemcitabine dosing and immediately after the infusion of MLN4924 is complete 
(10 min).
f
Hematology samples will be collected before dosing with study drug(s) during Cycle 2 and all subsequent cycles on Days 1, 8, 15; Day 22; and at the EOS 
visit. On Days 1, 8, and 15, samples can be drawn within 24 hours predose. For Day 1 dosing only:  if dosing falls on a Monday, the collection window 
may be extended to collect samples on the previous Friday.
g A coagulation panel at screening (see Schedules of Events:  Cycle 1: Arm 3) will include the following:  PT (INR), aPTT, fibrinogen, and D-dimer. If the 
initial coagulation screen is positive, subsequent coagulation studies should include all of these parameters.  If the initial coagulation screen is negative, 
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Cycle 2 and Beyond:  Arm 3
Arm 3 (MLN4924 + Gemcitabine)
Treatment Cycle (28 Days)a 
End of Studyb
Week 1
Week 2
Week 3 
Week 4
Day 1
Predose
Day 1
Postdose
Day 8
(1 day)
Day 15
(1 day)
Day 22
(4 days)
subsequent coagulation studies should include only PT (INR) and aPTT.
h Clinical chemistry samples will be collected before dosing with study drugs on Days 1, 8, and 15; Day 22; and at the EOS visit. On Days 1, 8, and 15, 
samples can be drawn within 24 hours predose. For Day 1 dosing only:  if dosing falls on a Monday, the collection window may be extended to collect 
samples on the previous Friday. 
i
Urinalysis samples will be analyzed at the site’s local laboratory.
j
Urine samples for safety assessments will be collected before any study drug dosing on Day 1 of each new cycle. These samples will be analyzed at a 
central laboratory.
k All 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). 
Refer to Section 10 for details regarding definitions, documentation, and reporting of pretreatment events, AEs, and SAEs.     
l
CT scans with IV contrast encompassing the known sites of disease will be performed at the end of Cycle 2 and then every other cycle thereafter, and at the 
EOS visit. For each site of disease, the imaging modality (CT or CT and MRI) used at screening must be used throughout the study. CT scans (or MRI) can 
be taken up to 6 days after the Day 22 visit.
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TABLE OF CONTENTS
LIST OF TABLES.............................................................................................................35
LIST OF FIGURES............................................................................................................35
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ..........................................36
1. BACKGROUND AND STUDY RATIONALE..............................................................39
1.1 Scientific Background ..............................................................................................39
1.1.1 Study Drug ........................................................................................................39
1.2 Nonclinical Experience.............................................................................................39
1.2.1 Single-Agent MLN4924.....................................................................................39
1.2.2 MLN4924 in Combination With Taxane-based Therapy ....................................42
1.2.3 MLN4924 in Combination With Platinum-based Therapy..................................42
1.2.4 MLN4924 in Combination With Gemcitabine....................................................43
1.3 Clinical Experience ..................................................................................................43
1.4 Study Rationale ........................................................................................................47
1.4.1 Antitumor Activity of MLN4924 in Solid Tumors .............................................48
1.4.2 Chemotherapy Regimens for Solid Tumors........................................................48
1.4.3 Rationale for Dose and Schedule........................................................................50
1.4.4 Rationale for Assessment of Biomarkers of Response ........................................54
1.5 Potential Risks and Benefits .....................................................................................54
1.5.1 Risks of MLN4924 Therapy...............................................................................54
1.5.2 Risks of Docetaxel Treatment ............................................................................58
1.5.3 Risks of Carboplatin and Paclitaxel Therapy......................................................59
1.5.4 Risks of Gemcitabine Therapy ...........................................................................61
2. STUDY OBJECTIVES ..................................................................................................62
2.1 Primary Objectives ...................................................................................................62
2.2 Secondary Objectives ...............................................................................................62
2.3 Exploratory Objectives .............................................................................................63
3. STUDY ENDPOINTS....................................................................................................63
3.1 Primary Endpoints....................................................................................................63
3.2 Secondary Endpoints................................................................................................63
3.3 Exploratory Endpoints..............................................................................................63
4. STUDY DESIGN...........................................................................................................64
4.1 Overview of Study Design........................................................................................64
4.2 Number of Patients...................................................................................................67
4.3 Duration of Study.....................................................................................................67
5. STUDY POPULATION.................................................................................................68
5.1 Inclusion Criteria......................................................................................................68
5.2 Exclusion Criteria.....................................................................................................70
6. STUDY DRUG..............................................................................................................73
6.1 Study Drug Administration.......................................................................................73
6.1.1 MLN4924 Administration..................................................................................74
6.1.2 Docetaxel Administration ..................................................................................75
6.1.3 Carboplatin Administration................................................................................75
6.1.4 Paclitaxel Administration...................................................................................76
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6.1.5 Gemcitabine Administration ..............................................................................76
6.2 Reference/Control Therapy.......................................................................................76
6.3 Definitions of Dose-Limiting Toxicity......................................................................76
6.4 Dose Escalation Rules ..............................................................................................78
6.5 Dose-Modification Guidelines (Dose Delays, Dose Reductions, and Dose 
Interruptions) ....................................................................................................82
6.5.1 Intrapatient Dose Escalation...............................................................................86
6.6 Excluded Concomitant Medications and Procedures.................................................87
6.7 Permitted Concomitant Medications and Procedures.................................................87
6.8 Precautions and Restrictions .....................................................................................88
6.8.1 MLN4924..........................................................................................................88
6.8.2 Docetaxel...........................................................................................................89
6.8.3 Carboplatin........................................................................................................90
6.8.4 Paclitaxel...........................................................................................................90
6.8.5 Gemcitabine.......................................................................................................91
6.9 Guidance for Clinical Assessment and Management of Hemodynamic 
Compromise .....................................................................................................91
6.10 Management of Clinical Events..............................................................................92
6.10.1 Guidance for Clinical Assessment and Management of Diarrhea......................92
6.10.2 Guidance for Clinical Assessment and Management of Nausea and 
Vomiting.....................................................................................................92
6.10.3 Guidance for Use of Granulocyte-Colony Stimulating Factor...........................92
6.10.4 Guidance for Clinical Assessment and Management of Anemia .......................93
6.11 Blinding and Unblinding ........................................................................................93
6.12 Description of Investigational Agents .....................................................................93
6.12.1 MLN4924 ........................................................................................................93
6.12.2 Docetaxel.........................................................................................................94
6.12.3 Carboplatin ......................................................................................................94
6.12.4 Paclitaxel .........................................................................................................94
6.12.5 Gemcitabine.....................................................................................................94
6.13 Preparation, Reconstitution, and Dispensation ........................................................94
6.14 Packaging and Labeling..........................................................................................95
6.15 Storage, Handling, and Accountability....................................................................95
7. STUDY CONDUCT ......................................................................................................96
7.1 Study Personnel and Organizations...........................................................................96
7.2 Arrangements for Recruitment of Patients ................................................................96
7.3 Treatment Group Assignments .................................................................................96
7.4 Study Procedures......................................................................................................96
7.4.1 Informed Consent ..............................................................................................97
7.4.2 Patient Demographics ........................................................................................98
7.4.3 Medical History.................................................................................................98
7.4.4 Physical Examination.........................................................................................98
7.4.5 Patient Height ....................................................................................................98
7.4.6 Patient Weight ...................................................................................................98
7.4.7 Eastern Cooperative Oncology Group Performance Status.................................98
7.4.8 Echocardiogram.................................................................................................98
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7.4.9 Vital Signs .........................................................................................................98
7.4.10 Pregnancy Test.................................................................................................99
7.4.11 Concomitant Medications and Procedures........................................................99
7.4.12 Adverse Events................................................................................................99
7.4.13 Enrollment .......................................................................................................99
7.4.14 Electrocardiogram............................................................................................99
7.4.15 Clinical Laboratory Evaluations.....................................................................100
7.4.16 Disease Assessment .......................................................................................101
7.4.17 Tumor Biopsies..............................................................................................101
7.4.18 Pharmacokinetic Measurements.....................................................................102
7.4.19 Whole Blood Sample for Genomic DNA .......................................................103
7.4.20 Banked Tumor Specimen Measurements........................................................103
7.4.21 Plasma Sample Collection..............................................................................103
7.5 Completion of Study...............................................................................................103
7.6 Discontinuation of Treatment with Study Drug, and Patient Replacement...............103
7.7 Study Compliance ..................................................................................................104
8. STATISTICAL AND QUANTITATIVE ANALYSES ................................................105
8.1 Statistical Methods .................................................................................................105
8.1.1 Determination of Sample Size..........................................................................105
8.1.2 Randomization and Stratification .....................................................................107
8.1.3 Populations for Analysis ..................................................................................107
8.1.4 Procedures for Handling Missing, Unused, and Spurious Data.........................107
8.1.5 Demographic and Baseline Characteristics.......................................................107
8.1.6 Efficacy Analysis.............................................................................................108
8.1.7 Pharmacokinetics and Biomarkers....................................................................108
8.1.8 Safety Analysis ................................................................................................109
8.1.9 Interim Analysis...............................................................................................110
9. STUDY COMMITTEES..............................................................................................110
9.1 Millennium Safety Assessments .............................................................................110
10. ADVERSE EVENTS .................................................................................................110
10.1 Definitions............................................................................................................110
10.1.1 Pretreatment Event Definition........................................................................110
10.1.2 Adverse Event Definition...............................................................................111
10.1.3 Serious Adverse Event Definition ..................................................................111
10.2 Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events...............................................................................................112
10.3 Monitoring of Adverse Events and Period of Observation.....................................113
10.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events......114
11. ADMINISTRATIVE REQUIREMENTS ...................................................................114
11.1 Good Clinical Practice..........................................................................................114
11.2 Data Quality Assurance ........................................................................................115
11.3 Electronic Case Report Form Completion.............................................................115
11.4 Study Monitoring .................................................................................................115
11.5 Ethical Considerations..........................................................................................116
11.6 Patient Information and Informed Consent............................................................116
11.7 Patient Confidentiality..........................................................................................116
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11.8 Investigator Compliance.......................................................................................116
11.9 On-site Audits ......................................................................................................117
11.10 Investigator and Site Responsibility for Drug Accountability..............................117
11.11 Product Complaints ............................................................................................117
11.12 Closure of the Study ...........................................................................................118
11.13 Record Retention................................................................................................118
12. USE OF INFORMATION..........................................................................................119
13. INVESTIGATOR AGREEMENT..............................................................................120
14. REFERENCES...........................................................................................................121
15. APPENDICES ...........................................................................................................124
15.1 Hematologic Toxicity of Carboplatin Alone and in Combination With Paclitaxel .124
15.2 Response Criteria .................................................................................................127
15.3 Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status.......128
15.4 Formula for Absolute Neutrophil Count Calculation.............................................128
15.5 Cockcroft-Gault Equation.....................................................................................128
15.6 New York Heart Association Classification of Cardiac Disease ............................129
15.7 Excluded CYP3A Inducers ...................................................................................129
15.8 Drugs Associated with Nephrotoxicity..................................................................130
15.9 Methods of Contraception Considered to be Effective ..........................................130
15.10 Amendment 1 Detailed Description of Amendments to Text...............................133
LIST OF TABLES 
Table 1-1
Potential Overlapping Toxicities With MLN4924 .......................................62
Table 6-1
Overview of MLN4924 and Standard of Care Dosing .................................74
Table 6-2
Planned MLN4924 Dose Levels..................................................................79
Table 6-3
Dose Modification Guidelines for Specific Toxicities..................................84
Table 6-4
Excluded Concomitant Medications and Procedures....................................87
Table 6-5
Permitted Concomitant Medications and Procedures ...................................87
Table 8-1
Operating Characteristics of Continual Reassessment Method Versus 
Traditional Escalation Rules (“3 + 3”).......................................................105
Table 15-1
Hematologic Adverse Experiences of in Patients With Ovarian Cancer 
Treated With Carboplatin or Cisplatin in Combination With 
Cyclophosphamide....................................................................................124
Table 15-2
Hematologic Toxicities and Associated Supportive Care in Patients With 
Advanced Ovarian Cancer Stratified by Treatment Arm and Toxicity 
Grade........................................................................................................125
Table 15-3
In Vivo Inducers of CYP3A......................................................................129
Table 15-4
Drugs Associated with Nephrotoxicity ......................................................130
LIST OF FIGURES 
Figure 6-1
Dose Escalation Scheme .............................................................................81
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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
AE
adverse event
a fib
atrial fibrillation
AIDS
acquired immunodeficiency syndrome
ALL
acute lymphoblastic leukemia
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myelogenous leukemia
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the plasma concentration versus time curve
AUC0-24 hr
AUC from time zero to 24 hours
BCRP
breast cancer resistance protein
BID
bis in die; twice a day
BRCA1
breast cancer susceptibility gene 1
BRCA2
breast cancer susceptibility gene 2
BSA
body surface area
BUN
blood urea nitrogen
CDL
cullin-dependent ubiquitin E3 ligases
Cdt-1
chromatin-licensing and DNA-replication factor-1
Cmax
single-dose maximum (peak) concentration  
CNS
central nervous system
CO2
carbon dioxide
CR
complete response   
Cri
incomplete blood count recovery
CRM
continual reassessment method
CRO
contract research organization
CT
computed tomography
CYP
cytochrome P450
DCSI
Development Core Safety Information
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
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Abbreviation
Term
EOS
End of Study (visit)
GCP
Good Clinical Practice
G-CSF
Granulocyte-colony stimulating factor
GFR
glomerular filtration rate
GGT
gamma glutamyl transferase
GI
Gastrointestinal
HCT
human colon tumor
HIV
human immunodeficiency virus
hr
hour(s)
HUS
hemolytic uremic syndrome
IB
Investigator’s Brochure
IC50
concentration producing 50% inhibition
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
independent ethics committee
INR
international normalized ratio
IP
intraperitoneally
IRB
institutional review board
IV
intravenous; intravenously
LDH
lactate dehydrogenase
LFT
liver function test(s)
LVEF
left ventricular ejection fraction
MDS
myelodysplastic syndromes
Med
medication
MedDRA
Medical Dictionary for Regulatory Activities
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
min
minute(s)
MRI
magnetic resonance imaging
MRP2
multidrug resistance associated protein 2
MTD
maximum tolerated dose
NAE
NEDD8-activating enzyme
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NCIC CTG
National Cancer Institute of Canada Clinical Trials Group
NEDD8
neural precursor cell expressed developmentally down-regulated protein 8
NF-∀B
nuclear (transcription) factor-kappa B
Nrf2
NFE2-related factor 2
NSCLC
non-small cell lung cancer
NYHA
New York Heart Association
OATP
organic anion-transporting polypeptides
CCI
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ously
usly
nase
ase
test(s)
st(s)
cular ejec
cular e
dysplastic
ysplas
dication
icatio
Medical
Medic
Mill
M
E
NCI CTC
NCI CT
NCIC
NC
N


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Abbreviation
Term
PD
progressive disease (disease progression)
PE
physical exam
P-gp
P-glycoprotein
PK
pharmacokinetic(s)
PMTD
predicted maximum tolerated dose
PR
partial response
PS
performance status
PT
prothrombin time
QTc
rate-corrected QT interval (millisec) of electrocardiograph
QW
every week
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
T/C
ratio of tumor volume of treated vs control group
ULN
upper limit of the normal range
US
United States
USP
United States Pharmacopeia
USPI
United States Package Insert
WHO
World Health Organization
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1.
BACKGROUND AND STUDY RATIONALE 
1.1
Scientific Background
1.1.1
Study Drug
MLN4924 is a first-in-class small molecule inhibitor of the neural precursor cell expressed 
developmentally down-regulated protein 8 (NEDD8)-activating enzyme (NAE) that is being 
developed for the treatment of malignancies. NAE 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. CDLs 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 
1.2.1
Single-Agent MLN4924
MLN4924 is a potent and selective inhibitor of NAE activity. It is approximately 300-fold 
and 1800-fold more selective for NAE over the close family members, ubiquitin-activating 
enzyme and sumo-activating enzyme, respectively.(2)  Moreover, MLN4924 is selective for 
NAE when compared to kinases and adenosine receptors.(2)
MLN4924 treatment of cultured tumor cells resulted in changes in protein levels 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 deoxyribonucleic acid (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.(2, 3, 4)  An exception to this was the OCI Ly10 
lymphoma cell line that is dependent on nuclear (transcription) factor-kappa B (NF-B) 
activity for survival.(5)  In this line, NAE inhibition led to an accumulation of cells at the G1 
phase of the cell cycle that was followed by cell death through apoptosis, suggesting that 
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there may be multiple consequences of NAE inhibition that lead to cell death, depending on 
the genetic background of the malignant cells. 
MLN4924 treatment inhibited the growth of a wide variety of solid tumor cell lines, with 
concentration producing 50% inhibition (IC50) < 200 nM in 2 or more bladder, brain, breast, 
cervix, colon, liver, lung, melanoma, prostate, ovary, sarcoma, and uterine cancer cell lines 
among a panel of 240 cell lines evaluated (Ricerca panel report, data on file). Analysis of an 
independent experiment investigating the sensitivity of a panel of 653 cell lines of various 
histologies to MLN4924 indicated that some histologies were on average more sensitive 
than others; the most sensitive histologies included bladder, squamous cell lung, esophageal, 
and head and neck squamous cell cancer (Massachusetts General Hospital panel analysis, 
data on file).
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. For example, treatment of 
mice bearing SC HCT116 tumor xenografts with a single SC dose of MLN4924 resulted in 
dose-dependent inhibition of NEDD8-cullin levels and stabilization of CDL substrates 
including Nrf2 and Cdt-1.(2)  MLN4924 showed significant single-agent antitumor activity 
in solid tumor xenograft models derived from colon (HCT116(2) and HT29 [Millennium 
Pharmaceuticals, Inc., and its affiliates (Millennium) data on file]), non-small cell lung
cancer (NSCLC) (Calu-6 and H522)(2), small cell lung cancer (SCLC) (NCI-H82 and 
NCI-H69 [Millennium data on file]), melanoma (PHTX50M),(6) breast (PHTX02B 
[Millennium data on file]), and esophageal cancer (ESM199 and ESM204 [Millennium data 
on file]). Despite antitumor activity in this wide variety of xenograft models, very few of the 
solid tumor models underwent complete regressions in response to MLN4924, and 
MLN4924 demonstrated limited single-agent activity in other xenograft models derived 
from these same types of cancer, such as the esophageal model ESM026 (Millennium data 
on file) and melanoma models including SK-MEL-24 and 1205Lu.(7)
Detailed information regarding the nonclinical pharmacology and toxicology of MLN4924
may be found in the Investigator’s Brochure (IB).
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1.2.1.1
Nonclinical Pharmacology:  Nonclinical Studies With MLN4924 in 
Combination With Agents Employed in Current Solid Tumor Clinical 
Practice
The observations of single-agent activity of MLN4924 described in Section 1.2.1 provided 
the rationale for evaluating MLN4924 in combination with standard anticancer agents to 
improve antitumor activity in nonclinical studies. Agents were selected for nonclinical 
testing based on several criteria: 1) their clinical use in tumor types showing highest 
sensitivity to MLN4924 in cell line screens described in Section 1.2.1 (for example, 
docetaxel is widely used to treat squamous NSCLC and esophageal cancer), and 
2) consideration of the DNA re-replication/DNA damage phenotype induced by MLN4924 
and the possibility of enhancing this effect with another agent that affects DNA replication 
(ie, gemcitabine) or causes DNA damage (ie, platinum-based drugs). NAE inhibition with 
MLN4924 has been shown to dysregulate multiple aspects of the DNA damage response, 
including the p53 pathway, the breast cancer susceptibility gene 1 (BRCA1)/breast cancer 
susceptibility gene 2 (BRCA2) complex, transcription-coupled nucleotide excision repair, 
and base excision repair.(8)  When functional, these DNA repair pathways can limit the 
extent of the damage caused by chemotherapeutic agents such as platins; therefore, the 
inhibition of the repair pathways by MLN4924 may sensitize cells to DNA damaging effects 
of chemotherapeutic agents.
In vitro and in vivo nonclinical studies were conducted to assess antitumor activity of 
MLN4924 in combination with selected standard of care (SoC) agents and to determine 
whether MLN4924 showed additive or synergistic antitumor activity with these combination 
agents, which could support the clinical evaluation of the combinations. In vitro experiments 
used 4 cell lines (HCT116 colorectal carcinoma, A375 melanoma, U2OS osteosarcoma, and 
A549 NSCLC) to test the combination of MLN4924 with widely-used chemotherapy agents. 
In vivo experiments used xenograft models derived from cancer types in which the SoC
agents are used in clinical practice. These included 2 derived from SCLC cell lines 
(NCI-H69 and NCI-H82) for evaluation with platinum-based drugs, 1 derived from a 
NSCLC cell line (NCI-H1650) for evaluation with docetaxel, and a primary human 
xenograft tumor model derived from a triple-negative breast cancer patient (PHTX02B) for 
evaluation with docetaxel and with gemcitabine. The nonclinical studies described below 
provide evidence of in vitro and/or in vivo combination benefit with taxanes, platins, and 
gemcitabine, and support the planned clinical investigation of the tolerability of these agents 
in combination with MLN4924 (Millennium data on file). Nonclinical combination studies 
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in additional xenograft models are ongoing, as are mechanistic studies to understand the 
basis for combination effects in vitro. 
1.2.2
MLN4924 in Combination With Taxane-based Therapy
MLN4924 and docetaxel exhibited additive antitumor activity in multiple in vitro and in 
vivo models. In particular, docetaxel and MLN4924 showed an additive effect in vitro in the 
HCT116 colorectal carcinoma, A375 melanoma, U2OS osteosarcoma, and A549 NSCLC 
cell lines with simultaneous addition of compounds. To determine whether the combination 
effect was influenced by the order and timing of compound addition, A549 cells were 
treated with MLN4924 for 8, 24, or 48 hours before docetaxel treatment, and conversely, 
cells were treated with docetaxel for 8, 24, or 48 hours before MLN4924 treatment. The 
combination was additive under all of these conditions, suggesting that within a 48-hour 
time frame, the order of compound addition did not alter the combination effect.
The combination of MLN4924 and docetaxel was evaluated in vivo in NCI-H1650 NSCLC 
xenograft-bearing mice and in PHTX02B primary human breast cancer xenograft-bearing 
mice and showed additive antitumor activity in both xenograft models compared to 
single-agent treatment with either MLN4924 or docetaxel alone. In the PHTX02B model, 
treatment with a combination of MLN4924 (60 mg/kg SC twice daily [BID] 5 days 
on/5 days off) and docetaxel (5 mg/kg intravenously [IV] every week [QW]) resulted in 
tumor regression or complete inhibition of tumor growth (ratio of tumor volume of treated 
vs control group [T/C] on Day 21=0.05), whereas treatment with the individual agents at 
these dose levels and schedules resulted in only partial tumor growth inhibition (T/C=0.26 
and 0.36 for MLN4924 and docetaxel, respectively). A pharmacodynamic study was 
conducted in the PHTX02B model to evaluate the level of cleaved caspase-3 (a marker of 
apoptosis) induced by MLN4924, docetaxel, or the combination of MLN4924 and 
docetaxel. Levels of cleaved caspase-3 in xenograft tumors from the MLN4924 and 
docetaxel combination group were higher than those in the single-agent groups, indicating 
that the combination resulted in enhanced apoptosis. This nonclinical evidence of improved 
antitumor activity of MLN4924 administered in combination with docetaxel supports further 
evaluation of taxane combinations with MLN4924 in the clinic.  
1.2.3
MLN4924 in Combination With Platinum-based Therapy
MLN4924 and platinum-based drugs exhibited synergistic antitumor activity in multiple in 
vitro and in vivo models. The in vitro combination of MLN4924 and cisplatin demonstrated 
synergy in HCT116, A549, and U2OS cell lines and additivity in the A375 cell line. 
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The combination of MLN4924 with carboplatin was evaluated in vivo in NCI-H69 SCLC 
xenograft-bearing mice and showed synergistic antitumor activity compared to treatment 
with either MLN4924 or carboplatin alone. The combination of MLN4924 (120 mg/kg SC 
BID Days 1, 4, 8, 11, 15, and 18) and carboplatin (50 mg/kg intraperitoneally [IP] QW) 
resulted in tumor stasis or regression (T/C=0.10), while treatment with either MLN4924 or 
carboplatin alone resulted in only partial tumor growth inhibition (T/C=0.44 and 0.53, 
respectively). Synergistic activity was also demonstrated using carboplatin at 50 mg/kg IP 
QW in combination with a lower dose of MLN4924 (60 mg/kg SC BID Days 1, 4, 8, 11, 15, 
and 18). Combination of MLN4924 with cisplatin showed additive and synergistic effects in 
the NCI-H69 and NCI-H82 SCLC xenograft models using 2 schedules of MLN4924 
(Days 1, 3, and 5 QW or Days 1 and 4 each week for 3 weeks) with 4 mg/kg of cisplatin 
dosed IP on Days 1, 5, and 9. Taken together, these nonclinical results demonstrate the 
benefit of MLN4924 in combination with platinum-based chemotherapy. Preliminary 
studies suggest that the ability of MLN4924 to inhibit the nucleotide excision repair pathway 
contributes to its synergy with platinum-based drugs; additional nonclinical studies are 
ongoing to further investigate the mechanism of synergy.
1.2.4
MLN4924 in Combination With Gemcitabine
MLN4924 and gemcitabine demonstrated a combination benefit in vitro and in vivo. The 
combination of MLN4924 and gemcitabine in vitro showed synergistic effects in HCT116 
and U2OS cell lines, but the compounds demonstrated subadditive effects in the A375 
melanoma and A549 NSCLC cell lines. The combination of MLN4924 with gemcitabine 
was evaluated in PHTX02B xenograft-bearing mice and showed additive antitumor activity 
compared to treatment with either MLN4924 or gemcitabine alone. Treatment with a 
combination of MLN4924 (30 mg/kg SC BID for 21 days) and gemcitabine (10 mg/kg IP 
dosed on Days 1, 4, 7, and 10) resulted in tumor stasis (T/C=0.12), whereas treatment with 
either MLN4924 or gemcitabine alone resulted in only partial tumor growth inhibition 
(T/C=0.39 and 0.46, respectively). Taken together, these results support the further 
investigation of MLN4924 in combination with gemcitabine in patients. Additional 
nonclinical work is planned to understand the mechanism of synergy in selected cell lines in 
vitro and to evaluate the combination in additional in vivo models, particularly of pancreatic 
cancer.
1.3
Clinical Experience  
Single-agent MLN4924 has been studied in phase 1 clinical trials in patients with advanced 
nonhematologic malignancies (Study C15001); lymphoma and multiple myeloma 
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(Study C15002); AML, myelodysplastic syndromes (MDS), or acute lymphoblastic 
leukemia (ALL) (Study C15003); and melanoma (Study C15005). These are all 
single-agent, dose escalation studies. Based on information available as of 22 January 2013, 
a total of 220 patients have been enrolled into these studies, and safety data are available and 
summarized for 217 of these patients (ie, those included in the safety population). 
MLN4924 is 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 began in April 2008, and 62 patients with solid tumors have been enrolled. 
The median age of the patients included in the safety population is 59.5 years, ranging 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 at a dose of 25 mg/m2. In addition, 
10 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 10 cycles:  colorectal 
carcinoma and melanoma (3 each), breast cancer (2), and SCLC and head and neck cancer 
(1 each). This study has been completed, and the database was locked on 06 December 
2012. 
Study C15002 began in June 2008, and 53 patients with multiple myeloma (21) or 
lymphoma (32) have been enrolled. The median age of the patients included in the safety 
population is 60.0 years, ranging from 26 to 91 years. Three PRs have been 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 158 days. Patient enrollment 
in the dose expansion cohorts was ongoing as of 22 January 2013.
Study C15003 is an ongoing, phase 1 study evaluating patients with AML (patients with 
MDS and ALL are also evaluated) using single-agent MLN4924. As of 22 January 2013, 
68 patients have been enrolled in this study, which was designed to test several 21-day dose 
schedules. For Schedule A (Days 1, 3, and 5), 4 dose levels have been 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. Enrollment 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: 
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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). Nine patients enrolled in a new 
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. 
There have been 7 responses in Study C15003, including complete responses (CRs). 
Four responses occurred in the first 27 patients treated on the Days 1, 3, and 5 schedule at 
25 mg/m2, 33 mg/m2, 44 mg/m2, and 59 mg/m2 and are further described below. Two PRs 
(in the next 26 patients treated) occurred on the Days 1, 4, 8, and 11 schedule, both at 
83 mg/m2. Four of the 6 responders remained on study drug for 8, 12, 13, and 19 cycles, 
respectively. One response occurred on the Days 1, 3, and 5 schedule (Schedule E) at 
50 mg/m2. 
The following patients had responses on the Days 1, 3, and 5 schedule: 

