Clinical trial NCT01425008
Conditions: Melanoma Metastatic Melanoma Solid Tumor Neoplasm
Keywords: Drug Therapy
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2011-09-15; Completion date: 2018-10-16
Enrollment: 149 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a phase 1, multicenter, nonrandomized, open-label, dose escalation study. The study will be conducted in 2 stages, Dose Escalation and Dose Expansion. The Dose Escalation phase will include participants with solid tumors (including melanoma) who have failed or are not candidates for standard therapies or for whom no approved therapy is available. The Dose Expansion phase will include participants with metastatic melanoma.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: MLN2480
Intervention descriptions: intervention 1: Dose Escalation Phase: participants will receive MLN2480 orally in escalating doses every other day or once weekly for three weeks of a 28-day cycle. Participants may continue treatment for additional cycles (up to 12 months) until disease progression, unacceptable toxicity, or the participant discontinues for any other reason. If it is determined that a participant would derive benefit from continued therapy beyond 12 months treatment may continue. Dose Expansion Phase: Participants will take MLN2480 at the maximum tolerated dose orally every other day or once weekly for three weeks of a 28-day cycle until disease progression, unacceptable toxicity, or the participant discontinues for any other reason. The maximum duration of treatment is 1 year unless determined that a participant would derive benefit from continued therapy beyond 12 months.

Protocol documents:
Prot_001.pdf: 



Title: An Open-Label, Phase 1, Dose Escalation Study of MLN2480 in Patients With Relapsed or 
Refractory Solid Tumors Followed by a Dose Expansion Phase in Patients With Metastatic 
Melanoma
NCT Number: NCT01425008
Protocol Approve Date: 16 May 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.


PPD


MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
2
Rationale for Amendment 9
This document describes the changes in reference to the protocol incorporating Amendment 
No. 9. The primary reason for this amendment is to reduce the investigational activity, such 
as scheduled visits and study procedures, for patients in the study for 4 years or longer.
Minor grammatical, editorial, and formatting changes are included for clarification purposes 
only. 
For specific descriptions of text changes and where the changes are located, see Section 
14.12.
Changes in Amendment 9
1. Changed the information for the signatories on the title page.
2. Added a Schedule of Events with reduced assessments (12-week [84-day] treatment
cycle) for patients in the study for 4 years or longer.
3. Introduced TAK-580, the new product code for MLN2480.
4. Added that patients in the study for 4 years or longer will take MLN2480 every other
day in 12-week (84-day) treatment cycles until disease progression, unacceptable
toxicity, or the patient discontinues for any other reason.
5. Added that when patients have been in the study for 4 years or longer, nonserious
adverse events will no longer be reported.
6. Changed the name and telephone number of the call center for product complaints.
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
3
PROTOCOL SUMMARY
Study Title: An Open-Label, Phase 1, Dose Escalation Study of MLN2480 in Patients With 
Relapsed or Refractory Solid Tumors Followed by a Dose Expansion Phase in Patients With 
Metastatic Melanoma 
Study Phase: 1
Name of Principal Investigator: Multicenter, global  
Number of Patients: Approximately 198 patients (54 in the Dose Escalation phase, 144 in the Dose 
Expansion phase)
Study Objectives
Primary
To evaluate the safety and tolerability of MLN2480 taken orally every other day (Q2D) or 
weekly (QW) by patients with relapsed or refractory solid tumors (Dose Escalation and Dose 
Expansion phase and pharmacokinetics [PK] Expansion cohort) or locally advanced, 
metastatic, and/or unresectable melanoma (Dose Expansion phase)
To determine the MTD of MLN2480 taken Q2D or QW by patients with relapsed or 
refractory solid tumors (Dose Escalation phase)
To determine the recommended phase 2 dose (RP2D) of MLN2480 taken Q2D or QW by 
patients with relapsed or refractory solid tumors (Dose Escalation phase)
Secondary

To evaluate the preliminary efficacy of MLN2480 as measured by Response Evaluation 
Criteria in Solid Tumors, version 1.1

To evaluate the pharmacokinetics of MLN2480

To evaluate the effect of MLN2480 on pharmacodynamic markers in paired tumor biopsies 
Exploratory
CCI
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
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Overview of Study Design: This is a phase 1, multicenter, nonrandomized, open-label, dose 
escalation study. The study will be conducted in 2 phases. In the Dose Escalation phase, a 3 + 3 dose 
escalation design will be used to evaluate MLN2480 orally in 2 dose schedules: every other day 
continuous dosing (Q2D) and once weekly dosing (QW). The Q2D and QW Dose Expansion Phases 
will test the MTD/RP2D established in the Dose Escalation phase of the corresponding dose 
schedule. 
Q2D Dose Escalation Phase
The Q2D arm will test an initial MLN2480 dose of 20 mg in a 22-day cycle (11 doses), with 
continuous dosing (no washout). Upon implementation of Amendment 3, any ongoing dose 
escalation cohort will continue enrollment on the 22-day cycle schedule until the cohort is full and 
all patients have been evaluated for dose-limiting toxicity (DLT) (see Section 6.2). In all subsequent 
Q2D cohorts, patients will be treated Q2D on a 28-day cycle (14 doses). Patients who began 
treatment on the 22-day cycle may switch to the 28-day cycle length upon safety evaluation of the 
28-day cycle. Patients will fast (with the exception of water) for at least 2 hours before and at least 
2 hours after taking their dose of MLN2480. Patients may continue treatment for additional cycles 
until disease progression, unacceptable toxicity, or the patient discontinues for any other reason. The 
maximum duration of treatment will be 12 months unless it is determined that a patient would derive 
benefit from continued therapy beyond 12 months.
Q2D Dose Expansion Phase
Once the MTD and/or RP2D of Q2D MLN2480 have been determined for the 28-day treatment 
cycle, or at the discretion of the sponsor, the study will continue to a Q2D Dose Expansion phase. 
The Dose Expansion phase will enroll approximately 96 patients with locally advanced, metastatic, 
and/or unresectable melanoma and 16 patients with any advanced solid tumor (excluding 
lymphoma). During expansion, patients with melanoma will be enrolled into 1 of 6 Q2D melanoma 
expansion cohorts (approximately 16 patients per cohort), based on tumor genotype and treatment 
history. Individual Dose Expansion cohorts may be opened or closed sequentially or in parallel at the 
sponsor’s discretion, based on emerging data. A seventh cohort in the Dose Expansion phase, the PK 
Expansion cohort, will enroll a sufficient number of patients (approximately 16) with any advanced 
solid tumor (excluding lymphoma) to ensure that 12 patients complete protocol-specified dosing and 
PK assessments scheduled during Cycle 1. 
Patients in the Q2D Dose Expansion phase will take MLN2480 orally Q2D for a 28-day cycle until 
disease progression, unacceptable toxicity, or the patient discontinues for any other reason. Patients 
in the PK Expansion cohort will take the selected dose of MLN2480 orally Q2D on Days 1-21 of the 
28-day cycle for Cycle 1; dosing for Cycle 2 and beyond will follow the standard Q2D dosing in 
28-day cycles. The maximum duration of treatment will be 1 year unless it is determined that a 
patient would derive benefit from continued therapy beyond 12 months. 
QW Dose Escalation Phase
The QW arm will test an initial MLN2480 dose of 400 mg once weekly (on Days 1, 8, 15, and 22) in 
a 28-day cycle. Patients will fast (with the exception of water) for at least 2 hours before and at least 
2 hours after taking their dose of MLN2480. Patients may continue treatment for additional cycles 
until disease progression, unacceptable toxicity, or the patient discontinues for any other reason. The 
maximum duration of treatment will be 12 months unless it is determined that a patient would derive 
benefit from continued therapy beyond 12 months.
QW Dose Expansion Phase
Once the MTD and/or RP2D of QW MLN2480 have been determined, or at the discretion of the 
sponsor, the study will continue to a QW Dose Expansion phase. The Dose Expansion phase will 
enroll up to approximately 32 patients (up to 16 patients per cohort) with locally advanced, 
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
5
metastatic, and/or unresectable melanoma into 1 of 2 QW dose expansion cohorts, based on tumor 
genotype and treatment history (Cohorts 8 and 9). Individual Dose Expansion cohorts may be opened 
or closed sequentially or in parallel at the sponsor’s discretion, based on emerging data. 
Note: Enrollment into Cohort 8 is discontinued as of this amendment (Amendment 8).
Patients in the QW Dose Expansion phase will take MLN2480 orally QW for a 28-day cycle until 
disease progression, unacceptable toxicity, or the patient discontinues for any other reason. The 
maximum duration of treatment will be 1 year unless it is determined that a patient would derive 
benefit from continued therapy beyond 12 months.
Study Population: This study will be conducted in patients 18 years of age with advanced solid 
tumors (excluding lymphoma) (Dose Escalation, Dose Expansion phase, and PK Expansion cohort) 
or locally advanced, metastatic, and/or unresectable melanoma (Dose Expansion phase). 
Dose Escalation Phase:
The Dose Escalation phase will include patients with advanced solid tumors (except lymphoma) who 
have failed or are not candidates for standard therapies or for whom no approved therapy is 
available. Tumor tissue is required for all patients at Screening to determine tumor genotype. 
Sufficient archival tumor tissue or fresh biopsy will meet this requirement. Patients with accessible 
lesions may additionally be consented for pre- and posttreatment biopsy for pharmacodynamic 
analysis. The optional posttreatment biopsy on Day 21 (Q2D) or Day 22 (QW) of Cycle 1 should be 
collected only if an evaluable fresh biopsy was collected at Screening.
Detailed criteria are described in Section 6.3 of the protocol.
Dose Expansion Phase:
The Dose Expansion phase will include patients with locally advanced, metastatic, and/or 
unresectable melanoma (melanoma expansion cohorts), or advanced solid tumors (excluding 
lymphoma) (PK Expansion cohort). 
Patients with melanoma will be enrolled into 1 of 8 melanoma expansion cohorts, based on tumor 
genotype and treatment history:
Q2D Melanoma Expansion Cohorts

Cohort 1: BRAF mutation-positive cutaneous melanoma, naïve to prior therapy with RAF 
and MEK inhibitors. 

Cohort 2: BRAF mutation-positive cutaneous melanoma, which in response to previous 
treatment with RAF inhibitors and/or MEK inhibitors, has 1) relapsed following an objective 
response, 2) failed to demonstrate an objective response, and/or 3) could not tolerate such a 
regimen due to unacceptable toxicity.

Cohort 3: NRAS mutation-positive cutaneous melanoma, naïve to prior therapy with RAF 
and MEK inhibitors. 

Cohort 4: NRAS mutation-positive cutaneous melanoma, which in response to previous 
treatment with MEK inhibitors, has 1) relapsed following an objective response, 2) failed to 
demonstrate an objective response, and/or 3) could not tolerate such a regimen due to 
unacceptable toxicity.

Cohort 5: BRAF/NRAS mutation-negative cutaneous melanoma (wild type), naïve to any 
prior anticancer therapy except ipilimumab, anti-PD-1, and anti-PDL-1 mAbs. 

Cohort 6: BRAF/NRAS mutation-negative melanoma (wild type), received at least 1 line of 
prior anticancer therapy. Melanoma of cutaneous, uveal, or mucosal origin may be enrolled 
in this cohort.
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
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
(Cohort 7: Not a melanoma cohort. See below for information on the PK expansion cohort) 
QW Melanoma Expansion Cohorts;

Cohort 8: BRAF mutation-positive cutaneous melanoma (approximately 16 patients total: 
approximately 8 patients who are naïve to prior therapy with RAF and MEK inhibitors, and 
approximately 8 patients relapsed/refractory to prior therapy with RAF or MEK inhibitors).
Note: Enrollment into Cohort 8 is discontinued as of this amendment (Amendment 8).