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 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.

A 51-year-old man with refractory AML following allogeneic stem cell 
transplantation achieved a marrow complete remission with incomplete blood count 
recovery (CRi) after Cycle 1 at 59 mg/m2. This patient also had extramedullary 
disease (awaiting restaging). He received 2 doses of study drug in Cycle 2 before 
dying of an intracranial hemorrhage resulting from a fall.

A 71-year-old man with de novo AML refractory to standard cytarabine plus 
daunorubicin induction achieved a CRi during Cycle 1 at 44 mg/m2. Although this 
response was not maintained, the patient continued to benefit from MLN4924 
treatment, which was subsequently escalated to 59 mg/m2. The patient was taken off 
study after completing 19 cycles. He was hospitalized with pneumonia and 
subsequently died of sepsis.
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
An 82-year-old man with high-risk, azacitidine-refractory MDS that had evolved into 
AML before receiving study drug had a partial remission in Cycle 8, a CRi in 
Cycle 10 (at 33 mg/m2), and became transfusion-independent before progressing 
after Cycle 12.

A 73-year-old woman with de novo AML had a PR on Schedule E at 50 mg/m2.
Study C15005 began in December 2009, and 37 patients with melanoma have been enrolled. 
The median age of the patients in the safety population is 61.8 years, ranging from 33 to 
79 years. Six patients stayed on the study for at least 5 cycles and achieved a best response 
of SD, and 1 patient achieved a PR. This study has been completed, and the clinical database 
was locked on 06 December 2012. Additional information on the clinical experience with 
MLN4924 in patients with solid tumors is provided in Section 1.4.3. 
Overall, the intermittent schedule of drug administration was better tolerated than the daily 
schedule. Based on the observation that doses of MLN4924 equal to or above 110 mg/m2
were associated with an increased frequency of Cycle 1 Day 1 SAEs, patients enrolled 
across phase 1 studies were to receive MLN4924 at doses equal to or below 100 mg/m2. 
A maximum dose of 50 mg/m2 was selected for Arms 1 and 2 (both on the Days 1, 3, and 
5 schedule), and 100 mg/m2 was selected for Arms 3 (Days 1, 8, and 15) in this study (see 
Section 1.4.3 for additional information). 
The pharmacokinetics (PK) of MLN4924 following single and multiple IV administrations 
have been evaluated based on preliminary data from these phase 1 studies. Plasma 
concentrations of MLN4924 declined in a multi-exponential manner at the end of a 1-hour 
IV infusion, with little or no notable drug accumulation following once-daily dosing for 
5 consecutive days or more intermittent dosing. This observation is consistent with a mean 
terminal elimination half-life of approximately 5 to 8 hours estimated across doses and 
schedules. MLN4924 PK is linear over the dose range studied based on a daily area under 
the plasma concentration versus time curve from time zero to 24 hours (AUC0-24hr) that 
increased proportionately with dose from 25 to 261 mg/m2; single dose maximum (peak) 
concentration (Cmax; theoretically end-of-infusion concentration) appeared to increase 
slightly more than dose proportionally at the highest doses (fewer observations available). 
MLN4924 systemic clearance and volume of distribution appear to increase with increasing 
body size (body surface area [BSA] range 1.48-2.72 m2), supporting BSA-normalized 
dosing to reduce variation in systemic exposure.
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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.(9)  
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). 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, PK, 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 1.5.1.
1.4
Study Rationale 
MLN4924 demonstrated broad-based antitumor activity in a variety of cell lines of solid 
tumor origin including squamous cell lung cancer, small cell lung cancer, head and neck 
squamous cell carcinoma, esophageal cancer, and bladder cancer. In vivo data support 
combinations including taxane-based treatments, gemcitabine, and platinum-based 
treatments.
Clinical experience with single-agent MLN4924 demonstrated potential activity in a variety 
of solid tumor malignancies in 2 phase 1 studies:  C15001 (all solid tumors, N=62) and 
C15005 (melanoma, N=37). Despite treatment failure on multiple lines of prior therapy, a 
number of these patients benefited from treatment with single-agent MLN4924 as evidenced 
by durable stable disease (5 cycles or higher), including colorectal carcinoma (3), breast 
cancer (2), SCLC and head and neck cancer (1 each), and melanoma (9). Two patients with 
melanoma achieved PR.
Based on the broad-based nonclinical antitumor activity of MLN4924 discussed above, and 
additive/synergistic antitumor preclinical activity of MLN4924 when combined with 
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chemotherapeutic agents, the present study was designed to assess the combination of 
MLN4924 plus docetaxel, paclitaxel + carboplatin, and gemcitabine.
1.4.1
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 carried out in patients with any solid tumors for whom prior therapies had 
failed, and C15005 study was carried out in melanoma patients 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. 
In Study C15001, 10 patients with the following solid tumors stayed on the study for at least 
5 cycles:  colorectal carcinoma and melanoma (3 each); 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 current study builds on nonclinical data demonstrating sensitivity to MLN4924 in 
certain types of malignancies such as colon, NSCLC, SCLC, melanoma, breast, 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. 
1.4.2
Chemotherapy Regimens for Solid Tumors
Three chemotherapy regimens (docetaxel, paclitaxel + carboplatin, and gemcitabine) 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.
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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. 
Paclitaxel is also indicated for the second-line treatment of acquired immunodeficiency 
syndrome (AIDS)-related Kaposi’s sarcoma. 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 and/or radiation therapy.
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.
Gemcitabine is indicated for pancreatic cancer as a single agent.
Docetaxel, paclitaxel, carboplatin, and gemcitabine 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. Paclitaxel/ 
carboplatin is also widely used for treatment of newly diagnosed NSCLC.
For a detailed description of each of these medications, please see Section 6.12. 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 (all 3 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.
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Therefore, it is thought that the above SoCs would serve as reasonable partners in 
combination with MLN4924 for investigations in patients with various solid tumors in this 
study. 
1.4.3
Rationale for Dose and Schedule
No clinical data are currently available for treatment with MLN4924 in combination with 
docetaxel, paclitaxel + carboplatin, or gemcitabine. Each study arm will aim to establish the 
MTD of MLN4924 in combination with these agents. As such, MLN4924 in combination 
with docetaxel, paclitaxel + carboplatin, or gemcitabine will be administered to an initial 
3 patients at the lowest planned dose using a modified form of the Bayesian continual 
reassessment method first proposed by O’Quigley et al(10) (herein referred to as the CRM). 
The predicted MTD (PMTD) from the CRM model will be updated based on all observed 
DLTs (Section 6.3). Subsequent escalation, expansion, or de-escalation will be determined 
as described in Section 6.4. Once at least 6 patients are treated at any dose level and the 
algorithm does not recommend escalation or de-escalation, this dose level may be 
considered the MTD of MLN4924 in combination with the SoC.
1.4.3.1
Rationale for Dose and Schedule for Treatment With MLN4924 
In previous phase 1 studies, MLN4924 has been tested in various dosing schedules and at 
doses ranging from 25 to 278 mg/m2. Pharmacodynamic assessments have demonstrated 
NAE pathway inhibition at all dose levels tested, including 25 mg/m2, the lowest dose 
tested. 
To ensure exposure to both MLN4924 and chemotherapy partners and to potentially 
leverage their mechanisms of action, 2 dosing schedules will be used in this study:  for 
Arm 1 (docetaxel + MLN4924) and Arm 2 (paclitaxel + carboplatin + MLN4924), where 
chemotherapy regimens are given on Day 1 of each cycle, MLN4924 will be administered 
on Days 1, 3, and 5 of each cycle, whereas for Arm 3, both MLN4924 and gemcitabine will 
be administered on Days 1, 8, and 15.
The choice of MLN4924 doses was based on data from single-agent phase 1 studies. For 
Arms 1 and 2, MLN4924 will be given as a 1-hour IV infusion on Days 1, 3, and 5 of 
21-day cycle based on its acceptable safety profile. The planned doses are 15, 25, 37, and 
50 mg/m2. The maximum dose of 50 mg/m2 was selected because 50 mg/m2 was the lowest 
of the currently established MTDs for this schedule. The relevant MTDs included 50 mg/m2
in Study C15001 Schedule B; 67 mg/m2 in Study C15001 Schedule C; and 59 mg/m2 in 
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Study C15003 Schedule A; see the IB for additional details. Additionally, SAEs for patients 
receiving treatment on Cycle 1 Day 1 are less likely to occur at doses equal to or below 
50 mg/m2 given that higher doses have been associated with an increased safety risk (see 
Section 1.5.1). Dosing cycles for both Arm 1 and Arm 2 will last for 21 days. 
For Arms 1 and 2 where MLN4924 is given on Days 1, 3, and 5, a starting dose of 15 mg/m2
was chosen, which is 1 dose level below the lowest dose (25 mg/m2) tested as a single agent 
to provide a wider margin of safety. The maximum dose of MLN4924 for Arms 1 and 2 will 
be 50 mg/m2.
Because gemcitabine is normally given on Days 1, 8, and 15, in Arm 3, MLN4924 will be 
administered on the same dosing schedule to ensure that patients are exposed to both drugs 
on all the dosing days and to leverage the mechanism of action. In Arm 3, MLN4924 will be 
given as a 1-hour IV infusion on Days 1, 8, and 15 of a 28-day cycle. This dosing schedule 
has been studied in C15001 (solid tumor study), and the MTD was established at 
196 mg/m2. However, based on the observation that doses of IV MLN4924 110 mg/m2 are 
associated with more severe adverse events (AEs) (see Section 1.5.1), patients will be dosed 
up to a maximum of 100 mg/m2. The planned doses are 25, 50, 75, and 100 mg/m2. 
The likelihood of a clinically relevant PK interaction between MLN4924 and the selected 
SoC regimens is considered to be low. While the metabolic and disposition profiles of 
MLN4924 remained to be fully characterized in humans, the potential for drug interaction 
was assessed based on the available nonclinical and clinical data. MLN4924 is metabolized 
in vitro via hydroxylation oxidation, predominantly by cytochrome P450 (CYP) 3A4 with a 
small contribution from CYP2D6. Also, MLN4924 neither inhibits nor induces the activity 
of the 5 major CYPs. In rats and primates, urinary excretion of unchanged MLN4924 was 
found to be low (< 5%). 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 (IC50 [paclitaxel and digoxin] of 41.2-56.0 mM) and BCRP (IC50
[estrone-3-sulfate] of 6.3 mM) and is not likely to inhibit MRP2 (IC50 > 200 mM). 
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 mM) as well as of simvastatin (IC50 of 0.4-4.9 mM) and 
lovastatin (IC50 of 0.9 mM) from some, but not all, donors. Taking these data together and 
based on observed Cmax values at doses ≤110 mg/m2, MLN4924 is unlikely to affect the PK 
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of other drugs that are known CYP or P-gp substrates, whereas the potential exists, albeit 
low, for drug interactions with BCRP and OATP substrates at clinical concentrations. 
Hepatic metabolism is the major route of elimination of paclitaxel (mainly by CYP2C8 and 
to a lesser extent CYP3A4) and docetaxel (mainly by CYP3A4/5 and glutathione 
S-transferase); both of these agents are also substrates for the efflux (P-gp and/or MRP2) 
and uptake (OATP1B) transporters.(11, 12)  Gemcitabine is a prodrug phosphorylated 
intracellularly to gemcitabine triphosphate by nucleoside kinases; more than 90% of a 
gemcitabine dose is metabolized by cytidine deaminase and within 1 week, gemcitabine and 
its inactive uracil metabolite (dFdU) are excreted almost entirely in the urine.(13)  
Carboplatin is primarily eliminated unchanged via urinary excretion. While some overlap in 
the metabolizing enzymes and/or transporter proteins involved in the drug clearances exists 
with MLN4924, more importantly, none of these agents is a known inhibitor or inducer of 
CYP3A4 (or CPY2D6) in human liver microsomes.
In this study, limited (sparse) PK sampling for determination of MLN4924 plasma 
concentration will be performed during Cycle 1 of treatment to contribute to a population 
PK analysis of MLN4924 co-administered with docetaxel, or paclitaxel + carboplatin, or 
gemcitabine. During the dose escalation portion of the study, PK samples will be obtained 
on Cycle 1 Day 1 before and after the start of the MLN4924 infusion when MLN4924 is 
administered for the first time in combination with docetaxel, paclitaxel + carboplatin, or 
gemcitabine. During the MTD expansion portion of the study, and as permitted by the 
administration schedule of the combination therapy of MLN4924 with docetaxel or 
paclitaxel + carboplatin, PK samples will be collected on Cycle 1 Day 1 (MLN4924 + SoC) 
and Cycle 1 Day 5 (MLN4924 alone) before and after the start of the MLN4924 infusion to 
assess for possible changes in MLN4924 exposures at a tolerated dose of the combination 
therapy.
1.4.3.2
Dose and Schedule for Treatment With Docetaxel (Plus MLN4924, Arm 1) 
In the dose escalation phase, docetaxel will be administered by IV infusion over 60 minutes 
at a dose of 75 mg/m2 in combination with IV MLN4924 doses. Once the MTD of 
MLN4924 + docetaxel is reached, approximately 6 additional patients will be enrolled for a 
total of approximately 12 patients treated at the MTD to more fully characterize the safety, 
tolerability, and PK of MLN4924 with docetaxel and to evaluate disease response. 
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1.4.3.3
Dose and Schedule for Treatment With Paclitaxel + Carboplatin (Plus 
MLN4924, Arm 2)
Carboplatin Dose and Schedule (Lead-in Cohort)
Before enrolling patients in Arm 2 with paclitaxel + carboplatin, 3 patients will be treated 
with carboplatin AUC6 and MLN4924 at 15 mg/m2. The absence of a DLT in this lead-in 
cohort during Cycle 1 will trigger enrollment in the dose escalation phase of Arm 2. In the 
event that 1 DLT is observed in this lead-in, an additional 3 patients may be treated with the 
same combination. Observing no more than 1 DLT in this lead-in cohort will trigger 
enrollment on Arm 2 at AUC6 (MLN4924 [15 mg/m2] + paclitaxel [200 mg/m2] + 
carboplatin [AUC6]).
If a total of 2 or more DLTs are observed in this lead-in cohort, enrollment on Arm 2 will 
open at reduced doses of carboplatin (AUC5) and paclitaxel (175 mg/m2), and the patients 
will receive MLN4924 (15 mg/m2) + paclitaxel (175 mg/m2) + carboplatin (AUC5).
Paclitaxel + Carboplatin Dose and Schedule (Dose Escalation Phase)
In the dose escalation phase, paclitaxel will be administered by IV infusion at a dose 
of 200 mg/m2 (or 175 mg/m2 if the dose is modified in the lead-in phase), in combination
with carboplatin (AUC6 or AUC5 depending on results of the carboplatin lead-in cohort) 
and MLN4924 doses. Once the MTD of MLN4924 + paclitaxel + carboplatin is reached, 
approximately 6 additional patients will be enrolled for a total of approximately 12 patients 
treated at the MTD to more fully characterize the safety, tolerability, and PK of MLN4924 
with paclitaxel + carboplatin and to evaluate disease response. 
1.4.3.4
Dose and Schedule for Treatment With Gemcitabine (Plus MLN4924, 
Arm 3)
In the dose escalation phase, gemcitabine will be administered by IV infusion at a dose 
of 1000 mg/m2 in combination with MLN4924 doses. The planned doses of MLN4924 are 
25, 50, 75, and 100 mg/m2. Once the MTD of MLN4924 + gemcitabine is reached, 
approximately 6 additional patients will be enrolled for a total of approximately 12 patients 
treated at the MTD to more fully characterize the safety and tolerability of MLN4924 with 
gemcitabine and to evaluate disease response. 
Gemcitabine is initially dosed at 1000 mg/m2 in Arm 3. If it is determined by the sponsor 
that 1000 mg/m2 is poorly tolerated by multiple patients, then the initial dose for all patients 
subsequently enrolled in that arm may be reduced to a gemcitabine dose of 800 mg/m2. For 
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patients who start on a gemcitabine dose of 800 mg/m2, dose modification would be allowed 
by 1 level to 600 mg/m2. No further dose modification below 600 mg/m2 is allowed.
1.4.4
Rationale for Assessment of Biomarkers of Response
1.5
Potential Risks and Benefits 
Given limited existing clinical experience, it is not known whether tumors will respond to 
treatment with MLN4924. However, a number of patients treated with MLN4924 did 
demonstrate clinical benefit based primarily on prolonged SD (see Section 1.3). In addition, 
it is anticipated that the SoC therapies used in this study may provide additional clinical 
benefit to patients.
1.5.1
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 Development Core 
Safety Information (DCSI) to the IB.
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 (LFT) 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. Patients will be monitored for 
these potential toxicities and for unanticipated toxicities for at least 30 days after their last 
dose of MLN4924.
Potential Risks From Phase 1 Studies (at High Doses)
There are events that have been reported in phase 1 studies at doses and schedules 
substantially higher (≥110 mg/m2) than those being used in current clinical studies of 
MLN4924. These events are considered potential risks for the doses and schedules proposed 
in this study.

Multi-organ failure that could result in death.

Renal failure.

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. Refer to the current IB for additional 
information about multi-organ failure and dosing.
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
Cardiac arrhythmias.

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 a risk factor for cardiovascular disease (uncontrolled 
hypertension).

Gastrointestinal (GI) toxicity including or resulting in dehydration and electrolyte 
imbalance.

Acute phase response.

Myelosuppression with increased susceptibility to infection, bleeding, and anemia.

Hypophosphatemia.
Potential Risks Confounded by Underlying Disease or Malignancy
Events have been reported from clinical studies 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

All events were assessed by the investigator as unrelated; the majority 
occurred in the setting of thrombocytopenia.
Potential Risks Primarily Based on Findings From Animal Studies
Potential risks that are derived from findings in animal studies in rats and dogs include the 
following:

Cardiovascular changes that could result in tachycardia, decreased or increased 
systolic blood pressure (BP), and increased diastolic BP.

Enteropathy (including dehydration and electrolyte loss) with secondary sepsis.
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
Effects on the testes and ovaries that represent a reproductive hazard, including 
sterility.

Increased developmental risk to the fetus or embryo.

Myocardial degeneration and thrombosis.

Pulmonary hypertension.

Local tissue injury when administered SC.

Prolongation of the activated partial thromboplastin time (aPTT).