Cohort 9: NRAS mutation-positive cutaneous melanoma, naïve to prior therapy with RAF 
and MEK inhibitors. 
A fresh tumor biopsy for genotyping will be required for all patients in the 6 Q2D dose expansion 
cohorts and will be requested for QW Expansion cohorts at Screening; archived tumor tissue will 
also be requested, if available. A postdose fresh biopsy on Day 21 of Cycle 1 will also be collected 
from at least 8 patients in each Q2D melanoma expansion cohort. The postdose fresh biopsy may 
need to be collected in more than the specified patients in each cohort/treatment schedule to ensure 
evaluable biopsies are collected. After the specified pairs of Screening and postdose biopsies have 
been confirmed to be evaluable from a cohort, the postdose biopsy for the remaining patients in that 
cohort will be optional. The postdose fresh biopsy should be collected in a patient only if an 
evaluable fresh biopsy was collected at Screening. For patients on the QW dose schedule, a predose 
fresh biopsy will be requested on Day 22 of Cycle 1 from at least 8 evaluable patients for 
pharmacodynamic assessment. Evaluable biopsy pairs collected at Screening and Day 21 (Q2D) or 
Day 22 (QW) of Cycle 1 will be used for pharmacodynamic biomarker analysis. 
A seventh Q2D expansion cohort, the PK Expansion cohort, will enroll patients with any advanced 
solid tumor (excluding lymphoma, but including melanoma) who have failed or are not candidates 
for standard therapies or for whom no approved therapy is available. In addition to contributing to 
the evaluation of safety, tolerability, and preliminary antitumor activity, the PK Expansion cohort 
will be used to more fully characterize MLN2480 PK. Archived or fresh tumor will be obtained at 
Screening for genotyping. No paired biopsies for pharmacodynamic analysis will be collected in the 
PK Expansion cohort. 
Detailed criteria are described in Section 6.4 of the protocol.
Number of Study Center(s): Approximately 14 to 22 study sites (approximately 4 to 8 sites in the 
United States [US] for the Dose Escalation phase and approximately 10 to 18 US and International 
sites for the Dose Expansion phase.)
Duration of Study: The study period will consist of the Screening and Treatment periods.
During the Screening period, patient eligibility for the study will be determined within 28 days prior 
to Day 1. During the Treatment period, patients will take MLN2480 orally Q2D in 22- or 28-day 
treatment cycles until disease progression, unacceptable toxicity, or the patient discontinues for any 
other reason. The maximum duration of treatment will be 12 months unless it is determined that a 
patient would derive benefit from continued therapy beyond 12 months. 
When patients discontinue study treatment, they should return to the study site 30 days after 
administration of the last dose of study drug to complete the End of Study visit procedures.
All MLN2480-related toxicities will be followed until the End of Study visit or until the toxicities 
have resolved, stabilized, or returned to baseline, whichever occurs later.
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
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Dose Escalation Algorithm
Q2D Dose Escalation Phase
The Q2D dose escalation will follow a modified Fibonacci schema (sequential dose 
escalation increments of approximately 100%, 100%, 67%, 50%, 40%, and 33% thereafter; 
see Table 6-1). 
When the cycle length is changed from 22 days to 28 days (per Amendment 3), the same 
unit dose of the previously tolerated cohort at the 22-day schedule will be repeated for the 
first cohort at 28 days. After tolerability is confirmed when the same unit dose is 
administered every other day (Q2D) in a 28-day cycle instead of a 22-day cycle, subsequent 
dose escalations in a 28-day cycle will consist of a 33% increase in both unit and total cycle 
dose. If an MTD is established in the 22-day cycle before transition to the 28-day cycle has 
occurred, the MTD and/or RP2D will be confirmed in the 28-day cycle. 
In the absence of more than 1 dose-limiting toxicity (DLT) occurring in a given cohort or 
the maximum tolerated dose (MTD) being established, it is anticipated that the MLN2480 
doses for the sequential Q2D cohorts will be 20, 40, 80, 135, 200, and 280 mg Q2D, with 
33% dose escalation increments thereafter until the Q2D MTD is established. Depending on 
the nature of the DLTs in the preceding dose cohort, an additional intermediate dose 
cohort may be evaluated before proceeding to the Q2D Dose Expansion phase of the study.
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
8
QW Dose Escalation Phase
The QW dose escalation phase (added per amendment 6) will test doses of MLN2480 on 
Days 1, 8, 15, and 22 of a 28-day cycle. Based on safety and pharmacokinetic (PK)
information learned from the Q2D Dose Escalation phase, a starting dose of 400 mg will be 
used in this phase. In the absence of more than 1 dose-limiting toxicity (DLT) occurring in a 
given cohort or the maximum tolerated dose (MTD) being established, it is anticipated that 
the MLN2480 doses for the sequential QW cohorts will be 400, 600, 800, and 1000 mg,
with 200 mg dose escalation increments thereafter until the QW MTD is established. For the 
initial dose increase (from 400 mg to 600 mg), patients will be enrolled in the 600 mg dose 
cohort in a staggered manner, with 1 week in between each patient.
More conservative dose escalation, evaluation of intermediate doses, and expansion of an 
existing dose level are all permissible following 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, exposure, or pharmacodynamics of MLN2480.
In the event that less than dose proportional increases in systemic exposure are observed 
Enroll 3 patients
If no patients in a dose cohort experience a 
DLT in the first 28-Day cycle
If 1/3 patients in a dose cohort experience a 
DLT in the first 28-Day cycle
Go to next 
cohort cycle
Stop MTD 
exceeded
Enroll 3 more 
patients
DLT in 1 of 6 
patients
DLT in >2 
patients
Dose 
escalation 
increment will 
be 200 mg 
Dose 
escalation 
increment will 
be 200 mg
Dose 
escalation 
increment will 
be 200 mg
If 0/3 or 1/6
DLT at dose 
400 mg
If 0/3 or 1/6
DLT at dose 
800 mg
If 0/3 or 1/6 DLT 
and/or dose 
>1000 mg in 
previous cohort
Go to 
next 
cohort
If 0/3 or 1/6
DLT at dose 
600 mg
Dose 
escalation 
increment will 
be 200 mg
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
9
during further dose escalation of MLN2480 in the QW dosing regimen, alternative QW 
dosing regimens may be explored to increase systemic exposures. This could include 
splitting a weekly dose in AM and PM (approximately 12-hr apart) on Day 1, 8, 15, and 
22 or splitting a weekly dose on Days 1 and 2, Days 8 and 9, Days 15 and 16, Days 22 and 
23. The PK and ECG sampling schedule for alternative QW dosing regimens are listed in 
the Pharmacokinetic and Electrocardiogram Sampling Schedule E: Alternative (Split Dose, 
Same Day) QW Dose Escalation and Dose Expansion Phases and in the Pharmacokinetic 
and Electrocardiogram Sampling Schedule F: Alternative (Split Dose, Sequential Days) QW 
Dose Escalation and Dose Expansion Phases.
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
10
Q2D Schedules of Events
Q2D 28-Day Treatment Cycle: Cycle 1 Schedule
Screening
Day 1
Day 2
Day 3
Day 
9
Day 
15
Day 21
Day 
22
Day 
23
Day 
24
Day 
25
Day 
26
Day 
28
≤28 Days 
Before 
Day 1
Pre 
dose
Post
dose
Pre 
dose
Post 
dose
Informed consent 
form
X
Inclusion/exclusion 
criteria
X
Demographics
X
Medical historyb
X
Complete physical 
examination, height, 
and body weight 
measurement
X
Xa
Dermatological 
examination with 
documentation of any 
suspicious lesionsc
X
Xc
Xc,d
Xc,d
Xc,d
Digital photographs of
skinc
X
ECHO or MUGA
X
12-lead ECG for 
safety (all patients) e
X
12-lead triplicate ECG 
(Dose Escalation 
phase)e
X
X
X
X
X
12-lead triplicate ECG 
(PK Expansion 
X
X
X
X
X
X
X
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
11
Q2D 28-Day Treatment Cycle: Cycle 1 Schedule
Screening
Day 1
Day 2
Day 3
Day 
9
Day 
15
Day 21
Day 
22
Day 
23
Day 
24
Day 
25
Day 
26
Day 
28
≤28 Days 
Before 
Day 1
Pre 
dose
Post
dose
Pre 
dose
Post 
dose
cohort)d
Vital signs
(temperature, blood 
pressure, pulse rate)f
X
Xg
Xg
Xg
Xg
ECOG performance 
status
X
Xa
Laboratory tests
Hematologyh
X
Xa, i
X
X
X
Blood chemistryj
X
Xa, i
X
X
X
Bone marrow 
aspirate and 
biopsyk,l
Coagulationm
X
X
Thyroid function
X
Pregnancy test 
(female patients of 
reproductive 
potential)
Xa
Xa,n
Urinalysisn
X
Xo
CCI
CCI
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
12
Q2D 28-Day Treatment Cycle: Cycle 1 Schedule
Screening
Day 1
Day 2
Day 3
Day 
9
Day 
15
Day 21
Day 
22
Day 
23
Day 
24
Day 
25
Day 
26
Day 
28
≤28 Days 
Before 
Day 1
Pre 
dose
Post
dose
Pre 
dose
Post 
dose
Blood sample for 
PK assessment 
(Dose Escalation 
phase)q,r
X
X
X
X
X
X
X
X
X
X
Blood sample for 
PK assessment (PK 
Expansion cohort)r,s
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood sample for 
PK assessment 
(melanoma 
expansion 
cohorts)r,t, u
X
X
X
X
X
X
Urine samples for 
PK assessment 
(Dose Escalation 
phase)v
X
X
Fresh tumor biopsyk
X
X
Disease assessment, 
including CT or MRI 
scanx
Xw
Concomitant therapy 
and procedures 
recordingy
X
Concomitant therapy and procedures must be recorded from Screening through the End of Study visit or the start of 
subsequent antineoplastic therapy, whichever comes first.
CCI
CCI
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
13
Q2D 28-Day Treatment Cycle: Cycle 1 Schedule
Screening
Day 1
Day 2
Day 3
Day 
9
Day 
15
Day 21
Day 
22
Day 
23
Day 
24
Day 
25
Day 
26
Day 
28
≤28 Days 
Before 
Day 1
Pre 
dose
Post
dose
Pre 
dose
Post 
dose
AE reporting
AEs will be recorded from first dose of study drug through 30 days after the last dose of study drug or the start 
of subsequent antineoplastic therapy, whichever occurs first.
SAEsy will be collected from signing of the informed consent form through 30 days after the last dose of study drug.
MLN2480 
administration
Q2D dose 
escalation phasez
MLN2480 dosing once every 2 days on Days 1-28 of a 28-day cycle (14 doses), starting on Day 1
Q2D melanoma 
expansion 
cohorts)z
MLN2480 dosing once every 2 days on Days 1-28 of a 28-day cycle (14 doses), starting on Day 1
Q2D PK 
Expansion 
cohortaa
MLN2480 dosing once every 2 days on Days 1-21 of a 28-day-cycle (11 doses) starting on Day 1, followed by a 1-week 
treatment-free period (Days 22-28)
Abbreviations: aPTT=activated partial thromboplastin time; AE=adverse event; ALT=alanine aminotransferase; ANC=Absolute Neutrophil Count; 
AST=aspartate aminotransferase; BUN=blood urea nitrogen; CRF=Case Report Form; CT=computed tomography; DLT=dose-limiting toxicity; 
ECG=Electrocardiogram; ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology Group; 
; 
ICF=informed consent form; MRI=magnetic resonance imaging; MUGA=multiple gated acquisition [scan]; PK=pharmacokinetic; PT=prothrombin time;
RBC=red blood cell; SAE=serious adverse event; WBC=white blood cell.
An End-of-Cohort meeting scheduled by the sponsor will occur after the last patient in each cohort in the Dose Escalation phase has completed the 
first treatment cycle/DLT observation period (ie, Day 1 to Day 28).
a Assessments need not be repeated if Screening assessments were performed within 72 hours before MLN2480 dosing, unless otherwise specified. Height is 
to be collected at Screening only. 
b AEs that occur during the Screening period (following informed consent, but prior to study drug administration) will be recorded as part of the patient’s 
medical history.
c All patients will be assessed by the investigator or a consulting dermatologist at the visits specified. Assessments need not be repeated if the prior 
assessment was performed within 72 hours. The examination for skin lesions will include the entire skin. At Screening, a complete dermatological exam 
will be performed and digital photographs will be taken to document patients’ baseline skin prior to treatment. Existing lesions will be monitored 
CCI
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
14
Q2D 28-Day Treatment Cycle: Cycle 1 Schedule
Screening
Day 1
Day 2
Day 3
Day 
9
Day 
15
Day 21
Day 
22
Day 
23
Day 
24
Day 
25
Day 
26
Day 
28
≤28 Days 
Before 
Day 1
Pre 
dose
Post
dose
Pre 
dose
Post 
dose
throughout the study and changes to the lesions will be recorded in the CRF and documented in digital photographs. For lesions developing during 
treatment that are suspected keratoacanthomas or squamous cell carcinomas, the dimensions and location on the body will be recorded in the CRF and they 
will be subsequently biopsied/adequately treated. Other lesions that develop during treatment should be recorded on the AE form and may be biopsied at 
the discretion of the investigator/ dermatologist.
d Assessment will be performed on the study day specified ± 5 days.
e A single 12-lead ECG will be collected at Screening in all patients to assess eligibility. Triplicate 12-lead ECGs will be collected as indicated in Table 1-3
and Table 1-6 for the Dose Escalation phase and PK Expansion cohorts, respectively. The triplicate ECG measurements should be completed after a 
5-minute rest period in a supine position and will be recorded at 2 to 5 minute intervals immediately before the corresponding PK blood draw. 
f
Blood pressure should be determined with the patient in a seated position after the patient has been sitting quietly for 5 minutes.
g On Days 1, 9, and 15 vital sign measurements will be performed within 15 minutes prior to dosing. On Cycle 1, Day 1 only, also perform vital sign 
measurements at 2 hours ± 10 minutes and 6 hours ± 10 minutes postdose. 
h Hematology will be tested at local laboratories and includes hemoglobin, hematocrit, platelet counts, RBC, WBC, absolute reticulocyte counts (only for 
patients who experience recurrent anemia with hemoglobin < 9 g/dL, despite blood transfusion), absolute differential, and ANC. If a patient develops an 
ANC < 500/μL or a platelet count < 25,000/μL, blood samples must be collected every 2 to 3 days and study treatment withheld until counts resolve or until 
ANC returns to > 1000/μL and platelet counts return to > 50,000/μL.
i
Hematology results (including hemoglobin, hematocrit, platelet counts, RBC, WBC, absolute reticulocyte counts [only for patients who experience 
recurrent anemia with hemoglobin < 9 g/dL, despite blood transfusion], absolute differential, and ANC) and blood chemistry results (including creatinine,
total bilirubin, AST, and ALT) will be evaluated before the patient is allowed to take their dose of MLN2480 on Day 1 of each cycle.
j
Blood chemistry results will include glucose, BUN, creatinine, sodium, potassium, chloride, CO2, total bilirubin, lactate dehydrogenase, alkaline 
phosphatase, AST, ALT, albumin, and calcium.
k Bone marrow aspirate and biopsy will be encouraged only for patients who experience recurrent anemia with hemoglobin < 9 g/dL, despite blood 
transfusion.
l
Fresh biopsy of tumor is required for all patients in the 6 Q2D melanoma expansion cohorts at Screening. The Screening tumor biopsy must be immediately 
formalin fixed, paraffin embedded, and have 5 slides cut from the block to be used for genetic analysis. The tissue on the slides must contain at least 4 mm2
tissue area with a minimum of 10% tumor content. A postdose fresh biopsy on Day 21 (3-9 hrs postdose) of Cycle 1 will also be collected from at least 
8 patients in each Q2D melanoma expansion cohort, to ensure 8 evaluable biopsies are collected in each cohort. After 8 pairs of Screening and Day 21 
biopsies have been confirmed to be evaluable from a cohort, the Day 21 biopsy for the remaining patients in that cohort will be optional. If possible, the 
Day 21 biopsy should be from the same lesion biopsied during Screening; however, an alternative lesion may be used if this is not possible. A fresh biopsy 
is required at Screening for patients in the Dose Escalation and PK Expansion cohorts if an archival tumor tissue sample is unavailable, inadequate, or was 
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
15
Q2D 28-Day Treatment Cycle: Cycle 1 Schedule
Screening
Day 1
Day 2
Day 3
Day 
9
Day 
15
Day 21
Day 
22
Day 
23
Day 
24
Day 
25
Day 
26
Day 
28
≤28 Days 
Before 
Day 1
Pre 
dose
Post
dose
Pre 
dose
Post 
dose
obtained more than 24 months prior to Screening. A postdose fresh biopsy on Day 21 (3-9 hours postdose) of Cycle 1 is optional for patients in the Dose 
Escalation phase if an evaluable biopsy was obtained at Screening (Table 1-13). 
m Within 48 hours of any invasive procedure (ie, tumor biopsy or bone marrow biopsy), aPTT and PT must be within the normal range. For tumor and bone 
marrow biopsies, platelet count should be 75,000/mm3.
n A urine or serum pregnancy test is permitted at this time point (C1D1) only. The Screening and EOS pregnancy tests must be serum.
o Urinalysis includes dipstick for blood, protein, pH, Specific gravity, Ketones, Bilirubin, Nitrite, Urobilinogen, Leukocytes and glucose (microscopic 
examination, if abnormal). Samples will be collected predose.
p
q
r
Refer to Table 1-1 for time points at which blood samples will be collected for PK assessments in the Dose Escalation phase. Refer to Laboratory Manual 
for details on collection, processing, storage, and shipment of plasma PK samples.
s In addition to the scheduled PK sample collections, a blood sample to measure MLN2480 plasma concentrations should be obtained, if clinically feasible, at 
the time of a serious or unusual AE that is judged by the investigator to be treatment-related, irrespective of the cycle or day of occurrence of the AE. See 
Section 7.4.18.
t
Refer to Table 1-4 for time points at which blood samples will be collected for PK assessments in the PK Expansion cohort. Refer to Laboratory Manual for 
details on collection, processing, storage, and shipment of plasma PK samples.
u Refer to Table 1-7 for time points at which blood samples will be collected for PK assessments in the Q2D melanoma expansion cohorts of the Dose
Expansion phase. Refer to Laboratory Manual for details on collection, processing, storage, and shipment of plasma PK samples. 
v Refer to Table 1-2 and Table 1-5 for time points at which urine samples will be collected for PK assessments in the Dose Escalation phase and the PK 
Expansion cohort, respectively.
w
x Refer to Section 7.4.15 and Section 14.3.
y
Concomitant therapies and procedures must be recorded from Screening through the End of Study visit or the start of subsequent antineoplastic therapy, 
whichever comes first. Refer to Section 6.6.1 for prohibited medications and therapies and Section 6.6.2.3 for medications or procedures that are restricted 
or should be used cautiously.
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
16
Q2D 28-Day Treatment Cycle: Cycle 1 Schedule
Screening
Day 1
Day 2
Day 3
Day 
9
Day 
15
Day 21
Day 
22
Day 
23
Day 
24
Day 
25
Day 
26
Day 
28
≤28 Days 
Before 
Day 1
Pre 
dose
Post
dose
Pre 
dose
Post 
dose
z Including serious pretreatment events; see Section 9.
aa On dosing days when the patient does not have a clinic visit (ie, Days 5, 7, 11, 13, 17, and 19), patients will take their dose of MLN2480 at home.
bbFor all subsequent cycles beyond Cycle 1, dosing in the PK Expansion cohort will be once every 2 days for a 28-day cycle.
Q2D 28-Day Treatment Cycle: Cycle 2 Schedule
Tests and Assessments
Cycle 2 (Day 1 through Day 28)
Day 1 2 Days
Day 15 2 Days
Day 27 2 Days
Physical examination and body weight measurement 
X
Dermatological examination with documentation of any 
suspicious lesionsa
X
X
ECHO or MUGA
X
12-lead Single ECG for Safety (melanoma expansion cohorts)
X 
12-lead Triplicate ECG (Dose Escalation Phase and PK 
Expansion cohort)b
X
Vital signs (temperature, blood pressure, pulse rate)c
X
X
Laboratory tests
Hematologyd
Xe
X
Blood chemistryf
Xe
X
Bone marrow aspirate and biopsyg
Coagulationh
Thyroid function
X 
Urinalysisi
X
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
17
Q2D 28-Day Treatment Cycle: Cycle 2 Schedule
Tests and Assessments
Cycle 2 (Day 1 through Day 28)
Day 1 2 Days
Day 15 2 Days
Day 27 2 Days
Plasma samples for biomarker assessment and circulating 
tumor DNA
Xj
Blood samples for PK assessment (All patients) 
Xk, l
Disease assessment, including CT or MRI scan 
Xm
Concomitant therapy and procedures recordingn
Concomitant therapy and procedures must be recorded from Screening through the End of 
Study visit or start of subsequent antineoplastic therapy, whichever comes first.
AE reporting
AEs will be recorded from first dose of study drug through 30 days after the last dose of 
study drug or the start of subsequent antineoplastic therapy, whichever occurs first.
SAEs will be collected from signing of the informed consent form through 30 days after the 
last dose of study drug. o
MLN2480 Q2D administration (all patients)p
MLN2480 dosing is once every 2 days on Days 1-28 of a 28 day cycle (14 doses)
Abbreviations: aPTT=activated partial thromboplastin time; AE=adverse event; ALT=alanine aminotransferase; ANC=Absolute Neutrophil Count; 
AST=aspartate aminotransferase; BUN=blood urea nitrogen; CT=computed tomography; ECG=Electrocardiogram; ECHO=echocardiogram; 
ECOG=Eastern Cooperative Oncology Group; MRI=magnetic resonance imaging; MUGA=multiple gated acquisition [scan]; PK=pharmacokinetic; 
PT=prothrombin time; RBC=red blood cell; RECIST=Response Evaluation Criteria in Solid Tumors; SAE=serious adverse event; WBC=white blood cell.
a All patients will be assessed by the investigator or a consulting dermatologist at the visits specified. Assessments need not be repeated if the prior 
assessment was performed within 72 hours. The examination for skin lesions will include the entire skin. Existing lesions will be monitored throughout the 
study and changes to the lesions will be recorded in the CRF. For lesions developing during treatment that are suspected keratoacanthomas or squamous 
cell carcinomas, the dimensions and location on the body will be recorded in the CRF and they will be subsequently biopsied/adequately treated. Other 
lesions that develop during treatment should be recorded on the AE form and may be biopsied at the discretion of the investigator/ dermatologist.
b The triplicate ECG measurements should be completed after a 5-minute rest period in the supine position and at 2- to 5-min intervals immediately before 
the corresponding PK blood draw. The triplicate ECGs will be collected predose (within 1 hour prior to dosing; see Table 1-3)
c Perform vital signs measurement within 15 minutes prior to dosing. Blood pressure should be determined with the patient in a seated position after the 
patient has been sitting quietly for 5 minutes.
d Hematology will be tested at local and central laboratories and includes hemoglobin, hematocrit, platelet counts, RBC, WBC, absolute reticulocyte counts 
(only for patients who experience recurrent anemia with hemoglobin < 9 g/dL, despite blood transfusion), absolute differential, and ANC. If a patient 
develops an ANC < 500/μL or a platelet count < 25,000/μL, blood samples must be collected every 2 to 3 days and study treatment withheld until counts 
resolve or until ANC returns to > 1,000/μL and platelet counts return to > 50,000/μL.
e Hematology results (including hemoglobin, hematocrit, platelet counts, RBC, WBC, absolute reticulocyte counts, absolute differential, and ANC) and 
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
18
Q2D 28-Day Treatment Cycle: Cycle 2 Schedule
Tests and Assessments
Cycle 2 (Day 1 through Day 28)
Day 1 2 Days
Day 15 2 Days
Day 27 2 Days
blood chemistry results (including creatinine, total bilirubin, AST, and ALT) will be evaluated before the patient is allowed to take their dose of MLN2480 
on Day 1 of each cycle. Hematology and blood chemistry for Cycle 2, Day 1 may be completed up to 72 hours prior to Day 1.
f
Blood chemistries will be tested at local laboratories and include glucose, BUN, creatinine, sodium, potassium, chloride, CO2, total bilirubin, lactate 
dehydrogenase, alkaline phosphatase, AST, ALT, albumin, and calcium.
g Bone marrow aspirate and biopsy will be encouraged for patients who experience recurrent anemia with hemoglobin < 9 g/dL, despite blood transfusion.
h Within 48 hours of any invasive procedure (ie, tumor biopsy or bone marrow biopsy), aPTT and PT must be within the normal range. For tumor and bone 
marrow biopsies, platelet count should be 75,000/mm3.
i
Urinalysis includes dipstick for blood, protein, and glucose (microscopic examination, if abnormal). Samples will be collected predose.
j
Sample should be collected within 1 hour prior to MLN2480 dosing on Cycle 2, Day 1.
k Refer to Tables 1-1, 1-4, and 1-7 for time points at which blood samples will be collected for PK assessments in the Q2D Dose Escalation Phase, PK 
Expansion cohort, and Q2D melanoma expansion cohorts, respectively. Refer to Laboratory Manual for details on collection, processing, storage, and 
shipment of plasma PK samples.
l
In addition to the scheduled PK sample collections, a blood sample to measure MLN2480 plasma concentrations should be obtained, if clinically feasible, at 
the time of a serious or unusual AE that is judged by the investigator to be treatment-related, irrespective of the cycle or day of occurrence of the AE. See 
Section 7.4.18.
m Disease assessments (including CT or MRI scans of all sites of disease) will be performed every 2 cycles after starting MLN2480 treatment, beginning on 
Cycle 2, Day 27 ± 2 days. Any complete response or partial response must be confirmed at least 4 weeks after the response is first documented. Clinical 
response and disease progression will be evaluated using RECIST, version 1.1, per investigator assessment.
n Concomitant therapies and procedures must be recorded from Screening through the End of Study visit or until the start of subsequent antineoplastic 
therapy, whichever occurs first. Refer to Section 6.6.1 for prohibited medications and therapies and Section 6.6.2.3 for medications or procedures that are 
restricted or should be used cautiously.
o Including serious pretreatment events; see Section 9.
p Patients will take MLN2480 orally once every 2 days and will fast (with the exception of water) for at least 2 hours before and at least 2 hours after taking 
their dose. On dosing days when the patient does not have a clinic visit (ie, Days 3, 5, 7, 9, 11, 13, 17, 19, 21, 23, and 25), patients will take their dose of 
MLN2480 at home.
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
19
Q2D 28-Day Treatment Cycle: Cycle 3 and Subsequent Cycles Schedule
Tests and Assessments
Cycle 3 and Subsequent Cycles
(Day 1 through Day 28)
End of Study 
Visita
Day 1 ± 2 Days
Day 15 ± 2 Days
Day 27 ± 2 Days
Physical examination and body weight measurement
X
X
Dermatological examination with documentation of any suspicious 
lesionsb
X
Xb
ECHO or MUGA
Xc
Single 12-Lead ECG for Safety (all patients)d
X
X
Vital signs (temperature, blood pressure, pulse rate)e
X
X
X
ECOG performance Status
X
Laboratory tests
Hematologyf
Xg
X
X
Blood chemistryh
Xg
X
X
Bone marrow aspirate and biopsyi
Coagulationj
Thyroid function
X
X
Serum pregnancy test (female patients of reproductive potential) 
X
Urinalysisk
X
X
Disease assessment, including CT or MRI scan 
Xl
Xm
Plasma samples for biomarker assessment and circulating tumor DNA 
Xn
X
Concomitant therapy and procedures recordingo
Concomitant therapy and procedures must be recorded from Screening through 
the End of Study visit or the start of subsequent antineoplastic therapy, 
whichever comes first.
AE reporting
AEs will be recorded from first dose of study drug through 30 days after the last 
dose of study drug or the start of subsequent antineoplastic therapy 
SAEs will be collected from signing of the informed consent form through 
30 days after the last dose of study drugp
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
20
Q2D 28-Day Treatment Cycle: Cycle 3 and Subsequent Cycles Schedule
Tests and Assessments
Cycle 3 and Subsequent Cycles
(Day 1 through Day 28)
End of Study 
Visita
Day 1 ± 2 Days
Day 15 ± 2 Days
Day 27 ± 2 Days
MLN2480 Q2D administrationq
MLN2480 dosing is once every 2 days on Days 1-28 of a 
28-day cycle (14 doses)
Abbreviations: AE=adverse event; ALT=alanine aminotransferase; ANC=Absolute Neutrophil Count; AST=aspartate aminotransferase; BUN=blood urea 
nitrogen; CRF=case report form; CT=computed tomography; ECG=Electrocardiogram; ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology 
Group; MRI=magnetic resonance imaging; MUGA=multiple gated acquisition [scan]; RBC=red blood cell; RECIST=Response Evaluation Criteria in Solid 
Tumors; SAE=serious adverse event; WBC=white blood cell
a The End of Study visit will occur 30 (+ 10) days after the last dose of study treatment or the start of subsequent antineoplastic therapy, whichever occurs 
first. Patients who discontinue study treatment early should complete the End of Study visit 30 (+ 10) days after the last dose of study treatment.
b All patients will be assessed by the investigator or a consulting dermatologist at the visits specified. Assessments need not be repeated if the prior 
assessment was performed within 72 hours. The examination for skin lesions will include the entire skin. Existing lesions will be monitored throughout the 
study and changes to the lesions will be recorded in the CRF. For lesions developing during treatment that are suspected keratoacanthomas or squamous 
cell carcinomas, the dimensions and location on the body will be recorded in the CRF and they will be subsequently biopsied/adequately treated. Other 
lesions that develop during treatment should be recorded on the AE form and may be biopsied at the discretion of the investigator/ dermatologist.
c To be performed on Cycle 2, Day 27; Cycle 4, Day 27; and every 4 cycles thereafter on Day 27 (ie, Cycle 8, Day 27; Cycle 12, Day 27). 
d
A single 12-lead ECG will be collected predose on Day 1 and at the EOS visit. When the timing of a blood sample coincides with the timing of ECG 
measurements, the ECG will be completed before the collection of the blood sample.
e Predose (within 15 minutes prior to dosing; except at End of Study visit where no study drug is administered). Blood pressure should be determined with 
the patient in a seated position after the patient has been sitting quietly for 5 minutes.
f
Hematology will be tested at local laboratories and includes hemoglobin, hematocrit, platelet counts, RBC, WBC, absolute reticulocyte counts (only for 
patients who experience recurrent anemia with hemoglobin < 9 g/dL, despite blood transfusion), absolute differential, and ANC. If a patient develops an 
ANC < 500/μL or a platelet count < 25,000/μL, blood samples must be collected every 2 to 3 days and study treatment withheld until counts resolve or until 
ANC returns to > 1000/μL and platelet counts return to > 50,000/μL.
g Hematology results (including hemoglobin, hematocrit, platelet counts, RBC, WBC, absolute reticulocyte counts, absolute differential, and ANC) and 
blood chemistry results (including creatinine, total bilirubin, AST, and ALT) will be evaluated before the patient is allowed to take their dose of MLN2480 
on Day 1 of each cycle. Hematology and blood chemistry for Cycle 3 and subsequent cycles Day 1 may be completed up to 72 hours prior to Day 1.
h Blood chemistry results include glucose, BUN, creatinine, sodium, potassium, chloride, CO2, total bilirubin, lactate dehydrogenase, alkaline phosphatase, 
AST, ALT, albumin, and calcium.
i
Bone marrow aspirate and biopsy will be encouraged for patients who experience recurrent anemia with hemoglobin < 9 g/dL, despite blood transfusion.
j
Within 48 hours of any invasive procedure (ie, tumor biopsy or bone marrow biopsy), aPTT and PT must be within the normal range. For tumor and bone 
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
21
Q2D 28-Day Treatment Cycle: Cycle 3 and Subsequent Cycles Schedule
Tests and Assessments
Cycle 3 and Subsequent Cycles
(Day 1 through Day 28)
End of Study 
Visita
Day 1 ± 2 Days
Day 15 ± 2 Days
Day 27 ± 2 Days
marrow biopsies, platelet count should be 75,000/mm3.
k Urinalysis includes dipstick for blood, protein, and glucose (microscopic examination, if abnormal). Samples will be collected predose.
l
Disease assessments (including CT or MRI scans of all sites of disease) will be performed every 8 weeks ± 2 days after starting MLN2480 treatment, 
beginning on Cycle 2, Day 27 ± 2 days. Any complete response or partial response must be confirmed at least 4 weeks after the response is first 
documented. Clinical response and disease progression will be evaluated using RECIST, version 1.1 (see Section 14.3), per investigator assessment.
m Disease assessments need not be repeated if performed within 4 weeks prior to the End of Study visit.
n On Cycle 3, Day 1 and beyond, the predose plasma sample will be taken within 1 hour prior to MLN2480 dosing.
o Concomitant therapies and procedures must be recorded from Screening through the End of Study visit or until the start of subsequent antineoplastic 
therapy, whichever occurs first. Refer to Section 6.6.1 for prohibited medications and therapies and Section 6.6.2.3 for medications or procedures that are 
restricted or should be used cautiously.
p Including serious pretreatment events; see Section 9.
q Patients will take MLN2480 orally once every 2 days and will fast (with the exception of water) for at least 2 hours before and at least 2 hours after taking 
their dose. On dosing days when the patient does not have a clinic visit (ie, Days 3, 5, 7, 9, 11, 13, 17, 19, 21, 23, and 25), patients will take their dose of 
MLN2480 at home.
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
22
QW Schedules of Events
QW 28-Day Treatment Cycle: Cycle 1 Schedule
Screening
Day 1
Day 
2
Day 
3
Day 
4
Day 
6
Day 
7
Day 
8
Day 
15
Day 22
Day 
23
Day 
24
Day 
25
Day 
27
Day 
28
≤28 Days 
Before 
Day 1
Pre 
dose
Post
dose
Pre 
dose
Post 
dose
Informed consent 
form
X
Inclusion/exclusion 
criteria
X
Demographics
X
Medical history
X
Complete physical 
examination, height, 
and body weight 
measurement
X
Xa
Dermatological 
examination with 
documentation of 
any suspicious 
lesionsc
X
X
Xc
Xc
Xc
Digital photographs 
of skinb
X
ECHO or MUGA
X
12-lead ECG for 
safety (all patients) d
X
12-lead triplicate 
ECG (Dose 
Escalation phase)d
X
X
X
X
Vital signs
X
Xf
Xf
Xf
Xf
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
23
QW 28-Day Treatment Cycle: Cycle 1 Schedule
Screening
Day 1
Day 
2
Day 
3
Day 
4
Day 
6
Day 
7
Day 
8
Day 
15
Day 22
Day 
23
Day 
24
Day 
25
Day 
27
Day 
28
≤28 Days 
Before 
Day 1
Pre 
dose
Post
dose
Pre 
dose
Post 
dose
(temperature, blood 
pressure, pulse rate)e
ECOG performance 
status
X
Xa
Laboratory tests
Hematologyg
X
Xa,h
X
X
X
Blood chemistryi
X
Xa,h
X
X
X
Bone marrow 
aspirate and 
biopsyj
Coagulationk
X
X
Thyroid function
X
Pregnancy test 
(female patients of 
reproductive 
potential)
Xa
Xa,l
Urinalysism
X
Xa
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
24
QW 28-Day Treatment Cycle: Cycle 1 Schedule
Screening
Day 1
Day 
2
Day 
3
Day 
4
Day 
6
Day 
7
Day 
8
Day 
15
Day 22
Day 
23
Day 
24
Day 
25
Day 
27
Day 
28
≤28 Days 
Before 
Day 1
Pre 
dose
Post
dose
Pre 
dose
Post 
dose
Blood sample for 
PK Sampling 
Schedule D 
(QW dosing; 
Dose Escalation & 
Dose Expansion 
phases)p,q
X
X
X
X
X
X
X
X
X
X
X
X
Blood sample for 
PK Sampling 
Schedule E 
(QW BID dosing; 
Dose Escalation & 
Dose Expansion 
phases)q,r
X
X
X
X
X
X
X
X
Blood sample for 
PK Sampling 
Schedule F 
(QW split 2-day 
dosing; 
Dose Escalation & 
Dose Expansion 
phases)q,s
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine samples for 
PK assessment 
(QW and QW 
BID; Dose 
Escalation phase)t
X
Xu
Urine samples for 
PK assessment 
X
Xu
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
25
QW 28-Day Treatment Cycle: Cycle 1 Schedule
Screening
Day 1
Day 
2
Day 
3
Day 
4
Day 
6
Day 
7
Day 
8
Day 
15
Day 22
Day 
23
Day 
24
Day 
25
Day 
27
Day 
28
≤28 Days 
Before 
Day 1
Pre 
dose
Post
dose
Pre 
dose
Post 
dose
(QW split 2-day 
dosing; Dose 
Escalation phase)t
Fresh tumor biopsyw
X
X
Disease assessment, 
including CT or 
MRI scan
Xx
Concomitant therapy 
and procedures 
recordingy
Concomitant therapy and procedures must be recorded from Screening through the End of Study visit or the start of subsequent 
antineoplastic therapy, whichever comes first.
AE reporting
AEs will be recorded from first dose of study drug through 30 days after the last dose of study drug
or the start of subsequent antineoplastic therapy, whichever occurs first.
SAEs will be collected from signing of the informed consent form through 30 days after the last dose of study drug.z
MLN2480 administration (Dose Escalation and Dose Expansion phases)aa
QW dosing 
MLN2480 dosing weekly, on Days 1, 8, 15, and 22 of a 28-day cycle (4 doses), starting on Day 1
QW BID dosing 
MLN2480 dosing weekly, BID, on Days 1, 8, 15, and 22 of a 28-day cycle (8 doses), 
starting on Day 1
QW split 2-day 
dosing
MLN2480 dosing weekly, on Days 1 & 2, 8 & 9, 15 & 16, and 22 & 23 of a 28-day cycle (8 doses), 
starting on Day 1
Abbreviations: aPTT=activated partial thromboplastin time; AE=adverse event; ALT=alanine aminotransferase; ANC=Absolute Neutrophil Count; 
AST=aspartate aminotransferase; BUN=blood urea nitrogen; CRF=Case Report Form; CT=computed tomography; DLT=dose-limiting toxicity; 
ECG=Electrocardiogram; ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology Group; 
; ICF=informed 
consent form; MRI=magnetic resonance imaging; MUGA=multiple gated acquisition [scan]; PK=pharmacokinetic; PT=prothrombin time; RBC=red blood 
cell; SAE=serious adverse event; WBC=white blood cell.
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
26
QW 28-Day Treatment Cycle: Cycle 1 Schedule
Screening
Day 1
Day 
2
Day 
3
Day 
4
Day 
6
Day 
7
Day 
8
Day 
15
Day 22
Day 
23
Day 
24
Day 
25
Day 
27
Day 
28
≤28 Days 
Before 
Day 1
Pre 
dose
Post
dose
Pre 
dose
Post 
dose
An End-of-Cohort meeting scheduled by the sponsor will occur after the last patient in each cohort in the Dose Escalation phase has completed the first 
treatment cycle/DLT observation period (ie, Day 1 to Day 28).
AEs that occur during the Screening period (following informed consent, but prior to study drug administration) will be recorded as part of the 
patient’s medical history.
a Assessments need not be repeated if Screening assessments were performed within 72 hours before MLN2480 dosing, unless otherwise specified. Height is to 
be collected at Screening only. 
b All patients will be assessed by the investigator or a consulting dermatologist at the visits specified. Assessments need not be repeated if the prior assessment 
was performed within 72 hours. The examination for skin lesions will include the entire skin. At Screening, a complete dermatological exam will be 
performed and digital photographs will be taken to document patients’ baseline skin prior to treatment. Existing lesions will be monitored throughout the study 
and changes to the lesions will be recorded in the CRF and documented in digital photographs. For lesions developing during treatment that are suspected 
keratoacanthomas or squamous cell carcinomas, the dimensions and location on the body will be recorded in the CRF and they will be subsequently 
biopsied/adequately treated. Other lesions that develop during treatment should be recorded on the AE form and may be biopsied at the discretion of the 
investigator/ dermatologist.
c Assessment will be performed  on the study day specified ± 5 days.
d A single 12-lead ECG will be collected at Screening in all patients to assess eligibility. Triplicate 12-lead ECGs will be collected as indicated in Table 1-12 for 
the QW Dose Escalation phase. The triplicate ECG measurements should be completed after a 5-minute rest period in a supine position and will be recorded at 
2 to 5 minute intervals immediately before the corresponding PK blood draw. 
e Blood pressure should be determined with the patient in a seated position after the patient has been sitting quietly for 5 minutes.
f
On Days 1, 8, and 15 vital sign measurements will be performed within 15 minutes prior to dosing. On Cycle 1, Day 1 only, also perform vital sign 
measurements at 2 hours ± 10 minutes and 6 hours ± 10 minutes postdose. 
g Hematology will be tested at local laboratories and includes hemoglobin, hematocrit, platelet counts, RBC, WBC, absolute reticulocyte counts (only for 
patients who experience recurrent anemia with hemoglobin < 9 g/dL, despite blood transfusion), absolute differential, and ANC. If a patient develops an 
ANC < 500/μL or a platelet count < 25,000/μL, blood samples must be collected every 2 to 3 days and study treatment withheld until counts resolve or until 
ANC returns to > 1000/μL and platelet counts return to > 50,000/μL.
h Hematology results (including hemoglobin, hematocrit, platelet counts, RBC, WBC, absolute reticulocyte counts [only for patients who experience recurrent 
anemia with hemoglobin < 9 g/dL, despite blood transfusion], absolute differential, and ANC) and blood chemistry results (including creatinine, total 
bilirubin, AST, and ALT) will be evaluated before the patient is allowed to take their dose of MLN2480 on Day 1 of each cycle.
i
Blood chemistry results will include glucose, BUN, creatinine, sodium, potassium, chloride, CO2, total bilirubin, lactate dehydrogenase, alkaline phosphatase, 
AST, ALT, albumin, and calcium.
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
27
QW 28-Day Treatment Cycle: Cycle 1 Schedule
Screening
Day 1
Day 
2
Day 
3
Day 
4
Day 
6
Day 
7
Day 
8
Day 
15
Day 22
Day 
23
Day 
24
Day 
25
Day 
27
Day 
28
≤28 Days 
Before 
Day 1
Pre 
dose
Post
dose
Pre 
dose
Post 
dose
j
Bone marrow aspirate and biopsy will be encouraged only for patients who experience recurrent anemia with hemoglobin < 9 g/dL, despite blood transfusion.
k Within 48 hours of any invasive procedure (ie, tumor biopsy or bone marrow biopsy), aPTT and PT must be within the normal range. For tumor and bone 
marrow biopsies, platelet count should be 75,000/mm3.
l
A urine or serum pregnancy test is permitted at this time point (C1D1) only. The Screening and EOS pregnancy tests must be serum.
m Urinalysis includes dipstick for blood, protein, pH, Specific gravity, Ketones, Bilirubin, Nitrite, Urobilinogen, Leukocytes and glucose (microscopic 
examination, if abnormal). Samples will be collected predose.
n
o
p See Pharmacokinetic and Electrocardiogram Sampling Schedule D: QW Dose Escalation and Dose Expansion Phases and Table 1-8 for time points at which 
blood samples will be collected for PK assessments. Refer to the Laboratory Manual for details on collection, processing, storage, and shipment of plasma PK 
samples.
q In addition to the scheduled PK sample collections, a blood sample to measure MLN2480 plasma concentrations should be obtained, if clinically feasible, at 
the time of a serious or unusual AE that is judged by the investigator to be treatment-related, irrespective of the cycle or day of occurrence of the AE. See 
Section 7.4.18.
r
If the QW BID dosing schedule is explored to increase systemic exposures, see Pharmacokinetic and Electrocardiogram Sampling Schedule E: Alternative 
(Split Dose, Same Day) QW Dose Escalation and Dose Expansion Phases and Table 1-9 for time points at which blood samples will be collected for PK 
assessments. Refer to the Laboratory Manual for details on collection, processing, storage, and shipment of plasma PK samples.
s If the QW split 2-day dosing schedule is explored to increase systemic exposures, see Pharmacokinetic Sampling Schedule F: Alternative (Split Dose, 
Sequential Days) QW Dose Escalation and Dose Expansion Phases and Table 1-10 for time points at which blood samples will be collected for PK 
assessments. Refer to the Laboratory Manual for details on collection, processing, storage, and shipment of plasma PK samples.
t
Refer to Table 1-11 for time points at which urine samples will be collected for PK assessments.
u Timing for QW PK assessments depends on which QW schedule is being followed. See Table 1-8 through Table 1-12 for more information.
v
w A fresh or archival biopsy of tumor is required for all patients in the 2 dose expansion cohorts at Screening. The Screening tumor biopsy must be immediately 
formalin fixed, paraffin embedded, and have 5 slides cut from the block to be used for genetic analysis. The tissue on the slides must contain at least 4 mm2
tissue area with a minimum of 10% tumor content. Paired fresh tumor biopsies at Screening and on Day 22 of Cycle 1 will also be collected from at least 8 
CCI
CCI
CCI
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
28
QW 28-Day Treatment Cycle: Cycle 1 Schedule
Screening
Day 1
Day 
2
Day 
3
Day 
4
Day 
6
Day 
7
Day 
8
Day 
15
Day 22
Day 
23
Day 
24
Day 
25
Day 
27
Day 
28
≤28 Days 
Before 
Day 1
Pre 
dose
Post
dose
Pre 
dose
Post 
dose
evaluable patients. After 8 pairs of Screening and Day 22 biopsies have been confirmed to be evaluable from a cohort, the Day 22 biopsy for the remaining 
patients in that cohort will be optional. If possible, the Day 22 biopsy should be from the same lesion biopsied during Screening; however, an alternative 
lesion may be used if this is not possible. A fresh biopsy may be required at Screening for patients if an archival tumor tissue sample is unavailable, 
inadequate, or was obtained more than 24 months prior to Screening. A fresh biopsy on Day 22 of Cycle 1 is optional for patients in the Dose Escalation phase 
if an evaluable fresh biopsy was obtained at Screening (see Table 1-13 for more information).
x Refer to Section 7.4.15 and Section 14.3.
y
Refer to Section 6.6.1 for prohibited medications and therapies and Section 6.6.2.3 for medications or procedures that are restricted or should be used 
cautiously.
z Including serious pretreatment events; see Section 9.
aa Timing for QW dosing depends on depends on which QW schedule is being followed. See Table 1-8 through Table 1-12 for more information. Patients will 
fast (with the exception of water) for at least 2 hours before and at least 2 hours after taking their dose.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
29
QW 28-Day Treatment Cycle: Cycle 2 Schedule 
Tests and Assessments
Cycle 2 (Day 1 through Day 28)
Day 1 2 Days
Day 15 2 Days
Day 27 2 Days
Physical examination and body weight measurement 
X
Dermatological examination with documentation of any 
suspicious lesionsa, b
X
X
ECHO or MUGA
X
12-lead Single ECG for Safety (all patients)
X 
Vital signs (temperature, blood pressure, pulse rate)c
X
X
Laboratory tests
Hematologyd
Xe
X
Blood chemistryf
Xe
X
Bone marrow aspirate and biopsy
At time of recurrent anemia with hemoglobin < 9 g/dL, despite blood transfusiong
Coagulationh
Thyroid function
X
Urinalysisi
X
Plasma samples for biomarker assessment and 
circulating tumor DNA
Xj
Blood samples for PK assessment (All patients) 
Xk, l
Disease assessment, including CT or MRI scan 
Xm
Concomitant therapy and procedures recordingn
Concomitant therapy and procedures must be recorded from Screening through the End of Study visit 
or start of subsequent antineoplastic therapy, whichever comes first.
AE reporting
AEs will be recorded from first dose of study drug through 30 days after the last dose of study drug or 
the start of subsequent antineoplastic therapy, whichever occurs first.
SAEs will be collected from signing of the informed consent form through 30 days after the last dose 
of study drug.o
MLN2480 QW administrationp
MLN2480 dosing is once weekly on Days 1, 8, 15, and 22 of a 28-day cycle (4 doses)
QW dosing 
MLN2480 dosing weekly, on Days 1, 8, 15, and 22 of a 28-day cycle (4 doses), starting on Day 1
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
30
QW 28-Day Treatment Cycle: Cycle 2 Schedule 
Tests and Assessments
Cycle 2 (Day 1 through Day 28)
Day 1 2 Days
Day 15 2 Days
Day 27 2 Days
QW BID dosing 
MLN2480 dosing weekly, BID, on Days 1, 8, 15, and 22 of a 28-day cycle (8 doses), 
starting on Day 1
QW split 2-day dosing
MLN2480 dosing weekly, on Days 1 & 2, 8 & 9, 15 & 16, and 22 & 23 of a 28-day cycle (8 doses), 
starting on Day 1
Abbreviations: aPTT=activated partial thromboplastin time; AE=adverse event; ALT=alanine aminotransferase; ANC=Absolute Neutrophil Count; 
AST=aspartate aminotransferase; BUN=blood urea nitrogen; CT=computed tomography; ECG=Electrocardiogram; ECHO=echocardiogram; ECOG=Eastern 
Cooperative Oncology Group; MRI=magnetic resonance imaging; MUGA=multiple gated acquisition [scan]; PK=pharmacokinetic; PT=prothrombin time; 
RBC=red blood cell; RECIST=Response Evaluation Criteria in Solid Tumors; SAE=serious adverse event; WBC=white blood cell.
a Assessments need not be repeated if the prior assessment was performed within 72 hours.
b All patients will be assessed by the investigator or a consulting dermatologist at the visits specified. The examination for skin lesions will include the entire 
skin. Existing lesions will be monitored throughout the study and changes to the lesions will be recorded in the CRF. For lesions developing during treatment 
that are suspected keratoacanthomas or squamous cell carcinomas, the dimensions and location on the body will be recorded in the CRF and they will be 
subsequently biopsied/adequately treated. Other lesions that develop during treatment should be recorded on the AE form and may be biopsied at the 
discretion of the investigator/ dermatologist.
c Perform vital signs measurement within 15 minutes prior to dosing. Blood pressure should be determined with the patient in a seated position after the patient 
has been sitting quietly for 5 minutes.
d Hematology will be tested at local and central laboratories and includes hemoglobin, hematocrit, platelet counts, RBC, WBC, absolute reticulocyte counts 
(only for patients who experience recurrent anemia with hemoglobin < 9 g/dL, despite blood transfusion), absolute differential, and ANC. If a patient develops 
an ANC < 500/μL or a platelet count < 25,000/μL, blood samples must be collected every 2 to 3 days and study treatment withheld until counts resolve or 
until ANC returns to > 1000/μL and platelet counts return to > 50,000/μL.
e Hematology results (including hemoglobin, hematocrit, platelet counts, RBC, WBC, absolute reticulocyte counts, absolute differential, and ANC) and blood 
chemistry results (including creatinine, total bilirubin, AST, and ALT) will be evaluated before the patient is allowed to take their dose of MLN2480 on Day 1 
of each cycle. Hematology and blood chemistry for Cycle 2, Day 1 may be completed up to 72 hours prior to Day 1.
f
Blood chemistries will be tested at local laboratories and include glucose, BUN, creatinine, sodium, potassium, chloride, CO2, total bilirubin, lactate 
dehydrogenase, alkaline phosphatase, AST, ALT, albumin, and calcium.
g Bone marrow aspirate and biopsy will be encouraged for patients who experience recurrent anemia with hemoglobin < 9 g/dL, despite blood transfusion.
h Within 48 hours of any invasive procedure (ie, tumor biopsy or bone marrow biopsy), aPTT and PT must be within the normal range. For tumor and bone 
marrow biopsies, platelet count should be 75,000/mm3.
i
Urinalysis includes dipstick for blood, protein, and glucose (microscopic examination, if abnormal). Samples will be collected predose.
j
Sample should be collected within 1 hour prior to MLN2480 dosing on Cycle 2, Day 1.
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
31
QW 28-Day Treatment Cycle: Cycle 2 Schedule 
Tests and Assessments
Cycle 2 (Day 1 through Day 28)
Day 1 2 Days
Day 15 2 Days
Day 27 2 Days
k Refer to Table 1-8, Table 1-9, and Table 1-10  for time points at which blood samples will be collected for PK assessments in the QW Dose Escalation and 
Dose Expansion phases. Refer to Laboratory Manual for details on collection, processing, storage, and shipment of plasma PK samples.
l
In addition to the scheduled PK sample collections, a blood sample to measure MLN2480 plasma concentrations should be obtained, if clinically feasible, at 
the time of a serious or unusual AE that is judged by the investigator to be treatment-related, irrespective of the cycle or day of occurrence of the AE. See 
Section 7.4.18.
m Disease assessments (including CT or MRI scans of all sites of disease) will be performed every 2 cycles after starting MLN2480 treatment, beginning on 
Cycle 2, Day 27 ± 2 days. Any complete response or partial response must be confirmed at least 4 weeks after the response is first documented. Clinical 
response and disease progression will be evaluated using RECIST, version 1.1, per investigator assessment.
n Refer to Section 6.6.1 for prohibited medications and therapies and Section 6.6.2.3 for medications or procedures that are restricted or should be used 
cautiously.
o Including serious pretreatment events; see Section 9.
p Timing for QW dosing depends on depends on which QW schedule is being followed. See Table 1-8 through Table 1-12 for more information. Patients will 
fast (with the exception of water) for at least 2 hours before and at least 2 hours after taking their dose.
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
32
QW 28-Day Treatment Cycle: Cycle 3 and Subsequent Cycles Schedule 
Tests and Assessments
Cycle 3 and Subsequent Cycles
(Day 1 through Day 28)
End of Study 
Visita
Day 1 ± 2 Days
Day 15 ± 2 Days
Day 27 ± 2 Days
Physical examination and body weight measurement
X
X
Dermatological examination with documentation of any suspicious lesionsb
X
Xb
ECHO or MUGA
Xc
Single 12-lead ECG for safety (all patients)d
X
X
Vital signs (temperature, blood pressure, pulse rate)e
X
X
X
ECOG performance status
X
Laboratory tests
Hematologyf
Xg
X
X
Blood chemistryh
Xg
X
X
Bone marrow aspirate and biopsyi
Coagulationj
Thyroid function
X
X
Serum pregnancy test (female patients of reproductive potential) 
X
Urinalysisk
X
X
Disease assessment, including CT or MRI scan 
Xl
Xm
Plasma samples for biomarker assessment and circulating tumor DNA 
Xn
X
Concomitant therapy and procedures recordingo
Concomitant therapy and procedures must be recorded from Screening through 
the End of Study visit or the start of subsequent antineoplastic therapy, whichever 
comes first.
AE reporting
AEs will be recorded from first dose of study drug through 30 days after the last 
dose of study drug or the start of subsequent antineoplastic therapy 
SAEs will be collected from signing of the informed consent form through 
30 days after the last dose of study drugp
MLN2480 QW administrationq
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
33
QW 28-Day Treatment Cycle: Cycle 3 and Subsequent Cycles Schedule 
Tests and Assessments
Cycle 3 and Subsequent Cycles
(Day 1 through Day 28)
End of Study 
Visita
Day 1 ± 2 Days
Day 15 ± 2 Days
Day 27 ± 2 Days
QW dosing 
MLN2480 dosing weekly, on Days 1, 8, 15, and 22 of a 28-day cycle (4 doses), starting on Day 1
QW BID dosing 
MLN2480 dosing weekly, BID, on Days 1, 8, 15, and 22 of a 28-day cycle (8 doses), 
starting on Day 1
QW split 2-day dosing
MLN2480 dosing weekly, on Days 1 & 2, 8 & 9, 15 & 16, and 22 & 23 of a 28-day cycle (8 doses), 
starting on Day 1
Abbreviations: AE=adverse event; ALT=alanine aminotransferase; ANC=Absolute Neutrophil Count; AST=aspartate aminotransferase; BUN=blood urea 
nitrogen; CRF=case report form; CT=computed tomography; ECG=Electrocardiogram; ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology 
Group; MRI=magnetic resonance imaging; MUGA=multiple gated acquisition [scan]; RBC=red blood cell; RECIST=Response Evaluation Criteria in Solid 
Tumors; SAE=serious adverse event; WBC=white blood cell
a The End of Study visit will occur 30 (+10) days after the last dose of study treatment or the start of subsequent antineoplastic therapy, whichever occurs first. 
Patients who discontinue study treatment early should complete the End of Study visit 30 (+10) days after the last dose of study treatment.
b All patients will be assessed by the investigator or a consulting dermatologist at the visits specified. Assessments need not be repeated if the prior assessment 
was performed within 72 hours. The examination for skin lesions will include the entire skin. Existing lesions will be monitored throughout the study and 
changes to the lesions will be recorded in the CRF. For lesions developing during treatment that are suspected keratoacanthomas or squamous cell carcinomas, 
the dimensions and location on the body will be recorded in the CRF and they will be subsequently biopsied/adequately treated. Other lesions that develop 
during treatment should be recorded on the AE form and may be biopsied at the discretion of the investigator/ dermatologist.
c To be performed on Cycle 2, Day 27; Cycle 4, Day 27; and every 4 cycles thereafter on Day 27 (ie, Cycle 8, Day 27; Cycle 12, Day 27). 
d A single 12-lead ECG will be collected predose on Day 1 and at the EOS visit. When the timing of a blood sample coincides with the timing of ECG 
measurements, the ECG will be completed before the collection of the blood sample.
e Predose (within 15 minutes prior to dosing; except at End of Study visit where no study drug is administered). Blood pressure should be determined with the 
patient in a seated position after the patient has been sitting quietly for 5 minutes.
f
Hematology will be tested at local laboratories and includes hemoglobin, hematocrit, platelet counts, RBC, WBC, absolute reticulocyte counts (only for 
patients who experience recurrent anemia with hemoglobin < 9 g/dL, despite blood transfusion), absolute differential, and ANC. If a patient develops an 
ANC < 500/μL or a platelet count < 25,000/μL, blood samples must be collected every 2 to 3 days and study treatment withheld until counts resolve or until 
ANC returns to > 1000/μL and platelet counts return to > 50,000/μL.
g Hematology results (including hemoglobin, hematocrit, platelet counts, RBC, WBC, absolute reticulocyte counts, absolute differential, and ANC) and blood 
chemistry results (including creatinine, total bilirubin, AST, and ALT) will be evaluated before the patient is allowed to take their dose of MLN2480 on Day 1 
of each cycle. Hematology and blood chemistry for Cycle 3 and subsequent cycles Day 1 may be completed up to 72 hours prior to Day 1.
h Blood chemistry results include glucose, BUN, creatinine, sodium, potassium, chloride, CO2, total bilirubin, lactate dehydrogenase, alkaline phosphatase, 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
34
QW 28-Day Treatment Cycle: Cycle 3 and Subsequent Cycles Schedule 
Tests and Assessments
Cycle 3 and Subsequent Cycles
(Day 1 through Day 28)
End of Study 
Visita
Day 1 ± 2 Days
Day 15 ± 2 Days
Day 27 ± 2 Days
AST, ALT, albumin, and calcium.
i
Bone marrow aspirate and biopsy will be encouraged for patients who experience recurrent anemia with hemoglobin < 9 g/dL, despite blood transfusion.
j
Within 48 hours of any invasive procedure (ie, tumor biopsy or bone marrow biopsy), aPTT and PT must be within the normal range. For tumor and bone 
marrow biopsies, platelet count should be 75,000/mm3.
k Urinalysis includes dipstick for blood, protein, and glucose (microscopic examination, if abnormal). Samples will be collected predose.
l
Disease assessments (including CT or MRI scans of all sites of disease) will be performed every 8 weeks ± 2 days after starting MLN2480 treatment, 
beginning on Cycle 2, Day 27 ± 2 days. Any complete response or partial response must be confirmed at least 4 weeks after the response is first documented. 
Clinical response and disease progression will be evaluated using RECIST, version 1.1 (see Section 14.3), per investigator assessment.
m Disease assessments need not be repeated if performed within 4 weeks prior to the End of Study visit.
n On Cycle 3, Day 1 and beyond, the predose plasma  sample will be taken within 1 hour prior to MLN2480 dosing.
o Refer to Section 6.6.1 for prohibited medications and therapies and Section 6.6.2.3 for medications or procedures that are restricted or should be used 
cautiously.
p Including serious pretreatment events; see Section 9.
q Timing for QW dosing depends on depends on which QW schedule is being followed. See Table 1-8 through Table 1-12 for more information. Patients will 
fast (with the exception of water) for at least 2 hours before and at least 2 hours after taking their dose.
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
35
12-Week (84-Day) Treatment Cycle for Patients in the Study for 4 Years or Longer
Tests and Assessments
Day 1 ±14 Days
Every 6 Months ±14 Days
Physical examination and body weight 
X
Dermatological exam 
X
Vital signs (temperature, blood pressure, pulse 
rate)a
X
Laboratory tests
Thyroid function
X
Urinalysis
X
Hematologyb
X
Blood chemistryc
X
Disease assessment, including CT or MRI scan
X
Creatine kinase
X
12-lead ECG
X
SAE reporting
SAEs will be collected from signing of informed consent 
form through 30 days after the last dose of study drugd
MLN2480 Q2D administratione
Continuous dosing
a Predose.
b Hematology will be tested at local laboratories and includes hemoglobin, hematocrit, platelet counts, 
RBC, WBC, absolute reticulocyte counts (only for patients who experience recurrent anemia with 
hemoglobin <9 g/dL, despite blood transfusion), absolute differential, and ANC. 
c Blood chemistry results include glucose, BUN, creatinine, sodium, potassium, chloride, CO2, total 
bilirubin, lactate dehydrogenase, alkaline phosphatase, AST, ALT, albumin, and calcium.
d Including serious pretreatment events; see Section 9.
e Patients will fast (with the exception of water) for at least 2 hours before and at least 2 hours after taking 
their dose.
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
36
Pharmacokinetic and Electrocardiogram Sampling Schedule A: Q2D Dose Escalation 
Phase
Table 1-1
MLN2480 Plasma Pharmacokinetic Assessment Time Points 
(Q2D Dose Escalation Phase)
Cycle 1, Day 1:

Predose (within 1 hour prior to dose)a

30 minutes postdose (5 minutes)

1 hour postdose (10 minutes)

2 hours postdose (30 minutes)

4 hours postdose (30 minutes)

6 hours postdose (30 minutes)

8 hours postdose (45 minutes)
Cycle 1, Day 2:

24 hours post Cycle 1, Day 1 dose (1 hour)
Cycle 1, Day 3b:

48 hours post Cycle 1a, Day 1 dose (predose within 1 hour prior to Cycle 1, Day 3 dose)
Cycle 1, Day 9 b:

Predose (within 1 hour prior to dose) a
Cycle 1, Day 15 b:

Predose (within 1 hour prior to dose) a
Cycle 1, Day 21 b:

Predose (within 1 hour prior to dose) a

30 minutes postdose (5 minutes)

1 hour postdose (10 minutes)

2 hours postdose (30 minutes)

4 hours postdose (30 minutes)

6 hours postdose (30 minutes)

8 hours postdose (45 minutes)
Cycle 1, Day 22:

24 hours post Cycle 1, Day 21 dose (1 hour)
Cycle 1, Day 23 b,c:

48 hours post Cycle 1, Day 21 dose (predosea, within 1 hour prior to Cycle 1, Day 23 dose)
Cycle 2, Day 1:

predose, within 1 hour prior to Cycle 2, Day 1 dosea
a All predose PK samples should be collected prior to dosing in the clinic.
b Predose samples should be collected at approximately the same time as the morning dosing times on 
previous days of the cycle. Patients should be instructed to refrain from taking their morning dose before 
coming to the clinic.
c 28-day cycle only.
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
37
Table 1-2
MLN2480 Urine Samples for Pharmacokinetic Assessments 
(Q2D Dose Escalation Phase)
Cycle 1, Day 1:

Predose
Cycle 1, Day 21:

0-8-hour collection after Cycle 1, Day 21 dosea
a The 0-8-hour collection should be completed immediately prior to collection of the 8-hour plasma PK 
sample.
Table 1-3
MLN2480 Triplicate ECG Assessment Time Points 
(Q2D Dose Escalation Phase)
Cycle 1, Day 1:

Predose (within 1 hour prior to dose)

2 hours postdose 

4 hours postdose 

6 hours postdose 
Cycle 1, Day 3:

48 hours post Cycle 1, Day 1 dose (predose within 1 hour prior to Cycle 1, Day 3 dose)
Cycle 1, Day 21 :

Predose (within 1 hour prior to dose)

2 hours postdose 

4 hours postdose 

6 hours postdose 
Cycle 2, Day 1:

Predose (within 1 hour prior to Cycle 2, Day 1 dose)
Triplicate 12-lead ECG measurements should be performed after a 5-minute rest period in the supine 
position and will be recorded at 2- to 5-minute intervals immediately before the collection of the 
corresponding blood PK sample.
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
38
Pharmacokinetic and Electrocardiogram Sampling Schedule B: Q2D PK Expansion 
Cohort (Dose Expansion Phase)
Dosing Q2D C1: D1-D21of a 28-day cycle (D1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21; no dosing 
D22-D28)
Dosing Q2D C2 and beyond: 28-day cycle (D1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27)
Table 1-4
MLN2480 Plasma Pharmacokinetic Assessment Time Points 
(Q2D PK Expansion Cohort)
Cycle 1, Day 1:

Predose (within 1 hour prior to dose)a

30 minutes postdose (5 minutes)

1 hour postdose (10 minutes)

2 hours postdose (30 minutes)

4 hours postdose (30 minutes)

6 hours postdose (30 minutes)

8 hours postdose (45 minutes)
Cycle 1, Day 2:

24 hours post Cycle 1, Day 1 dose (1 hour)
Cycle 1, Day 3b:

48 hours post Cycle 1, Day 1 dose (predose within 1 hour prior to Cycle 1, Day 3 dose)a
Cycle 1, Day 9 b:

Predose (within 1 hour prior to dose) a
Cycle 1, Day 15 b:

Predose (within 1 hour prior to dose) a
Cycle 1, Day 21 b:

Predose (within 1 hour prior to dose) a

30 minutes postdose (5 minutes)

1 hour postdose (10 minutes)

2 hours postdose (30 minutes)

4 hours postdose (30 minutes)

6 hours postdose (30 minutes)

8 hours postdose (45 minutes)
Cycle 1, Day 22:

24 hours post Cycle 1, Day 21 dose (1 hour)
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
39
Table 1-4
MLN2480 Plasma Pharmacokinetic Assessment Time Points 
(Q2D PK Expansion Cohort)
Cycle 1, Day 23 :

48 hours post Cycle 1, Day 21 dose (1 hour)
Cycle 1, Day24

72 hours post Cycle 1, Day 21 dose (2 hours)
Cycle 1, Day 25

96 hours post Cycle 1, Day 21 dose (4 hours)
Cycle 1, Day 26

120 hours post Cycle 1, Day 21 dose (6 hours)
Cycle 2, Day 1:

192 hours post Cycle 1, Day 21 dose (predosea, within 1 hour prior to Cycle 2, Day 1 dose)
a All predose PK samples should be collected prior to dosing in the clinic.
b Predose samples should be collected at approximately the same time as the morning dosing times on 
previous days of the cycle. Patients should be instructed to refrain from taking their morning dose before 
coming to the clinic.
Table 1-5
MLN2480 Urine Samples for Pharmacokinetic Assessments 
(Q2D PK Expansion Cohort)
Cycle 1, Day 1:

Predose
Cycle 1, Day 21:

0-8-hour collection post-Cycle 1, Day 21 dosea
a The 0-8 hour collection should be completed immediately prior to collection of the 8-hour plasma PK 
sample.
Table 1-6
MLN2480 Triplicate ECG Assessment Time Points 
(Q2D PK Expansion Cohort)
Cycle 1, Day 1:

Predose (within 1 hour prior to dose)

2 hours postdose 

4 hours postdose 

6 hours postdose 
Cycle 1, Day 3:

48 hours post Cycle 1, Day 1 dose (predose within 1 hour prior to Cycle 1, Day 3 dose)
Cycle 1, Day 21 :

Predose (within 1 hour prior to dose)

2 hours postdose 

4 hours postdose 
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
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Table 1-6
MLN2480 Triplicate ECG Assessment Time Points 
(Q2D PK Expansion Cohort)

6 hours postdose 
Cycle 1, Day 23

48 hours post-Cycle 1, Day 21 dose
Cycle 1, Day 25

96 hours post-Cycle 1, Day 21 dose
Cycle 2, Day 1:

192 hours post-Cycle 1, Day 21 dose (pre-Cycle 2, Day 1 dose)
Triplicate 12-lead ECG measurements should be performed after a 5-minute rest period in the supine 
position and will be recorded at 2- to 5-minute intervals immediately before the collection of the 
corresponding blood PK sample.
Pharmacokinetic and Electrocardiogram Sampling Schedule C: Q2D Melanoma 
Expansion Cohorts (Dose Expansion Phase)
Dosing: Q2D, 28-day cycle (D1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27)
Table 1-7
MLN2480 Plasma Pharmacokinetic Assessment Time Points 
(Melanoma Expansion Cohorts)
Cycle 1, Day 1:

Predose (within 1 hour prior to dose)a

2 to 4 hours postdose 
Cycle 1, Day 9 b:

Predose (within 1 hour prior to dose) a
Cycle 1, Day 21 b:

Predose (within 1 hour prior to dose) a

2 to 4 hours postdose 
Cycle 1, Day 22:

22 to 30 hours post Cycle 1, Day 21 dose 
Cycle 2, Day 1:

Predose (within 1 hour prior to dose)a

2 to 4 hours postdose
a All predose PK samples should be collected prior to dosing in the clinic.
b Samples should be collected at approximately the same time as the morning dosing times on previous 
days of the cycle. Patients should be instructed to refrain from taking their morning dose before coming 
to the clinic.
Note: No urine PK or triplicate ECG assessments will be done in the Q2D melanoma 
expansion cohorts.
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
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Pharmacokinetic and Electrocardiogram Sampling Schedule D: QW Dose Escalation 
and Dose Expansion Phases
Dosing: QW, 28-day cycle (D1, 8, 15, 22)
Table 1-8
MLN2480 Plasma Pharmacokinetic Assessment Time Points 
(QW Dose Escalation and Dose Expansion Phase)
Cycle 1, Day 1:

Predose (within 1 hour prior to dose)a

1 hour postdose (10 minutes)

2 hours postdose (15 minutes)

3 hours postdose (15 minutes)

4 hours postdose (15 minutes)

5 hours postdose (15 minutes)

6 hours postdose (30 minutes)

8 hours postdose (45 minutes)
Cycle 1, Day 2:

24 hours post Cycle 1, Day 1 dose (1 hour)
Cycle 1, Day 3:

48 hours post Cycle 1a, Day 1 dose (4 hours) 
Cycle 1, Day 6:

120 hours post Cycle 1, Day 1 dose (24 hours)
Cycle 1, Day 8:

Predose (within 1 hour prior to dose) a
Cycle 1, Day 15 :

Predose (within 1 hour prior to dose) a
Cycle 1, Day 22 b:

Predose (within 1 hour prior to dose)a

1 hour postdose (10 minutes)

2 hours postdose (15 minutes)

3 hours postdose (15 minutes)

4 hours postdose (15 minutes)

5 hours postdose (15 minutes)

6 hours postdose (30 minutes)

8 hours postdose (45 minutes)
Cycle 1, Day 23:

24 hours post Cycle 1, Day 22 dose (1 hour)
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
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Table 1-8
MLN2480 Plasma Pharmacokinetic Assessment Time Points 
(QW Dose Escalation and Dose Expansion Phase)
Cycle 1, Day 24 b:

48 hours post Cycle 1, Day 22 dose (4 hours)
Cycle 1, Day 27:

120 hours post Cycle 1, Day 22 dose (24 hours)
Cycle 2, Day 1:

Predose (within 1 hour prior to dose)a
a All predose PK samples should be collected prior to dosing in the clinic. Predose samples should be 
collected at approximately the same time as the morning dosing times on previous days of the cycle.
b Patients should be instructed to refrain from taking their morning dose before coming to the clinic.
Pharmacokinetic and Electrocardiogram Sampling Schedule E: Alternative (Split 
Dose, Same Day) QW Dose Escalation and Dose Expansion Phases
Dosing: QW with BID dosing on Day 1, 8, 15, and 22 in the 28-day cycle
Table 1-9
MLN2480 Plasma Pharmacokinetic Assessment Time Points 
(Alternative QW1 Dose Escalation and Expansion Phase)
Cycle 1, Day 1:

Predose (within 1 hour prior to AM dose)a

1 hour postdose (10 minutes)

2 hours postdose (15 minutes)

3 hours postdose (15 minutes)

4 hours postdose (15 minutes)

5 hours postdose (15 minutes)

6 hours postdose (30 minutes)

8 hours postdose (45 minutes)

12 hours post dose (60 minutes, prior to PM dose)
Cycle 1, Day 8:

Predose (within 1 hour prior to AM dose) a
Cycle 1, Day 15 :

Predose (within 1 hour prior to AM dose) a
Cycle 1, Day 22 b:

Predose (within 1 hour prior to AM dose)a

1 hour postdose (10 minutes)

2 hours postdose (15 minutes)

3 hours postdose (15 minutes)

4 hours postdose (15 minutes)
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
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Table 1-9
MLN2480 Plasma Pharmacokinetic Assessment Time Points 
(Alternative QW1 Dose Escalation and Expansion Phase)

5 hours postdose (15 minutes)

6 hours postdose (30 minutes)

8 hours postdose (45 minutes)

12 hours postdose (60 minutes prior to PM dose)
Cycle 1, Day 23:

24 hours post Cycle 1, Day 22 AM dose (1 hour)
Cycle 1, Day 24:

48 hours post Cycle 1, Day 22 AM dose (4 hours)
Cycle 1, Day 27:

120 hours post Cycle 1, Day 22 AM dose (24 hours)
Cycle 2, Day 1:

Predose (within 1 hour prior to AM dose)a,b
a All predose PK samples should be collected prior to dosing in the clinic. Predose samples should be 
collected at approximately the same time as the morning dosing times on previous days of the cycle. 
b Patients should be instructed to refrain from taking their morning dose before coming to the clinic.
Pharmacokinetic and Electrocardiogram Sampling Schedule F: Alternative (Split 
Dose, Sequential Days) QW Dose Escalation and Dose Expansion Phases
Dosing: QW with dosing on Days 1 & 2, Days 8 & 9, Days 15 & 16 and Days 22 & 23 in 
the 28-day cycle
Table 1-10
MLN2480 Plasma Pharmacokinetic Assessment Time Points 
(Alternative QW2 Dose Escalation and Expansion Phase)
Cycle 1, Day 1:

Predose (within 1 hour prior to dose)a

2 hours postdose (15 minutes)

3 hours postdose (15 minutes)

6 hours postdose (30 minutes)
Cycle 1, Day 2:

Predose (~ 24 hr post D1 dose, prior to D2 dose)

1 hour postdose (10 min)

2 hour postdose (15 min)

3 hour postdose (15 min)

4 hour postdose (15 min)

5 hour postdose (15 min)

6 hour postdose (30 min)

8 hour postdose (30 min)
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
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Table 1-10
MLN2480 Plasma Pharmacokinetic Assessment Time Points 
(Alternative QW2 Dose Escalation and Expansion Phase)
Cycle 1, Day 3:

24 hours post Cycle 1, Day 2 dose (4 hours)
Cycle 1, Day 4:

48 hours post Cycle 1, Day 2 dose (4 hours)
Cycle 1, Day 7:

120 hours post Cycle 1, Day 2 dose (24 hours)
Cycle 1, Day 8:

Predose (within 1 hour prior to dose) a
Cycle 1, Day 15 :

Predose (within 1 hour prior to dose) a
Cycle 1, Day 22 b:

Predose (within 1 hour prior to dose)a

2 hours postdose (15 minutes)

3 hours postdose (15 minutes)

6 hours postdose (30 minutes)
Cycle 1, Day 23:

Predose (within 1 hour prior to dose)a

1 hour postdose (10 minutes)

2 hours postdose (15 minutes)

3 hours postdose (15 minutes)

4 hours postdose (15 minutes)

5 hours postdose (15 minutes)

6 hours postdose (30 minutes)

8 hours postdose (45 minutes)
Cycle 1, Day 24:

24 hours post Cycle 1, Day 23 dose (4 hours)
Cycle 1, Day 25

48 hours post Cycle 1, Day 23 dose (4 hours)
Cycle 1, Day 28:

120 hours post Cycle 1, Day 23 dose (24 hours)
Cycle 2, Day 1:

Predose (within 1 hour prior to dose)a
a All predose PK samples should be collected prior to dosing in the clinic. Predose samples should be 
collected at approximately the same time as the morning dosing times on previous days of the cycle.
b Patients should be instructed to refrain from taking their morning dose before coming to the clinic.
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
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Table 1-11
MLN2480 Urine Samples for Pharmacokinetic Assessments 
(QW and Alternative QW Dose Escalation Phase)
Cycle 1, Day 1:

Predose
Cycle 1, Day 22 (QW and Alternative QW1):

0-8-hour collection after Cycle 1, Day 22 dosea
Cycle 1, Day 23 (only for Alternative QW2 cohorts)

0-8-hour collection after Cycle 1, Day 23 dosea
a The 0-8 hour urine collection should be completed immediately prior to collection of the 8-hour plasma 
PK sample.
Table 1-12
MLN2480 Triplicate ECG Assessment Time Points 
(QW and Alternative QW Dose Escalation Phase)
Cycle 1, Day 1:

Predose (within 1 hour prior to dose)

2 hours postdose 

3 hours postdose

4 hours postdose 

5 hours postdose

6 hours postdose 
Cycle 1, Day 22a :

Predose (within 1 hour prior to dose)