Decreased trabecular bone (graded minimal to moderate) was noted in the femur and 
in the sternum in rats at all dose groups (low, medium, high), but not in dogs. This 
finding was considered adverse in the high-dose group; however, no bone fractures 
were noted at any of the doses.
It is possible that MLN4924 will have toxicities, which may be severe or fatal, that were not 
observed in or predicted from the studies completed in rats and dogs or have not yet been 
identified in patients.
Hepatotoxicity has been noted following administration of MLN4924 in patients with 
advanced malignancy, including elevations of liver transaminases, alkaline phosphatase
(ALP), and bilirubin. Liver enzymes and liver function are frequently monitored during 
clinical studies of MLN4924. Agents such as acetaminophen and acetaminophen-containing 
products should not be administered to patients 24 hours before, the day of, and 24 hours 
after dosing with MLN4924 (see Section 6.6).
Patients must be carefully evaluated at screening and before each MLN4924 dose for early 
symptoms and signs of hemodynamic compromise and/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 6.9. 
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 
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 for these anticipated and potential toxicities and for 
unanticipated toxicities when they are receiving this agent and for at least 30 days after their 
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last dose. Monitoring will include the following: laboratory assessments, physical 
examinations, SAE and AE reporting, and safety review before each dose escalation (see 
Section 9.1). Although therapeutic efficacy is a desired outcome of treatment with the study 
drugs, it is unknown whether patients will benefit from this study.  In this dose escalation 
study, the dose will be escalated by cohort.
To limit the risks to patients, the first patient enrolled at each dose level of MLN4924 with 
SoC, as applicable, will be observed for 7 days before the remaining 2 patients of the cohort 
are treated. These 3 patients will be observed through completion of the first cycle, before 
additional patients are treated at the next dose level. The requirement for this 1-week wait 
period may be removed in subsequent cohorts if it is judged by the sponsor that combination 
therapy administered in a given arm may be administered without a major safety concern.
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
and the applicable regulatory requirements (including International Council for 
Harmonisation [ICH] guidelines).
1.5.2
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) United States (US) Package Insert.(16)
1.5.2.1
Hepatotoxicity Warning
Docetaxel should not be given if total bilirubin is greater than the upper limit of the normal 
range (ULN), or if aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
are greater than 1.5 times the ULN. LFT elevations increase the risk of severe or 
life-threatening complications. LFTs should be obtained before each treatment cycle.
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1.5.2.2
Hematologic Warning
Docetaxel should not be given if the absolute neutrophil count (ANC) is less than
1500 cells/mm3.
1.5.2.3
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.
1.5.3
Risks of Carboplatin and Paclitaxel Therapy
See Section 15.1 for information on the hematologic toxicity of carboplatin alone and in 
combination with paclitaxel.
1.5.3.1
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) US Package Insert.(17)
Nephrotoxicity Warning
The renal effects of nephrotoxic compounds may be potentiated by carboplatin.
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Hematologic Warning
Bone marrow suppression is dose related and may be severe, resulting in infection and/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. 
1.5.3.2
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) US Package Insert.(18)
Hematologic Warning
Paclitaxel Injection, 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.
1.5.3.3
Risks of MLN4924 and Paclitaxel + Carboplatin as Combination Therapy
Based on the known individual safety profiles of MLN4924 and paclitaxel + carboplatin, the 
following potential risks of combination therapy may apply:  bone marrow suppression, 
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hypersensitivity/anaphylaxis reactions, and hepatotoxicity. Renal effects of nephrotoxic 
compounds (see Section 15.8) may be potentiated by carboplatin.
1.5.4
Risks of Gemcitabine Therapy
The most common adverse reactions for the single agent (≥ 20%) are nausea and vomiting, 
anemia, elevated liver enzymes (ALT and AST), neutropenia, leukopenia, ALP, proteinuria, 
fever, hematuria, rash, thrombocytopenia, and dyspnea. 
Gemcitabine is contraindicated in patients with a known hypersensitivity to gemcitabine.
For more details, please refer to the Gemzar® (gemcitabine) US Package Insert.(19)
1.5.4.1
Hematologic Warning
Myelosuppression can be a DLT; blood counts should be monitored.
1.5.4.2
Renal Warning
Renal function should be monitored before initiation of therapy and periodically thereafter. 
Gemcitabine should be used with caution in patients with renal impairment. Cases of 
hemolytic uremic syndrome (HUS) and/or renal failure, some fatal, have occurred. 
Discontinue gemcitabine for HUS or severe renal toxicity.
1.5.4.3
Hepatic Warning
Hepatic function should be monitored before initiation of therapy and periodically 
thereafter. Gemcitabine should be used with caution in patients with hepatic impairment. 
Serious hepatotoxicity, including liver failure and death, has occurred. Discontinue 
gemcitabine for severe hepatic toxicity.
1.5.4.4
Risks of MLN4924 and Gemcitabine as Combination Therapy
Based on the known individual safety profiles of MLN4924 and gemcitabine, the following 
potential risks of combination therapy may apply:  myelosuppression, renal toxicity, and 
hepatotoxicity. 
1.5.4.5
Summary of Risks of Standard of Care Therapies in Combination With 
MLN4924
Potential overlapping toxicities of 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
Standard of Care
Potential Overlapping Toxicities With MLN4924
Docetaxel
Deatha
Hypersensitivity
Hepatoxicity
Neutropenia 
Fluid retention (cardiac/pulmonary)
Paclitaxel/Carboplatin
Bone marrow suppression
Hypersensitivity/anaphylaxis reactions
Hepatotoxicity
Renal effects of nephrotoxic compounds may be potentiated by carboplatin
Gemcitabine
Renal toxicity
Hepatic toxicity
Myelosuppression
a
Docetaxel treatment-related mortality increases with abnormal liver function, occurs at higher doses, and in 
patients with non-small cell lung cancer who received prior platinum-based therapy and are receiving 
docetaxel at 100 mg/m2.
2.
STUDY OBJECTIVES
2.1
Primary Objectives 
The primary objectives are:

To establish the MTD and assess the safety and tolerability of MLN4924 in 
combination with docetaxel in patients with solid tumors

To establish the MTD and assess the safety and tolerability of MLN4924 in 
combination with paclitaxel and carboplatin in patients with solid tumors

To establish the MTD and assess the safety and tolerability of MLN4924 in 
combination with gemcitabine in patients with solid tumors
2.2
Secondary Objectives
The secondary objectives are:

To evaluate disease response that may be observed with the combination of 
MLN4924 and docetaxel
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!
To evaluate disease response that may be observed with the combination of 
MLN4924, paclitaxel, and carboplatin
!
To evaluate disease response that may be observed with the combination of 
MLN4924 and gemcitabine
!
To measure plasma MLN4924 concentrations to contribute to a population PK 
analysis of MLN4924 co-administered with docetaxel, or paclitaxel + carboplatin, or 
gemcitabine in patients with solid tumors
2.3
Exploratory Objectives 
The exploratory objectives include:
3.
STUDY ENDPOINTS
3.1
Primary Endpoints 
The primary endpoints include AEs, SAEs, assessments of clinical laboratory values and 
clinically important laboratory abnormalities, and vital sign measurements.
3.2
Secondary Endpoints 
The secondary endpoints include:
!
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) 
!
MLN4924 plasma concentration%time data for population PK analysis
3.3
Exploratory Endpoints 
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4.
STUDY DESIGN 
4.1
Overview of Study Design 
This is an open-label, multicenter, phase 1b, dose escalation study of MLN4924 in 
combination with docetaxel, paclitaxel + carboplatin, or gemcitabine in adult patients with 
solid tumors (patients in the carboplatin lead-in cohort will receive MLN4924 + carboplatin 
only). The patient population will consist of patients 18 years of age or older with 
nonhematologic malignancies who, according to the investigator’s medical judgment, could 
potentially benefit from treatment with any of the 3 SoC therapies being studied.
It is expected that approximately 69 patients will be enrolled in this study. During the dose 
escalation portion of this study, the following dose levels of IV MLN4924 are planned to be 
studied in combination with docetaxel (Arm 1), paclitaxel + carboplatin (Arm 2), or 
gemcitabine (Arm 3).
MLN4924 + Docetaxel (Arm 1):  A total of 4 dose levels of IV MLN4924 (15, 25, 37, and 
50 mg/m2) are planned to be studied in combination with 75 mg/m2 of docetaxel. On Day 1 
of each cycle when both drugs are administered, docetaxel will be administered first at a 
dose of 75 mg/m2 IV over 1 hour. After a mandatory approximately 15-minute time out 
(MLN4924-free period), MLN4924 will be administered IV. On Days 3 and 5, only
MLN4924 will be given. The duration of each cycle will be 21 days. No dose reduction of 
MLN4924 below 15 mg/m2 is allowed.
MLN4924 + Carboplatin Lead-in Cohort (before Arm 2):  Before patients are enrolled in 
Arm 2 with paclitaxel + carboplatin, a cohort of approximately 3 to 6 patients will be treated 
with AUC6 dose of carboplatin in combination with MLN4924 at a dose of 15 mg/m2. On 
Day 1 of each cycle, both compounds will be given. On Days 3 and 5, only MLN4924 will 
be given. The duration of each cycle will be 21 days. If 1 DLT is seen in this cohort, 
3 additional patients will be treated with the same combination regimen. The carboplatin 
dose may be reduced to AUC5 for safety as needed (see Section 6.5 for further details). No 
dose reduction of MLN4924 below 15 mg/m2 is allowed. No dose escalation of MLN4924 is 
planned in this cohort. The only chemotherapy agent that patients in this lead-in cohort will 
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receive is carboplatin; these patients will not enroll on the MLN4924 + paclitaxel + 
carboplatin phase (Arm 2).
Observing no more than 1 DLT in this lead-in cohort will trigger enrollment in Arm 2 at 
AUC6 (MLN4924 [15 mg/m2] + paclitaxel [200 mg/m2] + carboplatin [AUC6]), and 
patients will be treated as described below for Arm 2.
If a total of 2 or more DLTs are observed in this cohort, enrollment in Arm 2 will open at 
reduced paclitaxel and carboplatin doses (MLN4924 [15 mg/m2] + paclitaxel [175 mg/m2] + 
carboplatin [AUC5]), and patients will be treated as described below for Arm 2.
MLN4924 + Paclitaxel + Carboplatin (Arm 2):  During the dose escalation phase, a total of 
4 dose levels of IV MLN4924 (15, 25, 37, and 50 mg/m2) are planned to be studied in 
combination with paclitaxel and carboplatin. On Day 1 of each cycle when all 3 drugs are 
administered, paclitaxel is given first at a dose of 200 mg/m2 (or 175 mg/m2, if the dose was 
reduced in the carboplatin lead-in cohort) IV over 3 hours followed by carboplatin AUC6 
(or AUC5 if the dose was reduced in carboplatin lead-in cohort) over 30 minutes. After a 
mandatory approximately 15-minute time out (MLN4924-free period) 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. 
MLN4924 + Gemcitabine (Arm 3):  A total of 4 dose levels of IV MLN4924 (25, 50, 75, 
and 100 mg/m2) are planned to be studied in combination with 1000 mg/m2 of gemcitabine. 
Gemcitabine will be administered IV at a dose of 1000 mg/m2 over 30 to 60 minutes or per 
current prescribing guidelines. After a 15-minute time out, MLN4924 will be administered. 
Patients will receive both agents on Days 1, 8, and 15, and the duration of each cycle will be 
28 days.
After the determination of the MTD of MLN4924 with docetaxel (Arm 1), 
paclitaxel + carboplatin (Arm 2), and gemcitabine (Arm 3), approximately 6 additional 
patients will be enrolled to each arm for a total of approximately 12 patients treated in each 
arm at the MTD to more fully characterize the safety, tolerability, and PK of MLN4924 in 
combination with each SoC regimen and to evaluate disease response. 
An adaptive approach using a CRM will be used for dose escalation (see Section 6.4). The 
CRM models the relationship between toxicities and dose level, which yields accurate and 
precise estimates of the MTD.(10, 20, 21)  The dose toxicity relationship and the PMTD level 
will be updated as new data become available. The recommendation to escalate, de-escalate, 
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or expand at the same dose level will be determined by comparing the PMTD level from the 
dose toxicity model to the prespecified dose levels. From the starting dose, subsequent 
increases will be made according to the dose levels indicated for each arm; however, for 
safety reasons, no dose level will be skipped, and a minimum of 3 patients is required before 
escalating to the next dose level. Once at least 6 patients are treated at any dose level and the 
algorithm does not recommend escalation or de-escalation, this dose level may be 
considered the MTD. 
Toxicity will be evaluated according to National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), Version 4.03, effective date 14 June 2010.(1)  
DLTs are defined in Section 6.3.
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 to evaluate the safety and tolerability of MLN4924 in 
combination with docetaxel, paclitaxel + carboplatin, and gemcitabine (patients in the 
carboplatin lead-in cohort will receive MLN4924 + carboplatin only).
Blood samples (sparse sampling) for the determination of MLN4924 plasma concentrations 
and, if appropriate, its metabolites will be collected from each patient during Cycle 1 of 
treatment to contribute to a population PK analysis of MLN4924 co-administered with 
docetaxel, or paclitaxel + carboplatin, or gemcitabine. During the dose escalation portion of 
the study (excluding the Arm 2 carboplatin lead-in cohort), blood samples will be collected 
from each patient for the determination of MLN4924 plasma concentrations during the first 
cycle of treatment at the time points indicated in the Schedules of Events. During the MTD 
expansion portion of the study, serial blood samples will be collected from all patients at the 
time points indicated in the Schedules of Events before and after the start of MLN4924 
infusion. 
Computed tomography (CT) scans with IV contrast of the chest, abdomen, and pelvis will 
be performed during screening.  CT scans with IV contrast encompassing the known sites of 
disease will be performed at the end of Cycle 2 and then every other cycle thereafter 
(Cycles 4-12) or after completion of every sixth cycle after the patient’s previous scan (after 
completion of Cycle 12 and implementation of Amendment 1), and at the End of Study 
(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 
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imaging (MRI) may be used to evaluate sites of disease. Tumor response will be assessed by 
the investigator at these times using the RECIST, version 1.1.(22)
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 
(extended 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 6.5) upon return from a treatment break, before treatment.
Paraffin-embedded tumor tissue or unstained slides of the tumor tissue will be collected at 
screening to enable genetic characterization of the patient’s tumor 
 
 
 
 
4.2
Number of Patients 
Approximately 69 total patients (approximately 6 patients in the MLN4924 + carboplatin 
lead-in cohort, approximately 15 patients in each arm of the dose escalation phase, and 
approximately 6 additional patients in each arm of the MTD dose expansion phase) will be 
enrolled in this study in approximately 10 study centers in the US. The definition of 
enrollment is provided in Section 7.4.13.
For determination of the MTD in the dose escalation phase, patients will be replaced if 
withdrawn from treatment during Cycle 1 for reasons other than DLT.
4.3
Duration of Study 
Patients are treated for up to 12 cycles or until they experience symptomatic deterioration or 
progressive disease (PD) (see definition in Section 15.2), until their treatment is 
discontinued for another reason (see Section 7.6), or until the study is stopped. The 
maximum duration of treatment will be 12 cycles; however, if it is determined after 
discussion between by the investigator and the sponsor that a patient would derive benefit 
from continued treatment, the patient may remain on the current combination therapy or 
receive MLN4924 as a single agent beyond 12 cycles. 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 (extended 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 6.5) upon return 
CCI
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from a treatment break, before treatment. The final analyses for the clinical study report will 
be conducted after all patients enrolled in the study have had the opportunity to complete at 
least 4 cycles of treatment with MLN4924 in combination with docetaxel, paclitaxel + 
carboplatin, or gemcitabine. 
The duration of enrollment, inclusive of dose escalation and MTD expansion, will be 
approximately 13 months.
5.
STUDY POPULATION
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. ECOG PS 0 or 1 (refer to Section 15.3).
3. Patients must have a histologically or cytologically confirmed metastatic or locally 
advanced and incurable solid tumor that is felt to be appropriate for treatment with 
1 of the 3 chemotherapy regimens in 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 and/or measurable.
4. Recovered (ie, Grade 1 toxicity) from the effects of prior antineoplastic therapy.
5. Suitable venous access for the study-required blood sampling for MLN4924 PK 
assessments. 
6. 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.
7. Clinical laboratory values as specified below within 3 days before the first dose of 
study drug:

ANC ≥ 1,500/mm3 (refer to Section 15.4)

Platelet count ≥ 100,000/mm3

Total bilirubin ≤ the ULN
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
Prothrombin time (PT) and aPTT ≤1.5 ULN

ALT, AST, and ALP ≤2.5 ULN
o
For patients to be enrolled in Arm 1 (MLN4924 + docetaxel) only:  
AST/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 15.5)
8. Female patients who:

Are postmenopausal for at least 1 year before the screening visit, OR

Are surgically sterile, OR

As of Amendment 1, if they are of childbearing potential, agree to practice 
1 highly effective method and 1 additional effective (barrier) method of 
contraception (see Section 15.9), 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 1], and lactational amenorrhea [as of Amendment 1] 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], withdrawal, spermicides only [as of 
Amendment 1], and lactational amenorrhea [as of Amendment 1] are not 
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acceptable methods of contraception. Female and male condoms should not be 
used together.)
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.
10. Availability of fixed tumor specimen (block or slides) for exploratory biomarker 
analysis.  If no slides or block are available, fresh tumor biopsies should be obtained 
and used for these assessments.
5.2
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
1. 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 the first dose of study drug.
2. Major surgery within 14 days before the first dose of study treatment.
3. Active uncontrolled infection or severe infectious disease, such as pneumonia, 
meningitis, septicemia, or methicillin-resistant Staphylococcus aureus infection.
4. Receiving antibiotic therapy within 14 days before the first dose of study treatment.
5. Life-threatening illness unrelated to cancer.
6. Known hypersensitivity to study-assigned chemotherapy.
7. Prior treatment with MLN4924; however, prior treatment with docetaxel, paclitaxel, 
carboplatin, and gemcitabine is allowed.
8. History of severe hypersensitivity reactions to docetaxel (polysorbate 80-based 
formulations) for patients to be enrolled in Arm 1 (MLN4924 + docetaxel), history 
of hypersensitivity to carboplatin for patients to be enrolled in carboplatin lead-in 
cohort or Arm 2 (MLN4924 + paclitaxel + carboplatin), or history of severe 
hypersensitivity to paclitaxel (cremophor-based formulations) for patients to be 
enrolled in Arm 2. 
9. Persistent diarrhea (Grade 2) lasting > 3 days within 2 weeks before the first dose 
of study treatment. 
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10. Systemic antineoplastic therapy within 21 days preceding the first dose of study 
treatment.
11. Radiotherapy within 14 days preceding the first dose of study treatment.
12. Prior treatment with radiation therapy involving ≥ 25% of the hematopoietically 
active bone marrow.
13. Treatment with CYP3A inducers within 14 days before the first dose of MLN4924.  
Treatment with CYP3A inhibitors within 14 days before the first dose of MLN4924; 
however, voriconazole and fluconazole need only be stopped for 3 days before 
MLN4924 (see Section 6.7 for criteria for restarting these azole antifungals).  
Moderate and strong CYP3A inhibitors and CYP3A inducers were not permitted. 
Following implementation of Amendment 1 and completion of at least 12 cycles of 
treatment, concomitant use of moderate and strong CYP3A inhibitors is permitted in 
Arm 2 (study arm with active patients) (see Table 6-4 and Section 15.7).  Patients 
must have no history of amiodarone use in the 6 months before the first dose of 
MLN4924.
14. Clinically significant central nervous system (CNS) disease defined as untreated, 
progressive, or requiring steroids for control of symptoms. 
15. Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol.
16. Treatment with any investigational products within 21 days preceding the first dose 
of study treatment.
17. Patients currently taking statins who are unwilling or unable to refrain from using 
statins 24 hours before, the day of, and 24 hours after each MLN4924 administration.
18. Known human immunodeficiency virus (HIV) positive or hepatitis B surface 
antigen-positive status, or known 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.
19. Known hepatic cirrhosis.
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20. Known cardiac/cardiopulmonary disease, defined as 1 of the following:

Uncontrolled high blood pressure (ie, systolic blood pressure > 180 mm Hg, 
diastolic blood pressure > 95 mm Hg)

Congestive heart failure New York Heart Association (NYHA) Class III or IV, or 
Class II with a recent decompensation requiring hospitalization within 4 weeks 
before screening (Section 15.6)

Unstable angina, myocardial infarction, or angioplasty procedure with coronary 
artery stent placement within 12 months before screening

Arrhythmia (history of polymorphic ventricular fibrillation; torsade de pointes; 
permanent atrial fibrillation [a fib], defined as continuous a fib for 6 months; 
and persistent a fib, defined as sustained a fib lasting > 7 days and/or requiring 
cardioversion in the 4 weeks before screening. Patients with paroxysmal a fib are 
permitted to enroll, provided that they are rate controlled on a stable regimen.)

Implantable cardioverter defibrillator

Grade 3 or greater valvular disease

Grade 3 or greater pulmonary hypertension

Prolonged rate corrected QT (QTc) interval 500 msec, calculated according to 
institutional guidelines
21. Left ventricular ejection fraction (LVEF) < 50% as assessed by echocardiogram or 
radionuclide angiography.
22. 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)
23. History of severe intolerance to cytotoxic agent(s) given in the assigned arm
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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 
prior to drug administration. Study drug will be administered only to eligible patients under 
the supervision of the investigator or identified subinvestigator(s).
See Table 6-1 for an overview of MLN4924 and SoC dosing. All doses must be taken as 
outlined in the Schedules of Events. However, Day 1 dosing may be delayed by up to 2 days 
(Cycles 1-12) or up to 2 weeks (after completion of Cycle 12; extended up to 4 weeks after 
consulting with the sponsor) to accommodate inclement weather, holidays, vacations, or 
other administrative reasons. If extenuating circumstances prevent a patient from beginning 
treatment within this time, the patient may continue the study only with the written 
permission of the Millennium project clinician or designee. See Section 7.4 for information 
about corresponding study procedures if dosing is delayed for reasons as 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 (extended 
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 6.5) upon return from a treatment break, before treatment. Refer to the Study 
Manual for additional instructions regarding study drug administration.
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Table 6-1
Overview of MLN4924 and Standard of Care Dosing 
Arm
Cycle 
Duration 
(days)
Starting 
Dosea 
(mg/m2)
Dosing Day
1
3
5
8
15
Arm 1
   MLN4924
21
15
X
X
X
   Docetaxel
21
75
X
Arm 2 
Carboplatin 
Lead-in Cohort
   MLN4924
21
15
X
X
X
   Carboplatin
21
AUC6
X
Arm 2
   MLN4924
21
15
X
X
X
   Paclitaxel
21
200b
X
   Carboplatin
21
AUC6b
X
Arm 3
   MLN4924
28
25
X
X
X
   Gemcitabine
28
1000
X
X
X
Abbreviations:  MTD=maximum tolerated dose.
a In the dose escalation phase, the MLN4924 dose will be increased until the MTD is reached. The 
following planned dose levels will be evaluated for Arm 1, Arm 2 carboplatin lead-in cohort, and Arm 2:  
15, 25, 37, and 50 mg/m2; and for Arm 3:  25, 50, 75, and 100 mg/m2. The MTD of MLN4924 will be 
administered during the dose expansion phase. 
b If the dose of carboplatin is reduced from AUC6 to AUC5 in the carboplatin lead-in cohort, enrollment in 
Arm 2 will open at a reduced dose of carboplatin and paclitaxel (MLN4924 [15 mg/m2] + paclitaxel 
[175 mg/m2] + carboplatin [AUC5]).
6.1.1
MLN4924 Administration
Patients will receive MLN4924 diluted with 5% dextrose in a 250-mL bag via a 1-hour 
(±10 minutes as of Amendment 1) IV infusion. MLN4924 should be administered through 
central or peripheral venous access. The infusion may be slowed or stopped and restarted for 
any associated infusion-related reactions. All infusion times must be recorded. The total 
time from drug reconstitution to end of infusion must not exceed 6 hours. 
The entire content of the MLN4924 IV bag will be infused at a constant rate over 1 hour 
(±10 minutes as of Amendment 1). The start and end time of 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. The volume used for line 
flushing is not considered part of the volume of the MLN4924 IV bag to be documented.
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6.1.2
Docetaxel Administration
Docetaxel will be administered as a 1-hour IV infusion at a dose of 75 mg/m2 on Day 1 
combined with escalating IV doses of MLN4924 on Days 1, 3, and 5. Refer to the most 
recent prescribing information for further details regarding docetaxel administration.
6.1.2.1
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 BID for 3 days), which should start 
24 hours before docetaxel administration.
6.1.3
Carboplatin Administration
Carboplatin will be administered as a 30-minute IV infusion at a dose of AUC6 on Day 1 
combined with escalating IV doses of MLN4924 on Days 1, 3, and 5. Refer to the most 
recent prescribing information for further details regarding carboplatin administration.
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.
For a target AUC=6, the maximum dose is 6 150=900 mg
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
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Source:  fda.gov, “Carboplatin dosing,” accessed 19 February 2013.
6.1.4
Paclitaxel Administration
Paclitaxel will be administered as a 3-hour IV infusion at a dose of 200 mg/m2 on Day 1 
combined with escalating IV doses of MLN4924 on Days 1, 3, and 5. Refer to the most 
recent prescribing information for further details regarding paclitaxel administration.
6.1.4.1
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 methylprednisolone (solu-Medrol) immediately before paclitaxel 
dosing. 
6.1.5
Gemcitabine Administration
Gemcitabine will be administered as a 30- to 60-minute IV infusion before MLN4924 on 
Days 1, 8, and 15 or per current prescribing guidelines. Refer to the most recent prescribing 
information for further details regarding gemcitabine administration.
Gemcitabine is initially dosed at 1000 mg/m2 in Arm 3. If it is determined by the sponsor 
that 1000 mg/m2 is poorly tolerated by multiple patients, then the initial dose for all patients 
subsequently enrolled in that arm may be reduced to a gemcitabine dose of 800 mg/m2. For 
patients who start on a gemcitabine dose of 800 mg/m2, dose modification would be allowed 
by 1 level to 600 mg/m2. No further dose modification below 600 mg/m2 is allowed.
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 combination with docetaxel, paclitaxel + carboplatin, or 
gemcitabine. Patients in the carboplatin lead-in cohort will receive MLN4924 + carboplatin 
only.
6.3
Definitions of Dose-Limiting Toxicity 
Toxicity will be evaluated according to the NCI CTCAE, Version 4.03, effective 
14 June 2010.(1)  These criteria are provided in the Study Manual. DLT will be defined as 
any of the following events that are considered by the investigator to be at least possibly 
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related to therapy with MLN4924, docetaxel, carboplatin, paclitaxel and carboplatin, or 
gemcitabine. 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 or chemotherapy-related 
toxicities that may have been exacerbated by MLN4924 in a combination setting.
Hematologic Dose-Limiting Toxicities

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

A delay in the initiation of Cycle 2 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) of 4 weeks or greater due to hematologic toxicity believed not 
related to tumor infiltration (bone marrow evaluation may be required)
Nonhematologic Dose-Limiting Toxicities

Grade 3 or greater diarrhea that is uncontrolled despite maximal supportive therapy

Grade 3 or greater nausea and/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
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o
Hypophosphatemia that can be controlled with appropriate medical 
management

A delay in the initiation of Cycle 2 of more than 2 weeks due to a lack of adequate 
recovery from non-hematologic 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) 

Other study drug-related, nonhematologic toxicities Grade 2 or greater that, in the 
opinion of the investigator, require a dose reduction or discontinuation of therapy 
with MLN4924
Other Dose-Limiting Toxicities
In addition, the following will also be considered DLTs 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, 
paclitaxel, carboplatin, or gemcitabine) in the next cycle.