2 hours postdose 

3 hours postdose

4 hours postdose 

5 hours postdose

6 hours postdose 
Triplicate 12-lead ECG measurements should be performed after a 5-minute rest period in the supine 
position and will be recorded at 2- to 5-minute intervals immediately before the collection of the 
corresponding blood PK sample.
a For Alternative QW2 dosing schedule, the triplicate ECG assessment will be performed on Cycle 1 Day 
23.
Note: No urine PK or triplicate ECG assessments will be done in the QW dose expansion 
cohorts.
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
46
Tumor Tissue Samples for Pharmacodynamic and Correlative Biomarker Analysis: 
Q2D and QW (Including Alternative QW Schedules)
Required Tissue Sample
Optional Tissue Sample
CCI
CCI
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
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CCI
CCI
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
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TABLE OF CONTENTS
LIST OF TABLES.............................................................................................................50
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ..........................................52
1. BACKGROUND AND STUDY RATIONALE..............................................................54
1.1 Scientific Background ..............................................................................................54
1.1.1 Disease Under Treatment...................................................................................55
1.1.2 Study Drug ........................................................................................................58
1.2 Nonclinical Experience.............................................................................................58
1.3 Clinical Experience ..................................................................................................61
1.4 Study Rationale ........................................................................................................61
1.5 Rationale for Dose and Schedule Selection...............................................................62
2. STUDY OBJECTIVES ..................................................................................................64
2.1 Primary Objectives ...................................................................................................64
2.2 Secondary Objectives ...............................................................................................65
2.3 Exploratory Objectives.............................................................................................65
3. STUDY ENDPOINTS....................................................................................................66
3.1 Primary Endpoints....................................................................................................66
3.2 Secondary Endpoints................................................................................................66
3.3 Exploratory Endpoints..............................................................................................67
4. STUDY DESIGN...........................................................................................................67
4.1 Overview of Study Design........................................................................................67
4.1.1 Q2D Dose Schedule...........................................................................................68
4.1.2 QW Dose Schedule............................................................................................69
4.2 Number of Patients...................................................................................................69
4.3 Duration of Study.....................................................................................................70
5. STUDY POPULATION.................................................................................................71
5.1 Inclusion Criteria......................................................................................................71
5.2 Exclusion Criteria.....................................................................................................74
6. STUDY DRUG..............................................................................................................76
6.1 Study Drug Administration.......................................................................................76
6.2 Definitions of Dose-Limiting Toxicity......................................................................77
6.3 Dose Escalation Phase..............................................................................................79
6.4 Dose Expansion Phase..............................................................................................83
6.5 Dose Modification Guidelines ..................................................................................86
6.5.1 Dose Escalation Phase .......................................................................................86
6.5.2 Dose Expansion Phase .......................................................................................86
6.6 Concomitant Medications and Procedures ................................................................87
6.6.1 Excluded Concomitant Medications and Procedures ..........................................87
6.6.2 Precautions and Restrictions ..............................................................................88
6.7 Recommendations for Management of Clinical Events: Dose Expansion Phase........91
6.8 Description of Investigational Agents.......................................................................94
6.9 Preparation, Reconstitution, and Dispensation ..........................................................95
6.10 Storage, Handling, and Accountability....................................................................95
7. STUDY CONDUCT ......................................................................................................96
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7.1 Study Personnel, Organizations, and Systems...........................................................96
7.1.1 Contract Research Organization.........................................................................96
7.1.2 Remote Data Capture.........................................................................................96
7.2 Arrangements for Recruitment of Patients ................................................................97
7.3 Treatment Group Assignments .................................................................................97
7.4 Study Procedures......................................................................................................98
7.4.1 Informed Consent ..............................................................................................98
7.4.2 Patient Demographics ........................................................................................98
7.4.3 Medical History.................................................................................................99
7.4.4 Physical Examination.........................................................................................99
7.4.5 Eastern Cooperative Oncology Group Performance Status.................................99
7.4.6 Height and Weight.............................................................................................99
7.4.7 Vital Signs .........................................................................................................99
7.4.8 Pregnancy Test ..................................................................................................99
7.4.9 Concomitant Medications and Procedures........................................................100
7.4.10 Adverse Events..............................................................................................100
7.4.11 Enrollment .....................................................................................................100
7.4.12 Multiple Gated Acquisition Scan and/or Echocardiogram ..............................100
7.4.13 Electrocardiograms ........................................................................................100
7.4.14 Clinical Laboratory Evaluations.....................................................................101
7.4.15 Disease Assessment .......................................................................................102
7.4.16 Dermatological Examination..........................................................................103
7.4.17 Dermatological Photographs ..........................................................................103
7.4.18 Pharmacokinetic Measurements.....................................................................103
7.4.19 Pharmacodynamic Assessment/ Fresh Tumor Biopsies ..................................104
7.4.20 Archival/ Fresh Tumor Specimen Measurements for Tumor Genotyping .......105
7.4.21 Pharmacogenomic Assessment.......................................................................106
7.5 Completion of Study...............................................................................................106
7.6 Withdrawal of Patients From Study........................................................................106
7.7 Study Stopping Rules .............................................................................................107
8. STATISTICAL AND QUANTITATIVE ANALYSES ................................................108
8.1 Statistical Methods .................................................................................................108
8.1.1 Determination of Sample Size..........................................................................108
8.1.2 Randomization and Stratification .....................................................................108
8.1.3 Populations for Analysis ..................................................................................109
8.1.4 Procedures for Handling Missing, Unused, and Spurious Data.........................109
8.1.5 Demographic and Baseline Characteristics.......................................................109
8.1.6 Efficacy Analysis.............................................................................................110
8.1.7 Pharmacokinetic Analysis ................................................................................110
8.1.8 Pharmacodynamic Analysis .............................................................................111
8.1.9 Pharmacogenomic Analysis .............................................................................112
8.1.10 Safety Analysis ..............................................................................................112
8.1.11 Interim Analysis.............................................................................................114
9. ADVERSE EVENTS ...................................................................................................114
9.1 Definitions..............................................................................................................114
9.1.1 Pretreatment Event Definition..........................................................................114
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9.1.2 Adverse Event Definition.................................................................................114
9.1.3 Serious Adverse Event Definition ....................................................................115
9.1.4 Prescheduled or Elective Procedures or Routinely Scheduled Treatments ........116
9.2 Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events...............................................................................................116
9.3 Monitoring of Adverse Events and Period of Observation.......................................118
9.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events........119
10. ADMINISTRATIVE REQUIREMENTS ...................................................................119
10.1 Good Clinical Practice..........................................................................................119
10.2 Data Quality Assurance ........................................................................................119
10.3 Electronic Case Report Form Completion.............................................................119
10.4 Study Monitoring .................................................................................................120
10.5 Ethical Considerations..........................................................................................120
10.6 Patient Information and Informed Consent............................................................121
10.7 Patient Confidentiality..........................................................................................121
10.8 Investigator Compliance.......................................................................................121
10.9 On-site Audits ......................................................................................................121
10.10 Investigator and Site Responsibility for Drug Accountability..............................122
10.11 Product Complaints ............................................................................................122
10.12 Closure of the Study ...........................................................................................122
10.13 Record Retention................................................................................................123
11. USE OF INFORMATION..........................................................................................124
12. INVESTIGATOR AGREEMENT..............................................................................126
13. REFERENCES...........................................................................................................127
14. APPENDICES ...........................................................................................................130
14.1 Eastern Cooperative Oncology Group Scale for Performance Status.....................130
14.2 22-Day Treatment Cycle Schedule of Events Tables.............................................130
14.3 Response Evaluation Criteria in Solid Tumors (Version 1.1) ................................141
14.4 Amendment 1 Summary of Changes.....................................................................143
14.5 Amendment 2 Summary of Changes.....................................................................146
14.6 Amendment 3 Summary of Changes.....................................................................147
14.7 Amendment 4 Summary of Changes.....................................................................148
14.8 Amendment 5 Summary of Changes.....................................................................149
14.9 Amendment 6 Summary of Changes.....................................................................151
14.10 Amendment 7 Summary of Changes...................................................................152
14.11 Amendment 8 Summary of Changes...................................................................153
14.12 Detailed Description of Amendments to Text .....................................................155
LIST OF TABLES
Table 1-1
MLN2480 Plasma Pharmacokinetic Assessment Time Points 
(Q2D Dose Escalation Phase)......................................................................36
Table 1-2
MLN2480 Urine Samples for Pharmacokinetic Assessments 
(Q2D Dose Escalation Phase)......................................................................37
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
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Table 1-3
MLN2480 Triplicate ECG Assessment Time Points 
(Q2D Dose Escalation Phase)......................................................................37
Table 1-4
MLN2480 Plasma Pharmacokinetic Assessment Time Points 
(Q2D PK Expansion Cohort).......................................................................38
Table 1-5
MLN2480 Urine Samples for Pharmacokinetic Assessments 
(Q2D PK Expansion Cohort).......................................................................39
Table 1-6
MLN2480 Triplicate ECG Assessment Time Points 
(Q2D PK Expansion Cohort).......................................................................39
Table 1-7
MLN2480 Plasma Pharmacokinetic Assessment Time Points 
(Melanoma Expansion Cohorts)..................................................................40
Table 1-8
MLN2480 Plasma Pharmacokinetic Assessment Time Points  (QW Dose 
Escalation and Dose Expansion Phase)........................................................41
Table 1-9
MLN2480 Plasma Pharmacokinetic Assessment Time Points 
(Alternative QW1 Dose Escalation and Expansion Phase)...........................42
Table 1-10
MLN2480 Plasma Pharmacokinetic Assessment Time Points 
(Alternative QW2 Dose Escalation and Expansion Phase)...........................43
Table 1-11
MLN2480 Urine Samples for Pharmacokinetic Assessments (QW and 
Alternative QW Dose Escalation Phase)......................................................45
Table 1-12
MLN2480 Triplicate ECG Assessment Time Points  (QW and Alternative 
QW Dose Escalation Phase)........................................................................45
Table 1-13
Tumor Tissue Samples for Pharmacodynamic and Correlative Biomarker 
Analysis......................................................................................................47
Table 6-1
Q2D Planned Dose Levels...........................................................................82
Table 6-2
QW Planned Dose Levels............................................................................82
Table 6-3
Management of Elevated Creatine Kinase Levels........................................92
Table 6-4
Management of Rash...................................................................................93
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MLN2480 (TAK-580)
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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the plasma concentration versus time curve
BID
bis in die; twice daily
CLr
renal clearance
Cmax
maximum plasma concentration
CR
complete response 
CRO
contract research organization
CT
computed tomography
Ctrough
trough concentration
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DLT
dose-limiting toxicity
DOR
duration of response
DTIC
dacarbazine
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
ERK
extracellular signal-regulated kinase
EU
European Union
FDA
United States Food and Drug Administration
FFPE
formalin-fixed paraffin-embedded 
FIH
first in human
GCP
Good Clinical Practice
GLP
Good Laboratory Practices
HNSTD
highest nonseverely toxic dose
IB
Investigator’s Brochure
IC50
concentration producing 50% inhibition
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IL
interleukin
IRB
institutional review board
mAbs
monoclonal antibodies
MAPK
mitogen-activated protein kinase
MedDRA
Medical Dictionary for Regulatory Activities
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MLN2480 (TAK-580)
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Abbreviation
Term
MEK
MAPK or extracellular signal-regulated kinase
MET
mesenchymal-epithelial transition factor
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI
National Cancer Institute
NPO
nothing by mouth
ORR
overall response rate
OS
overall survival
PD
progressive disease (disease progression)
pERK
phosphorylated extracellular signal-regulated kinase
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
partial response
PT
prothrombin time
QD
quaque die; each day; once daily
Q2D
every other day
QOL
quality of life
QTc
rate-corrected QT interval (millisec) of electrocardiograph
QW
weekly dosing
RDC
remote data capture
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended phase 2 dose
SAE
serious adverse event
SD
stable disease
SUSAR
suspected unexpected serious adverse reaction
t1/2
half-life
TAK-580
New product code for MLN2480
TEAE
treatment-emergent adverse event
Tmax
first time to maximum plasma concentration
ULN
upper limit of the normal range
US
United States
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MLN2480 (TAK-580)
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1.
BACKGROUND AND STUDY RATIONALE
1.1
Scientific Background 
MLN2480, currently known as TAK-580, is a potent, small molecule pan-RAF kinase 
inhibitor being developed for the treatment of solid tumors, including locally advanced, 
metastatic, and/or unresectable melanoma. The RAF kinases (A-RAF, B-RAF, and C-RAF) 
are key components of the mitogen-activated protein kinase (MAPK) pathway that controls 
cell proliferation and survival signaling.[1,2] The MAPK pathway, which is composed of 
RAS, RAF, MAPK or extracellular signal-regulated kinase kinase (MEK), and extracellular 
signal-regulated kinase (ERK), integrates signals from receptors on the cell surface 
including cancer-related receptor tyrosine kinases such as the epidermal growth factor 
receptor, mesenchymal-epithelial transition factor (MET), and vascular endothelial growth 
factor receptor.[3] Genetic alterations in the MAPK pathway are among the most common 
in human cancers. Up to 60% of melanomas harbor B-RAF mutations[4] and K-RAS
mutations have been estimated in roughly 60%, 30%, and 15% of pancreatic, colon, and 
lung tumors, respectively.[5] B-RAF mutations are also found in 40% of papillary or 
anaplastic thyroid cancers[6] and in a small percentage of several other types of tumor.[5] A 
majority of reported B-RAF mutations are a substitution of glutamic acid for valine at the 
amino acid position of 600 (the V600E mutation). The B-RAF V600E mutation 
constitutively activates B-RAF and downstream signal transduction in the MAPK 
pathway.[4]
To address these RAF pathway-driven cancers, small molecule RAF kinase inhibitors have 
been developed and are currently under clinical investigation or commercially available. In 
cells carrying the B-RAF V600E mutation, RAF compounds inhibit signaling through MEK 
and ERK, resulting in the expected anti-proliferative effects. PLX4032 (vemurafenib, 
Plexxikon in collaboration with Roche Pharmaceuticals [Roche ID RG7204]) is a potent 
inhibitor of B-RAF V600E. Nonclinical studies showed that PLX4032 and its analog 
PLX4720 inhibit the kinase activity of B-RAF V600E at low nanomolar concentrations, 
abrogate signaling through the MAPK pathway, and block proliferation of cells carrying the 
B-RAF V600E mutation in vitro at high nanomolar concentrations.[7,8] Orally administered 
PLX4032 inhibits the growth and, at higher doses, induces the regression of human 
melanoma tumors transplanted into immunocompromised mice. The results of this 
completed phase 1 study were published recently. Of the patients receiving doses of 240 mg 
or more twice daily (BID) in the dose escalation cohort, 16 had melanoma tumors with the 
B-RAF V600E mutation. Among these 16 patients, the overall response rate (ORR) was 69% 
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(11 of 16 patients), with 10 partial responses (PRs) and 1 complete response (CR). Among 
32 patients with the B-RAF V600E mutation in the expansion cohort, 24 had a PR and 2 had 
a CR.[9] PLX4032 was also investigated in a single-arm phase 2 study evaluating best ORR 
in 132 previously treated patients with B-RAF V600E metastatic melanoma. Preliminary 
results indicate a confirmed response rate of 52%, including 3 confirmed CRs (no evidence 
of disease) and 66 confirmed PRs (tumor shrinkage of at least 30%).[10] A recent phase 3 
randomized trial has demonstrated that previously untreated B-RAF V600E 
mutation-positive melanoma patients treated with PLX4032 had an improved overall 
survival (OS) compared to those treated with a standard-of-care agent, dacarbazine 
(DTIC).[11] Clinical activity was also observed in the first-in-human (FIH) study for the 
pan-RAF inhibitor XL281, with a clinical benefit rate of 43%, including a confirmed PR in 
an ocular melanoma patient.[12]
Melanocytes rely on the MAPK and cyclic adenosine monophosphate signaling pathways to 
maintain the balance between proliferation and differentiation that is critical for normal 
function.[13] In normal melanocytes, B-RAF alone is responsible for MEK activation, but 
upon oncogenic activation of RAS, cells switch their signaling dependency from B-RAF to 
C-RAF.[14] Recently published data using RAS mutant preclinical models has highlighted 
significant differences in the action of pan-RAF and B-RAF specific inhibitors that may be 
critical for their clinical application in the treatment of RAS mutant cancers.[15,16] The 
inhibition of B-RAF by B-RAF specific inhibitors such as PLX4032 induced strong binding 
of B-RAF to C-RAF in N-RAS mutant melanoma and K-RAS mutant colorectal cancer cell 
lines, resulting in C-RAF phosphorylation and activation. These observations may indicate 
that in the presence of activating RAS mutations, B-RAF selective inhibitors are involved in 
the activation of MEK signaling in a C-RAF-dependent fashion. Although pan-RAF 
inhibitors are involved in B-RAF and C-RAF heterodimerization in these RAS mutant 
models, they also inhibit signaling for the heterodimer.[16] Therefore, this differentiation 
could be relevant not only in the treatment of RAS mutant tumors, but also in the 
management of B-RAF mutant tumors that become resistant to B-RAF selective inhibition 
through activation of RAS.[17] Taken together, MLN2480 has a broad therapeutic potential 
in the treatment of melanoma and other B-RAF and RAS mutant tumors.
1.1.1 Disease Under Treatment
Overview of Melanoma
The incidence of melanoma varies considerably with geography, as would be expected since 
sun exposure (both the intensity of individual episodes of sun exposure and cumulative 
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ultraviolet light exposure) is the dominant etiologic risk factor. The publication Cancer 
Incidence in Five Continents by the International Agency for Research on Cancer volume IX 
covers the period from 1998 to 2002 and states that the highest recorded incidence of 
melanoma worldwide is in Queensland, Australia, at a figure of 55.8/100,000/annum for 
males and 41.1/100,000/annum for females.[18,19] The Surveillance, Epidemiology, and 
End Results data for the United States (US) lists a melanoma incidence in non-Hispanic 
whites of 19.4 and 14.4 per 100,000/annum in males and females, respectively. Reported 
melanoma incidence rates vary for Europe and are highest in Switzerland (16.6 and 19.6 per 
100,000/annum in males and females, respectively) and the Scandinavian countries of 
Norway, Sweden, and Denmark (11.9 to 14.2 and 12.1 to 14.6 per 100,000/annum in males 
and females, respectively).[19] Data from the majority of countries show that at a time when 
the incidence of many tumor types is decreasing, melanoma incidence continues to increase.
Approximately 80% of cutaneous melanoma lesions are diagnosed as Stage I tumors, 
conferring a 90% 5-year survival rate when treated with surgery with or without adjuvant 
interferon. However, once malignant melanoma becomes metastatic and beyond the scope of 
surgical resection, it represents one of the most treatment-refractory malignancies.
Current Therapies for Metastatic Melanoma
In metastatic melanoma, single-agent chemotherapeutic agents, including DTIC and 
temozolomide, produce responses in 10% to 20% of patients, with a median survival of 
approximately 9 months and a 2-year survival rate of 13%.[20] Response rates for the 
biologic therapies interferon and interleukin (IL)-2 are also in the range of 10% to 20%. 
Therefore, none of these therapies appear superior to best supportive care and provide 
benefit to a majority of patients. Combination chemotherapy regimens, including 
cisplatin-vinblastine-DTIC and cisplatin-DTIC-carmustine-tamoxifen (Dartmouth regimen), 
result in improved response rates of 30% to 50%. However, these superior response rates 
fail to translate into an improvement in median survival and the negative impact on 
tolerability is significant.[21]
A variety of therapeutic approaches have reached late-stage development or have been 
approved for treatment of metastatic melanoma,[22] including the immunomodulatory 
antibody ipilimumab,[23] vermurafenib (PLX-0432), dabrafenib, and trametinib.
Ipilimumab was approved based on a three-armed phase 3 study (MDX010-20); ipilimumab 
and gp100 (an experimental melanoma vaccine) in combination, versus ipilumimab and 
gp100 placebo in combination, versus ipilimumab placebo and gp100 in combination. The 
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median overall survival for ipilimumab was 10.1 months compared with 6.4 months for 
gp100; the investigator-assessed objective response rate was 10.9% in the ipilimumab arm 
and 1.5% in the gp100 arm.[24] The safety profile showed that ipilimumab was most 
commonly associated with AEs resulting from increased or excessive immune activity. 
These immune-related AEs (irAEs) primarily involved the gastrointestinal (GI) tract and 
skin, and less frequently, the liver, endocrine glands, and nervous system. While most irAEs 
occurred during the induction period, onset has also been reported months after the last dose 
of ipilimumab, making monitoring of these events challenging.[25]
The results of another phase 3 study comparing ipilimumab and DTIC in combination 
against DTIC alone in patients with previously untreated metastatic melanoma have been 
published.[26] Overall survival was significantly longer in the group receiving ipilimumab 
and DTIC than in the group receiving DTIC alone (11.2 and 9.1 months, respectively). 
However, Grade 3 or 4 adverse events (AEs) occurred in 56.3% of patients treated with 
ipilimumab and DTIC, as compared with 27.5% treated with DTIC alone. 
The oral targeted therapy vemurafenib (PLX-4032) was additionally approved for patients 
with melanoma whose tumors have the BRAF V600E mutation. The phase 3 trial 
demonstrated an OS advantage over DTIC.[11] However, roughly one half of patients 
enrolled in PLX-4032 vemurafenib clinical studies eventually progressed, indicating that 
acquired resistance may impact long-term clinical activity[27] and one of resistance 
mechanisms has been demonstrated as activation of RAS.[17,28]
Most recently approved for patients with BRAF V600E positive melanoma are dabrafenib 
(BRAF inhibitor) and trametinib (MEK inhibitor). Both drugs significantly improved the 
median progression-free survival compared with chemotherapy in phase 3 studies. However, 
as is the case with vemurafenib, these responses are considered short-lived.30  Ongoing trials 
examine the use of these 2 drugs in combination.[29,30]
Other therapies, including anti-PD-1 and anti-PDL-1 monoclonal antibodies (mAbs) and a 
variety of signaling pathway inhibitors, are currently in various stages of clinical 
development.[31,32] Given the rapid rise in the incidence of melanoma and the limited
options for effective treatment of metastatic melanoma as well as resistance developed in 
patients treated with vemurafenib and high incidence of AEs with ipilimumab, the 
evaluation of different treatment strategies, including targeted therapies such as pan-RAF 
inhibitors to overcome these clinical challenges, is warranted. 
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1.1.2 Study Drug
MLN2480 is a potent, small-molecule, pan-RAF kinase inhibitor being developed for the 
treatment of solid tumors, including locally advanced, metastatic, and/or unresectable
melanoma. 
1.2
Nonclinical Experience
Pharmacology
Nonclinical studies support the potential therapeutic benefits of MLN2480 in solid tumors, 
including metastatic melanoma and colon cancer. MLN2480 was tested in a variety of 
in vitro biochemical and cell-based assays to measure its potency, selectivity, and activity in 
cancer cell lines. In biochemical kinase inhibition assays, MLN2480 potently inhibited each 
RAF kinase isoform tested: B-RAF V600E mutant, B-RAF wild-type, and C-RAF 
wild-type. To gage its selectivity, MLN2480 was screened on a large panel of human 
kinases and non-kinase targets and showed a high degree of selectivity for RAF kinases. To 
determine the activity of MLN2480 on cancer cells, MLN2480 was tested in a panel of 
42 cancer cell lines from a variety of different tumor types and with different genetic 
mutations for its antiproliferative activity. Inhibition of phosphorylated ERK (pERK) 
signaling was measured in a subset of 23 of these cell lines to correlate inhibition of RAF 
signaling with antiproliferative activity. These cancer cell lines exhibited a range of 
sensitivities to MLN2480, with the B-RAF mutant cell lines being the most sensitive. A 
subset of the B-RAF wild-type cell lines, including the RAS mutant cell lines, was also 
sensitive. To assess the in vivo potency and pan-RAF activity of MLN2480, several tumor 
pharmacodynamic studies were conducted. In these studies, tumor-bearing mice were 
administered a single oral dose of MLN2480 and the degree of pERK suppression was 
measured at different time points, along with plasma and tumor drug levels to assess the 
pharmacokinetic (PK)/pharmacodynamic correlation. MLN2480 showed strong and 
sustained suppression of the pERK biomarker in both B-RAF mutant and wild-type tumor 
xenograft models, indicating that MLN2480 is a potent pan-RAF inhibitor in vivo. The in 
vivo antitumor activity of MLN2480 was evaluated by testing MLN2480 in 12 different 
tumor xenograft models with oral dosing on an every other day (Q2D) or once daily (QD) 
schedule. The tumor models tested included melanoma, colon, lung, pancreatic, and prostate 
cancer models that differed in their B-RAF mutation and RAS mutation status. MLN2480 
showed significant antitumor activity in 9 of these 12 models on the QD schedule, including 
models of melanoma, colon, lung, and pancreatic cancer. The 9 models in which MLN2480 
showed significant antitumor activity included 4 B-RAF mutant and 5 B-RAF wild-type 
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models, consistent with the in vivo pan-RAF activity of MLN2480. B-RAF mutant tumor 
models were the most sensitive to MLN2480 with regressions of large, established tumors 
observed in 2 melanoma models: WM-266-4 B-RAFV600D and A-375 B-RAFV600E. On 
the Q2D schedule, MLN2480 was efficacious at several doses in the 2 models where this 
schedule was tested, the WM-266-4 melanoma B-RAF mutant model and the Colo-205 
B-RAF mutant model. The efficacy of MLN2480 was also evaluated in combination with 
several oncology therapeutics in some of these tumor models, including oxaliplatin, 
irinotecan, bevacizumab, carboplatin, and gemcitabine. These combination data may support 
clinical testing of MLN2480 following the initial phase 1 study.
Pharmacokinetics
Nonclinical studies were conducted to evaluate PK characteristics of MLN2480. Results 
indicated that MLN2480 was well absorbed after oral administration and was cleared 
slowly, demonstrating a relatively long plasma elimination half-life (t1/2). Apparent volumes 
of distribution estimates suggest that MLN2480 is distributed to peripheral tissues. Every
other day dosing in rats and monkeys did not result in notable MLN2480 accumulation.
In vitro studies indicated that MLN2480 was not a potent, reversible inhibitor of cytochrome 
P450 (CYP) 1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4. The 
concentration producing 50% inhibition (IC50) values were 100M for CYP1A2, 
CYP2B6, CYP2D6, CYP2E1, and CYP3A4 (midazolam). The IC50 values for CYP2C9, 
CYP2C19, and CYP3A4 (testosterone) were 46.5, 82.8, and 40.5 μM, respectively. In 
addition, no time-dependent inhibition of CYP3A4 was observed. Studies in human 
hepatocytes indicated that MLN2480 is not an inducer of CYP1A2 and CYP2C9 and 
suggested a low potential for CYP3A4, CYP2B6, and CYP2C19 induction. Overall, these 
results suggest there is a low probability for MLN2480 to cause drug-drug interactions via 
CYP induction, or via inhibition of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, 
CYP2E1, or CYP3A4.
In contrast to the above enzymes, MLN2480 reversibly inhibited CYP2C8 with an IC50 of 
7.8 M. When considered in the context of MLN2480 exposures, it is inferred that there is a 
potential risk for MLN2480 administration to result in increased exposures of 
co-administered agents that are predominantly metabolized by CYP2C8 due to inhibition of 
this enzyme. Therefore, co-administration of CYP2C8 substrates with MLN2480 should be 
used with caution.
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In vitro data indicates that MLN2480 is metabolized by aldehyde oxidase and CYPs 2C8, 
2C9, 2C19, and 3A4, with relative contributions of 49%, 33%, 8%, 7%, and 4%, 
respectively. Based on this data, concomitant use of strong and moderate inducers of 
CYP3A and CYP2C enzymes, and strong inhibitors of CYP2C8, is prohibited during the 
study. 
Toxicology
Non-Good Laboratory Practice (GLP), 14-day, pilot, repeat-dose tolerability studies of 
MLN2480 in rats (0, 50, 150, 500, and 1,000 mg/kg) and monkeys (0, 3, 10, and 30 mg/kg) 
were performed to evaluate MLN2480 administered orally QD. Accumulation of MLN2480 
was observed with daily dosing. MLN2480 was well tolerated in male rats at up to 
1,000 mg/kg QD and in female rats at 50 or 150 mg/kg QD orally for 14 days. Several 
female rats and several monkeys were sacrificed in moribund condition after 7 or more 
doses. Target organ toxicity in female rats at 150 and 500 mg/kg QD included the ovaries 
(presence of corpora hemorrhagicum and/or hemorrhage), vagina (increased thickness of the 
vaginal mucosa), and skin (ulceration and accumulation of neutrophils along the epidermis). 
Additional target organs at 500 mg/kg QD in female rats included the thymus (lymphocyte 
necrosis in the thymic cortex, occasional mineralized blood vessels [predominately in the 
medulla] and thinning of the cortex), small intestine (increased frequency of crypt 
microabscesses), and lymph nodes (erythrophagocytosis, hemorrhage, and/or lymphocyte 
necrosis in 1 or more lymph nodes). In monkeys, target organs in moribund and 
non-moribund animals at all doses included the bone marrow (hypercellularity in myeloid 
lines and hypocellularity of the erythroid lines), thymus (lymphoid depletion), and 
gastrointestinal tract (infiltration of mixed cells in the lumen and mucosa). Cause of death 
was not determined in this study.
With less frequent repeat dosing compared to QD, non-GLP and GLP toxicology studies 
showed that MLN2480 was better tolerated (no mortality) in nonclinical species and showed 
no evidence of persistent MLN2480 accumulation. In 4-week, Q2D, repeat-dose, GLP 
studies, the target organ of toxicity common to both monkey (0, 3, 10, and 30 mg/kg) and rat 
(0, 50, 150, and 500 mg/kg) was bone marrow (focal precursor depletion in rat and erythroid 
hypocellularity in monkey). Additionally, decreases in mean red blood cells, hemoglobin, 
hematocrit, and absolute reticulocyte counts, and increases in serum transaminases were 
observed in both species. Target organs of toxicity specific to rats included the duodenum 
(crypt microabscesses), ileum (crypt ectasia), ovaries (increased size and/or numbers of 
corpora hemorrhagicum and/or hemorrhage), and vagina (increased thickness of the vaginal 
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mucosa). The relevance of the ovarian and vaginal findings to humans is unclear, as the 
estrus cycle and pathways for luteolysis differ between rodents and humans. However, these 
findings were not observed in monkeys. Increases in serum bilirubin and decreases in mean 
white blood cells were also noted in rats. Target organs of toxicity specific to monkeys 
included thymus (decreases in the thickness of the thymic cortex and medulla), thyroid 
(decreases in the size and numbers of follicles, fibrosis and occasional mononuclear cell 
infiltrates and hemorrhage), and large intestine (mixed cell infiltrates in the mucosa and 
occasional accumulations of neutrophils and necrotic debris in the lumen and crypts). 
Increases in mean white blood cells and absolute neutrophil counts were also monkey-
specific, as well as decreases in serum albumin with associated decreases in the 
albumin:globulin ratio, serum calcium, and serum phosphorous and associated increases in 
parathyroid hormone. The majority of findings were completely reversible, with the only 
exceptions being ovarian findings in rats and thymus changes in monkeys.
Safety pharmacology and genotoxicology studies indicated that MLN2480 is not mutagenic 
or clastogenic, and that MLN2480 has a low risk for central nervous system, respiratory, and 
cardiovascular liabilities.
Please refer to the Investigator’s Brochure (IB) for more details on these nonclinical studies.
1.3
Clinical Experience
This study is the first evaluation of MLN2480 in humans; therefore, no previous human 
experience is available. 
1.4
Study Rationale
Given the rapid rise in the incidence of melanoma and the limited options for effective 
treatment of metastatic melanoma, a pan-RAF inhibitor like MLN2480 that produces MAPK 
blockade at the level of RAF could provide clinical benefit and unmet medical need in 
patients with locally advanced, metastatic, and/or unresectable melanoma. This FIH study 
will be conducted in 2 phases. The Dose Escalation phase will evaluate the safety profile 
and determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose 
(RP2D) of MLN2480, taken as monotherapy by patients with advanced relapsed or 
refractory solid tumors. Two dosing schedules of Q2D and QW will be tested to further 
determine the optimal dosing regimen for MLN2480.
Once the MTD and/or RP2D has been identified for the 28-day treatment cycle, the Dose 
Expansion phase will commence at that dose level in patients with locally advanced, 
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metastatic, and/or unresectable melanoma (Q2D Cohorts 1-6 and QW Cohort 9), or in 
patients with advanced solid tumors, excluding lymphoma, but including melanoma (Q2D 
Cohort 7). The Dose Expansion phase may commence before establishing the MTD/RP2D 
upon medical determination of a safe dose that is lower than MTD/RP2D. Tumor genotype 
is likely to serve as a predictor of response for patients with melanoma, and patients in dose 
expansion will be assigned to 1 of 8 cohorts based on tumor genotype and treatment history. 
Safety and preliminary antitumor activity of MLN2480 will be further characterized in 
patients in the dose expansion cohorts. 
Cohort 7 in the Q2D Dose Expansion phase, the PK Expansion cohort, will include patients 
with any advanced solid tumor (excluding lymphoma, but including melanoma) who have 
failed or are not candidates for standard therapies or for whom no approved therapy is 
available. In addition to contributing to the evaluation of safety, tolerability, and preliminary 
antitumor activity, the PK Expansion cohort will be used to more fully characterize 
MLN2480 PK including half-life.
1.5
Rationale for Dose and Schedule Selection
A sustained, high degree of target suppression in tumor tissue has been reported to be 
necessary for maximal activity with RAF and MEK inhibitors, both in nonclinical models 
and in the PLX4032 phase 1 clinical study.[27,33-35] In mouse tumor pharmacodynamic 
models, MLN2480 caused strong and sustained suppression of the pERK biomarker at a 
dose of 50 mg/kg (> 80% suppression for > 16 hours following a single, oral dose), which 
also demonstrated antitumor activity in multiple tumor xenograft models, on both QD and 
Q2D dosing schedules. This strong and sustained inhibition of RAF is expected to translate 
to the clinical setting, since the t1/2 of MLN2480 in humans is greater than 24 hours, which 
is significantly longer than that in mice (approximately 8 hours). Therefore, it is anticipated 
that administering MLN2480 on a Q2D schedule will provide the required degree of target 
inhibition over the 48-hour dosing interval.
In nonclinical studies, MLN2480 Q2D dosing was better tolerated than QD dosing in 
monkeys. Therefore, MLN2480 Q2D dosing is expected to provide an acceptable 
tolerability profile in humans, while still providing efficacious MLN2480 exposures. The 
MLN2480 starting dose of 20 mg is equivalent to one-sixth of the highest non-severely toxic 
dose (HNSTD)[36] established in GLP monkey toxicology studies and corrected for 
differences in MLN2480 exposures between GLP monkey toxicology studies (using 
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polyethylene glycol as vehicle) and monkey pharmacokinetic studies using the FIH clinical 
formulation (tablet). 
The magnitude of individual dose escalation increments and the specifics of the dose 
escalation design are based on the observed toxicities in the monkey (the most sensitive 
toxicology species), the estimated safety margins with respect to the HNSTD at each human 
dose, and the likely effective dose range in humans (calculated to be > 160 mg for 
MLN2480).
Amendment 3 redefines the study cycle length from 22 days (11 doses) to 28 days 
(14 doses) to improve clinical feasibility and better facilitate future combination with other 
drugs. Upon implementation of Amendment 3, any ongoing dose escalation cohort will 
continue enrollment on the 22-day cycle schedule until the cohort is full and all patients 
have been evaluated for dose-limiting toxicity (DLT) (see Section 6.2). For all subsequent 
dose escalation cohorts and all dose expansion cohorts, patients will be treated Q2D on a 
28-day cycle (14 doses). Patients who began treatment on the 22-day cycle will remain on 
the original treatment schedule for the duration of their participation in the study. 
For the Q2D dosing schedule, regardless of cycle length, dosing is every other day, on a 
continuous basis, with no treatment-free period between cycles (except for cycle 1 in the PK 
Expansion cohort). Administration of the same unit dose every other day in a 28-day cycle 
instead of a 22-day cycle represents a 27% increase in total cycle dose, which is less than the 
smallest (33%) increase in total cycle dose originally planned for the 22-day cycle in the 
Dose Escalation phase. After tolerability is confirmed when the same unit dose is 
administered every other day in a 28-day cycle instead of a 22-day cycle, subsequent dose 
escalations in a 28-day cycle will consist of a 33% increase in both unit and total cycle dose. 
The rationale for evaluation of weekly dosing as an alternate dosing schedule is as follows: 
Analysis of exposure-efficacy relationships in preclinical mouse xenograft models of tumor 
growth inhibition indicate that more robust MAP kinase pathway inhibition may be required 
for antitumor activity in NRAS/ KRAS mutant tumors when compared to BRAF mutant 
tumors. A weekly dosing schedule can therefore be expected to achieve higher unit doses, 
which may allow achievement of higher MLN2480 concentrations, and therefore a higher 
degree of pathway inhibition for a window of time within the dosing interval, without 
compromising overall dose density. The starting dose of the QW schedule is 400 mg, which 
is approximately 43% increase from the maximum administered unit dose of 280 mg Q2D. 
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However, the total cycle dose density for 400 mg QW is 43% lower than that of the current 
MTD of MLN2480 at 200 mg Q2D.
In addition, AEs observed to date in the first week of treatment at doses up to 280 mg Q2D 
that were considered to be drug related were generally mild in nature. One case of each of 
the following was observed within the first week of Q2D treatment (4 doses):