A patient who has received 2 of 3 gemcitabine doses (eg, Day 1 and Day 8, or Day 1 
and Day 15) and has had a drug-related toxicity that does not qualify as a DLT per 
the guidelines above may continue with the next regularly scheduled cycle of 
treatment, and the missed dose will not constitute a DLT. However, if the patient 
receives only 1 gemcitabine dose per cycle due to a drug-related toxicity, then this 
toxicity will constitute a DLT.
Although AEs meeting the protocol-specified definition of DLT may occur at any point 
during treatment, only those AEs meeting the DLT definition occurring during Cycle 1 of 
treatment will necessarily influence decisions regarding dose escalation, expansion of a dose 
level, or evaluation of intermediate dose levels. Patients will be monitored through all cycles 
of therapy for treatment-related toxicities.
6.4
Dose Escalation Rules 
An adaptive approach using a CRM will be used for dose escalation, as shown in Table 6-2. 
The starting dose for Arms 1 and 2 will be 15 mg/m2, and the starting dose for Arm 3 will be 
25 mg/m2. The intervals between dose levels are prespecified and are not determined by the 
CRM algorithm. For Arms 1 and 2, the increases will be approximately 1.67-, 1.5-, and 
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1.33-fold over the previous dose level, and for Arm 3, the increases will be 2-, 1.5-, and 
1.33-fold over the previous dose level (see Table 6-2). 
Table 6-2
Planned MLN4924 Dose Levels
Arm 1 (MLN4924 + Docetaxel) 
Dose Level
Approx. Dose Increase Factor
MLN4924 Dose (unit)
1
(starting)
15 mg/m2 (in combination with docetaxel)
2
1.67
25 mg/m2 (in combination with docetaxel)
3
1.5
37 mg/m2 (in combination with docetaxel)
4
1.33
50 mg/m2 (in combination with docetaxel)
Arm 2 Carboplatin Lead-in (MLN4924 + Carboplatin)
Dose Level
Approx. Dose Increase Factor
MLN4924 Dose (unit)
1
(starting)
15 mg/m2 (in combination with carboplatin)
Arm 2 (MLN4924 + Paclitaxel + Carboplatin)
Dose Level
Approx. Dose Increase Factor
MLN4924 Dose (unit)
1
(starting)
15 mg/m2 (in combination with paclitaxel + 
carboplatin)
2
1.67
25 mg/m2 (in combination with paclitaxel + 
carboplatin)
3
1.5
37 mg/m2 (in combination with paclitaxel + 
carboplatin)
4
1.33
50 mg/m2 (in combination with paclitaxel + 
carboplatin)
Arm 3 (MLN4924 + Gemcitabine)
Dose Level
Approx. Dose Increase Factor
MLN4924 Dose (unit)
1
(starting)
25 mg/m2 (in combination with gemcitabine)
2
2
50 mg/m2 (in combination with gemcitabine)
3
1.5
75 mg/m2 (in combination with gemcitabine)
4
1.33
100 mg/m2 (in combination with gemcitabine)
Three patients will be dosed at the initial dose level. The PMTD from the CRM model will 
be updated based on the observed DLTs (as defined in Section 6.3) after patients have 
completed the first cycle of therapy. The following criteria will be used to determine the 
dose for the next patients (example values are provided for Arms 1 and 2; the same criteria 
will be used to determine the MTD for Arm 3):
1. If no DLTs are observed, the PMTD will be greater than the midpoint between 
15 and 25 mg/m2 (ie, 20 mg/m2), and 3 patients will be dosed at 25 mg/m2 (see 
below).
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2. If 1 DLT is observed, the PMTD will be between 15 and 20 mg/m2, and 3 additional 
patients will be dosed at 15 mg/m2.
3. If 2 or more DLTs are observed, the arm will be stopped.
If 3 additional patients (a total of 6 patients) are dosed at the initial dose of 15 mg/m2 (as 
described in Criterion 2 above), the decision to enroll additional patients or escalate to the 
next higher dose level will depend on the following criteria:
1. If a total of 1 DLT in the 6 patients is observed, the PMTD will be greater than 
20 mg/m2, and 3 patients will be dosed at 25 mg/m2 (see below).
2. If a total of 3 or more DLTs in the 6 patients are observed, the arm will be stopped.
3. If a total of 2 DLTs in the 6 patients are observed, 2 additional patients (a total of 
8 patients) will be dosed at 15 mg/m2. If no DLTs are observed in the 2 additional 
patients, 15 mg/m2 will be the MTD. If any DLTs are observed in the 2 additional 
patients, the arm will be stopped.
During treatment at the subsequent dose levels, dose escalation will depend upon the 
observed DLT rate in all previously treated patients. 
A minimum of 3 patients at the current dose level is required before escalating to the next 
higher dose level, and no scheduled dose levels may be skipped. If a re-escalation occurs 
after a de-escalation, 3 patients will be treated at the next higher dose level. To decide 
whether to enroll additional patients to the current dose level, escalate to the next higher 
dose level, or de-escalate to the prior dose level, the midpoint between the current dose level 
and the next scheduled higher dose level (Midhigh) and the midpoint between the previous 
dose level and the current dose level (Midlow) will be calculated. These assessments will be 
conducted by the sponsor, and the following rules will then be used:
1. If the PMTD is greater than or equal to Midhigh, 3 patients will be treated at the next 
higher dose level. 
2. If the PMTD is between Midlow and Midhigh, 3 additional patients will be treated at 
the current dose level.
3. If the PMTD is less than Midlow, 3 additional patients will be treated at the dose level 
that is nearest to the PMTD.
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Once at least 6 patients are treated at any dose level and the algorithm does not recommend 
escalation or de-escalation, this dose level may be considered the MTD of MLN4924 in 
combination with the SoC. Figure 6-1 is a diagrammatical representation of these rules.
Figure 6-1
Dose Escalation Scheme
Abbreviations:  CRM=continual reassessment method; DLT=dose-limiting toxicity; Midhigh=midpoint between 
current dose level and next dose level; Midlow=midpoint between previous dose level and current dose level; 
MTD=maximum tolerated dose; PMTD=predicted MTD.
a The intervals between dose levels are prespecified and are not determined by the CRM algorithm.
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After the determination of the MTD of MLN4924 with each SoC, approximately 
6 additional patients will be enrolled to each arm, for a total of approximately 12 patients 
treated at the MTD, to more fully characterize the safety, tolerability, and PK of MLN4924 
with SoC. 
Although AEs meeting the protocol-specified definition of DLTs may occur at any point 
during treatment, only those AEs meeting the DLT definition occurring during Cycle 1 of 
treatment will necessarily influence decisions regarding dose escalation, expansion of a dose 
level, or evaluation of intermediate dose levels. 
Patients who discontinue the study; experience dosing delay or dosing reduction in either 
MLN4924 or SoC, for reasons other than a DLT before they have completed all 21 days of 
Cycle 1 for Arms 1 and 2 or 28 days for Arm 3; or are administered MLN4924 in 
combination with SoC on unscheduled days in Cycle 1 will not be included in the 
assessment of the DLT rate at any given dose level. Such patients will be replaced. Patients 
who experience a DLT may be allowed to continue treatment with the study drugs at a dose 
level below that which was associated with the DLT.
More conservative dose escalation, evaluation of intermediate doses, and expansion of an 
existing dose level are all permissible after discussions between the sponsor and the 
investigators, if such measures are needed for patient safety or for a better understanding of 
the dose-related toxicity or exposure of MLN4924 in combination with SoC.
6.5
Dose-Modification Guidelines (Dose Delays, Dose Reductions, and Dose 
Interruptions)
The following apply to DLTs occurring during any cycle:  for individual patients 
experiencing a DLT, treatment for each new cycle will be delayed until toxicity is reduced 
to ≤ Grade 1 or patient’s baseline. 

Alopecia of any duration will not lead to dose modification or treatment delay. 

Patients can have a maximum of 2 dose modifications (if applicable) of 
chemotherapy agents and/or MLN4924 as outlined below. Patients who require more 
than 2 dose modifications will be discontinued from the study.

Patients in the carboplatin lead-in cohort are initially dosed at AUC6. If ≥ 2 DLTs 
are seen in this cohort (see Section 1.4.3.3 for further details), further dosing with the 
carboplatin-containing regimen will be at AUC5. 
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
If the dose of carboplatin is reduced from AUC6 to AUC5 in the carboplatin lead-in 
cohort, enrollment on Arm 2 will open at a reduced dose of carboplatin and 
paclitaxel (MLN4924 [15 mg/m2] + paclitaxel [175 mg/m2] + carboplatin [AUC5]).

Regardless of initial carboplatin dosing, patients in Arm 2 (MLN4924 + carboplatin 
+ paclitaxel) may have their carboplatin dose reduced to no lower than AUC4. 
Patients who require further dose modifications will be discontinued from the study.
o
Paclitaxel is initially dosed at 200 mg/m2. Up to 2 dose reductions to 
175 mg/m2 and 135 mg/m2 may be considered.
o
Docetaxel is initially dosed at 75 mg/m2. Up to 2 dose modifications to 
60 mg/m2 and 45 mg/m2 may be considered.
o
Gemcitabine is initially dosed at 1000 mg/m2. Up to 2 dose modifications to 
800 mg/m2 and 600 mg/m2 may be considered.
o
MLN4924 is initially dosed at 15 mg/m2 in Arms 1 and 2 or 25 mg/m2 in 
Arm 3. Up to 2 dose modifications (to lower dose levels) may be considered. 
The lowest dose of MLN4924 cannot be lower than 15 mg/m2 for Arms 1 and 
2 or 25 mg/m2 for Arm 3. Patients who require dose modifications below 
15 mg/m2 (in Arms 1 and 2) or below 25 mg/m2 (in Arm 3) will be 
discontinued from the study.

For the gemcitabine arm (Arm 3), the following dose modification will apply to the 
Day 8 and Day 15 dosing of each cycle: 
o
Treat with full dose if the ANC is ≥ 1000 cells/L and platelet count is 
≥100,000 cells/L. 
o
Dose reduce gemcitabine to 800 mg/m2 if the ANC is 500 to 999 cells/L or 
the platelet count is 50,000 to 99,999 cells/L.
o
Hold treatment if the ANC is < 500 cells/L or platelet count is 
< 50,000 cells/L.

In the event of a DLT, hold treatment and provide supportive care until the patient 
recovers to Grade 1 toxicity or baseline level before considering a dose 
modifications as specified above. Patients with unresolved toxicities Grade 1 
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lasting 3 weeks or longer from the date of the next scheduled treatment will not be 
permitted to continue on the study.

When a dose modification is warranted for safety, 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 
or chemotherapy-related toxicities that may have been exacerbated by MLN4924 in a 
combination setting. 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 resuming treatment. Treatment breaks must be no longer than 
2 weeks in duration (extended up to 4 weeks after consulting with the sponsor); 
treatment breaks may not be taken consecutively.

The decision to treat at a reduced dose level of any therapy is at the discretion of the 
investigator. Discussions with the project clinician are encouraged.
Table 6-3 outlines the dose modification guidelines for specific toxicities.
Table 6-3
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 Day 1 
of Cycles ≥ 2
Initiation (Day 1) of 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.
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Table 6-3
Dose Modification Guidelines for Specific Toxicities 
NCI CTCAE Category
Severity
Action on Study Drug
Grade 4 
thrombocytopenia 
lasting more than 
7 days  or the  platelet 
count is 
< 25,000 cells/L at 
any time
Initiation (Day 1) of 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.
Hematologic
Modification applies 
only to the Day 8 and 
Day 15 dosing of 
gemcitabine
Gemcitabine arm (Arm 
3) only:
Days 8 and 15 of each cycle: 
Treat with full dose if the ANC is ≥1000 cells/L and 
the platelet count is ≥100,000 cells/L. 
If the ANC is 500 to 999 cells/L or platelet count is 
50,000 to 99,999 cells/L, dose reduce gemcitabine 
1 dose level below that of the Day 1 dose of the current 
cycle (eg, if the Day 1 dose of the current cycle is 
1000 mg/m2, dose reduce to 800 mg/m2; if the Day 1 
dose of the current cycle is 800 mg/m2, dose reduce to 
600 mg/m2).
Hold treatment if the ANC is < 500 cells/L or the 
platelet count is < 50,000 cells/L. For patients who 
had a dose withheld on Day 8 or Day 15, gemcitabine 
may be dose reduced by 1 dose level on subsequent 
cycles. 
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).
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. 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 CYP3A4 inducers 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 
one level. This is a permanent dose reduction.
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Table 6-3
Dose Modification Guidelines for Specific Toxicities 
NCI CTCAE Category
Severity
Action on Study Drug
Hepatic toxicity
ALT/AST Grade 3 at 
any time 
If ALT or AST Grade 3 at any time, even during off-
dosing days, then dose reduce MLN4924 by 1 dose 
level on subsequent dosing days.
This dose reduction is permanent. LFTs must have 
recovered to Grade 1 before each subsequent dosing.
In addition, if toxicity is felt to be attributable to the 
chemotherapy agent(s), then 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 
and/or MLN4924 by 1 level.
Cardiac toxicity
Symptomatic 
arrhythmia during 
infusion
Stop infusion, manage arrhythmia according to 
institutional guideline. Report as AE and discontinue 
further dosing.
Cardiac toxicity
Chest pain and/or 
symptomatic 
hypotension 
(< 90/60/mmHg)
Stop infusion. Perform an ECG. Give intravenous 
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 of 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, 
gemcitabine, or MLN4924 are not to be dose modified.
Allergic reaction
(paclitaxel or docetaxel 
only
Moderate symptoms
Stop infusion. Give intravenous diphenhydramine 25 to 
50 mg and intravenous dexamethasone 10 mg and/or 
treatment as 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 intravenous diphenhydramine and 
dexamethasone and/or treatment as per institutional 
guidelines as above. Add epinephrine or bronchodilators 
if indicated. Report as an adverse event and discontinue 
patient.
Abbreviations:  AE=adverse event; ANC=absolute neutrophil count; ALT=alanine aminotransferase; 
AST=aspartate aminotransferase; ANC=absolute neutrophil count; CYP=cytochrome P450; 
ECG=electrocardiogram; LFTs=liver function tests; ULN=upper limit of normal. 
6.5.1
Intrapatient Dose Escalation
No intrapatient dose escalation is allowed in this study.
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6.6
Excluded Concomitant Medications and Procedures
Medications and procedures that are prohibited are listed in Table 6-4.
Table 6-4
Excluded Concomitant Medications and Procedures
Therapy
Comment
Acetaminophen and acetaminophen-containing products
Excluded only 24 hours before dosing, day of 
dosing, and 24 hours after dosing with MLN4924
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 Section 6.7
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 Section 6.7
Clinically significant CYP3A4 inducers (Section 15.7)
Excluded within 14 days before dosing with 
MLN4924 and during the study 
Abbreviations:  BCRP=breast cancer-resistance protein; CYP=cytochrome P450; P-gp=P-glycoprotein. 
6.7   
Permitted Concomitant Medications and Procedures 
Medications and procedures that are specifically permitted during the study are listed in 
Table 6-5.
Table 6-5
Permitted Concomitant Medications and Procedures
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.
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Table 6-5
Permitted Concomitant Medications and Procedures
Therapy
Comment
Nephrotoxic medications, 
including nonsteroidal anti-
inflammatory drugs
Whenever possible, caution should be used with nephrotoxic concomitant 
medications (Section 15.8). 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/or 
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.
6.8
Precautions and Restrictions
Concomitant medications and procedures that are excluded or must be used with caution are 
described in Section 6.6 and Section 6.7, respectively.
Certain situations may warrant further caution, such as modifying the dose of study drug(s). 
Dose modification guidelines are provided in Section 6.5. 
6.8.1
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 15.9.
Female patients must meet 1 of the following: 

Postmenopausal for at least 1 year before the screening visit, OR

Surgically sterile, OR
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
As of Amendment 1, 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 1], and 
lactational amenorrhea [as of Amendment 1] are not acceptable methods of 
contraception. Female and male condoms should not be used together.)
As of Amendment 1, female patients must agree to not donate eggs (ova) during the course 
of this study or for 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 
Amendment 1], and lactational amenorrhea [as of Amendment 1] are not acceptable 
methods of contraception. Female and male condoms should not be used together.) 
As of Amendment 1, male patients must agree to not donate sperm during the course of this 
study or for 4 months after receiving their last dose of study drug(s).
6.8.2
Docetaxel
TAXOTERE is a pregnancy Category D drug. Please refer to the TAXOTERE US package 
insert (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.(16)  
6.8.3
Carboplatin
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.(17)  
6.8.4
Paclitaxel
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.(18)  
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6.8.5
Gemcitabine
Gemcitabine is a pregnancy Category D drug. Please refer to the Gemcitabine USPI for 
more information.
Gemcitabine for injection can cause fetal harm when administered to a pregnant 
woman. In pre-clinical studies in mice and rabbits, gemcitabine was teratogenic, 
embryotoxic, and fetotoxic. There are no adequate and well-controlled studies of 
gemcitabine for injection in pregnant women. If this drug is used during pregnancy, 
or if the patient becomes pregnant while taking this drug, the patient should be 
apprised of the potential hazard to the fetus.(19)  
6.9
Guidance for Clinical Assessment and Management of Hemodynamic 
Compromise
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/or 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/or hospital guidelines; each red 
blood cell transfusion should be recorded in the eCRFs. Transfusions should be administered 
before study drug administration (ie, at least 1 day before dosing).
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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6.10
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, paclitaxel + carboplatin, and 
gemcitabine are described in Section 1.5. 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.
6.10.1
Guidance for Clinical Assessment and Management of Diarrhea 
Diarrhea should be treated promptly with appropriate supportive care, including 
administration of an antidiarrheal agent according to standard practice or institutional 
guidelines. Antidiarrheal agents should not be taken prophylactically. Patients should be 
instructed to begin taking antidiarrheal medication at the first sign of (1) poorly formed or 
loose stool, (2) occurrence of more bowel movements than usual in 1 day, or (3) unusually 
high volume of stool. Antidiarrheal agents should be deferred if blood or mucus is present in 
the stool or if diarrhea is accompanied by fever. In this setting, appropriate diagnostic 
microbiological specimens should be obtained to exclude an infectious etiology. Patients 
should also be advised to drink liberal quantities of clear fluids to help prevent dehydration.
6.10.2
Guidance for Clinical Assessment and Management of Nausea and Vomiting 
Nausea and vomiting should be treated aggressively, and strong consideration should be 
given to the administration of prophylactic antiemetic therapy according to standard 
institutional practice. Patients should be strongly encouraged to maintain liberal oral fluid 
intake. Supportive care with moderate or strong CYP3A4 inhibitors/inducers should be 
avoided.
6.10.3
Guidance for Use of Granulocyte-Colony Stimulating Factor
Use of growth factors such as granulocyte-colony stimulating factor (G-CSF) during Cycle 1 
is permitted for the docetaxel arm but not recommended for the carboplatin, 
paclitaxel + carboplatin, or gemcitabine arms/cohorts. However, they may be considered for 
Cycle 2 and beyond, per the investigator’s discretion, if there is persistent neutropenia or 
febrile neutropenia despite dose reductions in the previous course. If G-CSF is used, it 
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should be used in accordance with the Revised American Society of Clinical Oncology 
(ASCO) guidelines as published in the Journal of Clinical Oncology (Smith et al, 2006).(23)
6.10.4
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/or hospital guidelines; each red 
blood cell transfusion should be recorded in the eCRFs. Transfusions should be administered 
before study drug administration (ie, at least 1 day before dosing).
Use of Erythropoietin
Use of erythropoietin during Cycle 1 is not recommended; however, it may be considered in 
Cycle 2 or beyond, per the investigator’s discretion and per institutional guidelines.
6.11
Blinding and Unblinding
This is an open-label study. 
6.12
Description of Investigational Agents 
6.12.1
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 US 
Pharmacopeia (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.
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Details are available in the IB.
6.12.2
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 
prescribing information.
6.12.3
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 
prescribing information.
6.12.4
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 
prescribing information.
6.12.5
Gemcitabine 
Gemcitabine is obtained from commercial sources according to local practice standards, and 
it is provided as a commercially available dosage formulation. Please refer to the 
gemcitabine prescribing information.
6.13
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, paclitaxel, carboplatin, and gemcitabine are anticancer drugs, and as 
with other potentially toxic compounds, caution should be exercised when handling 
MLN4924 and chemotherapy agents.
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 a detailed 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 
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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.
Please refer to the package inserts for the SoCs (docetaxel, paclitaxel, carboplatin, and 
gemcitabine) for instructions and precautions regarding preparation.
6.14
Packaging and Labeling
MLN4924 (MLN4924-003 concentrate for solution for infusion) will be provided in 8 or 
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.
Docetaxel, paclitaxel, carboplatin, and gemcitabine 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.
6.15
Storage, Handling, and Accountability  
Vials of MLN4924 (MLN4924-003 concentrate for solution for infusion) are to be stored at 
2°C to 8°C.
Please refer to the package inserts for the SoCs (docetaxel, paclitaxel, carboplatin, and 
gemcitabine) for instructions and precautions regarding preparation.
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.
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7.
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, GCP, applicable regulatory 
requirements, and ICH guidelines.
7.1
Study Personnel and Organizations 
The contact information for the project clinician for this study, the central laboratory and 
any additional clinical laboratories, the contract research organization (CRO) 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 
The investigator will assign each patient to 1 of the 3 study arms (MLN4924 + docetaxel, 
MLN4924 + paclitaxel + carboplatin, or MLN4924 + gemcitabine) or the carboplatin lead-in 
cohort based on his/her medical judgment until enrollment in each arm/cohort is filled.
Patients assigned to the carboplatin lead-in cohort will receive carboplatin in combination 
with MLN4924. These patients will not enroll in Arm 2 (MLN4924 + paclitaxel + 
carboplatin).
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. 
Baseline procedures/tests are to be performed within 3 days before Cycle 1 Day 1. If 
screening values or results were obtained and acceptable within 3 days before Cycle 1 
Day 1, those procedures/tests need not be repeated at Cycle 1 Day 1. Day 1, 3, 5, 8, or 15 
dosing (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 
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accommodate inclement weather, holidays, vacations, or other administrative reasons; 
treatment breaks may not be taken consecutively. 
Refer to the following Schedules of Events for timing of assessments. 
Cycle 1 Only

Cycle 1:  Arm 1 and Arm 2

Cycle 1: Arm 3
Cycle 2 and Beyond

Cycle 2 and Beyond:  Arm 1, and Cycle 2 through Cycle 12:  Arm 2

Cycle 13 and Beyond:  Arm 2 (as of Amendment 1)

Cycle 2 and Beyond:  Arm 3
Dose Escalation Phase

Cycle 1:  Arm 1 Dose Escalation Pharmacokinetics Schedule

Cycle 1:  Arm 2 Dose Escalation Pharmacokinetics Schedule

Cycle 1:  Arm 3 Dose Escalation Pharmacokinetics Schedule
MTD Expansion Phase

Cycle 1:  Arm 1 Maximum Tolerated Dose Expansion Pharmacokinetics Schedule

Cycle 1:  Arm 2 MTD Expansion Pharmacokinetics Schedule

Cycle 1:  Arm 3 MTD Expansion Pharmacokinetics Schedule
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 
(within 28 days before the first dose of any study drug).
7.4.3
Medical History
During screening, a complete medical history will be compiled for each patient. 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 3, 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. 
Symptom-directed physical examinations will also be conducted at 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 before MLN4924 dosing as indicated in the Schedules of Events.
7.4.7
Eastern Cooperative Oncology Group Performance Status
ECOG PS (Section 15.3) will be assessed as indicated in the Schedules of Events.
7.4.8
Echocardiogram
LVEF should be assessed by echocardiogram or radionuclide angiography at screening.
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 of 
these measurements are taken with the patient in a sitting position (and/or supine after 
completion of Cycle 12) as noted in the Schedules of Events. 
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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 to 4 minutes.   
7.4.10
Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential at screening. 
The results from these tests 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 6.6 and Section 6.7 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.
The ECGs performed after infusion should be reviewed by the investigator or his/her 
delegate before the patient leaves the clinic.
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7.4.15
Clinical Laboratory Evaluations
Hematology, Clinical Chemistry, Coagulation, Urinalysis, and Urine Safety Assessment
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 (ANC)
Serum Chemistry

Blood urea nitrogen 
(BUN)

Creatinine

Bilirubin (total)

Direct bilirubin

Urate

Lactate dehydrogenase 
(LDH)

Gamma glutamyl 
transferase (GGT) a

Phosphate

Albumin

ALP

AST

ALT

Glucose

Sodium

Potassium

Calcium

Chloride

Carbon dioxide 
(CO2)