Grade 2 intermittent fatigue (onset on Day 2)

Grade 1 intermittent constipation (onset on Day 3)

Grade 3 diarrhea (onset Day 5)

Grade 2 intermittent myalgia (onset on Day 5)

Grade 1 chills (onset on Day 6)

Grade 1 intermittent arthralgia (onset on Day 7)
The Grade 3 event of diarrhea, which was reported in a patient in the 280 mg Dose 
Escalation cohort, resolved in 2 days. These data, taken together, support the starting dose of 
400 mg QW. 
2.
STUDY OBJECTIVES
2.1
Primary Objectives
The primary objectives of the study are as follows:

To evaluate the safety and tolerability of MLN2480 taken orally Q2D or QW by 
patients with relapsed or refractory solid tumors (Dose Escalation and Dose 
Expansion phase and PK Expansion cohort) or locally advanced, metastatic, and/or 
unresectable melanoma (Dose Expansion phase)

To determine the MTD of MLN2480 taken Q2D or QW by patients with relapsed or 
refractory solid tumors (Dose Escalation phase)

To determine the recommended phase 2 dose (RP2D) of MLN2480 taken Q2D or 
QW by patients with relapsed or refractory solid tumors (Dose Escalation phase)
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2.2
Secondary Objectives
The secondary objectives in this study population are as follows: 

To evaluate the preliminary efficacy of MLN2480 as measured by Response 
Evaluation Criteria in Solid Tumors (RECIST), version 1.1

To evaluate the pharmacokinetics of MLN2480

To evaluate the effect of MLN2480 on pharmacodynamic markers in paired tumor 
biopsies 
2.3
Exploratory Objectives
The exploratory objectives in this study population are as follows:
CCI
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3.
STUDY ENDPOINTS
3.1
Primary Endpoints
The primary endpoints are the safety and tolerability of MLN2480 (incidence of adverse 
events [AEs], serious adverse events [SAEs], dose-limiting AEs within the first cycle, and 
deaths; results of physical examinations, vital sign measurements, electrocardiogram [ECG] 
changes, Eastern Cooperative Oncology Group [ECOG] performance status, and 
hematology, blood chemistry, and urinalysis parameters).
3.2
Secondary Endpoints
The secondary endpoints are as follows:

Preliminary antitumor activity of MLN2480 (overall response rate [ORR], 
progression-free survival [PFS], and duration of response [DOR])

Pharmacokinetics of MLN2480 (maximum observed concentration [Cmax], trough 
concentration [Ctrough], first time to maximum concentration [tmax], t1/2, renal 
clearance (CLr), and area under the concentration-time curve [AUC])

Pharmacodynamic activity of MLN2480 (such as inhibition of pERK and Ki67, and 
cPARP staining) based on tissue availability from tumor biopsy
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3.3
Exploratory Endpoints 
The exploratory endpoints are as follows:
4.
STUDY DESIGN 
4.1
Overview of Study Design
This is a phase 1, multicenter, nonrandomized, open-label, dose escalation study designed to 
evaluate the safety, tolerability, PK, pharmacodynamics, and antitumor activity of 
MLN2480. This study will be the first to administer MLN2480 in humans. The study will be 
conducted in 2 phases (dose escalation and dose expansion) and will test 2 dosing schedules 
(Q2D and QW). 
In the Dose Escalation phase, a 3 + 3 dose escalation design will be implemented to evaluate 
MLN2480 Q2D or QW in dose intervals with continuous dosing (no washout) prespecified 
in the Dose Escalation Algorithm. Patients in the Dose Escalation cohorts will be evaluated 
for dose-limiting toxicity (DLT) during the first cycle of treatment, and decisions regarding 
escalation to the next dose level, expansion of a dose level, or evaluation of an intermediate 
dose level will be determined based on DLT evaluation. Patients in the Dose Escalation 
phase may continue treatment for additional cycles until disease progression, unacceptable 
toxicity, or the patient discontinues for any other reason. The maximum duration of 
treatment will be 12 months unless it is determined that a patient would derive benefit from 
continued therapy beyond 12 months.
CCI
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The dose used for the Dose Expansion phase (MTD and/or RP2D) will be selected based on 
data from the Dose Escalation phase at the corresponding dosing schedule (Q2D or QW). 
The Dose Expansion phase may commence before establishing the MTD/RP2D upon 
medical determination of a safe dose that is lower than MTD/RP2D. 
Patients will fast (with the exception of water) for at least 2 hours before and at least 2 hours 
after taking their dose of MLN2480. Patients in the Dose Expansion phase will take 
MLN2480 orally Q2D or QW in 28-day cycles until disease progression, unacceptable 
toxicity, or the patient discontinues for any other reason. The maximum duration of 
treatment will be 12 months unless it is determined that a patient would derive benefit from 
continued therapy beyond 12 months. 
Patients who discontinue study treatment during Cycle 1 for reasons other than 
MLN2480-related toxicity will be replaced in the Dose Escalation phase of the study.
4.1.1 Q2D Dose Schedule
Q2D Dose Escalation Phase
In the Q2D Dose Escalation phase, a 3 + 3 dose escalation design will be used to evaluate 
MLN2480 orally Q2D, with continuous dosing (no washout). In the Q2D escalation cohorts, 
the first 3 patients with advanced solid tumors will receive a MLN2480 starting dose of 
20 mg every other day for a 22-day cycle (11 doses). Upon implementation of Amendment 
3, any ongoing dose escalation cohort will continue enrollment on the 22-day cycle schedule 
until the cohort is full and all patients have been evaluated for dose-limiting toxicity (DLT) 
(see Section 6.2). For all subsequent dose escalation and expansion cohorts, patients will be 
treated Q2D on a 28-day cycle (14 doses). Patients who began treatment on the 22-day cycle 
may switch from the 22-day to 28-day cycle upon safety confirmation of the 28-day cycle 
and agreement from the investigator and sponsor. The first dose escalation cohort on the 
28-day cycle schedule will repeat the previously tolerated unit dose on the 22-day cycle. 
Administration of the same unit dose every other day in a 28-day cycle instead of a 22-day 
cycle represents a 27% increase in total cycle dose, which is less than the smallest (33%) 
increase in total cycle dose originally planned for the 22-day cycle in the Dose Escalation 
phase. After tolerability is confirmed when the same unit dose is administered every other 
day for 28 days, subsequent dose escalations in a 28-day cycle will consist of a 33% increase 
in both unit and total cycle dose. 
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Q2D Dose Expansion Phase
Once the MTD and/or RP2D of Q2D MLN2480 have been determined, or at the discretion 
of the sponsor, the study will continue to a Q2D Dose Expansion phase, which will enroll 
approximately 96 patients with locally advanced, metastatic, and/or unresectable melanoma 
and approximately 16 patients with any advanced solid tumor (excluding lymphoma). 
Patients with melanoma will be assigned to 1 of 6 Q2D melanoma cohorts based on tumor 
genotype and treatment history. Patients may be enrolled into 1 of 6 melanoma expansion 
cohorts based on previously documented genotype status, but may undergo a fresh biopsy at 
Screening for confirmation. A seventh cohort in the Q2D Dose Expansion phase, the PK 
Expansion cohort, will enroll a sufficient number of patients (approximately 16) with any 
advanced solid tumor (excluding lymphoma) to ensure that 12 patients complete 
protocol-specified dosing and PK assessments scheduled during Cycle 1. 
4.1.2 QW Dose Schedule
QW Dose Escalation Phase
In the QW Dose Escalation phase, a 3 + 3 dose escalation design will be used to evaluate 
MLN2480 orally Q2D on Days 1, 8, 15, and 22 of a 28-day cycle. The first 3 patients with 
advanced solid tumors will receive a MLN2480 QW starting dose of 400 mg. Dose increases 
of 200 mg (ie, 600 mg, 800 mg, 1000 mg) will be made in each subsequent cohort until the 
MTD/RP2D is reached.
QW Dose Expansion Phase
Once the MTD and/or RP2D of QW MLN2480 have been determined, or at the discretion of 
the sponsor, the study will continue to a QW Dose Expansion phase. Approximately 
32 patients, (up to 16 patients per cohort) with locally advanced, metastatic, and/or 
unresectable melanoma will be enrolled into 1 of 2 QW dose expansion cohorts based on 
tumor genotype and treatment history. Patients may be enrolled into the QW melanoma or 
solid tumor expansion cohorts based on previously documented genotype status, but may 
undergo a fresh biopsy at Screening for confirmation.
4.2
Number of Patients
A total of approximately 198 patients with solid tumors will be enrolled in this study. The 
first 15 to 30 patients will be recruited in approximately 2 US sites in the Q2D Dose 
Escalation phase; approximately 112 patients will be recruited in approximately 10 to 18 US 
and international sites for the Q2D Dose Expansion phase. Amendment 6 introduces new 
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dose cohorts that will follow a QW dosing schedule. Approximately 12 to 24 patients will be 
recruited in approximately 4 to 8 US sites in the QW Dose Escalation phase, and up to 
approximately 32 patients will be recruited in approximately 10 to 18 US and international 
sites for the QW Dose Expansion phase.
In the Q2D and QW Dose Escalation phases, the exact number of patients will depend on 
the number of dose escalation steps, and the number of patients per cohort, as per the 3 + 3 
dose escalation design.
4.3
Duration of Study
The study period will consist of the Screening and Treatment periods. During the Screening 
period, patient eligibility for the study will be determined within 28 days prior to Day 1.
During the Treatment period, patients will take MLN2480 orally Q2D in 22- or 28-day 
treatment cycles or QW in 28-day treatment cycles until disease progression, unacceptable 
toxicity, or the patient discontinues for any other reason. The maximum duration of 
treatment will be 12 months unless it is determined that a patient would derive benefit from 
continued therapy beyond 12 months. Patients in the study for 4 years or longer will take 
MLN2480 Q2D in 12-week (84-day) treatment cycles until disease progression, 
unacceptable toxicity, or the patient discontinues for any other reason.
When patients discontinue study treatment, they should return to the study site 30 (10) 
days after administration of the last dose of study drug or the start of subsequent 
antineoplastic therapy, whichever occurs first, to complete the End of Study visit 
procedures.
All MLN2480-related toxicities will be followed until the End of Study visit or until the 
toxicities have resolved, stabilized, or returned to baseline, whichever occurs later.
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5.
STUDY POPULATION
5.1
Inclusion Criteria
To be eligible to participate in this study, candidates must meet the following eligibility 
criteria at Screening or at the time point specified in the individual eligibility criterion listed:
1. Ability to understand the purpose and risks of the study and provide signed and dated 
informed consent and authorization to use protected health information in 
accordance with national and local patient privacy regulations.
2. Age ≥18 years at the time of informed consent or patient meets the minimum age of 
consent in accordance with national regulations (whichever is higher).
3. Dose Escalation phases (Q2D and QW): Patients with advanced solid tumors 
(excluding lymphoma, including melanoma) who have failed or are not candidates 
for standard therapies or for whom no approved therapy is available.
4. Dose Expansion phase (Q2D and QW): Patients with locally advanced, metastatic, 
and/or unresectable melanoma or solid tumors who meet the following cohort-
specific criteria:
Q2D Melanoma Expansion Cohorts

Cohort 1: BRAF mutation-positive cutaneous melanoma, naïve to prior therapy 
with RAF and MEK inhibitors. 

Cohort 2: BRAF mutation-positive cutaneous melanoma, which in response to 
previous treatment with RAF inhibitors and/or MEK inhibitors, has 1) relapsed 
following an objective response, 2) failed to demonstrate an objective response, 
and/or 3) could not tolerate such a regimen due to unacceptable toxicity.

Cohort 3: NRAS mutation-positive cutaneous melanoma, naïve to prior therapy 
with RAF and MEK inhibitors.

Cohort 4: NRAS mutation-positive cutaneous melanoma, which in response to 
previous treatment with MEK inhibitors, has 1) relapsed following an objective 
response, 2) failed to demonstrate an objective response, and/or 3) could not 
tolerate such a regimen due to unacceptable toxicity.
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
Cohort 5: BRAF/NRAS mutation-negative cutaneous melanoma (wild type), 
naïve to any prior anticancer therapy except ipilimumab, anti-PD-1, and 
anti-PDL-1 mAbs. 

Cohort 6: BRAF/NRAS mutation-negative melanoma (wild type), received at 
least 1 line of prior anticancer therapy. Cutaneous, uveal, or mucosal melanoma 
permitted in this cohort.

(Cohort 7: Not a melanoma cohort. See below for information on the PK 
expansion cohort) 
QW Melanoma Expansion Cohorts

Cohort 8: Patients with BRAF mutation-positive cutaneous melanoma 
(approximately 16 patients total: approximately 8 patients who are naïve to prior 
therapy with RAF and MEK inhibitors and approximately 8 patients who have 
relapsed/are refractory to prior therapy with RAF or MEK inhibitors).
Note: Enrollment into Cohort 8 is discontinued as of this amendment 
(Amendment 8).

Cohort 9: NRAS mutation-positive cutaneous melanoma, naïve to prior therapy 
with RAF and MEK inhibitors. 
5. Dose Expansion phase (Q2D): PK cohort: 

Cohort 7: Patients with any advanced solid tumor (excluding lymphoma, but 
including melanoma) who have failed or are not candidates for standard therapies 
or for whom no approved therapy is available.
6. Dose Expansion phases (Q2D and QW), excluding Cohort 7 (PK Cohort): At least 
1 measurable lesion, according to RECIST, version 1.1 (see Section 14.3), which has 
not been treated previously with radiotherapy. A newly arising lesion in a previously 
irradiated field is acceptable.
7. Q2D Dose Expansion phase, Cohorts 1-6 only: At least 8 patients per cohort must be 
able to have paired tumor biopsies conducted for analysis of pharmacodynamic 
biomarkers (see Table 1-13) 
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8. QW Dose Expansion phase (Cohorts 8 and 9): A minimum of 8 patients must be able 
to have paired tumor biopsies conducted for analysis of pharmacodynamic 
biomarkers (see Table 1-13) 
9. For patients undergoing biopsy procedures: Prothrombin time (PT) and activated 
partial thromboplastin time (aPTT) must be within the normal range and platelet 
count > 75,000/mm3 within 48 hours of biopsy.
10. ECOG performance status ≤1.
11. Dose Escalation and PK Expansion cohorts: Adequate tissue sample from either 
archival 
 tissue or fresh biopsy of tumor at Screening for tumor 
genotyping (Table 1-13).
12. Previous chemotherapy and hormone therapy must be completed at least 4 weeks or 
4 half lives, whichever occurs first, prior to administration of MLN2480. Previous 
immunotherapy/ monoclonal antibody use must be completed at least 4 weeks prior 
to administration of MLN2480. In addition, radiation therapy must be completed at 
least 3 weeks prior to administration of MLN2480. All associated toxicity from 
previous therapies must be resolved to ≤Grade 1 prior to administration of 
MLN2480. Prior treatment with anti-PD-1 and anti-PDL-1 mAbs is permitted with a 
washout period of 6 weeks, provided there is no observed tumor shrinkage during 
that time relative to the previous progression scan.
13. Expected survival time of at least 3 months in the opinion of the investigator.
14. Thyroid function tests consistent with stable thyroid function. (Patients on a stable 
dose of thyroid replacement therapy for a suggested minimum of 12 weeks prior to 
Cycle 1, Day 1 are eligible.)
15. Left ventricular ejection fraction (LVEF) of 50% or greater, as measured by 
echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA), within 
28 days before the first dose of MLN2480. 
16. Must be able to swallow and retain oral medication.
17. Female patients who:

Are postmenopausal for at least 1 year before the Screening visit, OR
CCI
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
Are surgically sterile, OR

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 
through 120 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. (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods] and withdrawal are not acceptable 
methods of contraception.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study treatment  
period and through 120 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. (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods] and withdrawal are not acceptable 
methods of contraception.)
For further details of contraceptive requirements for this study, please refer to 
Section 6.6.2.2.
18. Suitable venous access for the study-required blood sampling, including PK 
assessments of MLN2480.
5.2
Exclusion Criteria
Candidates will be excluded from study entry if any of the following exclusion criteria exist 
at Screening, or at the time point specified in the individual criterion listed:
1. History of any major disease that might interfere with safe protocol participation, as 
determined by the investigator.
2. Dose Expansion phase, Cohorts 1, 3, and 5 only: Previous treatment with RAF or 
MEK inhibitors.
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3. Laboratory values:

Absolute neutrophil count (ANC) ≤1500/μL

Platelet count ≤75,000/μL

Hemoglobin < 9 g/dL (hemoglobin may be supported by transfusion, 
erythropoietin, or other approved hematopoietic growth factors)

Serum bilirubin ≥1.5 × upper limit of normal (ULN) or 2 ULN if patient is 
known to have Gilbert’s Disease as the only underlying hepatic disorder

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≥2.5 × 
ULN (AST and ALT ≥5 × ULN for patients with liver metastasis)

Serum creatinine ≥2.0 mg/dL

Brain metastasis, unless previously treated with surgery, whole-brain radiation, 
or stereotactic radiosurgery and the disease has been stable for at least 2 months 
without steroid use or on a stable dose of steroids for at least 1 month prior to the 
first dose of MLN2480
4. Dose Expansion phase: No other active malignancy
5. Current enrollment in any other investigational treatment study.
6. Evidence of current uncontrolled cardiovascular conditions, including but not limited 
to clinically significant cardiac arrhythmias, congestive heart failure, angina, or 
myocardial infarction, within the past 6 months.
7. Prior investigational agents for malignant or non-malignant disease within 4 weeks 
prior to Day 1.
8. Active hepatitis or human immunodeficiency virus infection.
9. Active bacterial or viral infection.
10. Female patients who are pregnant or currently breastfeeding.
11. Major surgery within 28 days of Day 1.
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12. Inability to comply with study requirements.
13. Refractory nausea and vomiting, malabsorption, or significant bowel or stomach 
resection that would preclude adequate absorption of MLN2480.
14. Treatment with any of the following strong or moderate CYP3A/CYP2C inducers 
within 14 days before the first dose of study drug: rifampin, rifapentine, rifabutin, 
phenytoin, carbamazepine, phenobarbital, primidone, St. John’s Wort, bosentan, 
nafcillin, and modafinil.
15. Treatment with gemfibrozil (strong CYP2C8 inhibitor) within 14 days before the 
first dose of study drug.
16. Other unspecified reasons that, in the opinion of the investigator or Millennium,
make the patient unsuitable for enrollment.
6.
STUDY DRUG
6.1
Study Drug Administration
Millennium will provide MLN2480 to study sites. Refer to Sections 6.9 through 6.10 for 
specifics on the preparation, storage, handling, disposal, and accountability of study 
treatment.
Patients in the Dose Escalation phase will receive MLN2480 Q2D for a 22- or 28-day cycle 
(11 or 14 doses) or QW for a 28-day cycle (4 doses). Patients in the Dose Expansion phase 
will receive MLN2480 Q2D for a 28-day cycle (14 doses) or QW for a 28-day cycle 
(4 doses), followed by additional cycles until disease progression, unacceptable toxicity, or 
the patient discontinues for any other reason. Patients in the Q2D PK Expansion cohort will 
have a modified dosing schedule only for Cycle 1: MLN2480 Q2D on Days 1 through 21 of 
the 28-day cycle (11 doses), with no drug administered on Days 22 through 28. For Cycle 2 
and beyond, the PK Expansion cohort will follow the standard dosing schedule of MLN2480 
(Q2D for a 28-day cycle [14 doses], followed by additional 28-day cycles until disease 
progression, unacceptable toxicity, or the patient discontinues for any other reason). The 
maximum duration of treatment will be 12 months unless it is determined that a patient 
would derive benefit from continued therapy beyond 12 months. If MLN2480 is proven to 
be beneficial, all regulatory requirements regarding poststudy access will be met.
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Patients will fast (with the exception of water) for at least 2 hours before and at least 2 hours 
after taking their dose of MLN2480. Patients should take their MLN2480 tablets at the same 
time with approximately 6 ounces (180 mL) of water on dosing days. Patients should be 
encouraged to take their doses at approximately the same time on each dosing day.
Other oral medications should not be taken within 1 hour before or after taking MLN2480. 
If emesis occurs after taking MLN2480, symptoms should be managed with standard 
antiemetic therapy, and a repeat (replacement) dose of MLN2480 should not be taken. Refer 
to the Pharmacy Manual for details on administration.
Missed doses should be taken within 12 hours. If the patient does not remember to take the 
dose within 12 hours, this dose should be skipped and the next dose should be taken as 
scheduled. Doses should not be doubled to make up for missed doses. All missed doses or 
doses administered within approximately 1 hour before a vomiting episode should be 
recorded in the electronic case report form (eCRF).
The Treatment period will consist of continuous 22- or 28-day cycles. Eligible patients will 
report to the study site to receive study treatment on days specified in the corresponding 
Schedules of Events.
On dosing days when the patient does not have a clinic visit, patients will take their dose of 
MLN2480 at home. Patients will continue to take MLN2480 orally Q2D in 22- or 28-day 
treatment cycles or QW in 28-day treatment cycles until disease progression, unacceptable 
toxicity, or the patient discontinues for any other reason.
6.2
Definitions of Dose-Limiting Toxicity 
Toxicity will be evaluated according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.03. Dose-limiting toxicity is 
defined as an AE that the investigator considers to be at least possibly related to study 
treatment. Toxicities will be graded according to NCI CTCAE, version 4.03. Dose-limiting 
toxicities will be assessed for each patient during the DLT observation period and will be 
defined as any of the following:

Grade 4 neutropenia lasting ≥7 consecutive days

Febrile neutropenia (defined as ANC ≤1000 cells/μL and fever ≥38.5°C) or 
documented infection ≥Grade 3 with ANC ≤1000 cells/μL
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
Grade 4 thrombocytopenia (< 25,000/μL), MLN2480-related thrombocytopenia 
requiring platelet transfusion, or MLN2480-related bleeding requiring medical 
attention

Treatment delays of ≥14 days due to any toxicity

ALT or AST toxicities:
o
ALT or AST > 7.5 × ULN for greater than 14 days
o
AST or ALT > 7.5 × ULN that is accompanied by an elevation in total bilirubin 
of > 3 × ULN (not explained by obstruction) regardless of duration

Nonhematological toxicity ≥Grade 3 with the following exceptions:
o
Nausea, vomiting, and diarrhea will be considered DLTs only if they persist at 
≥Grade 3 for > 3 days despite adequate supportive care measures. At the 
investigator’s discretion, patients who experience nausea, vomiting, or diarrhea 
after taking MLN2480 may receive antiemetic or antidiarrheal medication prior 
to subsequent doses of MLN2480
o
Isolated laboratory abnormalities ≥Grade 3 that resolve to ≤Grade 1 in ≤7 days 
without clinical sequelae or need for therapeutic intervention will not be 
considered a DLT
o
Fatigue ≥Grade 3 for ≤7 days will not be considered a DLT
o
Development of keratoacanthomas or skin carcinoma will not be considered a 
DLT unless unusually aggressive or metastatic.
If a patient develops an ANC < 500/μL or a platelet count < 25,000/μL, blood samples must 
be collected every 2 to 3 days and study treatment withheld until counts resolve or until 
ANC returns to > 1000/μL and platelet counts return to > 50,000/μL.
Patients will be evaluable for DLT if they either experience DLT in Cycle 1 or they receive 
at least 75% of the planned doses of study drug and have sufficient follow-up data to 
determine whether DLT occurred. Although DLTs may occur at any point during treatment, 
only DLTs occurring during Cycle 1 of treatment will necessarily influence decisions 
regarding dose escalation, expansion of a dose level, or evaluation of intermediate dose 
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levels. Patients will be monitored through all cycles of therapy for treatment-related 
toxicities and if there is evidence for cumulative MLN2480-related toxicity, this may 
influence decisions regarding dose escalation and the dose recommended for use in 
subsequent clinical trials. 
If no DLT is observed during the first cycle of treatment in the initial 3 patients enrolled to a 
given dose level, then 3 new patients will be enrolled at the next higher dose level. 
Alternatively, if 1 of the initial 3 patients treated at a given dose level experiences a DLT, 
then 3 additional patients will be added to that same dose level. Dose escalation can proceed 
only if none of these additional 3 patients experiences DLT. Dose escalation is stopped if 
DLT occurs in 2 patients at any given dose level, regardless of the total number of patients 
treated at that dose level. The highest dose level that generates DLT in 0/3 or 1/6 patients is 
then considered to be the MTD. Once the MTD has been identified, additional patients will 
be treated at the MTD and/or the RP2D in the Dose Expansion phase to establish greater 
confidence in its safety and suitability for use in subsequent clinical trials (see the Dose 
Escalation Algorithm).
Patients will not be included in either the numerator or denominator when calculating the 
nominal rate of DLT at any given dose level if 1 of the following occurs: 

A patient receives less than 75% of the planned doses during the first cycle of 
therapy or does not have sufficient follow-up data to allow the investigators and 
sponsor to determine whether DLT occurred.

A patient discontinues the study for reasons other than DLT before they have 
completed Cycle 1 of treatment.
Such patients will be replaced. Patients who experience a DLT during the Dose Expansion 
phase may be allowed to continue treatment with MLN2480 at a dose level below that which 
was associated with the DLT (see Section 6.5).
6.3
Dose Escalation Phase
The Dose Escalation phases will include approximately 54 patients (30 in the Q2D 
escalation cohorts and 24 in the QW escalation cohorts) with solid tumors, including locally 
advanced, metastatic, and/or unresectable melanoma; who have failed or are not candidates 
for standard therapies or for whom no approved therapy is available. A 3 + 3 dose escalation 
design will be used, with the first 3 Q2D patients receiving the starting dose of 20-mg 
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MLN2480 orally Q2D for a 22-day cycle (11 doses; first dose on Day 1 and last dose on 
Day 21) and first 3 QW patients receiving the starting dose of 400 mg MLN2480 orally QW 
for a 28-day cycle (4 doses; first dose on Day 1 and last dose on Day 22), followed by 
additional cycles until disease progression, unacceptable toxicity, or the patient discontinues 
for any other reason, or until 12 months of treatment have been administered. Upon 
implementation of Amendment 3, any ongoing dose escalation cohort will continue 
enrollment on the 22-day cycle schedule until the cohort is full and all patients have been 
evaluated for dose-limiting toxicity (DLT) (see Section 6.2). For all subsequent dose 
escalation cohorts, patients will be treated Q2D on a 28-day cycle (14 doses). Patients who 
began treatment on the 22-day cycle may switch from the 22-day to 28-day cycle upon 
safety confirmation of the 28-day cycle and agreement from the investigator and sponsor. 
The previously tolerated unit dose administered Q2D in the 22-day cycle will be 
administered as the first unit dose for the 28-day cycle. Administration of the same unit dose 
every other day in a 28-day cycle instead of a 22-day cycle represents a 27% increase in 
total cycle dose, which is less than the smallest (33%) increase in total cycle dose originally 
planned for the 22-day cycle in the Dose Escalation phase. After tolerability is confirmed 
when the same unit dose is administered every other day in a 28-day cycle instead of a 
22-day cycle, subsequent dose escalations in a 28-day cycle will consist of a 33% increase in 
both unit and total cycle dose. Regardless of cycle length, dosing is every other day on a 
continuous basis, with no treatment-free period between cycles (except for Cycle 1 in the PK 
Expansion cohort).
Patients will fast (with the exception of water) for at least 2 hours before and at least 2 hours 
after taking their dose of MLN2480.
Dose Escalation Guidelines
The DLT observation period for a dose cohort is defined as Cycle 1, Day 1 to either Cycle 1, 
Day 22 (22-day cycle), or Cycle 1, Day 28 (28-day cycle). Safety data and available PK data 
from the DLT observation period of a given dose cohort will be reviewed prior to escalating 
the dose to the next cohort (see Dose Escalation Algorithm). 
To provide patients the opportunity to derive maximum clinical benefit from study drug, 
patients in the dose escalation phase in dose cohorts below the MTD/RP2D may be allowed 
to dose escalate provided that, during the most recent cycle, there have been no 
nonhematologic AEs ≥ Grade 2 related to study drug, no dose interruptions related to study 
drug toxicities, and no delays of greater than 1 week in starting a cycle due to study drug 
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toxicities. In order for a patient to escalate to the next dose level, the level above the 
proposed escalated dose must be deemed safe.
The Sponsor, in collaboration with the Principal Investigators, will determine if intrapatient 
dose escalation is appropriate on a case-by-case basis. Patients who have had any dose 
reductions will not be permitted to dose escalate.
For Q2D dose escalation, the first patient in each dose cohort must be observed for safety for 
at least 6 days before the next 2 patients can be enrolled. No waiting period will be required 
between the 2 subsequent patients. For the initial dose increase in the QW Dose Escalation 
phase (from 400 mg to 600 mg), patients will be enrolled in the 600 mg dose cohort in a 
staggered manner, with 1 week in between each patient. No waiting period will be required 
in subsequent QW dose cohorts. 
Enrollment of patients in successive cohorts will not begin until at least 21 days for 22-day 
cycles or 27 days for 28-day cycles after the last patient in the previous cohort has received 
their first dose of MLN2480 and the End-of-Cohort meeting has occurred.
An End-of-Cohort meeting scheduled by the sponsor will occur after the last patient in each 
cohort in the Dose Escalation phase has completed the first treatment cycle/DLT observation 
period (ie, Days 1 to 22 or 28). During this meeting, the sponsor and investigators will 
review and discuss AEs, laboratory results, available pharmacokinetics data, and other 
relevant data to determine if the dose escalation criteria have been met and if dose escalation 
may proceed. Subsequent cohorts will only be opened for enrollment after all investigators 
have agreed to the dose escalation. 
The Q2D dose escalation will follow a modified Fibonacci schema (sequential dose 
escalation increments of approximately 100%, 100%, 67%, 50%, 40%, and 33% thereafter) 
(see Table 6-1). During the transition from a 22-day to a 28-day cycle, the unit dose will not 
be increased but the total cycle dose will be increased by 27%.
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Table 6-1
Q2D Planned Dose Levels
Dose Level
Dose Increase Factor
Dose (mg/day)
1
Starting dose
20
2
100%
40
3
100%
80
4
67%
135
5
50%
200
6
40%
280a
Abbreviations: DLT=dose-limiting toxicity.
The first cohort dosed at the 28-day cycle will repeat the last safe unit dose at the 22-day cycle.
a Additional dose levels will continue to be explored at a dose increase factor of 33% until 1 out of 
6 patients has a DLT.
Consequently, in the absence of more than 1 DLT occurring in a given cohort or the MTD 
being established, it is anticipated that the doses for the sequential cohorts will be 20, 40, 80, 
135, 200, and 280 mg MLN2480 Q2D, with 33% dose escalation increments thereafter until 
the MTD is established. 
The QW dose escalation will follow sequential dose escalation increments of 200 mg 
increments QW until MTD is reached) (see Table 6-2).
Table 6-2
QW Planned Dose Levels
Dose Level
Dose Increase Factor
Dose (mg/wk)
1
Starting dose
400
2
50%
600
3
33%
800
4
25%
1000
Abbreviations: DLT=dose-limiting toxicity.
a Additional dose levels increasing by 200 mg will continue to be explored until 1 out of 6 patients has a 
DLT.
Consequently, in the absence of more than 1 DLT occurring in a given cohort or the MTD 
being established, it is anticipated that the doses for the sequential cohorts will be 400, 600, 
800, and 1000 mg MLN2480 QW, with 200 mg QW dose escalation increments thereafter 
until the MTD is established.
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Dose escalation parameters are as follows:

If 0 of 3 patients in a dose cohort experience a DLT in the DLT observation period, 
enrollment of patients into the next dose cohort will begin following the 
End-of-Cohort meeting.

If 1 of 3 patients in a dose cohort experiences a DLT in the DLT observation period, 
an additional 3 patients will be treated in this dose cohort. If < 2 patients in a given 
dose cohort experience a DLT, enrollment into the next dose cohort can begin 
following the End-of-Cohort meeting.

If ≥2 patients in a dose cohort experience a DLT in the DLT observation period, that 
dose will be considered to have exceeded the MTD.

Depending on the nature of the DLTs in the preceding dose cohort, an additional 
intermediate dose cohort may be evaluated before proceeding to the Dose Expansion 
phase of the study.
More conservative dose escalation, evaluation of intermediate doses, and expansion of an 
existing dose level are all permissible following 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, exposure, or pharmacodynamics of MLN2480.
6.4
Dose Expansion Phase
The Dose Expansion phase will include patients with locally advanced, metastatic, and/or 
unresectable melanoma (melanoma expansion cohorts), Approximately 128 patients with 
melanoma will be enrolled into 1 of 8 dose expansion cohorts (approximately 16 patients per 
cohort), based on tumor genotype and treatment history.
Q2D Dose Expansion Cohorts

Cohort 1: BRAF mutation-positive cutaneous melanoma, naïve to prior therapy with 
RAF and MEK inhibitors. 

Cohort 2: BRAF mutation-positive cutaneous melanoma, which in response to 
previous treatment with RAF inhibitors and/or MEK inhibitors, has 1) relapsed 
following an objective response, 2) failed to demonstrate an objective response, 
and/or 3) could not tolerate such a regimen due to unacceptable toxicity.
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
Cohort 3: NRAS mutation-positive cutaneous melanoma, naïve to prior therapy with 
RAF and MEK inhibitors. 

Cohort 4: NRAS mutation-positive cutaneous melanoma, which in response to 
previous treatment with MEK inhibitors, has 1) relapsed following an objective 
response, 2) failed to demonstrate an objective response, and/or 3) could not tolerate 
such a regimen due to unacceptable toxicity.

Cohort 5: BRAF/NRAS mutation-negative cutaneous melanoma (wild type), naïve to 
any prior anticancer therapy except ipilimumab, anti-PD-1, and anti-PDL-1 mAbs. 

Cohort 6: BRAF/NRAS mutation-negative melanoma (wild type), received at least 
1 line of prior anticancer therapy. Cutaneous, uveal, or mucosal melanoma permitted 
in this cohort.

(Cohort 7: Not a melanoma cohort. See below for information on the PK expansion 
cohort)
QW Melanoma Expansion Cohorts

Cohort 8: BRAF mutation-positive cutaneous melanoma (approximately 16 patients 
total: approximately 8 patients who are naïve to prior therapy with RAF and MEK 
inhibitors, and approximately 8 patients who relapsed/refractory to prior therapy with 
RAF or MEK inhibitors).
Note: Enrollment into Cohort 8 is discontinued as of this amendment 
(Amendment 8).

Cohort 9: NRAS mutation-positive cutaneous melanoma, naïve to prior therapy with 
RAF and MEK inhibitors. 
Individual Dose Expansion cohorts may be opened or closed sequentially or in parallel at the 
sponsor’s discretion, based on emerging data. Patients in the Q2D melanoma expansion 
cohorts will take the selected dose of MLN2480 orally every other day in 28-day cycles until 
disease progression, unacceptable toxicity, or the patient discontinues for any other reason. 
Patients in the QW dose expansion cohorts will take the selected dose of MLN2480 orally 
once weekly (on Days 1, 8, 15, and 22) in 28-day cycles until disease progression, 
unacceptable toxicity, or the patient discontinues for any other reason. 
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Patients will fast (with the exception of water) for at least 2 hours before and at least 2 hours 
after taking their dose of MLN2480. A fresh tumor biopsy for genotyping will be required 
for all patients in the 6 Q2D dose expansion cohorts and will be requested for the QW dose 
expansion cohorts at Screening; archived tumor tissue will also be requested if available. A 
postdose fresh biopsy on Day 21 of Cycle 1 will also be collected from at least 8 patients in 
each Q2D melanoma expansion cohort. The postdose fresh biopsy may need to be collected 
in more than the specified patients in each cohort/ treatment schedule to ensure evaluable 
biopsies are collected. After the specified pairs of Screening and postdose biopsies have 
been confirmed to be evaluable from a cohort, the postdose biopsy for the remaining patients 
in that cohort will be optional. The postdose fresh biopsy should be collected in a patient 
only if an evaluable fresh (or archived) biopsy was collected at Screening. For patients on 
the QW dose schedule, a predose fresh biopsy will also be requested on Day 22 of Cycle 1 
from up to 8 evaluable patients (if archived tissue not available or not evaluable). Evaluable 
biopsy pairs collected at Screening and Day 21 (Q2D) or Day 22 (QW) of Cycle 1 will be 
used for pharmacodynamic biomarker analysis.
A seventh cohort in the Q2D Dose Expansion phase, the PK Expansion cohort, will include 
patients with any advanced solid tumor (except lymphoma but including melanoma) who 
have failed or are not candidates for standard therapies or for whom no approved therapy is 
available. In addition to contributing to the evaluation of safety, tolerability, and preliminary 
antitumor activity, the PK Expansion cohort will be used to more fully characterize 
MLN2480 PK. Patients in the PK Expansion cohort will take the selected dose of MLN2480 
orally Q2D on Days 1 through 21 of the 28-day cycle for Cycle 1; dosing for Cycle 2 and 
beyond will follow the standard Q2D dosing in 28-day cycles until disease progression, 
unacceptable toxicity, or the patient discontinues for any other reason. An archival or fresh 
tumor tissue sample will be obtained at Screening for genotyping of patients as specified in 
Table 1-13. No paired biopsies for PD analysis will be collected in the PK Expansion cohort.
The maximum duration of treatment for all patients in the Dose Expansion phase will be 
1 year unless it is determined that a patient would derive benefit from continued therapy 
beyond 12 months.
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6.5
Dose Modification Guidelines
6.5.1 Dose Escalation Phase
Any patient in the Dose Escalation phase whose toxicity meets a criterion of a DLT will 
discontinue study treatment. If necessary, MLN2480 dose reductions or dose interruptions 
will be allowed in the following circumstances:

If the patient experiences Grade 3 or 4 fatigue, the patient will stop taking 
MLN2480. The patient may resume taking the original dose of MLN2480 if the 
fatigue resolves to ≤Grade 1 within 7 days. Patients in the Dose Escalation phase 
will discontinue study treatment if they experience fatigue that resolves to ≤Grade 1 
in > 7 days. 

If the patient experiences an asymptomatic laboratory abnormality as outlined in 
Section 6.2, the patient will stop taking MLN2480. The patient may resume taking 
the original dose of MLN2480 if the laboratory abnormality resolves to ≤Grade 1 
within 7 days. Patients in the Dose Escalation phase will discontinue study treatment 
if they experience an asymptomatic laboratory abnormality that resolves to 
≤Grade 1 in > 7 days. 

If the patient experiences a ≥Grade 3 AE, the patient will stop taking MLN2480. If 
the AE resolves to ≤Grade 2 in ≤14 days, the patient can resume taking MLN2480. 
If the AE does not resolve to ≤Grade 2 after 14 days, the patient must discontinue 
study treatment.
6.5.2 Dose Expansion Phase
Depending on the nature and severity of an AE, and under discretion of the investigator with 
agreement from the sponsor, the following dose modifications are recommended:

Patients who experience a Grade 2 related AE may have their MLN2480 dose 
decreased to 160 mg Q2D or by 1 dose level (minus 200 mg QW).

Patients who experience a Grade 3 related AE may have their MLN2480 dose 
decreased to 140 mg Q2D or by 1 dose level (minus 200 mg QW).

Patients who experience an AE Grade 3 (regardless of relatedness to MLN2480) 
may stop taking MLN2480. If MLN2480 is held and the AE subsequently resolves to 
≤Grade 2 in ≤14 days, the patient can resume taking MLN2480 either at the original 
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dose or a reduced dose, per investigator and sponsor discretion. If the AE does not 
resolve to ≤Grade 2 after 14 days, the patient must discontinue study treatment.
In addition, consideration will be given on a case-by-case basis for patients on the Q2D dose 
schedule to transfer to the QW dose schedule for the management of toxicity. A patient may 
only be switched from the Q2D schedule to the QW schedule pending agreement between 
the investigator and Sponsor. 
The sponsor must be notified of any MLN2480 dose modifications.
6.6
Concomitant Medications and Procedures
Premedications and concomitant mediations and therapy will be recorded in the eCRF from 
Screening through the End of Study visit or the start of subsequent antineoplastic therapy, 
whichever occurs first.
See Section 6.6.1 for a list of prohibited medications and therapies and Section 6.6.2.3 for 
medications or procedures that are restricted or should be used cautiously. 
6.6.1 Excluded Concomitant Medications and Procedures
Concurrent anticancer therapy or any other investigational therapy is not permitted during 
the study.
In vitro data indicates that MLN2480 is metabolized by aldehyde oxidase and CYPs 2C8, 
2C9, 2C19, and 3A4, with relative contributions of 49%, 33%, 8%, 7%, and 4%, 
respectively. Based on this data, concomitant use of strong and moderate inducers of 
CYP3A and CYP2C enzymes and strong inhibitors of CYP2C8 is prohibited during the 
study.

Strong and Moderate Inducers of CYP3A and CYP2C enzymes: rifampin, 
rifapentine, rifabutin, phenytoin, carbamazepine, phenobarbital, primidone, St. 
John’s Wort, bosentan, nafcillin, and modafinil

Strong CYP2C8 inhibitor: gemfibrozil
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6.6.2 Precautions and Restrictions 
6.6.2.1
Hematology and Blood Chemistry
Hematology results and blood chemistry results will be evaluated before the patient is 
allowed to take their dose of MLN2480 on Day 1 of each cycle according to the Schedule of 
Events. If a patient develops an ANC < 500/μL or a platelet count < 25,000/μL, blood 
samples must be collected every 2 to 3 days and study treatment withheld until counts 
resolve or until ANC returns to > 1,000/μL and platelet counts return to > 50,000/μL.
6.6.2.2
Pregnancy
It is not known what effects MLN2480 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.
Female patients must meet 1 of the following: 

Postmenopausal for at least 1 year before the Screening visit, or

Surgically sterile, or

Agree to practice true abstinence from sexual intercourse, when this is in line with 
the preferred and usual lifestyle of the patient, from the time of signing of the 
informed consent form (ICF) through 120 days (4 months) after the last dose of 
study drug. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods] and withdrawal are not acceptable methods of 
contraception.), or
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
Agree to practice 2 reliable methods of contraception, at the same time, from the 
time of signing of the ICF through 120 days (4 months) after the last dose of study 
drug. The 2 methods of reliable contraception must include 1 highly effective 
method and 1 additional effective (barrier) method. 
The following are examples of highly effective and additional effective methods of 
contraception:
o
Highly effective methods:

Intrauterine device (IUD)

Hormonal (birth control pills, injections, implants)

Tubal ligation

Partner’s vasectomy
o
Additional effective methods:

Condom

Diaphragm

Cervical Cap
Female patients must also agree not to donate ova (egg cells) during participation in the 
study or for 120 days (4 months) following the last dose of study drug.
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 patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods] and withdrawal are not acceptable methods of 
contraception.) OR

Practice effective barrier contraception during the entire study Treatment period and 
through 120 days (4 months) after the last dose of study drug.
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Male patients must also agree not to donate sperm during participation in the study or for 
120 days (4 months) following the last dose of study drug.
6.6.2.3
Medications and Procedures
In vitro data indicates that MLN2480 may inhibit CYP2C8. Therefore, coadministration of 
MLN2480 with substrates predominantly or substantially metabolized by CYP2C8 should 
be used with caution, including but not limited to cerivastatin, rosuvastatin, repaglinide, 
rosiglitazone, pioglitazone, amiodarone, chloroquine, amodiaquine, and montelukast.
MLN2480 is an in vitro inhibitor of the efflux transporter BCRP. On the basis of clinical 
exposure observed to date, there is a potential risk for MLN2480 to inhibit transport of 
co-administered drugs that are substrates of BCRP. Although currently there are limited 
examples of clinically meaningful drug-drug interactions related to BCRP inhibition, 
information on BCRP-mediated drug interactions continues to evolve. Consequently, 
caution should be exercised when MLN2480 is administered concurrently with substrates of 
BCRP. These include, but are not limited to, HMG-CoA reductase inhibitors (rosuvastatin, 
pitavastatin, cerivastatin), antibiotics (ciprofloxacin, norfloxacin, ofloxacin erythromycin, 
nitrofurantoin), calcium channel blockers (dipyridamole, nitrendipene, azidopine), 
sulfasalazine, cimetidine, methotrexate, and glyburide. 
MLN2480 did not inhibit P-gp in vitro at concentrations up to 30 M. A clinically 
meaningful interaction with co-administered P-gp substrates is not anticipated at systemic 
sites of transport (liver, kidney, blood-brain barrier). However, as the possibility of 
inhibition of intestinal P-gp transport by clinical doses of MLN2480 cannot be ruled out due 
to potentially higher concentrations in the intestinal lumen (30 M), cautious use and close 
monitoring of patients is advised as a precautionary measure when an orally administered 
P-gp substrate with a narrow therapeutic index (eg, digoxin and cyclosporine) is taken 
concomitantly with MLN2480.
As a general precaution, patients receiving concomitant medications, particularly those with 
narrow therapeutic indices, should be carefully monitored as potential drug-drug interactions 
between MLN2480 and other drugs have not been studied in humans. Patients should also 
be instructed to consult with the investigator before taking any new medications, including 
over-the-counter products. 
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Blood transfusions are permitted after Cycle 1 but must be administered either before dosing 
or at least 1 hour after dosing. Growth factors may be administered after Cycle 1 is 
completed.
Prophylactic medications should not be administered until an AE occurs during Cycle 1. 
Prophylactic medications are allowed in subsequent cycles.
Patients undergoing tumor biopsy procedures who are receiving ongoing therapy with an 
anticoagulant (eg, aspirin, clopidogrel [Plavix®], warfarin, or heparin [including low 
molecular-weight heparin]) must be able to safely stop therapy with these medications 
7 days before the first biopsy and not resume therapy with these medications until 7 days 
after the last biopsy.
6.6.2.4
Food
Patients should not eat or drink (with the exception of water) for 2 hours before and 2 hours 
after administration of MLN2480 doses.
6.6.2.5
Photosensitivity
Photosensitivity is a recognized class effect of RAF kinase inhibitors. Patients should 
therefore use caution and minimize exposure to sunlight and UV light. 
6.7
Recommendations for Management of Clinical Events: Dose Expansion Phase
Ocular Disturbances
An eye exam will be performed by an ophthalmologist if visual abnormalities are described 
by the patient. Careful monitoring of eye complaints should be followed, and the eye exam 
should include slit lamp examination of the cornea, retinal photographs, and intraocular 
pressure measurement as clinically indicated. Patients must be instructed to report visual 
symptoms as soon as they occur.
Early and aggressive management of mild visual symptoms may avoid more serious ocular 
complications.
Increased Creatine Kinase Levels
Increased creatine kinase (CK) levels have been observed with MLN2480 administration. 
While an increase in CK level alone (asymptomatic) is not reason to reduce the dose of 
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MLN2480, it is important to rule out an accompanying clinical condition. See the following
recommendations in Table 6-3.
Table 6-3
Management of Elevated Creatine Kinase Levels
AE Grade
Event Definition
Recommendation
Grade 1
> ULN – 2.5 ULN

Rule out increased physical activity, trauma, falls, 
muscle injury

Rule out concomitant use of statins or excessive 
environmental and other causes (eg, alcohol, drugs, 
toxins, heat illness, seizures, etc.)

Adequate hydration is recommended to maintain fluid 
and electrolyte balance and tissue perfusion
Grade 2
> 2.5 ULN – 5 
ULN

Rule out increased physical activity, trauma, falls, 
muscle injury

Rule out concomitant use of statins or excessive 
environmental or other causes (eg, alcohol, drugs, 
toxins, heat illness, seizures, etc.)

BUN, creatinine, urinalysis

Myoglobin test in urine (urine dipstick, heme +, RBC -)

NOTE: Consider reducing dose of MLN2480 from 
200 mg Q2D to 160 mg Q2D
Grade 3/
Grade 4
> 5 ULN – 10 
ULN
> 10 ULN

Rule out increased physical activity, trauma, falls, 
muscle injury

Rule out concomitant use of statins or excessive 
environmental causes or other causes (eg, alcohol, drugs, 
toxins, heat illness, seizures, etc.)

BUN, creatinine, urinalysis

Myoglobin test in urine (urine dipstick, heme +, RBC)

In the presence of chest pain, test levels of Troponin I or 
Troponin T

NOTE: Consider holding administration of MLN2480 
until value has decreased to Grade 1 or baseline
Source: Common Terminology Criteria for Adverse Events (CTCAE), v4.03.[37]
Rash
Rashes (maculo-papular, dermatitis acneiform, and pruritus) have been observed with 
MLN2480 administration. Patients should avoid excess exposure to sunlight and use broad-
spectrum sunscreen (containing titanium dioxide or zinc oxide) with a skin protection factor 
SPF > 15. 
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Should a rash occur, the following recommendations should be followed:
Table 6-4
Management of Rash
AE Severity
Event Definition
Recommendation
Grade 1
Macular or papular eruption or 
erythema without associated 
symptoms

Cold compresses 

Oral anti-histamines

Initiate use of topical steroids 
(ie, hydrocortisone cream 1-2.5% or 
triamcinolone cream 0.1)
Grade 2
Macular or papular eruption or 
erythema with pruritus or other 
associated symptoms; localized 
desquamation or other lesions 
covering < 50% of body surface 
area (BSA)

Follow at least weekly

Assess with bacterial and fungal cultures and 
treated with systemic agents as appropriate 
(Level of Evidence II). Initiate treatment with 
minocycline 100 mg BID with or without 
topical clindamycin BID until Grade 1 or 
resolved

Consider dose reduction to 160 mg Q2D after 
discussion between the investigator and 
sponsor.
Grade 3 or 
Higher
Severe, generalized erythroderma 
or macular, papular or vesicular 
eruption; desquamation covering 
≥50% BSA 
Generalized exfoliative, 
ulcerative, or bullous dermatitis 

MLN2480 should be delayed until the rash 
improves

A dermatologist should be consulted, a biopsy 
could be considered for rash characterization

Initiate treatment with minocycline 100 mg 
BID with or without topical clindamycin BID 
until Grade 1 or resolved

Consider dose reduction to 140 mg or holding 
administration of MLN2480 until resolved to 
Grade 1 or baseline
Source: Guidelines for Rash/Dermatitis adapted from Lemech and Arkenau, 2012.[38]
NOTE: Should a Grade 2 or 3 rash occur, photographic documentation is recommended.
Management of Cardiac Events
Cardiac events, including heart failure and atrial fibrillation, have been observed with 
MLN2480 administration. Should a cardiac event occur, the following recommendations 
should be followed:
Event Definition
Recommendation
Asymptomatic, absolute decrease in LVEF of 10%-
20% from pretreatment value
Do not modify the dose of MLN2480. 
Symptomatic congestive heart failure, or
Asymptomatic absolute decrease in LVEF of 
greater than 20% from baseline 
Withhold MLN2480 for up to 4 weeks, if 
improved to Grade 1 or baseline, then resume at 
140 mg (QD) or to the next lower dose level (QW).
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6.8
Description of Investigational Agents
MLN2480 may be provided to investigator sites with 2 slightly different formulations. 
Initially, sites will be supplied study drug with the formulations as described below:
The initial drug product consists of MLN2480 active substance and other commonly used, 
compendial excipients that include microcrystalline cellulose, colloidal silicon dioxide, 
magnesium stearate, vinylpyrrolidone-vinyl acetate copolymer (copovidone), and sodium 
croscarmellose.
In the summer of 2015, MLN2480 will be provided in an optimized formulation as 
described below:
The optimized drug product consists of MLN2480 active substance and other commonly 
used, compendial excipients that include microcrystalline cellulose, colloidal silicon 
dioxide, magnesium stearate, vinylpyrrolidone-vinyl acetate copolymer (copovidone), 
sodium croscarmellose and Opadry.
The availability of the optimized drug product to investigator sites will be dependent on 
country regulatory approvals. Until appropriate approvals are in place for the optimized drug 
product, the investigator will receive only the initial drug product. 
The MLN2480 drug product is formulated as an immediate-release tablet for oral 
administration. The description of the 3 dosage strengths (initial and optimized 
formulations) and the color of their bottle label are described as follows. The global booklet 
labels have a colored cover page. 

20 mg: white-to-off-white round tablet. Initial: light blue.

20 mg: red round tablet. Optimized: light blue.

70 mg: yellow oblong tablet. Optimized: yellow.

100 mg: white-to-off-white oval tablet. Initial: white.