Magnesium
a
No longer required after completion of Cycle 12 (as of Amendment 1). 
Coagulation
Screening

PT (international 
normalized ratio [INR])

aPTT

Fibrinogen 

D-dimer
Cycle 1 and Beyond

PT (INR)

aPTT
If the initial coagulation screen is positive, follow-up coagulation studies should include a 
full coagulation panel rather than PT (INR)/aPTT alone. If the initial coagulation screen is 
negative, follow-up coagulation studies should include only PT (INR) and aPTT.
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Urinalysis With Microscopic Analysis
!
Turbidity and color
!
pH
!
Specific gravity
!
Protein
!
Ketonesa
!
Bilirubina
!
Occult blood
!
Nitrite
!
Urobilinogena
!
Glucosea
!
Leukocytes
!
Microscopic assessment
a
Removed after completion of Cycle 12 (as of Amendment 1).
Urine Safety Assessmenta
!
Albumin
!
Creatinine
!
Phosphate 
!
Kidney injury molecule-1
a
Removed after completion of Cycle 12 (as of Amendment 1). 
7.4.16
Disease Assessment 
CT scans with IV contrast (unless medically contraindicated) of the chest, abdomen, and 
pelvis will be performed during screening. CT scans with IV contrast encompassing the 
known sites of disease will be performed at the end of Cycle 2 and then every other cycle 
thereafter (Cycles 4-12) or after completion of every sixth cycle after the patient’s previous 
scan (after completion of Cycle 12 and implementation of Amendment 1), and at the EOS 
visit. Additional CT scans may be performed, per the investigator’s discretion, if clinically 
indicated. 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 screening assessment. For 
each site of disease, the imaging modality (CT or MRI) used at screening must be used 
throughout the study. Tumor response will be assessed by the investigator at these times 
using RECIST, version 1.1.(22)
7.4.17
Tumor Biopsies
Tumor biopsy is not required in this study for patients with adequate archived tumor 
material. Banked paraffin-embedded tumor tissue or a minimum of 10 unstained slides of 
the tumor tissue is required for study entry and will be collected at screening to enable 
genetic characterization of the tumor 
 
 In the event that no 
banked tumor tissue or archived slides are available, a fresh tumor biopsy will be required 
before enrollment in this study.
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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7.4.18
Pharmacokinetic Measurements 
Blood samples for the determination of MLN4924 plasma concentrations and, if appropriate, 
its metabolites, will be collected only during Cycle 1 of treatment. The timing, but not the 
number, of PK blood samples may be changed if emerging data indicate that an alteration in 
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. In the case that only a single arm is available, blood 
should be drawn as distal to the site of IV infusion as feasible, and the site of blood draw 
should be documented.
Dose Escalation Phase
During the dose escalation portion of the study (excluding the Arm 2 carboplatin lead-in 
cohort), blood samples will be collected from each patient for the determination of 
MLN4924 plasma concentrations during the first cycle of treatment at the time points 
indicated in the Schedules of Events. 
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 the recording 
of blood sampling times that occur close to the infusion. 
MTD Expansion Phase
During the MTD expansion portion of the study, serial blood samples will be collected from 
all patients at the time points indicated in the  Schedules of Events before and after the start 
of MLN4924 infusion. 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 the recording of blood sampling times that occur close to the infusion. 
Details regarding the preparation, handling, and shipping of samples are provided in the 
Study Manual.
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 additionally 
analyzed to determine plasma concentrations of MLN4924 major metabolites in humans.
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7.4.19
Whole Blood Sample for Genomic DNA
During screening, a blood sample will be collected for generation of genomic DNA for 
interpretation of the presence of somatic DNA mutations. These samples will be retained 
until drug is approved by regulatory authorities or discontinuation of the MLN4924 
program; if at that time they have not been consumed during research, they will be 
destroyed.
7.4.20
Banked Tumor Specimen Measurements
Banked paraffin-embedded tumor tissue or a minimum of 10 unstained slides of the tumor 
tissue (ie, tumor tissue obtained at the time of the patient’s original diagnosis and/or at the 
time of subsequent procedures conducted as part of the patient’s standard care) will be
collected 
 
 
 
 
 
 
7.4.21
Plasma Sample Collection
During screening, a blood sample will be collected to generate a plasma sample 
 
 
7.5
Completion of Study 
Patients will be considered to have completed the study if they discontinue treatment for any
of the reasons outlined in Section 7.6.
7.6
Discontinuation of Treatment with Study Drug, and Patient Replacement 
Treatment with study drug may be discontinued for any of the following reasons: 
!
AE
!
Protocol violation
!
PD
CCI
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
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. 
For determination of the MTD in the dose escalation phase, patients will be replaced if 
withdrawn from treatment during Cycle 1 for reasons other than DLT.
Note:  Patients may receive MLN4924 until they experience PD or unacceptable 
MLN4924-related toxicities. The maximum duration of treatment will be 12 cycles; 
however, if it is determined after discussion between the investigator and the sponsor that a 
patient would derive benefit from continued treatment, the patient may remain on 
combination therapy (MLN4924 + SoC) or receive MLN4924 as a single agent beyond 
12 cycles.
Patients who are resistant to the SoC AND 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 under these circumstances at the same dose and schedule upon request by the 
investigator and agreement by the sponsor.
7.7
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.


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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. A formal statistical analysis plan (SAP) will 
be developed and finalized before database lock. Deviations from the statistical analyses 
outlined in this protocol will be indicated in the SAP; any further modifications will be 
noted in the final clinical study report.
8.1.1
Determination of Sample Size
It is anticipated that approximately 69 patients will be enrolled combining the dose 
escalation for the determination of MTD for each combination, the cohort expansion at each 
MTD, and estimating approximately 6 patients enrolled in the carboplatin lead-in cohort.
An adaptive approach using a Bayesian CRM will be used for dose escalation. Based on the 
observed toxicities in the DLT-evaluable population (Section 8.1.3), the CRM algorithm 
will predict the MTD of MLN4924 with SoC, defined as the dose level closest to that 
predicted to result in a DLT rate of 25%, also known as the target toxicity rate. The dose 
toxicity relationship is modeled by a single-parameter (α) logistic model. Table 8-1 shows 
the operating characteristics of the CRM using Monte Carlo simulations versus the 
traditional “3 + 3” escalations rules for several assumptions of the true MTD.
Table 8-1
Operating Characteristics of Continual Reassessment Method Versus 
Traditional Escalation Rules (“3 + 3”)
Scenario
Dose 
Levels 
(mg/m2)
True 
DLT
Rate
Method
MTD
Median
(P5, P95)
Accuracy 
Rate 
(%)a
Number of 
Patients
Median
(P5, P95)
Number of 
DLTs
Median
(P5, P95)
1
15; 25; 
37; 50
0.10; 
0.15; 
0.20; 0.25
CRM
37 (15, 50)
65.76
15 (8, 21)
2 (1, 4)
3 + 3
37 (0, 50)
50.88
15 (6, 21)
2 (1, 4)
2
15; 25; 
37; 50
0.20; 
0.25; 
0.30; 0.35
CRM
25 (0, 50)
64.12
12 (3, 21)
3 (2, 5)
3 + 3
15 (0, 50)
62.16
12 (3, 21)
3 (2, 5)
3
15; 25; 
37; 50
0.40; 
0.45; 
0.50; 0.55
CRM
0 (0, 25)
---
6 (3, 15)
3 (2, 6)
3 + 3
0 (0, 25)
---
6 (3, 15)
2 (2, 5)
4
25; 50; 
75; 100
0.10; 
0.15; 
0.20; 0.25
CRM
75 (25, 100)
65.82
15 (8, 21)
2 (1, 5)
3 + 3
75 (0, 100)
50.88
15 (6, 21)
2 (1, 4)


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Table 8-1
Operating Characteristics of Continual Reassessment Method Versus 
Traditional Escalation Rules (“3 + 3”)
Scenario
Dose 
Levels 
(mg/m2)
True 
DLT
Rate
Method
MTD
Median
(P5, P95)
Accuracy 
Rate 
(%)a
Number of 
Patients
Median
(P5, P95)
Number of 
DLTs
Median
(P5, P95)
5
25; 50; 
75; 100
0.20; 
0.25; 
0.30; 0.35
CRM
50 (0, 100)
63.68
12 (3, 21)
3 (2, 5)
3 + 3
25 (0, 100)
62.16
12 (3, 21)
3 (2, 5)
6
25; 50; 
75; 100
0.40; 
0.45; 
0.50; 0.55
CRM
0 (0, 50)
---
6 (3, 15)
3 (2, 6)
3 + 3
0 (0, 50)
---
6 (3, 15)
2 (2, 5)
Abbreviations:  CRM=continual reassessment method; DLT=dose-limiting toxicity; 3 + 3=traditional “3 + 3” 
escalation rules; MTD=maximum tolerated dose; P5=5th percentile; P95=95th percentile. 
a Accuracy rate is defined as the proportion of simulated trials that identify the MTD as a dose with true DLT 
rate within the interval (0.20, 0.30). Results are based on 5000 simulations per scenario.
In all scenarios, the CRM and 3 + 3 designs require similar numbers of patients and yield 
similar numbers of total DLTs. The CRM design generally yields a higher accuracy rate in 
predicting the MTD.
The starting dose for Arms 1 and 2 will be 15 mg/m2, and the starting dose for Arm 3 will be 
25 mg/m2. The intervals between dose levels are prespecified and are not determined by the 
CRM algorithm. For Arms 1 and 2, the increases will be approximately 1.67-, 1.5-, and 
1.33-fold over the previous dose level, and for Arm 3, the increases will be 2-, 1.5, and 
1.33-fold over the previous dose level (as described in Table 6-2). After the first 3 patients 
are dosed and have completed Cycle 1, the CRM algorithm will be updated based on the 
observed DLTs, and the PMTD will be calculated. The dose escalation rules are specified in 
Section 6.4. When the total number of patients in a dose level reaches at least 6 and the 
algorithm does not recommend escalation or de-escalation, that dose level may be 
considered the MTD. Based on an estimated toxicity rate of 25% at 50 mg/m2 in Arms 1 and 
2 and at 100 mg/m2 in Arm 3 (Scenarios 1 and 4 in Table 8-1), computer simulations 
estimate that approximately 15 patients will be enrolled in each arm to determine the MTD 
of MLN4924 with SoC. 
Once each MTD is determined, approximately 6 additional patients (MTD expansion 
cohort) will be enrolled in each arm such that a total of approximately 12 patients will be 
enrolled and treated at each MTD to more fully characterize the safety, tolerability, and PK 
of MLN4924 with SoC. These enrollment rules are based on the binomial probability 


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assumption that if a particular toxicity occurs in 12.5% of the entire patient population, there 
is an 80% probability of observing at least 1 occurrence of that toxicity in 12 patients.
8.1.2
Randomization and Stratification  
Patients will be enrolled according to the CRM, as described in Section 6.4 and Figure 6-1. 
No randomization is planned for this study.
8.1.3
Populations for Analysis
The populations used for analysis will include the following: 

Safety Population:  The Safety population is defined as all patients who receive at 
least 1 dose of any study drug. 

Response-Evaluable Population:  The Response-Evaluable population is defined as 
all patients who receive at least 1 dose of study drug, have measurable disease at 
baseline, and have at least 1 postbaseline disease assessment. 

PK Population:  The PK population is defined as all patients who have 
concentrationtime data to reliably estimate PK parameters.

DLT-Evaluable Population:  The DLT-Evaluable population is defined as all 
patients who either experience DLT during Cycle 1 or receive all scheduled doses of 
study drug during Cycle 1 without DLT. Patients in Arm 3 will still be considered 
DLT evaluable if they receive gemcitabine on Days 1 and 8 only or on Days 1 and 
15 only.
8.1.4
Procedures for Handling Missing, Unused, and Spurious Data
All available safety and efficacy data will be included in data listings and tabulations. 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.
8.1.5
Demographic and Baseline Characteristics
Demographic and baseline characteristics, including gender, age, race, weight, height, BSA, 
primary diagnosis, and other parameters as appropriate will be summarized. No inferential 
statistics will be carried out.


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8.1.6
Efficacy Analysis
Analysis of all efficacy measures 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 15.2).(22) The duration of 
response will be defined in patients with disease 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.
8.1.7
Pharmacokinetics and Biomarkers 
Pharmacokinetic Analysis
All individual concentration%time data will be pooled to describe the population PK of 
MLN4924. As data permit, a nonlinear regression mixed effects model (NONMEM 
software) will be used to assess MLN4924 exposure when administered in combination with 
the selected SoC therapies. Individual metabolite data may also be assessed, as deemed 
appropriate. If appropriate, historical data may be used in this analysis to increase the 
robustness of the model and precision of estimated PK parameters and compare with 
single-agent data. Details of the modeling approach will be provided in a separate analysis 
plan, and the results of these analyses will be reported separately. 
As data permit, individual and mean MLN4924 plasma concentration%time data will be 
tabulated and plotted for each combination therapy. 
Biomarkers
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8.1.8
Safety Analysis
The incidence of DLT will be tabulated for each dose group. In addition, to assess the 
relationship between toxicities and MLN4924 dose, the preferred term of individual 
toxicities will be summarized by their frequency and intensity for each dose group. The 
DLT-Evaluable population will be used for the analysis of DLT.
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and changes 
from baseline in the patient’s vital signs, weight, physical examination findings, ECG 
results, and clinical laboratory results using the Safety population. Exposure to study drug 
and reasons for discontinuation will be tabulated.
Treatment-emergent AEs that occur after administration of the first dose of study drug and 
through 30 days after the last dose of study drug will be tabulated. 
AEs will be tabulated according to the Medical Dictionary for Regulatory Activities 
(MedDRA) 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)

SAEs
A listing of treatment-emergent AEs resulting in study drug discontinuation will be 
provided.
Descriptive statistics for the actual values of clinical laboratory parameters (and/or 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.


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Descriptive statistics for the actual values (and/or the changes from baseline) of vital signs 
and weight over time will be tabulated by scheduled time point.
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.
Descriptive statistics for the actual values and changes from baseline in ECGs will be 
tabulated by time point, including any unscheduled measurements.
All concomitant medications collected from screening through the study period will be 
classified to preferred terms according to the World Health Organization (WHO) drug 
dictionary.
Additional safety analyses may be performed to most clearly enumerate rates of toxicities 
and to further define the safety profile of MLN4294.
8.1.9
Interim Analysis
No formal interim analysis is planned for this study. 
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 
participation.


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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.(1)  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.(1)  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 first dose of any 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 ICF up to first 
dose of study drug, but will not be recorded in the eCRF.
CCI


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
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) after administration of the last dose of study drug and recorded in 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 
data generated.


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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
Dohmen Life 
Science Services 
(DLSS)
1-844-662-8532 
Non-toll-free number: 
1-510-740-1273 
GlobalOncologyMedinfo@takeda.com
1-800-881-6092


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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. 
CCI


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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 C15010 Amendment 1:  A Phase 1b, Open-Label, Dose Escalation, 
Multi-arm Study of MLN4924 Plus Docetaxel, Gemcitabine, or Combination of Carboplatin 
and Paclitaxel in Patients With Solid Tumors
I agree to conduct the study as detailed herein and in compliance with International Council 
for 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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14.
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.
Soucy T.A. SPG, et al. An inhibitor of NEDD8-activating enzyme as a new approach 
to treat cancer. Nature 2009;458:732-6.
3.
Lin JJ, Milhollen MA, Smith PG, Narayanan U, Dutta A. NEDD8-targeting drug 
MLN4924 elicits DNA rereplication by stabilizing Cdt1 in S phase, triggering 
checkpoint activation, apoptosis, and senescence in cancer cells. Cancer Res 
2010;70(24):10310-20.
4.
Milhollen MA NU. Inhibition of NEDD8-activating enzyme induces rereplication 
and apoptosis in human tumor cells consistent with deregulating CDT1 turnover. 
Cancer Research 2011;71(8):3042-51.
5.
Milhollen MA TT, et al. MLN4924, a NEDD8-activating enzyme inhibitor, is active 
in diffuse large B-cell lymphoma models: rationale for treatment of NF-kB-
dependent lymphoma. Blood 2010;116(9):1515-23.
6.
Traore T, Milhollen M, Garnsey J, Berger A, Manfredi M, Cosmopolous K, et al. 
Antitumor activity of MLN4924, an investigational inhibitor of NEDD8-activating 
enzyme (NAE), in preclinical models of melanoma. J Clin Oncol (ASCO Meeting 
Abstracts) 2011;29(suppl):abstr 8594.
7.
Tentler JJ, Micel N, Selby HM, Tan AC, Brunkow K, Pitts TM, et al. Molecular 
determinants of response to the investigational small molecule inhibitor of Nedd8-
activating enzyme (NAE) MLN4924 in melanoma cell lines and patient-derived 
tumor explant models. Molecular Cancer Therapeutics 2011;10(11, suppl 1):abstr 
B178.
8.
Blank JL, Liu XJ, Cosmopoulos K, Bouck DC, Garcia K, Bernard H, et al. Novel 
DNA Damage Checkpoints Mediating Cell Death Induced by the NEDD8-Activating 
Enzyme Inhibitor MLN4924. Cancer Res 2013;73(1):225-34.
9.
Brownell JE, Sintchak MD, Gavin JM, Liao H, Bruzzese FJ, Bump NJ, et al. 
Substrate-assisted inhibition of ubiquitin-like protein-activating enzymes: the 
NEDD8 E1 inhibitor MLN4924 forms a NEDD8-AMP mimetic in situ. Mol Cell 
2010;37(1):102-11.
10.
O'Quigley J, Pepe M, Fisher L. Continual reassessment method: a practical design 
for phase 1 clinical trials in cancer. Biometrics 1990;46(1):33-48.
11.
TAXOL® (paclitaxel) INJECTION [package insert]. Princeton, NJ: Bristol-Myers 
Squibb Company; 2011.


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12.
TAXOTERE (docetaxel) [package insert]. Bridgewater, NJ: sanofi-aventis U.S. 
LLC; 2010.
13.
GEMZAR (gemcitabine for injection) Powder, Lyophilized, For Solution For 
Intravenous Use [package insert]. Indianapolis, IN: Eli Lilly and Company; 2011.
14.
Olaussen KA, Dunant A, Fouret P, Brambilla E, Andre F, Haddad V, et al. DNA 
repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant 
chemotherapy. New England Journal of Medicine 2006;355(10):983-91.
15.
Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN, Janakiraman M, et al. 
Genome sequencing identifies a basis for everolimus sensitivity. Science 
2012;338(6104):221.
16.
TAXOTERE (docetaxel) Injection Concentrate, Intravenous Infusion (IV) [package 
insert]. Bridgewater, NJ: sanofi-aventis U.S. LLC; 2011.
17.
CARBOPLATIN - carboplatin injection, solution [package insert]. Princeton, NJ: 
Sandoz Inc; 2011.
18.
PACLITAXEL - paclitaxel injection, solution [package insert]. Princeton, NJ: 
Sandoz; 2011.
19.
Gemcitabine HCl For Injection [package insert]. Princeton, NJ: Sandoz Inc; 2011.
20.
Goodman SN, Zahurak ML, Piantadosi S. Some practical improvements in the 
continual reassessment method for phase I studies. Statistics in Medicine 
1995;14(11):1149-61.
21.
Garrett-Mayer E. The continual reassessment method for dose-finding studies: a 
tutorial. Clinical Trials 2006;3(1):57-71.
22.
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.
23.
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.
24.
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.
25.
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.


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26.
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.
27.
Naughton CA. Drug-induced nephrotoxicity. American Family Physician 
2008;78(6):743-50.


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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 (NCIC CTG) and the Southwest Oncology Group (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 reevaluation. See Table 15-1 for the hematologic adverse experiences of 
patients treated with carboplatin.
Table 15-1
Hematologic Adverse Experiences of in Patients With Ovarian Cancer 
Treated With Carboplatin or Cisplatin in Combination With 
Cyclophosphamide
Adverse Experience
Laboratory Value
NCIC CTG Study
% Patients
(N=447)
SWOG Study
% Patients
(N=342)
Bone Marrow
   Thrombocytopenia
< 1000,000/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
Abbreviations:  NCIC CTG=National Cancer Institute of Canada Clinical Trials Group; SWOG=Southwest 
Oncology Group. 
Source:  Carboplatin US Package Insert (17)
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


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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
Source:  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.(24)
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; 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 bold. 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
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
Complete Response 
(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.
Progressive Disease 
(PD)
Appearance of one or more new lesions and/or unequivocal progression of existing 
nontarget lesions.
Source:  Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45 (2): 
228-47.(22)
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 EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45 (2): 
228-47.(22)
Abbreviations:  CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease.


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15.3
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 MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response 
criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5 (6):649-55.(25)
15.4
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
15.5
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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15.6
New York Heart Association Classification of Cardiac Disease
The following table presents the NYHA classification of cardiac disease.(26)
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.
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 15-3 should be avoided 
during MLN4924 therapy.
Table 15-3
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


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15.8
Drugs Associated with Nephrotoxicity
The drugs listed in Table 15-4 are permitted to be used during the conduct of this study but 
should be used with caution.
Table 15-4
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.(27)
15.9
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:


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
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

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 


MLN4924
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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.


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15.10
Amendment 1 Detailed Description of Amendments to Text 
The primary sections of the protocol affected by the changes in Amendment 1 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 6.5 Dose-Modification Guidelines (Dose Delays, 
Dose Reductions, and Dose Interruptions):
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 resuming treatment. Treatment breaks must be no 
longer than 2 weeks in duration (extended up to 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:

Section 4.1 Overview of Study Design.

Section 4.3 Duration of Study.

Section 6.1 Study Drug Administration.

Section 7.4 Study Procedures.
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:
Added 
text:
CT scans with IV contrast encompassing the known sites of disease will be 
performed at the end of Cycle 2 and then every other cycle thereafter (Cycles 4-
12) or after completion of every sixth cycle after the patient’s previous scan 
(after completion of Cycle 12 and implementation of Amendment 1), and at 
the EOS visit. Additional CT scans may be performed, per the investigator’s 
discretion, if clinically indicated.


MLN4924
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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:

Protocol Summary.

Schedules of Events:  Cycle 13 and Beyond:  Arm 2 (as of Amendment 1).

Section 4.1 Overview of Study Design.
Change 3: Reduce the frequency of hematology and clinical chemistry assessments and 
physical examinations.
The primary change occurs in Schedules of Events:  Cycle 13 and Beyond:  Arm 2 (as of 
Amendment 1):
Description 
of change:
Day 8 and 15 hematology, 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 Days 8 and 15, the clinic visits 
on these dates are not present in the new Schedule of Events. The complete 
physical examination on Day 1 was also replaced with a symptom-directed 
physical examination. 
Rationale for Change:
The Day 8 and 15 hematology 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 is considered sufficient.
Change 4: Remove ketones, bilirubin, urobilinogen, and glucose from the Urinalysis With 
Microscopic Analysis parameters.
The primary change occurs in Section 7.4.15 Clinical Laboratory Evaluations:
Description 
of change:
Ketones, bilirubin, urobilinogen, and glucose have been removed from the 
Urinalysis With Microscopic Analysis parameters after completion of 
Cycle 12.
Rationale for Change:
These changes to the urinalysis parameters were made to be consistent with program-wide 
recommendations.


MLN4924
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Change 5: Add a ±10-minute window to the MLN4924 infusion duration.
The primary change occurs in Section 6.1.1 MLN4924 Administration:
Initial 
wording: 
Patients will receive MLN4924 diluted with 5% dextrose in a 250-mL bag via a 
60-minute IV infusion…
The entire content of the MLN4924 IV bag will be infused at a constant rate over 
1 hour.
Amended 
new 
wording: 
Patients will receive MLN4924 diluted with 5% dextrose in a 250-mL bag via a 
60-minute 1-hour (±10 minutes as of Amendment 1) IV infusion…
The entire content of the MLN4924 IV bag will be infused at a constant rate over 
1 hour (±10 minutes as of Amendment 1).
Rationale for Change:
The addition of the ±10-minute window to the MLN4924 infusion duration was made to 
allow flexibility in MLN4924 infusion duration.
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 C15010 data analyzed during independent 
data monitoring committee meetings, and only 2 patients remain active in the study; 
therefore, as of Amendment 1 implementation, the independent data monitoring committee
will no longer be required to monitor Study C15010.
Section 1.5.1 Risks of MLN4924 Therapy also contains this change.


MLN4924
Clinical Study Protocol C15010 Amendment 1
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Change 7: Adjust contraception requirements to be consistent with Clinical Trial 
Facilitation Group recommendations.
The primary change occurs in Section 6.8.1 MLN4924:
Initial 
wording:
6.8.1
MLN4924
Female patients must meet 1 of the following: 
…

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:
6.8.1
MLN4924
Female patients must meet 1 of the following: 
…

As of Amendment 1, 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 
informed consent form ICF through 30 days 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 1], and lactational amenorrhea [as 
of Amendment 1] are not acceptable methods of contraception. Female 
and male condoms should not be used together.) 
As of Amendment 1, female patients must agree to not donate eggs (ova) 
during the course of this study or for 4 months after receiving their last dose 
of study drug(s).