100 mg: red-to-yellowish-red oval tablet. Optimized: white.
The drug product is labeled MLN2480. MLN2480 tablets, 20 mg, 70 mg, and 100 mg, are 
packaged with desiccant and cotton in 40 cc white, wide-mouth, round, high-density 
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polyethylene bottles equipped with 33 mm polypropylene child-resistant caps and induction 
sealed.
There are 15 tables in each bottle for the initial formulation study. With the optimized 
material, the number of tablets per bottle will increase to 16 in each bottle for the 20 mg, 
70 mg, and 100 mg dosage strengths.
Each bottle of MLN2480 study medication will be labeled with a multi-panel booklet label 
containing pertinent study information and a regulatory caution statement. The study drug is 
labeled to be used across protocols within the MLN2480 program. Therefore, the bottle 
booklet label will identify the study number as “C2800_”. The last digit should be written in 
based on the identified protocol number noted on the Packing List. In addition, if the 
investigational pharmacy is participating in multiple MLN2480 studies, it is mandatory that 
the study drug is segregated based on the protocol number. 
MLN2480 is manufactured in accordance with Good Manufacturing Practices.
6.9
Preparation, Reconstitution, and Dispensation
The pharmacist or medically qualified staff will dispense MLN2480 tablets to enrolled 
patients. The individual preparing MLN2480 should first review dispensing instructions 
provided in the Pharmacy Manual.
If the packaging is damaged, or if there is anything unusual about the appearance or 
attributes of the bottles or drug, it should not be used. The packaging or bottle in question 
should be saved at the study site and the problem immediately reported to Millennium. 
Contact information is supplied in the Pharmacy Manual.
6.10
Storage, Handling, and Accountability
MLN2480 tablets (20 mg, 70 mg, and 100 mg) are to be stored at 20°C to 25°C (68°F-77°F) 
and protected from excessive humidity, in a monitored, locked storage cabinet with limited 
access. Refer to the Pharmacy Manual for allowable storage and shipping temperature 
excursions.
Study treatment must be stored in a secure location. Accountability for study treatment is the 
responsibility of the investigator. Study site staff must instruct patients on how to store 
MLN2480 tablets. 
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The investigator must destroy or return all unused MLN2480 study drug as instructed by 
Millennium. Refer to the Pharmacy Manual for complete drug destruction policies.
The study site must maintain accurate records demonstrating dates and amount of study 
treatment received, to whom dispensed (patient-by-patient accounting), amount returned by 
the patient, and accounts of any study treatment accidentally or deliberately destroyed.
Unless otherwise notified, all unused MLN2480 study drug supply must be saved for study 
treatment accountability. At the end of the study, reconciliation must be made between the 
amount of MLN2480 supplied, dispensed, and subsequently destroyed or returned to 
Millennium. A written explanation must be provided for any discrepancies.
Refer to the Pharmacy Manual for complete instructions regarding storage, handling, and 
accountability.
7.
STUDY CONDUCT
This study will be conducted in compliance with the protocol, Good Clinical Practice 
(GCP), applicable regulatory requirements, and International Conference on Harmonisation 
(ICH) guidelines.
7.1
Study Personnel, Organizations, and Systems
The contact information for the Millennium project clinician for this study, clinical 
laboratories, and the Contract Research Organization (CRO) may be found in the Study 
Manual. A full list of investigators is available in the sponsor’s investigator database.
7.1.1 Contract Research Organization
A CRO will be responsible for administrative aspects of the study including, but not limited 
to, study initiation, monitoring for the Dose Expansion phase, and management of SAE 
reports. Before patients are screened at each study site, the CRO will review study 
responsibilities with the investigators and other study site staff, as appropriate.
7.1.2 Remote Data Capture
Patient information will be captured and managed by study sites on electronic CRFs by a 
remote data capture (RDC) system (Inform).
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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 patient to coercion or exploitation) will be enrolled into this study.
7.3
Treatment Group Assignments 
This is a phase 1 study that incorporates a Dose Escalation phase and a Dose Expansion 
phase at the MTD and/ or RP2D. In the Dose Escalation phase, a 3 + 3 dose escalation 
design will be used, with the first 3 Q2D patients receiving the MLN2480 starting dose of 
20 mg orally Q2D for a 22-day cycle (11 doses) and the first 3 QW patients receiving the 
MLN2480 starting dose of 400 mg orally QW for a 28-day cycle (4 doses). Upon 
implementation of Amendment 3, any ongoing dose escalation cohort will continue 
enrollment on the 22-day cycle schedule until the cohort is full and all patients have been 
evaluated for dose-limiting toxicity (DLT) (see Section 6.2). For all subsequent dose 
escalation and dose expansion cohorts, patients will be treated Q2D or QW on a 28-day 
cycle (14 doses or 4 doses, respectively). Patients who began treatment on the 22-day cycle 
may switch from the 22-day to 28-day cycle upon safety confirmation of the 28-day cycle 
and agreement from the investigator and sponsor. The previously tolerated unit dose 
administered Q2D in a 22-day cycle will be readministered Q2D in a 28-day cycle. 
Escalation from the last safe dose at a 22-day cycle to a 28-day cycle represents a 27% 
increase in total cycle dose, which is less than the smallest (33%) increase in total cycle dose 
originally planned for the Dose Escalation phase. 
Once the MTD and/or RP2D of MLN2480 have been determined for a 28-day cycle, or 
upon discretion of the sponsor, the study will continue to a Dose Expansion phase. The dose 
used for the Dose Expansion phase will be selected based on data from the Dose Escalation 
phase (MTD and/ or RP2D). The Dose Expansion phase will test MLN2480 in patients with 
locally advanced, metastatic, and/or unresectable melanoma (for Q2D dosing, Cohorts 1-6, 
for QW dosing Cohort 9), or in patients with advanced solid tumors, excluding lymphoma 
but including melanoma (Cohort 7). Tumor genotype is likely to serve as a predictor of 
response for patients with melanoma, and patients in dose expansion will be assigned to 1 of 
8 overall cohorts on the basis of tumor genotype and treatment history. Patients may be 
enrolled into 1 of the 8 expansion cohorts on the basis of previously documented genotype 
status, but may undergo a fresh biopsy at Screening for confirmation. 
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Cohort 7 in the Q2D Dose Expansion phase, the PK Expansion cohort, will include patients 
with any advanced solid tumor (excluding lymphoma but including melanoma) who have 
failed or are not candidates for standard therapies or for whom no approved therapy is 
available. 
7.4
Study Procedures
Each patient must sign and date an informed consent form (ICF) before undergoing any 
study-specific procedures unless those procedures are performed as part of the patient’s 
standard of care.
Enrollment in the study is defined as the time of initiation of the first dose of study drug. 
Additional procedures for completion of the enrollment information are described in the 
Study Manual.
A detailed visit-by-visit schedule of study procedures is provided in the Q2D Schedules of 
Events and the QW Schedules of Events.
Patients will be evaluated at scheduled visits over the following study periods: Screening, 
Treatment, and End of Study. Evaluations during the Screening period are to be conducted 
within 28 days before the first dose of MLN2480. Procedures conducted during the 
Screening period that are performed within 3 days of Cycle 1, Day 1 may also be used as the 
predose evaluation and do not need to be repeated, unless otherwise specified. All End of 
Study evaluations should occur 30 (+10) days after administration of the last dose of study 
drug or the start of subsequent antineoplastic therapy, whichever occurs first. Refer to the 
Q2D Schedules of Events for timing of all assessments. Additional details are provided as 
necessary in the sections that follow.
7.4.1 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.
7.4.2 Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during Screening.
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7.4.3 Medical History
During the Screening period, 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. In addition, concomitant medications will be 
recorded as specified in Section 7.4.9. All AEs that occur during the Screening period 
(following informed consent, but prior to study drug administration) will be recorded as part 
of the patient’s medical history.
7.4.4 Physical Examination
A physical examination will be completed per standard of care at the times specified in the 
Q2D Schedules of Events or the QW Schedules of Events. Any clinically relevant findings 
are to be documented.
7.4.5 Eastern Cooperative Oncology Group Performance Status
Performance status is to be assessed using the ECOG scale (see Section 14.1 for a 
description of the scale) at the times specified in the Q2D Schedules of Events or the QW 
Schedules of Events.
7.4.6 Height and Weight
Height will be measured only during Screening. Body weight will be measured at the times 
specified in the Q2D Schedules of Events or the QW Schedules of Events.
7.4.7 Vital Signs
Vital sign measurements, including body temperature, measurement of diastolic and systolic 
blood pressure, and heart rate will be assessed as specified in the Q2D Schedules of Events
or the QW Schedules of Events. Blood pressure should be determined with the patient in a 
seated position after the patient has been sitting quietly for 5 minutes.
7.4.8 Pregnancy Test
A pregnancy test will be obtained for women of childbearing potential as specified in the 
Q2D Schedules of Events or the QW Schedules of Events. A serum pregnancy test is 
required at the Screening and EOS visits; the Cycle 1, Day 1 pregnancy test can be serum or 
urine. 
The Screening results must be available and negative prior to enrollment. 
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7.4.9 Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures completed by the patient will 
recorded in the eCRF from Screening through the End of Study visit or the start of 
subsequent antineoplastic therapy, whichever occurs first. See Sections 6.6.1 and 6.6.2.3 for 
a list of medications and therapies that are prohibited or to be used cautiously during the 
study.
For patients in the expansion cohorts only, details of prior medications will be collected as 
part of their medical history; however, details of prior medications may also be 
retrospectively collected for patients of interest in the Dose Escalation phase.
7.4.10 Adverse Events
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as 
specified in the Q2D Schedules of Events or the QW Schedules of Events. Refer to 
Section 9 for details regarding definitions, documentation, and reporting of pretreatment 
events, AEs, and SAEs.
7.4.11 Enrollment
Enrollment is defined as the time of initiation of the first dose of study drug.
Procedures for completion of the enrollment information are described in the Study Manual.
7.4.12 Multiple Gated Acquisition Scan and/or Echocardiogram
An ECHO or MUGA will be administered at the time points specified in the Schedule of 
Events.
7.4.13 Electrocardiograms
ECGs will be reviewed at the site, including single safety ECGs and triplicate ECGs. All 
ECGs will also be sent to a central vendor for storage for potential future analysis.
Additional information regarding the collection and transferring of ECGs can be found in 
the ECG manual.
Any findings from ECGs collected after study drug administration on Cycle 1, Day 1 will be 
captured as AEs if, in the opinion of the investigator, there has been a clinically significant 
change from baseline.
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Predose ECGs should be completed within 1 hour before the start of dosing. When the 
timing of a PK, biomarker, or safety laboratory blood sample coincides with the timing of 
ECG measurements, the ECG will be completed before the collection of the blood sample.
The dates and exact times of ECG recordings should be recorded. Although the number of 
ECG measurements will not be increased, the timing of ECG measurements may be changed 
if emerging data indicate that an alteration in ECG sampling scheme is needed.
Electrocardiogram parameters will include PR, RR, QT, QTc, QRS, and ventricular rate.
7.4.13.1
Single ECGs
A single 12-lead ECG will be collected at Screening in all patients to assess eligibility. 
Additional single ECGs will be collected in Cycle 2 in all cohorts of the Expansion Phase 
and in Cycle 3 and all subsequent cycles in all patients (including at the End of Study visit). 
Refer to the Q2D Schedules of Events for timing of single ECGs.
7.4.13.2
Triplicate ECGs
All triplicate ECGs will be stored at a central reading laboratory for potential future reading 
if deemed necessary by the sponsor.
Triplicate 12-lead ECG recordings will be required in the Dose Escalation and PK 
Expansion cohorts at the time points specified in the Q2D Schedules of Events, Table 1-3, 
Table 1-6, and Table 1-12. They will not be performed in the dose expansion cohorts.
The triplicate ECG recordings will be performed in triplicate (approximately 2 to 5 minutes 
apart) after a 5-minute period of rest in the supine position and should be completed 
immediately before the corresponding PK blood draw.
7.4.14 Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed locally.
Blood samples for analysis of the following clinical chemistry and hematological parameters 
and urine samples for urinalysis will be obtained as specified in the Q2D Schedules of 
Events or the QW Schedules of Events.
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Hematology

Hemoglobin

Hematocrit

Platelet (count)

Red blood cells

White blood cells

Absolute reticulocyte count (only for patients who 
experience recurrent anemia with hemoglobin < 9 
g/dL, despite blood transfusion)

Absolute differential

Neutrophils (ANC)
Blood Chemistry

Blood urea nitrogen

Creatinine

Bilirubin (total)

ALT

Glucose 

Albumin

Alkaline phosphatase

AST

Lactate 
dehydrogenase

Thyroid function test

Calcium

Chloride

Carbon dioxide

Creatine kinase

Potassium

Sodium
Urinalysis

pH

Specific gravity

Protein

Ketones

Bilirubin

Occult blood

Nitrite

Urobilinogen

Glucose

Leukocytes
If a patient develops an ANC < 500/μL or a platelet count < 25,000/μL, blood samples must 
be collected every 2 to 3 days and study treatment withheld until counts resolve or until 
ANC returns to > 1000/μL and platelet counts return to > 50,000/μL.
7.4.15 Disease Assessment
At Screening, all sites of disease should be imaged by computed tomography (CT). If the 
anatomic region cannot be adequately imaged by CT, magnetic resonance imaging (MRI) 
may be used instead. The same imaging modality utilized at Screening for a particular site of 
disease must remain consistent throughout all subsequent disease assessments, which will be 
performed every 2 cycles after starting MLN2480 treatment, as described in the Q2D 
Schedules of Events or the QW Schedules of Events. Objective assessments will be 
performed at each time point, using modified RECIST criteria (version 1.1). RECIST 
criteria are described in Section 14.3. When possible, the same qualified physician will 
interpret results to reduce variability. Radiographic images will be maintained at the site, 
and test results and physician’s findings will be filed in patient source documents.
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In the event of antitumor response, the sponsor may request electronic images for those 
patients who demonstrate tumor reduction.
7.4.16 Dermatological Examination
All patients will be assessed by the investigator or a consulting dermatologist for skin 
lesions, especially for keratoacanthomas and squamous cell carcinomas; examination will 
include the entire skin. For each skin lesion observed, the dimensions and location on the 
body will be recorded. Existing lesions will be monitored throughout the study and changes 
to the lesions should be recorded in the CRF. Lesions developing during therapy that are 
suspected keratoacanthomas or squamous cell carcinomas will be biopsied and adequately 
treated; other lesions may be biopsied per the discretion of the investigator/dermatologist.
7.4.17 Dermatological Photographs
All patients will have dermatological photographs taken at Screening to document any 
pretreatment skin lesions. Any patient with new or changing skin lesions during the course 
of treatment will have repeat photographs taken to document the lesion. Refer to the Study 
Manual for further details.
7.4.18 Pharmacokinetic Measurements
The primary objective of all PK sampling in this study (plasma and urine) is to measure 
concentrations of MLN2480. A validated liquid chromatography/mass spectroscopy method 
will be used to quantify concentrations of MLN2480 in plasma and urine. However, pending 
technical feasibility, these plasma and/or urine samples may additionally be used for 
exploratory analysis of MLN2480 metabolites to further understand the pathways of 
metabolism/excretion of MLN2480. 
Plasma samples will be collected predose and at prespecified time points following 
administration of MLN2480 in the dose escalation cohorts, dose expansion cohorts, and the 
PK expansion cohort. Urine samples will be collected predose and at prespecified time 
points postdose in the dose escalation cohorts and the PK expansion cohort to estimate the 
extent of renal excretion of MLN2480. 
The predose urine sample on Cycle 1, Day 1 will represent a single void collected before the 
start of the Day 1 dose. The exact date and time of collection should be recorded.
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The postdose urine collection (on Cycle 1, Day 21[Q2D] or Day 22 [QW]) will include all 
voids collected from 0 to 8 hours after the dose. The patient should be instructed to empty 
their bladder prior to dosing; this predose void should be discarded unless needed for non-
PK purposes. The final urine void of the postdose urine collection should be collected prior 
to the blood sample for plasma PK scheduled at 8 hours after the dose. The exact date, start 
and stop times, and total volume of the postdose urine collection should be recorded.
Refer to Table 1-1, Table 1-4, and Table 1-7 for the timing of blood samples for PK 
assessments in the Q2D Dose Escalation phase, the Q2D PK Expansion cohort, and the Q2D 
melanoma expansion cohorts, respectively. Refer to Table 1-2 and Table 1-5 for the timing 
of urine samples for PK assessments in the Q2D Dose Escalation phase and the Q2D PK 
Expansion cohort, respectively. Refer to Table 1-8, Table 1-9, and Table 1-10 for the timing 
of blood samples for PK assessments in the QW Dose Escalation and Dose Expansion 
phases. Refer to Table 1-11 for the timing of urine samples for PK assessments in the QW 
Dose Escalation phase. 
In addition to the scheduled PK sample collections, a blood sample to measure MLN2480 
plasma concentrations should be obtained, if clinically feasible, at the time of a serious or 
unusual AE that is judged by the investigator to be treatment related, irrespective of the 
cycle or day of occurrence of the AE. The date and exact time of the unscheduled sample 
collection should be recorded, along with the date and exact time of dosing prior to the 
unscheduled sample collection.
Although the number of PK samples will not be increased, the timing of PK samples may be 
modified during the study conduct based on preliminary results from interim PK analyses 
performed during the study or in response to modifications of the dosing schedule.
The dates and exact times of dosing and all PK sample collections will be recorded in the 
eCRF based on site source documentation.
Details regarding the collection, processing, storage, handling, and shipping of the PK 
samples are provided in the Laboratory Manual.
7.4.19 Pharmacodynamic Assessment/ Fresh Tumor Biopsies 
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7.4.20 Archival/ Fresh Tumor Specimen Measurements for Tumor Genotyping
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7.4.21 Pharmacogenomic Assessment
7.5
Completion of Study
Patients will be considered to have completed the study if they complete up to 12 months of 
treatment with MLN2480 or if they experience disease progression.
Once study drug has been discontinued, all study procedures outlined for the End of 
Treatment visit will be completed as specified in the Q2D Schedules of Events or the QW 
Schedules of Events.
7.6
Withdrawal of Patients From Study
Patients will be informed that they have the right to discontinue study treatment at any time 
for any reason, without prejudice to their medical care.
A patient may be withdrawn from the study for any of the following reasons:

AE

CR

Completed maximum number of cycles per protocol

Lost to follow-up

Progressive disease (PD)
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
Protocol violation

Symptomatic deterioration

Unsatisfactory therapeutic response

Study terminated by sponsor

Withdrawal by patient

Other
At the time of study drug discontinuation, all study procedures outlined for the End of Study 
visit will be completed. The primary reason for study drug discontinuation will be recorded 
on the eCRF.
Patients who are withdrawn from study treatment during Cycle 1 for reasons other than DLT 
will be replaced in the Dose Escalation phase of the study.
7.7
Study Stopping Rules
Conditions that may warrant termination of the study include, but are not limited to, the 
following:

The discovery of an unexpected, serious, excessively frequent, or unacceptable risk 
to the patients enrolled in the study.

A decision on the part of the sponsor to suspend or discontinue testing, evaluation, or 
development of the product.
Millennium Pharmaceuticals, Inc. (Millennium) may terminate this study at any time, after 
informing investigators. Investigators will be notified by Millennium if the study is placed 
on hold, completed, or closed.
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8.
STATISTICAL AND QUANTITATIVE ANALYSES
8.1
Statistical Methods
This study is noncomparative in nature, ie, formal statistical comparisons will not be 
performed. Summary tabulations will be presented that will display the number of 
observations, mean, standard deviation, median, minimum, and maximum for continuous 
variables, and the number and percentage per category for categorical data. A formal 
statistical analysis plan will be developed and finalized before database lock.
In the Dose Escalation phase, statistical analyses will be primarily descriptive and graphical 
in nature. In the Dose Expansion phase, ORR in the response-evaluable population will be 
tabulated descriptively for each cohort and total melanoma expansion cohort (Cohorts 1-6); 
95% exact binomial confidence intervals will be provided for the total melanoma expansion 
cohort. Time-to-event data for the total melanoma expansion cohort will be analyzed by the 
Kaplan-Meier method and results will be summarized by 25th, 50th (median), and 75th
percentiles with associated 2-sided 95% confidence intervals, as well as the percentage of 
censored observations.
8.1.1 Determination of Sample Size
The total sample size for the study will be approximately 198 patients (approximately 
54 patients in the Dose Escalation phases (Q2D and QW) and approximately 144 patients in 
the Dose Expansion phase [Q2D and QW]). In the Dose Escalation phase, a 3 + 3 dose 
escalation design will be used; therefore, the sample size is dependent on the number of dose 
escalation steps and the number of patients per cohort. To further evaluate the safety and 
preliminary antitumor activity of the selected MLN2480 dose for the Dose Expansion phase, 
approximately 128 patients with locally advanced metastatic, and/or unresectable melanoma 
(each cohort will have a maximum of 16 evaluable patients), and 16 patients with advanced 
solid tumors (excluding lymphoma) will be enrolled in the Dose Expansion phase (Q2D and 
QW). 
8.1.2 Randomization and Stratification
Randomization will not be used in this study; however, patients will be assigned to 
1 of 8 expansion cohorts based on tumor type, mutational status, and/or treatment history 
(see Section 5.1). No stratification is planned for this study. An interactive voice response 
system will be used for cohort management. Refer to the Study Manual for details.
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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 any 
amount of MLN2480. This population will be used for all safety analyses, as well as 
pharmacogenomic analyses.

DLT-evaluable population: The DLT-evaluable population is defined as all patients 
in the Dose Escalation phase of the study who either experience DLT during Cycle 1 
or complete at least 75% of the planned doses of MLN2480 and have sufficient 
follow-up data to allow the investigators and sponsor to determine whether DLT 
occurred. This population will be used for analysis of MTD.

Response-evaluable population: The response-evaluable population is defined as all 
patients with measurable disease who receive any amount of MLN2480 and have at 
least 1 postbaseline response assessment. This population will be used for response 
rate and DOR analyses.

PK-evaluable population: The PK-evaluable population is defined as all patients who 
have sufficient dosing data and MLN2480 concentration-time data to permit 
calculation of MLN2480 PK parameters.

Pharmacodynamic-evaluable population: The pharmacodynamic-evaluable 
population is defined as all patients who have sufficient dosing data and available 
pharmacodynamic data. The patients to be included in pharmacodynamic analysis 
populations will be determined by the sponsor upon review of the data. 
8.1.4 Procedures for Handling Missing, Unused, and Spurious Data
All available efficacy and safety data will be included in data listings and tabulations. No 
imputation of values for missing data will be performed. Data that are potentially spurious or 
erroneous will be examined according to standard data management operating procedures.
8.1.5 Demographic and Baseline Characteristics
The demographic and baseline characteristics will be summarized in a descriptive fashion. 
Data to be evaluated will include age, sex, race, ethnicity, height, weight, and baseline 
disease characteristics.
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8.1.6 Efficacy Analysis
There will be no planned statistical comparisons for efficacy endpoints between dose 
cohorts in the Dose Escalation phase.
Overall response rate (ORR) is defined as the number of CR and PR in the 
response-evaluable population. In the Dose Escalation phase, ORR will be tabulated 
descriptively for each dose group and total. In the Dose Expansion phase, ORR in the 
response-evaluable population will be tabulated descriptively for each cohort and total dose 
expansion cohort (Cohorts 1-6, 8, and 9); 95% exact binomial confidence intervals will be 
provided for the total dose expansion cohort. CR, PR, SD, and PD will also be summarized 
and analyzed in the same way.
Duration of response (DOR) is defined as the time from the date of first documentation of a 
response to the date of first documented PD. In the Dose Escalation phase, DOR will be 
summarized descriptively for each dose group and total. In the Dose Expansion phase, DOR 
in the response-evaluable population will be summarized descriptively for each cohort and 
total dose expansion cohort (Cohorts 1-6, 8, and 9).
Progression-free survival (PFS) is defined as the time from the date of first study drug 
administration to the date of first documented PD or death due to any cause, whichever 
occurs first. PFS for the total dose expansion cohort will be analyzed by the Kaplan-Meier 
method, and results will be summarized by 25th, 50th (median), and 75th percentiles with 
associated 2-sided 95% confidence intervals, as well as the percentage of censored 
observations. PFS will be summarized in total for the safety population based on the Kaplan-
Meier life test method.
8.1.7 Pharmacokinetic Analysis
MLN2480 PK analyses will be performed on data from the PK-evaluable population.

PK evaluations from plasma samples collected in the Dose Escalation phase and the 
PK Expansion cohort will enable calculation of PK parameters, including, but not 
limited to, Cmax, Ctrough, t1/2, tmax, AUC, apparent oral clearance, peak-to-trough ratio, 
and accumulation ratio.

PK evaluation from limited sampling in the melanoma-specific expansion cohorts 
will contribute to population PK analysis.
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
PK evaluations from urine samples collected in the Dose Escalation phase and the 
PK Expansion cohort will enable calculation of MLN2480 renal clearance and 
percent dose excreted in urine.
The following analyses will be performed for all patients in the PK-evaluable population:

Plasma concentrations of MLN2480 will be summarized by time postdose, grouped 
by dose group and dosing cycle and day. Mean and individual plasma concentration-
time profiles will be plotted by dose group and dosing cycle and day.

PK parameters will be calculated for MLN2480 by noncompartmental analysis as 
permitted by the data. These parameters will include Cmax, Tmax, trough concentration 
(Ctrough), AUC0-, apparent oral clearance, renal clearance, half life, peak-to-trough 
ratio, and accumulation ratio. As appropriate, these parameters will be summarized 
by dose group and dosing cycle and day. Dose proportionality of Cmax and AUC0-
may be assessed graphically and by regression analysis using a power model. 
Pharmacokinetic Modeling
MLN2480 PK data collected in this study, together with PK data collected from future 
studies, may contribute to population PK analysis. The objectives of this analysis are to 
understand potential sources of PK variation, including patient-specific covariates (eg, age, 
gender, renal and hepatic function), and to enable exploratory analysis of the relationships 
between PK and drug effects, including pharmacodynamics, clinical response, and safety. If 
population PK analysis is considered feasible, the specifics of the modeling approaches will 
be described separately in a population PK analysis plan, and the results will be reported 
separately.
8.1.8 Pharmacodynamic Analysis
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8.1.9 Pharmacogenomic Analysis
8.1.10 Safety Analysis
Safety evaluations will be based on the incidence, intensity, and type of AEs; and clinically 
significant changes in the patient’s vital signs, weight, and clinical laboratory results. Safety 
variables will be tabulated and presented for the safety population. The incidence of DLT 
will be presented. Exposure to study drug and reasons for discontinuation of study treatment 
will be tabulated.
Adverse events will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) for the purpose of summarization. All AEs occurring on study will be listed in 
data listings. Treatment-emergent adverse events 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. 
Adverse events 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
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
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.
The most commonly reported treatment-emergent AEs (ie, those events reported by ≥10% 
of all patients in the safety population) will be tabulated in each dose group and total for 
dose escalation phase, as well as each cohort and total for the dose expansion phase by the 
MedDRA preferred term. Tabulation also will be provided that enumerates AEs by 
maximum intensity. Deaths, SAEs, and AEs resulting in study drug discontinuation will be 
tabulated.
Clinical laboratory parameters will be summarized at each scheduled time point in the Dose 
Escalation phase, as well as each cohort and total for the Dose Expansion phase. Shift tables 
will be produced for selected laboratory parameters. These tables will summarize the 
number of patients with each baseline NCI CTCAE grade and changes to the worst NCI 
CTCAE grade during study. 
Descriptive statistics for the actual values of vital signs and weight over time will be 
tabulated for Dose Escalation phase, as well as each cohort and total for the Dose Expansion 
phase by scheduled time point.
All concomitant medications collected from Screening through the study period will be 
classified by preferred term according to the World Health Organization drug dictionary.
Additional safety analyses may be determined at any time without prejudice, in order to 
enumerate rates of toxicities and to further define the safety profile of study drugs.
ECG Analysis
A summary of ECG abnormalities will be presented by visit for the dose escalation phase, as 
well as each cohort and total for the dose expansion phase. The ECG intervals (QT, QT 
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adjusted by an appropriate correction [QTcB (Bazzett) and QTcF], PR, QRS, and RR) and 
HR will be summarized by dose cohort (and gender, if deemed appropriate) at each 
scheduled time point, along with change from baseline to each posttreatment time point. 
The effects of MLN2480 on select ECG parameters (eg, QTc) may be evaluated using data 
from this and other studies using a population concentration-effect analysis approach. If 
conducted, this analysis will be reported separately.
8.1.11 Interim Analysis
No formal interim analysis will be performed. 
Safety and available PK data will be reviewed jointly by Millennium and investigators on an 
ongoing basis for the purposes of safety monitoring and dose escalation decisions.
9.
ADVERSE EVENTS
9.1
Definitions
9.1.1 Pretreatment Event Definition
A pretreatment event is any untoward medical occurrence in a patient or patient 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.
9.1.2 Adverse Event Definition
Adverse event means any untoward medical occurrence in a patient or patient 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.
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9.1.3 Serious Adverse Event Definition
Serious AE 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 
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.[37]  Clarification should be made between an 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) 
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does not necessarily need to be considered serious. For example, a leukocyte count of 
1000/mm3 to less than 2000/mm3 is considered Grade 3 (severe) but may not be considered 
serious. Seriousness (not intensity) serves as a guide for defining regulatory reporting 
obligations.
9.1.4 Prescheduled or Elective Procedures or Routinely Scheduled Treatments
A prescheduled or elective procedure or a routinely scheduled treatment will not be 
considered an SAE, even if the patient is hospitalized; the study site must document all of 
the following:

The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or was on a waiting list to be scheduled) prior to obtaining the patient’s 
consent to participate in the study.

The condition requiring the prescheduled or elective procedure or routinely 
scheduled treatment was present before and did not worsen or progress in the opinion 
of the investigator between the patient’s consent to participate in the study and the 
time of the procedure or treatment.

The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission.
9.2
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 9.3 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. When patients 
have been in the study for 4 years or longer, nonserious AEs will no longer be recorded.
Regardless of causality, SAEs and serious pretreatment events (as defined in Section 9.1) 
must be reported (see Section 9.3 for the period of observation) by the investigator to 
Cognizant, the designees of Millennium Pharmacovigilance, for SAE reporting (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 
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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 Cognizant or Millennium. Serious adverse event report information must be 
consistent with the data provided on the eCRF.
SAE Reporting Contact Information
Cognizant (US and Canada)
Toll-Free Fax#: 1-800-963-6290
Email: takedaoncocases@cognizant.com
----------------------------------------------------------------
Cognizant (All other countries [Rest of World])
Fax#: 1-202-315-3560
Email: takedaoncocases@cognizant.com
The sponsor will be responsible for reporting all suspected unexpected serious adverse 
reactions (SUSARs) and any other applicable SAEs to regulatory authorities, investigators, 
and ethics committees as applicable, in accordance with national regulations in the countries 
where the study is conducted. Specifically in the EU, the sponsor will ensure that all relevant 
information from SUSARs that are fatal or life-threatening is recorded and reported as soon 
as possible to the regulatory authorities in all the Member States concerned, and to the ethics 
committee, and in any case no later than 7 days after knowledge by the sponsor of such a 
case, and relevant follow-up information is subsequently communicated within an additional 
8 days. All other SUSARs shall be reported to the regulatory authorities concerned and to 
the ethics committee concerned as soon as possible within a maximum of 15 days of first 
knowledge by the sponsor. The sponsor will also inform all the investigators in the clinical 
trial.
Once a year throughout the conduct of the clinical trial, the sponsor will provide the 
regulatory authorities in whose territory the clinical trial is being conducted and the ethics 
committees with a listing of all SUSARs that have occurred over the past year and a report 
of the subjects’ safety.
Planned hospital admissions or surgical procedures for an illness or disease that existed 
before the patient signed the ICF are not to be considered AEs unless the condition 
deteriorated in an unexpected manner during the study (eg, surgery was performed earlier or 
later than planned).
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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. 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?
9.3
Monitoring of Adverse Events and Period of Observation
Adverse events, both nonserious and serious, will be monitored throughout the study as 
follows:

AEs will be reported from the start of the first dose of study drug through 30 days 
after administration of the last dose of study drug or the start of subsequent 
antineoplastic therapy, whichever occurs first, and recorded in the eCRFs. That is, if 
a patient begins a new antineoplastic therapy, the AE reporting period for nonserious 
AEs ends at the time the new treatment is started. When patients have been in the 
study for 4 years or longer, nonserious AEs will no longer be reported.