MLN4924
Clinical Study Protocol C15010 Amendment 1
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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 patient. (Periodic abstinence [eg, calendar, 
ovulation, symptothermal, and postovulation methods for the female 
partner], and withdrawal, spermicides only [as of Amendment 1], and 
lactational amenorrhea [as of Amendment 1] are not acceptable methods 
of contraception. Female and male condoms should not be used 
together.) 
As of Amendment 1, male patients must agree to not donate sperm during 
the course of this study or for 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. 

New Section 15.9 Methods of Contraception Considered to be Effective.
Change 8: Update the description of the drug product.
The primary change occurs in Section 6.14 Packaging and Labeling:
Initial 
wording:
MLN4924 (MLN4924-003 Injection) 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.
Amended or 
new wording:
MLN4924 (MLN4924-003 Injectionconcentrate for solution for infusion) 
will be provided in 8 or 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.
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.


MLN4924
Clinical Study Protocol C15010 Amendment 1
138
The following sections also contain this change:

Section 6.12.1 MLN4924.

Section 6.13 Preparation, Reconstitution, and Dispensation.

Section 6.15 Storage, Handling, and Accountability.
Change 9: Update the investigator responsibilities for compliance with updated 
International Council for 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 the dose-limiting toxicity observed in Study C15003 
to be consistent with final data.
The primary change occurs in Section 1.3 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 the DLT observed in Study C15003 was updated to be consistent with the 
final data presented in the IB and clinical study report.


MLN4924
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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 Schedules of Events:  Cycle 13 and Beyond:  Arm 2 (as of Amendment 1) also 
contains this change.
Change 12: Clarify that if needed, a red blood cell transfusion must occur at least 1 day 
before study drug administration.
The primary change occurs in Section 6.7 Permitted Concomitant Medications and 
Procedures:
Added 
text:
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.
Rationale for Change:
The timing of transfusions was revised to the day before study drug administration. 
The following sections also contain this change:

Section 6.9 Guidance for Clinical Assessment and Management of Hemodynamic 
Compromise.

Section 6.10.4 Guidance for Clinical Assessment and Management of Anemia.
Change 13: Updated clinical laboratory evaluations.
The primary changes occurs in Section 7.4.15 Clinical Laboratory Evaluations:


MLN4924
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Description 
of Change:
A footnote was added to the Serum Chemistry parameters list to indicate that 
assessment of gamma glutamyl transferase is no longer required after 
completion of Cycle 12.
Footnotes were added to the Urinalysis With Microscopic Analysis parameters 
to indicate that assessment of ketones, bilirubin, urobilinogen, and glucose are 
no longer required after completion of Cycle 12.
A footnote was added to the Urine Safety Assessment to indicate that all 
assessments are no longer required after completion of Cycle 12.
Rationale for Change:
Assessment of gamma glutamyl transferase, ketones, bilirubin, urobilinogen, glucose, and 
urine safety assessments are no longer considered necessary for patients continuing beyond 
12 cycles of treatment.
Change 14: Remove statins, 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 6.6 Excluded Concomitant Medications and 
Procedures:
Description 
of Change
Statins, known BCRP substrates, moderate and strong inhibitors of CYP3A4, 
and inhibitors of P-gp were removed from the list of excluded concomitant 
medications in Table 6-4.


MLN4924
Clinical Study Protocol C15010 Amendment 1
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Rationale for Change:
Statins, known BCRP substrates, moderate and strong inhibitors of CYP3A4, and inhibitors 
of P-gp are no longer prohibited for MLN4924 therapy. In vitro hepatocyte studies 
demonstrated that the risk of an MLN4924-statin interaction is low. A review of the 
available PK information showed that individual daily systemic exposures of MLN4924 
were generally similar between statin users (atorvastatin and simvastatin) and non-statin 
users. As a result of these investigations, the MLN4924 clinical/safety team and the 
MLN4924 independent data monitoring committee endorsed the removal of the protocol 
restriction on statin use.
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 MLN4924 PK indicated that systemic exposures of MLN4924 following IV 
administration at 20 mg/m2 in the presence of itraconazole were similar to those in the 
absence of itraconazole. These data support removing strong CYP3A inhibitors and P-gp 
inhibitors from the list of prohibited concomitant medications in ongoing and planned 
MLN4924 clinical studies. The rationale for removing substrates of BCRP from excluded 
concomitant medications is based on an assessment of the drug-drug interaction potential of 
MLN4924. When viewed in the context of the MLN4924 mean Cmax 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 6.5, Dose-Modification Guidelines (Dose Delays, Dose Reductions, and Dose 
Interruptions); Table 6-3, Dose Modification Guidelines for Specific Toxicities.

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 1.5.1 Risks of MLN4924 Therapy:
Initial 
wording:
Additional information on risks is provided in the IB and the Safety 
Management Attachment to the IB.
Amended or 
new wording:
Additional information on risks is provided in the IB and the Safety 
Management Attachment Development Core Safety Information (DCSI) to 
the IB.
Rationale for Change:
The content of the Safety Management Attachment has been incorporated into the DCSI, 
which renders the Safety Management Attachment obsolete.


MLN4924
Clinical Study Protocol C15010 Amendment 1
142
Section 6.10 Management of Clinical Events also contain this change.
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 a internal safety 
working group throughout the conduct of the study.  These reviews will 
include a safety physician and clinical physician from the study team, as well 
as 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 
committee 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 and clinical 
physician Global Safety Lead from the study team, as well as other 
representation from other departments at Millennium such as 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 committee 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.


MLN4924
Clinical Study Protocol C15010 Amendment 1
143
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 MedComm Solutions (see below) and report the 
event. Whenever possible, the associated product should be maintained in 
accordance with the label instructions pending further guidance from a 
Millennium Quality representative.
For Product Complaints,
call MedComm Solutions at
877-674-3784 (877 MPI DRUG)
(US and International)
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 MedComm Solutions (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.
For Product Complaints,
call MedComm Solutions at
877-674-3784 (877 MPI DRUG)
(US and International)
Call Center
Phone Number
Email
Fax
Dohmen 
Life 
Science 
Services 
(DLSS)
1-844-662-8532
Non-toll-free 
number: 
1-510-740-1273
GlobalOncologyMedinfo@takeda.com 1-800-881-6092
Rationale for Change:
This contact information was updated to reflect an administrative change.


MLN4924
Clinical Study Protocol C15010 Amendment 1
144
Change 18: Update contact information for serious adverse event reporting.
The primary change occurs in Section 10.2 Procedures for Recording and Reporting 
Adverse Events and Serious Adverse Events:
Initial 
wording:
SAE Reporting Contact Information - North and South America
Amended or 
new wording:
SAE Reporting Contact Information - North and South America
Rationale for Change:
This contact information was updated to reflect an administrative change.
Change 19: Update the risks of MLN4924 therapy to be consistent with the current version 
of the Investigator’s Brochure (IB).
The primary changes occur in 1.5.1 Risks of MLN4924 Therapy:
Initial 
wording:
Safety information gained from 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 
Safety Management Attachment to the IB.
Based on preliminary findings from the ongoing clinical studies and the 
toxicities noted in the toxicology studies done in rats and dogs, the risks of 
MLN4924 treatment are presented below.  It is of note that the identified risks 
are based on clinical experience with many doses and schedules no longer being 
CCI
CCI


MLN4924
Clinical Study Protocol C15010 Amendment 1
145
studied.
Identified Risks

Neutropenia

Increased heart rate

Diarrhea

Nausea

Vomiting

Pyrexia

Liver function test (LFT) abnormal

Musculoskeletal pain

Renal failure (see additional information described in detail below)
Potential Risks

Multi-organ failure that could result in death.

Gastrointestinal (GI) toxicity including or resulting in dehydration, 
electrolyte imbalance, and/or GI bleeding.

Endocardial and cardiac vascular changes that could result in tachycardia, 
cardiac arrhythmias, decreased or increased systolic blood pressure, and 
increased diastolic blood pressure.

Acute phase response.

Myelosuppression with increased susceptibility to infection, bleeding, and 
anemia.

Hypophosphatemia.

Effects on the testes and ovaries that represent a reproductive hazard, 
including sterility.

Increased developmental risk to the fetus or embryo.

Myocardial degeneration and thrombosis.

Pulmonary hypertension.

Local tissue injury when administered SC.

Prolongation of the activated partial thromboplastin time (aPTT).

Decreased trabecular bone (graded minimal to moderate) was noted in the 
femur and in the sternum in rats at all dose groups (low, medium, high).  
This finding was considered adverse in the high-dose group; however, no 
bone fractures were noted at any of the doses.
A comprehensive review of the clinical trial safety data has shown that toxicities 
on Cycle 1 Day 1, including some events of renal failure with a fatal outcome, 
have been observed in all MLN4924 studies.  Based on the observation that 
initial doses of IV MLN4924 equal to or above 110 mg/m2 are associated with 
more severe AEs, including renal failure, the sponsor has determined that new 


MLN4924
Clinical Study Protocol C15010 Amendment 1
146
patients will receive MLN4924 at doses equal to or below 100 mg/m2.  The 
current understanding of the renal toxicity observed with MLN4924 suggests 
that it is not a primary event but is likely secondary to hemodynamic changes 
occurring in the setting of a type of acute phase response.
Multi-organ failure (including hepatic, renal, and/or cardiac) has been reported 
as an adverse drug reaction with a fatal outcome in patients who have received 
MLN4924 on Cycle 1 Day 1 at doses equal to or greater than 110 mg/m2.  In 
addition, a treatment-related death from multi-organ failure was reported in 
Study C15001 in a patient with breast cancer who received 5 consecutive daily 
doses of MLN4924 (Cycle 1 Day 5) at 61 mg/m2.  To mitigate the risk of multi-
organ failure, studies with MLN4924 doses equal to or greater than 110 mg/m2
are no longer being initiated in newly enrolled patients.  Additionally, a 
consecutive daily dosing schedule (Days 1-5) is no longer being used.  In this 
study, patients will be administered MLN4924 on a Day 1, 3, and 5 schedule at 
doses up to 50 mg/m2 or on a Day 1, 8, and 15 schedule at doses up to 100 
mg/m2.  Patients will be monitored closely for events of multi-organ failure after 
MLN4924 dosing.
Hepatotoxicity has been noted following administration of MLN4924 in patients 
with advanced malignancy, including elevations of liver transaminases, alkaline 
phosphatase (ALP), and bilirubin.  Liver enzymes and liver function are 
frequently monitored during clinical studies of MLN4924.  Agents such as 
acetaminophen and acetaminophen-containing products should not be 
administered to patients 24 hours before, the day of, and 24 hours after dosing 
with MLN4924 (see Section 6.6).
Patients must be carefully evaluated at screening and before each MLN4924 
dose for early symptoms and signs of hemodynamic compromise and/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 6.9. 
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 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 for these anticipated and potential toxicities 
and for unanticipated toxicities when they are receiving this agent and for at least 
30 days after their last dose.  Monitoring will include the following:  laboratory 
assessments, physical examinations, SAE and AE reporting, and safety review 
before each dose escalation (see Section 9.1).  In addition, an independent data 
monitoring committee (IDMC, see Section 9.2) is in place that will monitor the 
safety data from studies within the MLN4924 program.  Although therapeutic 
efficacy is a desired outcome of treatment with the study drugs, it is unknown 
whether patients will benefit from this study.  In this dose escalation study, the 
dose will be escalated by cohort.
To limit the risks to patients, the first patient enrolled at each dose level of 


MLN4924
Clinical Study Protocol C15010 Amendment 1
147
MLN4924 with SoC, as applicable, will be observed for 7 days before the 
remaining 2 patients of the cohort are treated.  These 3 patients will be observed 
through completion of the first cycle, before additional patients are treated at the 
next dose level.  The requirement for this 1-week wait period may be removed in 
subsequent cohorts if it is judged by the sponsor that combination therapy 
administered in a given arm may be administered without a major safety 
concern.
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).
Amended 
or new 
wording:
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 Development Core Safety Information (DCSI) Safety Management 
Attachment to the IB.
Based on preliminary findings from the ongoing 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.  It is of note that the identified risks 
are based on clinical experience with many doses and schedules no longer being 
studied.
Identified Risks

Neutropenia

Increased heart rate

Diarrhea

Nausea

Vomiting

Pyrexia

Liver function test (LFT) abnormal

Musculoskeletal pain

Myalgia Renal failure (see additional information described in detail 
below)
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. Patients will be monitored for these potential 
toxicities and for unanticipated toxicities for at least 30 days after their last 
dose of MLN4924.
Potential Risks From Phase 1 Studies (at High Doses)


MLN4924
Clinical Study Protocol C15010 Amendment 1
148
There are events that have been reported in phase 1 studies at doses and 
schedules substantially higher (≥110 mg/m2) than those being used in 
current clinical studies of MLN4924. These events are considered potential 
risks for the doses and schedules proposed in this study.

Multi-organ failure that could result in death.

Renal failure.
–
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. Refer to the current IB
for additional information about multi-organ failure and dosing.

Cardiac arrhythmias.
–
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 a risk factor for cardiovascular 
disease (uncontrolled hypertension).

Gastrointestinal (GI) toxicity including or resulting in dehydration, and
electrolyte imbalance, and/or GI bleeding.

Endocardial and cardiac vascular changes that could result in tachycardia, 
cardiac arrhythmias, decreased or increased systolic blood pressure, and 
increased diastolic blood pressure.

Acute phase response.

Myelosuppression with increased susceptibility to infection, bleeding, and 
anemia.

Hypophosphatemia.
Potential Risks Confounded by Underlying Disease or Malignancy
Events have been reported from clinical studies 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
–
All events were assessed by the investigator as unrelated; the 
majority occurred in the setting of thrombocytopenia.
Potential Risks Primarily Based on Findings From Animal Studies
Potential risks that are derived from findings in animal studies in rats and 
dogs include the following:


MLN4924
Clinical Study Protocol C15010 Amendment 1
149

Cardiovascular changes that could result in tachycardia, decreased or 
increased systolic blood pressure (BP), and increased diastolic BP.

Enteropathy (including dehydration and electrolyte loss) with 
secondary sepsis.

Effects on the testes and ovaries that represent a reproductive hazard, 
including sterility.

Increased developmental risk to the fetus or embryo.

Myocardial degeneration and thrombosis.

Pulmonary hypertension.

Local tissue injury when administered SC.

Prolongation of the activated partial thromboplastin time (aPTT).

Decreased trabecular bone (graded minimal to moderate) was noted in the 
femur and in the sternum in rats at all dose groups (low, medium, high), but 
not in dogs.  This finding was considered adverse in the high-dose group; 
however, no bone fractures were noted at any of the doses.
A comprehensive review of the clinical trial safety data has shown that toxicities 
on Cycle 1 Day 1, including some events of renal failure with a fatal outcome, 
have been observed in all MLN4924 studies.  Based on the observation that 
initial doses of IV MLN4924 equal to or above 110 mg/m2 are associated with 
more severe AEs, including renal failure, the sponsor has determined that new 
patients will receive MLN4924 at doses equal to or below 100 mg/m2.  The 
current understanding of the renal toxicity observed with MLN4924 suggests 
that it is not a primary event but is likely secondary to hemodynamic changes 
occurring in the setting of a type of acute phase response.
Multi-organ failure (including hepatic, renal, and/or cardiac) has been reported 
as an adverse drug reaction with a fatal outcome in patients who have received 
MLN4924 on Cycle 1 Day 1 at doses equal to or greater than 110 mg/m2.  In 
addition, a treatment-related death from multi-organ failure was reported in 
Study C15001 in a patient with breast cancer who received 5 consecutive daily 
doses of MLN4924 (Cycle 1 Day 5) at 61 mg/m2.  To mitigate the risk of multi-
organ failure, studies with MLN4924 doses equal to or greater than 110 mg/m2
are no longer being initiated in newly enrolled patients.  Additionally, a 
consecutive daily dosing schedule (Days 1-5) is no longer being used.  In this 
study, patients will be administered MLN4924 on a Day 1, 3, and 5 schedule at 
doses up to 50 mg/m2 or on a Day 1, 8, and 15 schedule at doses up to 100 
mg/m2.  Patients will be monitored closely for events of multi-organ failure after 
MLN4924 dosing.
It is possible that MLN4924 will have toxicities, which may be severe or 
fatal, that were not observed in or predicted from the studies completed in 
rats and dogs or have not yet been identified in patients.
Hepatotoxicity has been noted following administration of MLN4924 in patients 
with advanced malignancy, including elevations of liver transaminases, alkaline 


MLN4924
Clinical Study Protocol C15010 Amendment 1
150
phosphatase (ALP), and bilirubin.  Liver enzymes and liver function are 
frequently monitored during clinical studies of MLN4924.  Agents such as 
acetaminophen and acetaminophen-containing products should not be 
administered to patients 24 hours before, the day of, and 24 hours after dosing 
with MLN4924 (see Section 6.6).
Patients must be carefully evaluated at screening and before each MLN4924 
dose for early symptoms and signs of hemodynamic compromise and/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 6.9. 
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 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 for these anticipated and potential toxicities 
and for unanticipated toxicities when they are receiving this agent and for at least 
30 days after their last dose.  Monitoring will include the following:  laboratory 
assessments, physical examinations, SAE and AE reporting, and safety review 
before each dose escalation (see Section 9.1).  In addition, an independent data 
monitoring committee (IDMC, see Section 9.2) is in place that will monitor the 
safety data from studies within the MLN4924 program.  Although therapeutic 
efficacy is a desired outcome of treatment with the study drugs, it is unknown 
whether patients will benefit from this study.  In this dose escalation study, the 
dose will be escalated by cohort.
To limit the risks to patients, the first patient enrolled at each dose level of 
MLN4924 with SoC, as applicable, will be observed for 7 days before the 
remaining 2 patients of the cohort are treated.  These 3 patients will be observed 
through completion of the first cycle, before additional patients are treated at the 
next dose level.  The requirement for this 1-week wait period may be removed in 
subsequent cohorts if it is judged by the sponsor that combination therapy 
administered in a given arm may be administered without a major safety 
concern.
This trial will be conducted in compliance with the protocol, Good Clinical 
Practice (GCP), and the applicable regulatory requirements (including 
International Conference on Council for Harmonisation [ICH] guidelines).
Rationale for Change:
The language and content of this section were updated based on the current version of the 
IB.


MLN4924
Clinical Study Protocol C15010 Amendment 1
151
Change 20: Clarify the duration of gemcitabine administration per the prescribing 
information guidelines, as stated in Administrative Letter 1.
The primary change occurs in 6.1.5 Gemcitabine Administration: 
Initial 
wording:
Gemcitabine will be administered as a 1-hour IV infusion at a dose of 1000 
mg/m2 on Day 1 combined with escalating IV doses of MLN4924 on Days 1, 
8, and 15. Refer to the most recent prescribing information for further details 
regarding gemcitabine administration.
Amended or 
new wording:
Gemcitabine will be administered as a 1-hour 30- to 60-minute IV infusion at 
a dose of 1000 mg/m2 on Day 1 combined with escalating IV doses of before
MLN4924 on Days 1, 8, and 15 or per current prescribing guidelines. Refer 
to the most recent prescribing information for further details regarding 
gemcitabine administration.
Rationale for Change:
The prescribing information for gemcitabine dictates that gemcitabine can be given over 
various durations, therefore the text has been modified for clarity and to reflect study 
conduct.
The following sections also contain this change:

Protocol Summary.

Section 4.1 Overview of Study Design.
Change 21: Clarify the collection time points for the urine safety assessment at screening 
and Cycle 1 Day 1 (predose), as stated in Administrative Letter 2.
The primary change occurs in the Schedules of Events:  Cycle 1:  Arm 1 and Arm 2:
Description 
of change:
Footnote “e” was removed from the Urine Safety Assessment in the Cycle 1 
Day l assessment tables for all arms.
The following language in footnote “l” has been removed: (within 3 days of 
Cycle 1 Day 1). Footnote “l” now states: “Urine samples for safety 
assessments will be collected at screening; before any study drug dosing on 
Days 1, 3, and 5; and on Day 2. These samples will be analyzed at a central 
laboratory.”


MLN4924
Clinical Study Protocol C15010 Amendment 1
152
Rationale for Change: 
The collection time points for urine safety assessment at screening and Cycle 1 Day 1 are 
unclear because of footnotes “e” and “l”, which provide contradicting information. The 
intent of the protocol is to obtain 2 baseline urine safety assessments before dosing on Cycle 
1 Day l.
The Schedules of Events:  Cycle 1: Arm 3 also contains this change.


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PPD

SAP_000.pdf: 


• 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 1b, Open-Label, Dose Escalation, Multi-arm Study of MLN4924 Plus Docetaxel, 
Gemcitabine, or Combination of Carboplatin and Paclitaxel in Patients With Solid Tumors
NCT Number: NCT01862328
SAP Approve Date: 22 March 2016
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


PPD


PPD
only and subject to the applicable Terms o


MLN4924
Statistical Analysis Plan, Study C15010
NexDoc Template Version 1.4
3
TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.........................................5
1. INTRODUCTION............................................................................................................7
1.1 Study Design..............................................................................................................7
1.2 Study Objectives ......................................................................................................10
1.2.1 Primary Objectives ............................................................................................10
1.2.2 Secondary Objectives.........................................................................................10
1.2.3 Exploratory Objectives ......................................................................................10
2. POPULATIONS FOR ANALYSIS................................................................................11
2.1 Intent-to-Treat Population.........................................................................................11
2.2 Per-Protocol Population............................................................................................11
2.3 Response-Evaluable Population................................................................................11
2.4 Safety Population .....................................................................................................11
2.5 Pharmacokinetics Population....................................................................................11
2.6 Pharmacodynamics Population.................................................................................11
2.7 DLT Evaluable Population .......................................................................................12
3. HYPOTHESES AND DECISION RULES.....................................................................12
4. INTERIM ANALYSIS...................................................................................................12
5. STATISTICAL METHODOLOGY ...............................................................................12
5.1 Sample Size Justification..........................................................................................12
5.2 Randomization and Stratification..............................................................................13
5.3 Unblinding ...............................................................................................................13
5.4 Data Handling ..........................................................................................................13
5.4.1 Methods for Handling Missing Data...................................................................13
5.4.2 Definition of Baseline Values ............................................................................13
5.4.3 Windowing of Visits..........................................................................................14
5.4.4 Justification of Pooling ......................................................................................14
5.4.5 Withdrawals, Dropouts, Loss to Follow-up ........................................................14
5.5 Patient Disposition ...................................................................................................14
5.6 Demographics and Baseline Disease Characteristics.................................................14
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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MLN4924
Statistical Analysis Plan, Study C15010
NexDoc Template Version 1.4
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5.6.1 Demographics....................................................................................................14
5.6.2 Inclusion/Exclusion Criteria...............................................................................15
5.6.3 Medical History.................................................................................................15
5.6.4 Baseline Disease Status......................................................................................15
5.7 Treatments and Medications .....................................................................................19
5.7.1 Concomitant Medications ..................................................................................19
5.7.2 Study Treatments...............................................................................................20
5.8 Efficacy Analyses.....................................................................................................22
5.8.1 Primary Efficacy Endpoint.................................................................................24
5.8.2 Secondary Efficacy Endpoints ...........................................................................24
5.8.3 Other Efficacy Endpoints...................................................................................24
5.9 Pharmacokinetic and Biomarker Analysis.................................................................24
5.9.1 Pharmacokinetic Analyses .................................................................................24
5.9.2 Biomarker Analysis ...........................................................................................27
5.10 Safety Analyses ......................................................................................................27
5.10.1 Adverse Events................................................................................................27
5.10.2 Laboratory Data...............................................................................................33
5.10.3 Electrocardiograms ..........................................................................................35
5.10.4 Vital Signs .......................................................................................................36
5.10.5 Disseminated Intravascular Coagulation (DIC) and PT/PTT.............................37
5.10.6 Echocardiograms .............................................................................................37
5.10.7 Urine Safety Assessment..................................................................................38
6. CHANGES TO PLANNED ANALYSES FROM PROTOCOL .....................................39
7. PROGRAMMING CONSIDERATIONS .......................................................................39
7.1 Statistical Software...................................................................................................39
7.2 Rules and Definitions ...............................................................................................39
8. REFERENCES...............................................................................................................39
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE(s)
adverse event (or events)
ALT
Alanine aminotransferase (SGPT)
ANC
absolute neutrophil count
AST
Aspartate aminotransferase (SGOT)
AUC
Area under the plasma concentration-time curve
AUMC
Area under the first moment curve
BSA
body surface area
CKD-epi
chronic kidney disease epidemiology collaboration
Cmax
Maximum plasma concentration
CR
complete response
CRM
continual reassessment method
CT
computed tomography
CV
coefficient of variation
DBP
diastolic blood pressure
DIC
disseminated intravascular coagulation
DLT
dose limiting toxicity
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EOS
End of Study (visit)
FEK
Fractional Excretion of Potassium
FENA
Fractional Excretion of Sodium
FEPO4
Fractional Excretion of Phophate
GFR
glomerular filtration rate
HLT
high level term
IDMC
Independent Data Monitoring Committee
IV
intravenous
KIM-1
kidney injury molecule-1
LFT
liver function test
LLQ
limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NAE
NEDD8-activating enzyme
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NF-κB
Nuclear (transcription) factor-kappa B
PD
progressive disease
CCI
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PK
pharmacokinetic(s)
PMTD
predicted maximum tolerated dose
PR
partial response
PT
preferred term
PT/PTT
Prothrombin/partial thromboplastin times
QTcB
QT interval corrected for heart rate using Bazett’s formula
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RECIST
Response Evaluation Criteria in Solid Tumors
SAP
statistical analysis plan
SAE
serious adverse event
SBP
systolic blood pressure
SD
stable disease
SOC 
system organ class
t1/2
half-life   
TAD
time after dosing
Vss
volume of distribution at steady state   
WHO
World Health Organization
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1.   
INTRODUCTION
In general, the purpose of the statistical analysis plan (SAP) is to provide a framework that 
addresses the protocol objectives in a statistically rigorous fashion, with minimized bias or 
analytical deficiencies.  Specifically, this plan has the following purpose:
To prospectively (a priori) outline the types of analyses and data presentations that will 
address the study objectives outlined in the protocol, and to explain in detail how the data 
will be handled and analyzed, adhering to commonly accepted standards and practices of 
biostatistical analysis in the pharmaceutical industry.
1.1   
Study Design
This is an open-label, multicenter, phase 1b, dose-escalation study of MLN4924 in 
combination with docetaxel, paclitaxel and carboplatin, or gemcitabine in adult patients with 
solid tumors.  The study includes a carboplatin lead-in phase where subjects receive 
MLN4924 + carboplatin only.   The patient population will consist of patients 18 years of 
age or older with nonhematologic malignancies who, according to the investigator’s medical 
judgment, could potentially benefit from treatment with any of the 3 standard of care
therapies being studied.
It is expected that approximately 69 patients will be enrolled in this study.  During the dose 
escalation portion of this study, the following dose levels of intravenous (IV) MLN4924 are 
planned to be studied in combination with docetaxel (Arm 1), paclitaxel + carboplatin (Arm 
2), or gemcitabine (Arm 3).
MLN4924 + Docetaxel (Arm 1):  A total of 4 dose levels of IV MLN4924 (15, 25, 37, and 
50 mg/m2) are planned to be studied in combination with 75 mg/m2 of docetaxel.  On Day 1 
of each cycle when both drugs are administered, docetaxel will be administered first at a 
dose of 75 mg/m2 IV over 1 hour.  After a mandatory approximately15-minute time out
(MLN4924-free period), MLN4924 will be administered IV.   On Days 3 and 5, only 
MLN4924 will be given.  The duration of each cycle will be 21 days.  No dose reduction of 
MLN4924 below 15 mg/m2 is allowed.
MLN4924 + Carboplatin Lead-in Phase (before Arm 2):  Before patients are enrolled in 
Arm 2 with paclitaxel + carboplatin, a cohort of approximately 3 to 6 patients will be treated 
with AUC6 dose of carboplatin in combination with MLN4924 at a dose of 15 mg/m2.  On 
Day 1 of each cycle, both compounds will be given.  On Days 3 and 5, only MLN4924 will 
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Statistical Analysis Plan, Study C15010
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be given.  The duration of each cycle will be 21 days.  If 1 dose limiting toxicity (DLT) is 
seen in this cohort, 3 additional patients will be treated with the same combination regimen.  
The carboplatin dose may be reduced to AUC5 for safety as needed.  No dose reduction of 
MLN4924 below 15 mg/m2 is allowed.  No dose escalation of MLN4924 is planned in this 
cohort.  The only chemotherapy agent that patients in this lead-in cohort will receive is 
carboplatin; these patients will not enroll on the MLN4924 + paclitaxel + carboplatin phase 
(Arm 2).
Observing no more than 1 DLT in this lead-in cohort will trigger enrollment in Arm 2 at 
AUC6 (MLN4924 [15 mg/m2] + paclitaxel [200 mg/m2] + carboplatin [AUC6]), and 
patients will be treated as described below for Arm 2.
If a total of 2 or more DLTs are observed in this cohort, enrollment on Arm 2 will open at
reduced paclitaxel and carboplatin doses (MLN4924 [15 mg/m2] + paclitaxel [175 mg/m2] + 
carboplatin [AUC5]), and patients will be treated as described below for Arm 2.
MLN4924 + Paclitaxel + Carboplatin (Arm 2):  During the dose escalation phase, a total of 
4 dose levels of IV MLN4924 (15, 25, 37, and 50 mg/m2) are planned to be studied in 
combination with paclitaxel and carboplatin.  On Day 1 of each cycle when all 3 drugs are 
administered, paclitaxel is given first at a dose of 200 mg/m2 (or 175 mg/m2, if the dose was 
reduced in the carboplatin lead-in cohort) IV over 3 hours followed by carboplatin AUC6 
(or AUC5 if the dose was reduced in the carboplatin lead-in cohort) over 30 minutes.  After 
a mandatory approximately 15-minute time out (MLN4924-free period) 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.  
MLN4924 + Gemcitabine (Arm 3):  A total of 4 dose levels of IV MLN4924 (25, 50, 75, 
and 100 mg/m2) are planned to be studied in combination with 1000 mg/m2 of gemcitabine.  
Gemcitabine will be administered IV at a dose of 1000 mg/m2 over 30 to 60 minutes, or as 
per current prescribing guidelines.  After a 15-minute time out, MLN4924 will be 
administered.  Patients will receive both agents on Days 1, 8, and 15, and the duration of 
each cycle will be 28 days.
After the determination of the maximum tolerated dose (MTD) of MLN4924 with docetaxel 
(Arm 1), paclitaxel + carboplatin (Arm 2), and gemcitabine (Arm 3), approximately 6 
additional patients will be enrolled to each arm for a total of approximately 12 patients 
treated in each arm at the MTD to more fully characterize the safety, tolerability, and 
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pharmacokinetics (PK) of MLN4924 in combination with each standard of care regimen and 
to evaluate disease response.
An adaptive approach using a continual reassessment method (CRM) will be used for dose 
escalation (not including the Carboplatin lead-in). The CRM models the relationship 
between toxicities and dose level, which yields accurate and precise estimates of the MTD (1, 
2, 3). The dose toxicity relationship and the predicted MTD (PMTD) level will be updated as 
new data become available. The recommendation to escalate, de-escalate, or expand at the 
same dose level will be determined by comparing the PMTD level from the dose toxicity 
model to the prespecified dose levels. From the starting dose, subsequent increases in dose 
will be made according to the dose levels indicated for each arm; however, for safety 
reasons, no dose level will be skipped, and a minimum of 3 patients is required before 
escalating to the next dose level. Once at least 6 patients are treated at any dose level and the 
algorithm does not recommend escalation or de-escalation, this dose level may be 
considered the MTD.
Toxicity will be evaluated according to National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), Version 4.03, effective date 14 June 2010 (4).  
DLTs are defined in Section 6.3.
Throughout the study, Eastern Cooperative Oncology Group (ECOG) performance status 
and adverse events (AEs) will be assessed, and laboratory values, vital signs, and 
electrocardiograms (ECGs) will be obtained and assessed to evaluate the safety and 
tolerability of MLN4924 in combination with docetaxel, paclitaxel + carboplatin, and 
gemcitabine (patients in the carboplatin lead-in cohort will receive MLN4924 + carboplatin 
only).
Blood samples (sparse sampling) for the determination of MLN4924 plasma concentrations 
and, if appropriate, its metabolites will be collected from each patient during Cycle 1 of 
treatment to contribute to a population PK analysis of MLN4924 co-administered with 
docetaxel, or paclitaxel + carboplatin, or gemcitabine. 
Computed tomography (CT) scans with IV contrast of the chest, abdomen, and pelvis will 
be performed during screening. CT scans with IV contrast encompassing the known sites of 
disease will be performed at the end of Cycle 2 and then every other cycle thereafter, and at 
the End of Study (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 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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assessed by the investigator at these times using the Response Evaluation Criteria in Solid 
Tumors (RECIST), version 1.1 (5).
1.2   
Study Objectives
1.2.1   Primary Objectives
!
To establish the MTD and assess the safety and tolerability of MLN4924 in 
combination with docetaxel in patients with solid tumors
!
To establish the MTD and assess the safety and tolerability of MLN4924 in 
combination with paclitaxel and carboplatin in patients with solid tumors
!
To establish the MTD and assess the safety and tolerability of MLN4924 in
combination with gemcitabine in patients with solid tumors   
1.2.2    Secondary Objectives
!
To evaluate disease response that may be observed with the combination of 
MLN4924 and docetaxel
!
To evaluate disease response that may be observed with the combination of 
MLN4924, paclitaxel, and carboplatin
!
To evaluate disease response that may be observed with the combination of 
MLN4924 and gemcitabine
!
To measure plasma MLN4924 concentrations to contribute to a population PK 
analysis of MLN4924 co-administered with docetaxel, or paclitaxel + carboplatin, or 
gemcitabine in patients with solid tumors
1.2.3   Exploratory Objectives
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2.   
POPULATIONS FOR ANALYSIS
2.1   
Intent-to-Treat Population
Not applicable for a phase 1 study.
2.2   
Per-Protocol Population
Not applicable for a phase 1 study.
2.3   
Response-Evaluable Population
The response-evaluable population is defined as all patients who receive at least 1 dose of 
MLN4924, have measurable disease at baseline, and have at least 1 post baseline disease 
assessment.  For the purposes of this study, all patients will be assumed to have measurable 
disease at baseline.  
Response analyses will be performed using the response-evaluable population.
2.4   
Safety Population
The safety population is defined as all patients who receive at least 1 dose of any study drug.
All safety analyses will be performed using the safety population.
2.5   
Pharmacokinetics Population
Not applicable for this study.
2.6       Pharmacodynamics Population
Not applicable for this study.
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2.7   
DLT Evaluable Population
The DLT-Evaluable population is defined as all patients who either experience DLT during 
Cycle 1 or receive all scheduled doses of study drug on scheduled days during Cycle 1 
without DLT. Patients in Arm 3 will still be considered DLT evaluable if they receive all 
doses of MLN4924 and receive gemcitabine on Days 1 and 8 only or on Days 1 and 15 only. 
3.   
HYPOTHESES AND DECISION RULES
Not applicable for a phase I study.
4.   
INTERIM ANALYSIS
As this is a phase I 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 Monitor Committee (IDMC).   
5.   
STATISTICAL METHODOLOGY
Analyses will be primarily descriptive in nature. No formal statistical tests will be 
performed. Summary tabulations will be presented that display the number of observations, 
mean, standard deviation, median, minimum, and maximum for continuous variables, and 
the number and percent (calculated using non-missing values) per category for categorical 
data, unless specified otherwise.
Due to the use of the CRM methodology for dose escalation, at a minimum, three patients 
will be dosed at any given dose level.  Data may be pooled across dose levels for summary 
purposes.   When appropriate, data will be summarized for the pooled dose levels below the 
MTD, at MTD, and for all patients.   Data from each drug may be summarized separately.  
Patients will be analyzed at the dose level to which they were originally assigned, including 
those who receive subsequent treatment at a lower dose level.
5.1   
Sample Size Justification
It is anticipated that approximately 69 patients will be enrolled combining the dose
escalation for the determination of MTD for each combination, the cohort expansion at each
MTD, and estimating approximately 6 patients enrolled in the carboplatin lead-in cohort.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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Based on an estimated toxicity rate of 25% at 50 mg/m2 in Arms 1 and 2 and at 100 mg/m2
in Arm 3, computer simulations estimate that approximately 15 patients will be enrolled in 
each arm to determine the MTD of MLN4924 with standard of care.
Once each MTD is determined, approximately 6 additional patients (MTD expansion
cohort) will be enrolled in each arm such that a total of approximately 12 patients will be
enrolled and treated at each MTD to more fully characterize the safety, tolerability, and PK
of MLN4924 with standard of care. These enrollment rules are based on the binomial 
probability assumption that if a particular toxicity occurs in 12.5% of the entire patient 
population, there is an 80% probability of observing at least 1 occurrence of that toxicity in 
12 patients.
5.2   
Randomization and Stratification
As this is a phase 1 study using a CRM algorithm to allocate patients to each dose level, 
there is no randomization in this study.  Patients will be assigned to a treatment arm based 
on investigator judgment.
5.3   
Unblinding
As this is an open-label study, no unblinding methodology is required.
5.4   
Data Handling
5.4.1   
Methods for Handling Missing Data
All available efficacy and safety data will be included in data listings and tabulations.  No 
imputation of values for missing efficacy and safety data will be performed.  Data that are 
potentially spurious or erroneous will be examined according to standard data management 
operating procedures. MLN4924 concentration values missing the corresponding sampling 
date and time records will be excluded from PK analysis.
5.4.2   
Definition of Baseline Values
Unless otherwise specified, for each safety parameter, the baseline value is defined as the 
value collected at the time closest to, but prior to, the start of study drug administration.  For 
the analysis of ECG data and urine safety data (e.g. Kidney Injury Molecule-1 (KIM-1)), the 
baseline value is the average of the screening and Cycle 1 Day 1 predose values, if both are 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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available. For KIM-1 only, the screening value will be within 3 days of the Cycle 1 Day 1 
dose.
5.4.3   
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 post dose.
5.4.4   
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.
5.4.5   
Withdrawals, Dropouts, Loss to Follow-up
Patients in the escalation phase who are withdrawn from treatment during Cycle 1 for 
reasons other than DLT will be replaced. Generally no additional patients will be enrolled 
due to withdrawals, dropouts, or loss to follow-up.    
5.5   
Patient Disposition
A tabulation of patient disposition data will include the number of patients for the following 
categories: patients treated (safety population), patients in the DLT-evaluable population, 
patients in the response-evaluable population, and patients discontinued from the study. The 
primary reason for study treatment discontinuation will also be summarized in this table.  
All data will be summarized by each arm and MLN4924 dose level.  Percentages will be 
based on the number of patients in the safety population, and they will be calculated for 
MTD, and the study total.
Data concerning patient disposition (eg reason for study termination, patient population) will 
be presented in by-patient listings.  
5.6   
Demographics and Baseline Disease Characteristics
5.6.1   
Demographics
Baseline demographics will be summarized separately for patients in the safety population
by each arm and MLN4924 dose level.  Baseline demographic data to be evaluated will 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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include age at date of informed consent, sex, ethnicity, race, height, weight and body surface 
area (BSA).   BSA is calculated by the Sponsor (or its designee) using the following formula 
based on the patient’s height and weight at baseline:
       BSA = 
No inferential statistics will be generated.
Demographic data will also be presented in a by-patient listing.
5.6.2   
Inclusion/Exclusion Criteria
All inclusion/exclusion information on enrolled patients will be included in a by-patient 
listing.  The listing 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 in the clinical trial management system will be reviewed, 
and significant protocol deviations will be identified and summarized 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.
5.6.3   
Medical History
5.6.3.1   General Medical History
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). 
5.6.3.2   Disease-Specific History
Not applicable for this study.
5.6.4   
Baseline Disease Status
Baseline disease characteristics (disease type, disease stage, sites of involvement, time since 
initial diagnosis) will be summarized separately for patients in the safety population by each 
3600
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Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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.6.3.2
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arm and MLN4924 dose level.  ECOG performance status will be summarized similarly in 
the same table.  Separate by-patient listings will also be presented for baseline disease 
characteristics and ECOG performance status.  
Information on prior therapies will be summarized separately for patients in the safety 
population by each arm and MLN4924 dose level (where applicable).  For each arm and 
MLN4924 dose level (where applicable), summarized information on prior therapies will 
include:
!
Number of patients with prior antieoplastic therapy
!
Months from last dose of prior chemotherapy to first dose
!
Number of patients with prior radiation
!
Months from last prior radiation to first dose
!
Number of patients with prior surgery or non-radiation procedures
In addition, prior chemotherapy regimens will be tabulated by MLN4924 dose level for each
study arm.  A second tabulation will summarize the following:
!
Percentage of patients in Arm 1 (MLN4924+Docetaxel) receiving any taxane-
containing regimen prior to dosing in MLN4924
!
Percentage of patients in Arm 2 Lead-In (MLN4924+Carboplatin) receiving any 
platinum-containing regimen prior to dosing in MLN4924
!
Percentage of patients in Arm 2 (MLN4924+ Paclitaxel+Carboplatin) receiving any 
regimen containing a taxane but not a platinum prior to dosing in MLN4924
!
Percentage of patients in Arm 2 (MLN4924+ Paclitaxel+Carboplatin) receiving any 
regimen containing a platinum but not a taxane prior to dosing in MLN4924
!
Percentage of patients in Arm 2 (MLN4924+ Paclitaxel+Carboplatin) receiving any 
regimen containing both a platinum and a taxane prior to dosing in MLN4924
!
Percentage of patients in Arm 3 (MLN4924+Gemcitibine) receiving any 
gemcitibine-containing regimen prior to dosing in MLN4924
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
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
y
and
nd
es 
es wil
will
se
se
ry or no
or n
y
will
ill b
l e ta
e
mmariz
mari
n Ar
Arm
or to dos
r to d
nts 
ts inin A
ning regi
ng reg
pati
atient
en
ontaining
ainin
age
ge of
of p
f
men
en cont
con
ercentag
ercenta
regimen
egim
!
Perc
Per
g
Th
T


MLN4924
Statistical Analysis Plan, Study C15010
NexDoc Template Version 1.4
17
CAPECITABINE+DOCETAXEL
CAPECITABINE+PACLITAXEL 
CARBOPLATIN+PACLITAXEL 
CARBOPLATIN+PACLITAXEL+TRASTUZUMAB 
CISPLATIN+DOCETAXEL 
CISPLATIN+DOCETAXEL+FLUOROURACIL 
CISPLATIN+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
PACLITAXEL+TRASTUZUMAB
Platinum-containing 
regimens
BEVACIZUMAB+CARBOPLATIN+PACLITAXEL 
BEVACIZUMAB+CISPLATIN+DOCETAXEL 
BEVACIZUMAB+CISPLATIN+PACLITAXEL 
CAPECITABINE+CISPLATIN 
CAPECITABINE+CISPLATIN+EPIRUBICIN 
CAPECITABINE+EPIRUBICIN+OXALIPLATIN 
CAPECITABINE+OXALIPLATIN 
CARBOPLATIN (PARAPLATIN-AQ) 
CARBOPLATIN+ETOPOSIDE 
CARBOPLATIN+FLUOROURACIL
CARBOPLATIN+PACLITAXEL 
CARBOPLATIN+PACLITAXEL+TRASTUZUMAB 
CETUXIMAB+CISPLATIN+VINBLASTINE 
CETUXIMAB+CISPLATIN+VINORELBINE 
CISPLATIN (PLATINOL) 
CISPLATIN+DOCETAXEL 
CISPLATIN+DOCETAXEL+FLUOROURACIL 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
OXORU
OXOR
IN+PA
N+PA
ACIL 
CIL
TAXEL
AXEL
ACLITA
CLITA
ACLIT
ACLI
(A
(AB
ON; APO
N; A
AXEL
XEL+
ms
tinum
num-co
re
ACIZU
ACIZU
BEVAC
EVA
BEV
BE
C
se
f T
me


MLN4924
Statistical Analysis Plan, Study C15010
NexDoc Template Version 1.4
18
CISPLATIN+EPIRUBICIN+FLUOROURACIL 
CISPLATIN+ETOPOSIDE 
CISPLATIN+FLUOROURACIL 
CISPLATIN+FLUOROURACIL+LEUCOVORIN 
CALCIUM 
CISPLATIN+GEMCITABINE 
CISPLATIN+IRINOTECAN 
CISPLATIN+PACLITAXEL 
CISPLATIN+PEMETREXED 
CISPLATIN+VINBLASTINE 
FLUOROURACIL+LEUCOVORIN 
CALCIUM+OXALIPLATIN 
FLUOROURACIL+OXALIPLATIN
OXALIPLATIN (ELOXATIN)
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
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 
CARBOPLATIN+FLUOROURACIL 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
LATIN
ATIN
TIN)
TIN)
ms
m
CLITAX
LITAX
DOCET
OCE
NE+PAC
+PA
OSPHA
SPH
PHOSP
HOS
CLOPHO
LOPH
DOCETA
DOCE
DOC
DO
D
bje
me
ke
f T


MLN4924
Statistical Analysis Plan, Study C15010
NexDoc Template Version 1.4
19
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
Gemcitibine-containing 
regimen
CISPLATIN+GEMCITABINE
GEMCITABINE (GEMZAR)
GEMCITABINE+PACLITAXEL
5.7   
Treatments and Medications
5.7.1   
Concomitant Medications
All concomitant medications will be mapped to generic terms according to the World Health
Organization (WHO) drug dictionary.  The number and percentage of patients in the safety 
population taking concomitant medications will be tabulated by WHO drug generic term. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
ORIN 
ORIN 
IN 
IN 
XALIPL
ALIPL
ELOXAT
OXA
ms
AB+CAR
B+CA
UMAB+
MAB
IZUMA
ZUM
RBOPLA
BOPL
CARBO
ARB
CISP
CIS
C
nd
me
containin
ontai
gimen
imen
c
F
5.7
5.7
5


MLN4924
Statistical Analysis Plan, Study C15010
NexDoc Template Version 1.4
20
Tabulations will be performed for patients in the safety population by MLN4924 dose level 
in each arm.  Concomitant procedures will not be coded.
Concomitant medications and procedures will be presented in separate by-patient listings.
5.7.2   
Study Treatments
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 approximately15-
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 the Arm 2 Lead-In Phase (MLN4924 + Carboplatin), patients will be treated with AUC6 
dose of carboplatin in combination with MLN4924.  On Day 1 of each cycle, both 
compounds will be given.  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 200 mg/m2 (or 175 
mg/m2, if the dose was reduced in the carboplatin lead-in cohort) IV over 3 hours followed 
by carboplatin AUC6 (or AUC5 if the dose was reduced in the carboplatin lead-in cohort)
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.  
For Arm 3 (MLN4924 + Gemcitabine), patients will be administered gemcitibine at a dose 
of 1000 mg/m2 IV over 30-60 minutes.  After a mandatory approximately15-minute time 
out, MLN4924 will be administered.  Patients will receive both agents on Days 1, 8, and 15, 
and the duration of each cycle will be 28 days.
All dosing information for each visit will be presented in a by-patient listing.
5.7.2.1   Extent of Exposure
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 dose level to which patients were initially assigned, as well as 
for all patients. Patients will be considered to have been treated for a cycle if they receive at 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
e of 
of
elyly15-
15-
y MLN49
MLN4
will be tr
will be
of
of each 
ea
f
24 will b
4 will
), pati
pat en
iven firs
en fir
boplat
oplatin
dose
ose w
ry
ry appro
appr
be adm
be adm
each cyc
ach c
24 + G
+ Gem
V over 
over 3
24 will b
will
uration o
uration
dosing 
osing
5.7.2
5.7.


MLN4924
Statistical Analysis Plan, Study C15010
NexDoc Template Version 1.4
21
least one dose of MLN4924 during the 21 (or 28) days of that cycle.  Percentages will be 
calculated by dose level and for all the patients.  
The mean number of doses per cycle will be calculated for each patient and summarized for 
each dose level and total for the arm.
For MLN4924, Percent Dosing Intensity will be calculated using the following equations for 
Daily Expected Dose (mg), Daily Prepared Dose (mg), and Daily Dose Received (mg):  
##
∃
%
&&
∋
(
)
)
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
Daily Expected Dose and Daily Prepared Dose may differ if there are dose decreases.  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 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 Dosing Intensity for MLN4924 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
ed
administer
 was
MLN4924
 that 
days
all
across
Received
Dose
Daily 
of
Sum
Received
Dose
Total
)
)
)
Total dose expected will be calculated based on the BSA measured at baseline.  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 dose level, as 
well as for all patients.
For each of the standard of care drugs, the extent of exposure will be summarized in a 
similar manner as MLN4924.  A separate column will be generated for each dose level of 
MLN4924, and the number of cycles of standard of care drug administered will be 
summarized. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
ons for 
ons for 
mg): 
mg):
he
me
(mL
(mL
used
sed
(m
(m
Area
Area
2
if th
there
e
ic case
cas
cal
calculat
cula
5% 
% chan
ch
xpected,
pected
o
T
Total
Tot
ity y 
Expect
Expec
y 
Do
D
Daily 
Daily 
)
expected
xpecte
reases
eases
nsisity
ty
i , 80
, 8
well as f
well as 
Fo
F


MLN4924
Statistical Analysis Plan, Study C15010
NexDoc Template Version 1.4
22
The mean number of doses per cycle will be calculated for each patient and summarized by
dose levels and the study total.
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
          
in)
(Carboplat
Dose
Prepared
Daily 
)
(m
Area
Surface
Body 
*
)
(mg/m
Level
Dose
Scheduled
          
)
Paclitaxel
and
e,
Gemcitibin
,
(Docetaxel
Dose
Prepared
Daily 
25)
rate
filtration
r 
(Glomerula
*
)
(AUC
Entry 
Study 
at 
Assigned
Level
Dose
          
=
in)
(Carboplat
Dose
Expected
Daily 
)
(m
Area
Surface
Body 
*
)
(mg/m
Entry 
Study 
at 
Assigned
Level
Dose
          
=
)
Paclitaxel
and
e,
Gemcitibin
,
(Docetaxel
Dose
Expected
Daily 
2
2
2
2
Dosing intensity for each standard of care drug will be summarized by MLN4924 dose level 
in a similar manner to MLN4924 dosing intensity.
5.7.2.2   Treatment Compliance and Modifications
The actions on study drugs (Dose Held, Dose Reduced, Dose Interrupted, Dose Delayed, 
Dose Incomplete, or Discontinued) will be summarized by MLN4924 dose level for 
MLN4924 and each standard of care drug.  Data will be summarized for Cycle 1 only as 
well as all cycles combined.  A patient will count only once for each type of action.  
5.8   
Efficacy Analyses
Since this is a phase I study, 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], and 
progressive disease [PD]) will be presented for each dose level.  Percentages will be 
calculated for all patients, and those at the MTD. All evaluations of response will be 
conducted using the response-evaluable population.
d s
∗
∗
Prepa
Pre
ac
bag
bag
IV
25)
25)
tete
25)
5)
drug
rug wi
w
ng intens
inten
nce and 
nce and
(Dose 
(Dose
iscont
scontini
h standa
stand
es co
comb
m
Efficacy 
fficacy
nce this i
ce this
overall
overa
wil
w


MLN4924
Statistical Analysis Plan, Study C15010
NexDoc Template Version 1.4
23
For each patient in the expansion cohorts, 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 across MTD expansion patients in each 
arm.  Unscheduled visits will also be included in such displays.
The duration of disease response (CR or PR) and the duration of CR will be presented in a 
by-patient listing for all response-evaluable patients with CR or PR.  Duration of response 
(or duration of CR) are the time, in both days and months, from the date of first documented 
response (or CR) per the investigator response assessment to the date of first documentation 
of PD after the first documented response (or CR), or the date of last disease assessment if 
the patient discontinues treatment before PD. In addition, the date of first response, the date 
of first CR, the date of first documentation of PD after the first response, the number of 
cycles of response, and the number of cycles of CR will be shown. The duration of response
(in months), the duration of CR (in months), the number of cycles of response, and the 
number of cycles of CR will also be summarized descriptively at each dose level of 
MLN4924 for all response-evaluable patients. The same table will also summarize the time 
to first response and time to first CR.  Separate summaries will be generated for each arm of 
the study.  
The duration of SD or better will be presented in a by-patient listing for all response-
evaluable patients.  Duration of SD or better is the time from the date of first dose to the date 
of first documentation of PD, 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 at each dose level of MLN4924 for all 
response-evaluable patients. Separate summaries will be generated for each arm of the 
study.  
A separate listing will be generated for patients who are on treatment for at least 5 cycles. 
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.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
a
onse
onse
ocument
cume
ocumen
cume
se asses
e asse
rst re
t resp
sp
ponse
onse, th
wn. 
wn. The
Th
cycles o
cycles
ptively 
ively
same tab
same t
summari
umma
resented
esente
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or be
r th
the da
e d
ore PD
e PD
documen
ocum
tion of 
on of S
be summ
e sum
aluable
uabl
separate
epara
This li
This 
did


MLN4924
Statistical Analysis Plan, Study C15010
NexDoc Template Version 1.4
24
5.8.1   
Primary Efficacy Endpoint
Not applicable for this study.
5.8.2   
Secondary Efficacy Endpoints
Not applicable for this study.
5.8.3   
Other Efficacy Endpoints 
Not applicable for this study.
5.9   
Pharmacokinetic and Biomarker Analysis
5.9.1   
Pharmacokinetic Analyses
Blood samples (~ 3 mL each) will be collected at the following time points:
Patients in Dose Escalation (Arms 1 and 2)  
!
Day 1:
o
Within 1 hour before the start of MLN4924 infusion
o
At the end of the MLN4924 infusion (immediately before switching off the
infusion pump)
o
At 1.5 hours (+ 15 minutes) and 3 hours (+ 30 minutes) after completion of 
the MLN4924 infusion
!
Day 2:  
o
20 hours (+ 2 hours) after end of MLN4924 Cycle 1, Day 1 infusion
!
Day 3:  Within 10 minutes before the start of the MLN4924 infusion
Patients in Dose Escalation (Arm 3)  
!
Day 1:
o
Within 1 hour before the start of MLN4924 infusion
o
At the end of the MLN4924 infusion (immediately before switching off the
infusion pump)
o
At 1.5 hours (+ 15 minutes) and 3 hours (+ 30 minutes) after completion of 
the MLN4924 infusion
!
Day 2:  
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
owing ti
wing 
start of 
art o
LN4924
N492
(+ 15
15 m
924 infu
4 inf
hours (
hours
: Wit
Withih
nts in Do
s in D
da
!


MLN4924
Statistical Analysis Plan, Study C15010
NexDoc Template Version 1.4
25
o
20 hours (+ 2 hours) after end of MLN4924 Cycle 1, Day 1 infusion 
Patients in MTD Expansion (Arm 1)  
!
Day 1:
o
Within 1 hour before the start of MLN4924 infusion
o
At the end of the MLN4924 infusion (immediately before switching off the
infusion pump)
o
At 1.5 hours (+ 15 minutes), 3 hours (+ 30 minutes), and 7 hours (+ 45
minutes) after completion of the MLN4924 infusion
!
Day 2:  
o
20 hours (+ 2 hours) after end of MLN4924 Cycle 1, Day 1 infusion
!
Day 3:  Within 10 minutes before the start of the MLN4924 infusion
!
Day 5:
o
Within 10 minutes before the start of MLN4924 infusion
o
At the end of the MLN4924 infusion (immediately before switching off the
infusion pump)
o
At 1.5 hours (+ 15 minutes), 3 hours (+ 30 minutes), and 7 hours (+ 45
minutes) after completion of the MLN4924 infusion
!
Day 6:
o
20 hours (+ 2 hours) after end of MLN4924 Cycle 1, Day 5 infusion
Patients in MTD Expansion (Arm 2)  
!
Day 1:
o
Within 1 hour before the start of MLN4924 infusion
o
At the end of the MLN4924 infusion (immediately before switching off the
infusion pump)
o
At 1.5 hours (+ 15 minutes), 3 hours (+ 30 minutes), and 6 hours (+ 45
minutes) after completion of the MLN4924 infusion
!
Day 2:  
o
20 hours (+ 2 hours) after end of MLN4924 Cycle 1, Day 1 infusion
!
Day 3:  Within 10 minutes before the start of the MLN4924 infusion
!
Day 5:
o
Within 10 minutes before the start of MLN4924 infusion
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
g off 
off th
th
7 hours
hou
1, Day
 Day 1
y
N4924 in
4924 i
MLN492
LN49
sion (i( m
tes),
es), 3 h
on o
n of th
the
our
urs) aft
s) a
nsio
sion (A
(
m
Wit
With
o
A


MLN4924
Statistical Analysis Plan, Study C15010
NexDoc Template Version 1.4
26
o
At the end of the MLN4924 infusion (immediately before switching off the
infusion pump)
o
At 1.5 hours (+ 15 minutes), 3 hours (+ 30 minutes), and 6 hours (+ 45
minutes) after completion of the MLN4924 infusion
!
Day 6:
o
20 hours (+ 2 hours) after end of MLN4924 Cycle 1, Day 5 infusion
Patients in MTD Expansion (Arm 3)  
!
Day 1:
o
Within 1 hour before the start of MLN4924 infusion
o
At the end of the MLN4924 infusion (immediately before switching off the
infusion pump)
o
At 1.5 hours (+ 15 minutes), 3 hours (+ 30 minutes), and 7 hours (+ 45
minutes) after completion of the MLN4924 infusion
!
Day 2:  
o
20 hours (+ 2 hours) after end of MLN4924 Cycle 1, Day 1 infusion
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.
All individual MLN4924 concentration-time data will be pooled to describe the population 
PK of MLN4924. As data permit, a nonlinear regression mixed effects model (NONMEM
software) will be used to assess MLN4924 exposure when administered in combination with 
docetaxel, or carboplatin/paclitaxel, or gemcitabine. Individual metabolite data may also be 
assessed, as deemed appropriate. If appropriate, historical data may be used in this analysis 
to increase the robustness of the model and precision of estimated PK parameters and 
compare with single agent data. Details of the modeling approach will be provided in a 
separate analysis plan, and the results of these analyses will be reported separately.
Plasma concentration values below the lower limit of quantification (<LLQ) of the 
bioanalytical assay will be set to zero for analysis. Actual PK sampling collection 
dates/times will be used in the analysis. 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.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
ly befor
befo
30 min
mi
24 infus
4 infu
f MLN4
MLN
collectio
ollec
accurate
curat
mes that o
es that 
concentr
oncen
data perm
ta pe
used to a
d to 
arboplat
rbopla
s deeme
deem
ase the
se the
mpare wi
pare w
m
separate
epara
P


MLN4924
Statistical Analysis Plan, Study C15010
NexDoc Template Version 1.4
27
As data permit, individual and mean MLN4924 plasma concentration-time data will be 
tabulated and plotted for each combination therapy.
5.9.2   
Biomarker Analysis
5.9.2.1 Candidate Tumor Biomarkers and Tumor Biomarkers of Response
Any biomarker related analysis including ERCC1 in Arm 2 of MLN4924 in combination 
with Paclitaxel and Carbophatin, PSMB1, NGS will be included in a separate biomarker 
analysis plan if appropriate.  
5.10   Safety Analyses
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.
The following analyses will be performed using the safety population.  
5.10.1   Adverse Events
5.10.1.1   Adverse Events
AEs will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA). Treatment-emergent is defined as any AE that occurs after administration of the 
first dose of study treatment and up through 30 days after the last dose of study drug, any 
event that is considered drug-related regardless of the start date of the event, or any event 
that is present at baseline but worsens in severity after baseline. 
AEs will be tabulated by system organ class (SOC), high level term (HLT), and preferred 
term (PT).  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 
!
Grade 4 or higher treatment-emergent AEs
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
atioion
omarker
marke
of f AEs
AE
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PT).  Sum
T).  
!
T


MLN4924
Statistical Analysis Plan, Study C15010
NexDoc Template Version 1.4
28
!
Grade 4 or higher drug-related treatment-emergent AEs
!
Grade 3 drug-related treatment-emergent AEs
!
Grade 4 drug-related treatment-emergent AEs
!
Treatment-emergent AEs resulting in study drug discontinuation
!
SAEs  
!
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 treatment cycle of 
onset (Cycle 1, Cycle 2-3, Cycle 4-5, Cycle 6+). Additionally, for patients dosed at MTD, a 
tabulation of AE (by SOC, HLT, and PT) vs grade intensity will be made.  Separate 
summaries will be generated for each arm.  All adverse events will also be reported in by-
patient listings.
All adverse events for patients who have dose modification in standard of cares will also be 
included in a by-patient listing. This listing should additionally include reduced doses during 
AE occurrence and omitted doses durign 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 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 MLN4924 and on or before 
the month and year of the date of the last dose of MLN4924 plus 30 days.
!
If the start date has year, but day and month are missing, the event will be considered 
treatment emergent if the year of the start date of the event is on or after the year of 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
ighest in
ighest 
gent AE
ent A
of all pat
f all pa
ummariz
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!


MLN4924
Statistical Analysis Plan, Study C15010
NexDoc Template Version 1.4
29
the date of the first dose of MLN4924 and on or before the year of the date of the last 
dose of MLN4924 plus 30 days.
!
If the start date of an event is completely missing, then the event is assumed to be 
treatment emergent.
5.10.1.2   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.
A by-patient listing of the SAEs will be presented (the patient listing will contain all SAEs 
regardless of treatment emergent AE status).
The drug-related SAEs will also be presented in a by-patient listing. 
An additional listing of treatment emergent C1D1 grade 2 or higher SAEs will also be 
generated.
5.10.1.3   Deaths
A by-subject listing of the deaths will be presented.  All deaths occurring on-study will be 
displayed (regardless of treatment emergent AE status). On-study death is defined as the 
death that occurs between the first dose of study drug and 30 days after the last dose of study 
drug.
5.10.1.4   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.
A by-patient listing of AEs resulting in discontinuation of study drug will be presented.  All 
AEs resulting in discontinuation of study drug occurring on-study will be displayed 
(regardless of treatment emergent AE status).
5.10.1.5   Dose Limiting Toxicities (DLTs)
A by-patient listing of DLTs in Cycle 1 will be presented by dose level for patients in the 
DLT-evaluable population. Patients will be grouped by the arm and MLN4924 dose level to 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
gent s
ent seri
e
will cont
l con
list
isting.
ing
de 2 or h
 2 or h
l be
be pre
t t emerg
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vents
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AEs 
AEs res
re
(rega
(reg


MLN4924
Statistical Analysis Plan, Study C15010
NexDoc Template Version 1.4
30
which they were originally assigned at enrollment, including those who receive subsequent
treatment at a lower dose level due to intra-patient dose modification. 
5.10.1.6   Myalgia Events
A listing of patients who experience treatment emergent myalgia events will be presented.
5.10.1.7   Acute Renal Failure Events
A listing of treatment-emergent acute renal failure events will be generated. 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
5.10.1.8   Liver Function Test (LFT) Elevations
A listing of treatment-emergent LFT elevations will be generated. The corresponding 
preferred terms are listed as below:
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
generated
nerate
da: For non-commercial u
ial u
rcia
merc
mme
tal
com
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ubje
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use o
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5.10
5.1


MLN4924
Statistical Analysis Plan, Study C15010
NexDoc Template Version 1.4
31
!
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
5.10.1.9    Tachycardia Events
A listing of treatment-emergent tachycardia events will be generated. 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
5.10.1.10   
Hypotension
A listing of treatment-emergent hypotension will be generated. The corresponding preferred 
terms are listed as below:
!
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
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
ed d
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Bl
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!


MLN4924
Statistical Analysis Plan, Study C15010
NexDoc Template Version 1.4
32
5.10.1.11   
Anemia
A separate table will display a cross-tabulation of patients who report a PT of anemia and 
those who receive a concomitant medication of red blood cells at any point during the study.
A listing of treatment-emergent anemia will also be generated. 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
5.10.1.12   
Neutropenia
A listing of treatment-emergent neutropenia will also be generated. 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
5.10.1.13   
Overall Summary
The number of patients who experience any of the following groups will be summarized by
dose level:
!
Any adverse event  (including separate summaries of maximum toxicity grade 
experienced (Grade 1 to  Grade 5))
!
Drug-related adverse event (including  separate summaries of maximum toxicity 
grade experienced (Grade 1 to  Grade 5))
!
Serious adverse event
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
ed
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!


MLN4924
Statistical Analysis Plan, Study C15010
NexDoc Template Version 1.4
33
!
Drug related serious adverse event
!
Adverse events resulting in study drug discontinuation
!
On-study deaths
Percentages will be calculated for each dose and all the patients.
5.10.2   Laboratory Data
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.  Graphical displays will be used to show 
changes in laboratory measures over time for patients:
1) Box graphs of individual tests over time for patients at MTD.  
2) Scatter plots of baseline versus worst post-baseline values for all patients.  Separate 
plotting characters will be used for each dose.  These will be generated for only 
selected labs (see table below).
Panel
Test
CTCAE 
Shift Table
MTD Box Plots
Scatter Plots
Chemistry
Albumin
X
X
Alanine aminotransferase (SGPT)
X
X
Aspartate aminotransferase (SGOT)
X
X
Alkaline Phosphatase
X
X
Carbon Dioxide
X
X
Direct Bilirubin
X
X
Total Bilirubin
X
X
Blood urea nitrogen
X
X
Blood urea nitrogen (mg/dL)/Creatinine 
(mg/dL)
X
X
Calcium
X
X
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
d d toto sta
st
ess s th
than
alue
alue wil
w
ime
me poi
p
aseline
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nts.
nts.
G
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for pa
p
ests ove
sts ov
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will
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r non-c
non c
Al
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o
Fo
a:
ed
ak
f T
f T
f T
f T


MLN4924
Statistical Analysis Plan, Study C15010
NexDoc Template Version 1.4
34
Panel
Test
CTCAE 
Shift Table
MTD Box Plots
Scatter Plots
Chloride
X
X
Creatinine
X
X
Creatinine clearance
X
X
Glomerular filtration rate (estimated)
X
X
Glucose
X
X
Gamma-glutamyl-transpeptidase
X
X
Lactate dehydrogenase
X
X
Magnesium
X
X
Phosphate
X
X
Potassium
X
X
Sodium
X
X
Urate
X
X
Hematology
Platelets
X
X
Hematocrit
X
X
Hemoglobin
X
X
White Blood Cells
X
X
Lymphocyte Count
X
X
Neutrophils (ANC)
X
X
Monocytes
X
X
Eosinophils
X
X
Basophils
X
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
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:
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
f
of
s o
m
Te
e
ab
ab
ab
ab
ab
lic
X
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the
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to
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X
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ub
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Then
The


MLN4924
Statistical Analysis Plan, Study C15010
NexDoc Template Version 1.4
35
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
)
)
All chemistry and hematology lab data will also be presented in by-patient listings.
In addition, a listing of selected urinalysis parameters will be presented to display the patient 
ID, visit and the results from protein, glucose, occult blood, erythrocytes (from microscopic 
evaluation), leukocyte esterase, and leukocytes (from microscopic evaluation).  Patients will 
be grouped by arm and MLN4924 dose level.  All urinalysis parameters will be presented in 
by-patient listings.  
5.10.3   Electrocardiograms
The number and percent of patients experiencing abnormal ECG results will be summarized 
for each time point on Days 1 by MLN4924 dosing levels.  
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
culated 
culated
ma
max(
*
1
black]
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/
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be
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MLN4924
Statistical Analysis Plan, Study C15010
NexDoc Template Version 1.4
36
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.  
5.10.4   Vital Signs
Graphical displays will be used to show vital sign parameters over time: 
!
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 
arm.  These will be summarized for measurements taken in the sitting position.
!
Boxplots over time for temperature, DBP, SBP, and heart rate during Cycle 1 will be 
generated at the MTD for each arm. These will be summarized for measurements 
taken in the sitting position.
!
Boxplots of change from baseline over time for temperature, DBP, SBP, and heart 
rate during Cycle 1 will be generated at the MTD for each arm.  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.
A table will be generated to summarize the following at baseline and post dose for each 
SOC and MLN4924 dose level:
!
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 post dose
!
Percentage of patients who had orthostatic heart rate post dose
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
me:
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 SBP, an
SBP, 
These
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SOC 
SOC


MLN4924
Statistical Analysis Plan, Study C15010
NexDoc Template Version 1.4
37
!
Percentage of patients who had both orthostatic hypotension and orthostatic heart 
rate post dose
Moreover, the summary table should also include the following:
!
Percentage of patients who had orthostatic hypotension post dose and did not have 
orthostatic hypotension at baseline
!
Percentage of patients who had orthostatic heart rate post dose and did not have 
orthostatic heart rate at baseline
!
Percentage of patients who had both orthostatic hypotension and orthostatic heart 
rate post dose 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 post dose
!
Percentage of patients who had orthostatic heart rate at baseline and did not have 
orthostatic heart rate post dose
!
Percentage of patients who had both orthostatic hypotension and orthostatic heart 
rate at baseline and had neither orthostatic hypotension nor orthostatic heart rate post 
dose
An additional listing of patients who had orthostatic hypotension or orthostatic heart rate
post dose will be presented.  The listing will include the baseline and post dose heart rate, 
SBP, and DBP in both the supine and standing positions.  The listing 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 if they are 
taking any of the following at C1D1:
Acebutolol, Atenolol, Atenolol, Betaxolol, Bisoprolol, Carteolol, Carteolol, Carvedilol, 
Celiprolol, Esmolol, Labetalol, Levobunolol, Metipranolol, Metoprolol, Nadolol, Nebivolol, 
Oxprenolol, Penbutolol, Pindolol, Propranolol, Sotalol, Timolol
All vital sign data will also be presented in a by-patient listing.
5.10.5   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.
5.10.6   Echocardiograms
Echocardiogram results (e.g. left ventricular ejection fraction) will be presented in by-patient 
listing.  The listing will also specify whether the values were captured via MUGA.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
have
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and di
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MLN4924
Statistical Analysis Plan, Study C15010
NexDoc Template Version 1.4
38
5.10.7   Urine Safety Assessment
Multi-panel line plots will be generated for each dose level and arm. Separate plots will be 
generated for Cycle 1 data and Cycle 2+ data. The following measures will be summarized::
!
Urine KIM-1/urine creatinine ratio (calculated value and percent change from 
baseline):
(mg/dL)
creatinine
urine
*
)
0.01(dL/mL
(ng/mL)
1
-
KIM
urine
!
Urine albumin/urine creatinine ratio:
(mg/dL)
creatinine
urine
*
)
0.01(dL/mL
g/mL)
(
albumin 
urine
.
!
Fractional Excretion of Phosphate (FEPO4): 
.3229
mmol/L)]/0
phosphate(
[serum
*
(mg/dL)]
creatinine
[urine
.4
mol/L)]/88
(
creatinine
[serum
*
mg/dL)]
phosphate(
[urine
.
*100
!
Fractional Excretion of Sodium (FENA): 
l/L)]
sodium(mmo
erum
(mg/dL)][s
creatinine
[urine
.4
mol/L)]/88
(
creatinine
m
l/L)][seru
sodium(mmo
[urine
.
*100
!
Fractional Excretion of Potassium (FEK)
mmol/L)]
potassium(
erum
(mg/dL)][s
creatinine
[urine
.4
mol/L)]/88
(
creatinine
erum
mmol/L)][s
potassium(
[urine
.
*100
Individual patients are represented by separate lines. A line representing the average for all 
patients in a given arm and dose level will also be included. 
For the plots of the ratio of Urine Albumin/ Urine Creatinine, two horizontal lines will be 
drawn at 30 mg/g and 300 mg/g, where the horizontal line of 30 mg/g will be labeled with 
“microalbuminuria: 30-300 mg/g”, and the line of 300 mg/g with “macroalbuminuria: > 300 
mg/g”.  In addition, an additional set of plots for the ratio of Urine Albumin/ Urine
Creatinine will be generated for patients whose baseline ratios of Urine Albumin/ Urine 
Creatinine are less than 50 mg/g.
Results of urine safety assessments will also be presented in by-patient listings. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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MLN4924
Statistical Analysis Plan, Study C15010
NexDoc Template Version 1.4
39
6.   
CHANGES TO PLANNED ANALYSES FROM PROTOCOL
Reference materials for this statistical plan include Clinical Study Protocol C15010 (dated 
08MAR2013), Administrative Change Letter #1 (dated 12 June 2013), and the
accompanying data collection documents (Annotated Case Report Form [CRF], version 2.0
dated  09JUL2013).
The following changes have been made to the planned analyses from the protocol:
-
Sections 5.10.2, 5.10.4 and 5.10.5: Due to the small number of patients in each dose 
level summary statistics for laboratory data, ECG, vital signs may not be presented.  
-
The definitions of the DLT-evaluable population was updated for clarity
-
The definition of the PK-evaluable population was removed as there will be no PK 
analysis to estimate PK parameters.
7.   
PROGRAMMING CONSIDERATIONS
7.1   
Statistical Software 
SAS version 9.2 (or higher) will be used for all analyses.  
7.2   
Rules and Definitions
Patient populations are defined in Section 2.
Baseline values are defined as in Section 5.4.2.
Treatment emergent AEs are defined as in Section 5.10.1.1.
8.   
REFERENCES
1. O'Quigley J, Pepe M, Fisher L. Continual reassessment method: a practical design
for phase 1 clinical trials in cancer. Biometrics 1990;46(1):33-48.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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MLN4924
Statistical Analysis Plan, Study C15010
NexDoc Template Version 1.4
40
2. Goodman SN, Zahurak ML, Piantadosi S. Some practical improvements in the
continual reassessment method for phase I studies. Statistics in Medicine
1995;14(11):1149-61.
3. Garrett-Mayer E. The continual reassessment method for dose-finding studies: a
tutorial. Clinical Trials 2006;3(1):57-71.
4. 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.
5. 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.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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