Serious pretreatment events will be reported to Cognizant (see Section 9.2) and 
recorded in the Safety database from the time of the signing of the ICF up to first 
dose of study drug, but will not be recorded in the eCRF. Pretreatment AEs 
(nonserious) will be recorded in the eCRF as part of the patient’s medical history. If 
a pretreatment event worsens following initiation of study drug, the corresponding 
TEAE is documented in the clinical database.

Related and unrelated SAEs will be reported to Cognizant from the start of the first 
dose of study drug through 30 days after administration of the last dose of study drug 
and recorded in 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). 
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9.4
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 Cognizant (see Section 9.2). 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 Cognizant (see Section 9.2). Every effort should be made to 
follow the pregnancy for the final pregnancy outcome.
10.
ADMINISTRATIVE REQUIREMENTS
10.1
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.
10.2
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.
Project clinicians 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.
10.3
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.
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Electronic CRFs 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 or other electronic media will be 
placed in the investigator’s study file.
10.4
Study Monitoring
Monitoring and auditing procedures developed or approved by Millennium will be followed 
to comply with GCP guidelines.
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.
10.5
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.
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10.6
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.
10.7
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.
10.8
Investigator Compliance
The investigator will conduct the study 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, 
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.
10.9
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.
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10.10
Investigator and Site Responsibility for Drug Accountability
Accountability for the study drug at the study 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.
10.11
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 contact the Medical 
Information Call Center (Dohmen Life Science Services [DLSS]) (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,
For more information call 1-844-ONC-TKDA (1-844-662-8532)
or email GlobalOncologyMedinfo@takeda.com
Product complaints and medication errors in and of themselves are not AEs. If a product 
complaint results in an SAE, an SAE form should be completed and sent to Cognizant (refer 
to Section 9.2).
10.12
Closure of the Study
Within 90 days of the end of the study, the sponsor will notify the competent authorities and 
the IECs in all member states where the study is being carried out that the study has ended.
Within 1 year of the end of the study, a summary of the clinical study results will be 
submitted to the competent authorities and IECs in all member states involved in 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 
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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.
Within 15 days of premature closure, Millennium must notify the competent authorities and 
IECs of any member state where the study is being conducted, providing the reasons for 
study closure.
10.13
Record Retention
The investigator will maintain all study records according to the ICH-GCP and applicable 
regulatory requirement(s). Records will be retained for at least 2 years after the last 
marketing application approval or 2 years after formal discontinuation of the clinical 
development of the investigational product or according to applicable regulatory 
requirement(s). If the investigator withdraws from the responsibility of keeping the study 
records, custody must be transferred to a person willing to accept the responsibility and 
Millennium notified. 
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11.
USE OF INFORMATION
All information regarding MLN2480 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 MLN2480 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 study results pursuant 
to the terms contained in the applicable Clinical Trial Agreement.
It is anticipated that the results of this study will be presented at scientific meetings and/or 
published in a peer-reviewed scientific or medical journal. A Publications Group comprising 
Millennium employees and study investigators will be formed to oversee the publication of 
the study results, which will reflect the experience of all participating study centers. 
Subsequently, individual investigators may publish results from the study in compliance 
with their agreements with Millennium.
A prepublication manuscript or abstract is to be provided to Millennium a minimum of 
30 days before the intended submission date of the manuscript or abstract to a publisher. 
Within 30 days after receipt by Millennium of the notification, Millennium shall inform the 
study centers whether it has objections to the publication for reasons including, but not 
limited to, those defined below:

If patentable patient matter is disclosed, the publication shall be delayed for a period 
not to exceed 90 days from Millennium’s receipt of the proposed publication to 
allow time for the filing of patent applications covering patentable patient matter.

If confidential information is contained in any proposed publication or public 
disclosure, such confidential information will be removed at Millennium’s request.
The overall principal investigator will be the last author on abstracts and publications of the 
data generated from this study. Other authors will be listed according to number of patients 
enrolled to the study. If the principal investigator has the highest enrollment, he/she may 
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choose to be either first or last author. This policy may be changed with the agreement of 
both the investigators and Millennium.
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12.
INVESTIGATOR AGREEMENT
I have read Protocol C28001 Amendment 8: An Open-Label, Phase 1, Dose Escalation 
Study of MLN2480 in Patients With Relapsed or Refractory Solid Tumors Followed by a 
Dose Expansion Phase in Patients With Metastatic Melanoma. I agree to conduct the study 
as detailed herein and in compliance with International Conference on Harmonisation 
Guidelines for Good Clinical Practice and applicable regulatory requirements and to inform 
all who assist me in the conduct of this study of their responsibilities and obligations.
Principal investigator printed name
Principal investigator signature
Date
Investigational site or name of institution and 
location (printed)
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13.
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treatment of advanced (unresectable or metastatic) melanoma in adults who have 
received prior therapy: summary of the scientific assessment of the Committee for 
Medicinal Products for Human Use. Eur J Cancer 2012;48(2):237-42.
26.
Robert C, Thomas L, Bondarenko I, O'Day S, M DJ, Garbe C, et al. Ipilimumab plus 
Dacarbazine for Previously Untreated Metastatic Melanoma. N Engl J Med 2011.
27.
Flaherty K, Puzanov I, Sosman J, Kim K, Ribas A, McArthur G, et al. Phase I study 
of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in 
human cancer. J Clin Oncol (ASCO Meeting Abstracts) 2009;27(15s):abstr 9000.
28.
McArthur G, Ribas A, Chapman P, Flaherty K, Kim K, Puzanov I, et al. Molecular 
analyses from a phase I trial of vemurafenib to study mechanism of action (MOA) 
and resistance in repeated biopsies from BRAF mutation–positive metastatic 
melanoma patients (pts). J Clin Oncol (ASCO Meeting Abstracts) 
2011;29(suppl):abstr 8502.
29.
Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. 
Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 
3 randomised controlled trial. Lancet 2012;380(9839):358-65.
30.
Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, et al. Improved 
survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 
2012;367(2):107-14.
31.
Hersey P, Bastholt L, Chiarion-Sileni V, Cinat G, Dummer R, Eggermont AM, et al. 
Small molecules and targeted therapies in distant metastatic disease. Ann Oncol 
2009;20 Suppl 6:vi35-40.
32.
Garber K. Industry makes strides in melanoma. Nat Biotech 2010;28(8):763-4.
33.
Davies BR, Logie A, McKay JS, Martin P, Steele S, Jenkins R, et al. AZD6244 
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(ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular 
signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, 
pharmacokinetic/pharmacodynamic relationship, and potential for combination in 
preclinical models. Mol Cancer Ther 2007;6(8):2209-19.
34.
Hoeflich KP, Herter S, Tien J, Wong L, Berry L, Chan J, et al. Antitumor efficacy of 
the novel RAF inhibitor GDC-0879 is predicted by BRAFV600E mutational status 
and sustained extracellular signal-regulated kinase/mitogen-activated protein kinase 
pathway suppression. Cancer Res 2009;69(7):3042-51.
35.
Wong H, Belvin M, Herter S, Hoeflich KP, Murray LJ, Wong L, et al. 
Pharmacodynamics of 2-[4-[(1E)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-3-
(pyridine-4-yl)-1H-pyrazol-1-yl]ethan-1-ol (GDC-0879), a potent and selective B-
Raf kinase inhibitor: understanding relationships between systemic concentrations, 
phosphorylated mitogen-activated protein kinase kinase 1 inhibition, and efficacy. J 
Pharmacol Exp Ther 2009;329(1):360-7.
36.
DeGeorge JJ, Ahn CH, Andrews PA, Brower ME, Giorgio DW, Goheer MA, et al. 
Regulatory considerations for preclinical development of anticancer drugs. Cancer 
Chemother Pharmacol 1998;41(3):173-85.
37.
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. U.S. 
Department of Health and Human Services National Cancer Institute. 14 June 2010.
38.
Lemech C, Arkenau HT. Novel treatments for metastatic cutaneous melanoma and 
the management of emergent toxicities. Clin Med Insights Oncol 2012;6:53-66.
39.
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.
40.
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.
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14.
APPENDICES
14.1
Eastern Cooperative Oncology Group 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.[39]
14.2
22-Day Treatment Cycle Schedule of Events Tables
The study cycle length was extended from 22 days to 28 days upon implementation of 
Protocol Amendment 3. For reference and clarity, this appendix contains the 22-Day 
Treatment Cycle Schedule of Events Tables. The 28-day Treatment Cycle Schedule of 
Events Tables are located in the body of the protocol.
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22-Day Treatment Cycle: Cycle 1 Schedule
Screening
Day 1
Day 2
Day 3
Day 9
Day 15
Day 21
Day 22
≤21 days 
Prior to Day 1
Predose
Postdose
Predose
Postdose
Informed consent form
X
Inclusion/exclusion criteria
X
Demographics
X
Medical history
X
Complete physical 
examination, height, and body 
weight measurement
X
Xa
Dermatological examination 
with documentation of any 
suspicious lesionsb
X
X
X
X
Xc
12-lead ECGd
X
X
X
X
X
X
Vital signs (temperature, blood 
pressure, pulse rate)e
X
Xf
Xf
Xf
Xf
ECOG performance status
X
Xa
Laboratory tests
Hematologyg
X
Xa, h
X
X
Blood chemistryi
X
Xa, h
X
X
Bone marrow aspirate and 
biopsyj
Optional tumor biopsyk
X
X
Coagulationl
Thyroid function
X
Serum pregnancy test 
(female patients of 
reproductive potential)
Xa
Xa
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Clinical Study Protocol C28001 Amendment 9
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22-Day Treatment Cycle: Cycle 1 Schedule
Screening
Day 1
Day 2
Day 3
Day 9
Day 15
Day 21
Day 22
≤21 days 
Prior to Day 1
Predose
Postdose
Predose
Postdose
Urinalysism
X
Xa
Serum samples for 
biomarker assessment
Xn
Xo
Blood sample for 
pharmacogenomic 
assessment (germline DNA)
X
Blood sample for PK 
assessment (Dose Escalation 
phase)p, q
X
X
X
X
X
X
X
X
X
Urine samples for PK 
assessment (Dose Escalation 
phase)r
X
X
Confirmation of available 
FFPE tumor tissues
X
Disease assessment, including 
CT or MRI scan
Xt
Concomitant therapy and 
procedures recordingu
Concomitant therapy and procedures must be recorded from Screening through the End of Study visit or 
the start of subsequent antineoplastic therapy, whichever comes first.
AE reporting
AEs will be recorded from first dose of study drug through 30 days after the last dose of study drug or the 
start of subsequent antineoplastic therapy 
SAEsv will be collected from signing of the informed consent form through 30 days after the last dose of study drug.
MLN2480 administration 
(Dose Escalation phase only)w
MLN2480 dosing is once every 2 days on Days 1-21 of a 22 day cycle (11 doses), starting on Day 1
Abbreviations: aPTT=activated partial thromboplastin time; AE=adverse event; ALT=alanine aminotransferase; ANC=Absolute Neutrophil Count; 
AST=aspartate aminotransferase; BUN=blood urea nitrogen; CRF=Case Report Form; CT=computed tomography; DLT=dose-limiting toxicity; 
ECG=Electrocardiogram; ECOG=Eastern Cooperative Oncology Group; FFPE=formalin-fixed paraffin-embedded; ICF=informed consent form; 
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MLN2480 (TAK-580)
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22-Day Treatment Cycle: Cycle 1 Schedule
Screening
Day 1
Day 2
Day 3
Day 9
Day 15
Day 21
Day 22
≤21 days 
Prior to Day 1
Predose
Postdose
Predose
Postdose
MRI=magnetic resonance imaging; PK=pharmacokinetic; PT=prothrombin time; RBC=red blood cell; SAE=serious adverse event; WBC=white blood cell.
An End-of-Cohort meeting scheduled by the sponsor will occur after the last patient in each cohort in the Dose Escalation phase has completed the 
first treatment cycle/DLT observation period (ie, Day 1 to Day 22).
a Assessments need not be repeated if Screening assessments were performed within 72 hours before MLN2480 dosing, unless otherwise specified. Height is 
to be collected at Screening only. 
b All patients will be assessed by the investigator or a consulting dermatologist at the visits specified. The examination for skin lesions will include the entire 
skin. Existing lesions will be monitored throughout the study and changes to the lesions will be recorded in the CRF. For lesions developing during 
treatment that are suspected keratoacanthomas or squamous cell carcinomas, the dimensions and location on the body will be recorded in the CRF and they 
will be subsequently biopsied/adequately treated. Other lesions that develop during treatment should be recorded on the AE form and may be biopsied at 
the discretion of the investigator/ dermatologist.
c Assessment will be performed on Cycle 1, Day 22 ± 5 days.
d A single 12-lead ECG will be collected at Screening to assess eligibility. Subsequent ECGs will be collected in triplicate at all time points. The triplicate 
ECG measurements should be completed after a 5-minute rest period in the supine position and will be recorded at 2 to 5 minute intervals immediately 
before the corresponding PK blood draw. The triplicate ECGs  will be collected predose on Day 1 (within 1 hour prior to dosing) and on Days 1 and 21 at 2, 
4, and 6 hours after dosing. Triplicate ECGs will also be collected 48 hours post Day 1 dose (predose within 1 hour prior to Day 3 dosing). 
e Blood pressure should be determined with the patient in a seated position after the patient has been sitting quietly for 5 minutes.
f
On Days 1, 9, and 15 vital sign measurements will be performed within 15 minutes prior to dosing. On Cycle 1, Day 1 only, also perform vital sign 
measurements at 2 hours ± 10 minutes and 6 hours ± 10 minutes postdose. 
g Hematology will be tested at local laboratories and includes hemoglobin, hematocrit, platelet counts, RBC, WBC, absolute reticulocyte counts (only for 
patients who experience recurrent anemia with hemoglobin < 9 g/dL, despite blood transfusion), absolute differential, and ANC. If a patient develops an 
ANC < 500/μL or a platelet count < 25,000/μL, blood samples must be collected every 2 to 3 days and study treatment withheld until counts resolve or until 
ANC returns to > 1,000/μL and platelet counts return to > 50,000/μL.
h Hematology results (including hemoglobin, hematocrit, platelet counts, RBC, WBC, absolute reticulocyte counts [only for patients who experience 
recurrent anemia with hemoglobin < 9 g/dL, despite blood transfusion], absolute differential, and ANC) and blood chemistry results (including creatinine, 
total bilirubin, AST, and ALT) will be evaluated before the patient is allowed to take their dose of MLN2480 on Day 1 of each cycle.
i
Blood chemistry results will include glucose, BUN, creatinine, sodium, potassium, chloride, CO2, total bilirubin, lactate dehydrogenase, alkaline 
phosphatase, AST, ALT, albumin, and calcium.
j
Bone marrow aspirate and biopsy will be encouraged only for patients who experience recurrent anemia with hemoglobin < 9 g/dL, despite blood 
transfusion.
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Clinical Study Protocol C28001 Amendment 9
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22-Day Treatment Cycle: Cycle 1 Schedule
Screening
Day 1
Day 2
Day 3
Day 9
Day 15
Day 21
Day 22
≤21 days 
Prior to Day 1
Predose
Postdose
Predose
Postdose
k Biopsy of tumor  will be performed at Screening and 3 to 12 hours after MLN2480 dosing on Cycle 1, Day 21. 
l
Within 48 hours of any invasive procedure (ie, tumor biopsy or bone marrow biopsy), aPTT and PT must be within the normal range. For tumor and bone 
marrow biopsies, platelet count should be 75,000/mm3.
m Urinalysis includes dipstick for blood, protein, and glucose (microscopic examination, if abnormal). Samples will be collected predose.
n Predose plasma sample will be taken within 1 hour prior to MLN2480 dosing.
o Postdose plasma samples for biomarker analysis will be taken 4 and 48 hours following MLN2480 dosing. (The 48-hour postdose sample corresponds to 
the Cycle 2, Day 1 predose sample.)
p Refer to Table 1-1 for details on assessment time points. Refer to Laboratory Manual for details on collection, processing, storage, and shipment of plasma 
PK samples.
q In addition to the scheduled PK sample collections, a blood sample to measure MLN2480 plasma concentrations should be obtained, if clinically feasible, at 
the time of a serious or unusual AE that is judged by the investigator to be treatment-related, irrespective of the cycle or day of occurrence of the AE. See 
Section 7.4.18
r
Refer to Table 1-2 for details on collection time points. Refer to Laboratory Manual for details on collection, processing, storage, and shipment of urine PK 
samples.
s FFPE tumor tissue or slides from the diagnostic biopsy or surgical specimen from the most recent diagnosis, or FFPE tumor tissue from a new biopsy if 
archival tumor tissue is unavailable or inadequate.
t
Refer to Section 7.4.15 and Section 14.3.
u Concomitant therapies and procedures must be recorded from Screening through the End of Study visit or the start of subsequent antineoplastic therapy, 
whichever comes first.
v Including serious pretreatment events; see Section 9.
w Patients will take MLN2480 orally once every 2 days and will fast (with the exception of water) for at least 2 hours before and at least 2 hours after taking 
their dose. On dosing days when the patient does not have a clinic visit (ie, Days 5, 7, 11, 13, 17, and 19), patients will take their dose of MLN2480 at 
home.
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MLN2480 (TAK-580)
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22-Day Treatment Cycle: Cycle 2 Schedule
Tests and Assessments
Cycle 2 (Day 1 through Day 22)
Day 1 2 Days
Day 9 2 Days
Day 21 2Days
Physical examination and body weight measurement 
X
Dermatological examination with documentation of any 
suspicious lesionsa
X
X
12-lead ECGb
X
Vital signs (temperature, blood pressure, pulse rate)c
X
X
Laboratory tests
Hematologyd
Xe
X
Blood chemistryf
Xe
X
Bone marrow aspirate and biopsyg
Coagulationh
Thyroid function
X
Urinalysisi
X
Serum samples for biomarker assessment
Xj
Blood samples for PK assessment (Dose Escalation 
phase) 
Xk, l
Disease assessment, including CT or MRI scan 
Xm
Concomitant therapy and procedures recordingn
X
X
X
AE reporting
AEs will be recorded from first dose of study drug through 30 days after the last dose of study 
drug or until the start of subsequent antineoplastic therapy, whichever occurs first.
SAEs will be collected from signing of the informed consent form through 30 days after the 
last dose of study drug. o
MLN2480 administration (Dose Escalation phase only)p
MLN2480 dosing is once every 2 days on Days 1-21 of a 22 day cycle (11 doses), starting on 
Day 1
Abbreviations: aPTT=activated partial thromboplastin time; AE=adverse event; ALT=alanine aminotransferase; ANC=Absolute Neutrophil Count; 
AST=aspartate aminotransferase; BUN=blood urea nitrogen; CT=computed tomography; ECG=Electrocardiogram; ECOG=Eastern Cooperative Oncology 
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
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22-Day Treatment Cycle: Cycle 2 Schedule
Tests and Assessments
Cycle 2 (Day 1 through Day 22)
Day 1 2 Days
Day 9 2 Days
Day 21 2Days
Group; MRI=magnetic resonance imaging; PK=pharmacokinetic; PT=prothrombin time; RBC=red blood cell; RECIST=Response Evaluation Criteria in 
Solid Tumors; SAE=serious adverse event; WBC=white blood cell.
a All patients will be assessed by the investigator or a consulting dermatologist at the visits specified. The examination for skin lesions will include the entire 
skin. Existing lesions will be monitored throughout the study and changes to the lesions will be recorded in the CRF. For lesions developing during 
treatment that are suspected keratoacanthomas or squamous cell carcinomas, the dimensions and location on the body will be recorded in the CRF and they 
will be subsequently biopsied/adequately treated. Other lesions that develop during treatment should be recorded on the AE form and may be biopsied at 
the discretion of the investigator/ dermatologist.
b The triplicate ECG measurements should be completed after a 5-minute rest period in the supine position and will be recorded at 2 to 5 minute intervals 
immediately before the corresponding PK blood draw. The triplicate ECGs will be collected predose (within 1 hour prior to dosing). 
c Perform vital signs measurement within 15 minutes prior to dosing. Blood pressure should be determined with the patient in a seated position after the 
patient has been sitting quietly for 5 minutes.
d Hematology will be tested at local and central laboratories and includes hemoglobin, hematocrit, platelet counts, RBC, WBC, absolute reticulocyte counts 
(only for patients who experience recurrent anemia with hemoglobin < 9 g/dL, despite blood transfusion), absolute differential, and ANC. If a patient 
develops an ANC < 500/μL or a platelet count < 25,000/μL, blood samples must be collected every 2 to 3 days and study treatment withheld until counts 
resolve or until ANC returns to > 1,000/μL and platelet counts return to > 50,000/μL.
e Hematology results (including hemoglobin, hematocrit, platelet counts, RBC, WBC, absolute reticulocyte counts, absolute differential, and ANC) and 
blood chemistry results (including creatinine, total bilirubin, AST, and ALT) will be evaluated before the patient is allowed to take their dose of MLN2480 
on Day 1 of each cycle. Hematology and blood chemistry for Cycle 2, Day 1 may be completed up to 72 hours prior to Day 1.
f
Blood chemistries will be tested at local laboratories and include glucose, BUN, creatinine, sodium, potassium, chloride, CO2, total bilirubin, lactate 
dehydrogenase, alkaline phosphatase, AST, ALT, albumin, and calcium.
g Bone marrow aspirate and biopsy will be encouraged for patients who experience recurrent anemia with hemoglobin < 9 g/dL, despite blood transfusion.
h Within 48 hours of any invasive procedure (ie, tumor biopsy or bone marrow biopsy), aPTT and PT must be within the normal range. For tumor and bone 
marrow biopsies, platelet count should be 75,000/mm3.
i
Urinalysis includes dipstick for blood, protein, and glucose (microscopic examination, if abnormal). Samples will be collected predose.
j
This serum biomarker sample corresponds to the Cycle 1, Day 21, 48-hour postdose biomarker sample. It will be collected within 1 hour prior to MLN2480 
dosing on Cycle 2, Day 1.
k Refer to Table 1-1 for details on assessment time points. Refer to Laboratory Manual for details on collection, processing, storage, and shipment of plasma 
PK samples.
l
In addition to the scheduled PK sample collections, a blood sample to measure MLN2480 plasma concentrations should be obtained, if clinically feasible, at 
the time of a serious or unusual AE that is judged by the investigator to be treatment-related, irrespective of the cycle or day of occurrence of the AE. See 
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22-Day Treatment Cycle: Cycle 2 Schedule
Tests and Assessments
Cycle 2 (Day 1 through Day 22)
Day 1 2 Days
Day 9 2 Days
Day 21 2Days
Section 7.4.18
m Disease assessments (including CT or MRI scans of all sites of disease) will be performed every 2 cycles after starting MLN2480 treatment, beginning on 
Cycle 2, Day 21 ± 2 days. Imaging and assessment may be conducted up to 3 days in advance of Day 21 (ie, Days 18 to 21). Any complete response or 
partial response must be confirmed at least 4 weeks after the response is first documented. Clinical response and disease progression will be evaluated using 
RECIST, version 1.1, per investigator assessment.
n Concomitant therapies and procedures must be recorded from  Screening through the End of Study visit or until the start of subsequent antineoplastic 
therapy, whichever occurs first.
o Including serious pretreatment events; see Section 9.
p Patients will take MLN2480 orally once every 2 days and will fast (with the exception of water) for at least 2 hours before and at least 2 hours after taking 
their dose. On dosing days when the patient does not have a clinic visit (ie, Days 3, 5, 7, 11, 13, 15, 17, and 19), patients will take their dose of MLN2480 at 
home
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22-Day Treatment Cycle: Cycle 3 and Subsequent Cycles
Tests and Assessments
Cycle 3 and Subsequent Cycles
(Day 1 through Day 22 ± 2 Days)
Day 1
Day 9
Day 21
End of Study 
Visita
Physical examination and body weight measurement
X
X
Dermatological examination with documentation of any suspicious 
lesionsb
X
X
Single 12-Lead ECGc
X
X
Vital signs (temperature, blood pressure, pulse rate)d
X
X
X
ECOG performance Status
X
Laboratory tests
Hematologye
Xf
X
X
Blood chemistryg
Xf
X
X
Bone marrow aspirate and biopsyh
Coagulationi
Thyroid function
X
X
Serum pregnancy test (female patients of reproductive potential) 
X
Urinalysisj
X
X
Disease assessment, including CT or MRI scan 
Xk
Xl
Serum samples for biomarker assessment 
Xm
X
Concomitant therapy and procedures recordingn
X
X
X
X
AE reporting
AEs will be recorded from first dose of study drug through 30 days after the last 
dose of study drug or until the start of subsequent antineoplastic therapy, 
whichever occurs first.
SAEs will be collected from signing of the informed consent form through 
30 days after the last dose of study drugo
MLN2480 administration (Dose Escalation phase only)p
MLN2480 dosing is once every 2 days on Days 1-21 of a 22 day cycle (11 
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MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
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22-Day Treatment Cycle: Cycle 3 and Subsequent Cycles
Tests and Assessments
Cycle 3 and Subsequent Cycles
(Day 1 through Day 22 ± 2 Days)
Day 1
Day 9
Day 21
End of Study 
Visita
doses), starting on Day 1
Abbreviations: AE=adverse event; ALT=alanine aminotransferase; ANC=Absolute Neutrophil Count; AST=aspartate aminotransferase; BUN=blood urea 
nitrogen; CRF=case report form; CT=computed tomography; ECG=Electrocardiogram; ECOG=Eastern Cooperative Oncology Group; MRI=magnetic 
resonance imaging; RBC=red blood cell; RECIST=Response Evaluation Criteria in Solid Tumors; SAE=serious adverse event; WBC=white blood cell
a The End of Study visit will occur 30 (+10) days after the last dose of study treatment or the start of subsequent antineoplastic therapy, whichever occurs 
first. Patients who discontinue study treatment early should complete the End of Study visit 30 (+10) days after the last dose of study treatment.
b All patients will be assessed by the investigator or a consulting dermatologist at the visits specified. The examination for skin lesions will include the entire 
skin. Existing lesions will be monitored throughout the study and changes to the lesions will be recorded in the CRF. For lesions developing during 
treatment that are suspected keratoacanthomas or squamous cell carcinomas, the dimensions and location on the body will be recorded in the CRF and they 
will be subsequently biopsied/adequately treated. Other lesions that develop during treatment should be recorded on the AE form and may be biopsied at 
the discretion of the investigator/ dermatologist.
c A single 12-lead ECG will be collected predose on Day 1 and the EOS visit. When the timing of a blood sample coincides with the timing of ECG 
measurements, the ECG will be completed before the collection of the blood sample.
d Predose (within 15 minutes prior to dosing; except at End of Study visit where no study drug is administered). Blood pressure should be determined with 
the patient in a seated position after the patient has been sitting quietly for 5 minutes.
e Hematology will be tested at local laboratories and includes hemoglobin, hematocrit, platelet counts, RBC, WBC, absolute reticulocyte counts (only for 
patients who experience recurrent anemia with hemoglobin < 9 g/dL, despite blood transfusion), absolute differential, and ANC. If a patient develops an 
ANC < 500/μL or a platelet count < 25,000/μL, blood samples must be collected every 2 to 3 days and study treatment withheld until counts resolve or until 
ANC returns to > 1,000/μL and platelet counts return to > 50,000/μL.
f
Hematology results (including hemoglobin, hematocrit, platelet counts, RBC, WBC, absolute reticulocyte counts, absolute differential, and ANC) and 
blood chemistry results (including creatinine, total bilirubin, AST, and ALT) will be evaluated before the patient is allowed to take their dose of MLN2480 
on Day 1 of each cycle. Hematology and blood chemistry for Cycle 3 and subsequent cycles Day 1 may be completed up to 72 hours prior to Day 1.
g Blood chemistry results include glucose, BUN, creatinine, sodium, potassium, chloride, CO2, total bilirubin, lactate dehydrogenase, alkaline phosphatase, 
AST, ALT, albumin, and calcium.
h Bone marrow aspirate and biopsy will be encouraged for patients who experience recurrent anemia with hemoglobin < 9 g/dL, despite blood transfusion.
i
Within 48 hours of any invasive procedure (ie, tumor biopsy or bone marrow biopsy), aPTT and PT must be within the normal range. For tumor and bone 
marrow biopsies, platelet count should be 75,000/mm3.
j
Urinalysis includes dipstick for blood, protein, and glucose (microscopic examination, if abnormal). Samples will be collected predose.
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MLN2480 (TAK-580)
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22-Day Treatment Cycle: Cycle 3 and Subsequent Cycles
Tests and Assessments
Cycle 3 and Subsequent Cycles
(Day 1 through Day 22 ± 2 Days)
Day 1
Day 9
Day 21
End of Study 
Visita
k Disease assessments (including CT or MRI scans of all sites of disease) will be performed every 6 weeks ± 2 days after starting MLN2480 treatment, 
beginning on Cycle 2, Day 21 ± 2 days. Imaging and assessment may be conducted up to 3 days in advance of Day 21 (ie, Days 18 to 21). Any complete 
response or partial response must be confirmed at least 4 weeks after the response is first documented. Clinical response and disease progression will be 
evaluated using RECIST, version 1.1 (see Section 14.3), per investigator assessment.
l
Disease assessments need not be repeated if performed within 4 weeks prior to the End of Study visit.
m On Cycle 3, Day 1 ± 2 days, and beyond, the predose serum sample will be taken within 1 hour prior to MLN2480 dosing.
n Concomitant therapies and procedures must be recorded from Screening through the End of Study visit or until the start of subsequent antineoplastic 
therapy, whichever occurs first.
o Including serious pretreatment events; see Section 9.
p Patients will take MLN2480 orally once every 2 days and will fast (with the exception of water) for at least 2 hours before and at least 2 hours after taking 
their dose. On dosing days when the patient does not have a clinic visit (ie, Days 3, 5, 7, 11, 13, 15, 17, and 19), patients will take their dose of MLN2480 at 
home.
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14.3
Response Evaluation Criteria in Solid Tumors (Version 1.1)
All sites of disease, target and nontarget lesions must be assessed at Baseline. Objective 
disease status is to be recorded at each evaluation using the response categories and 
definitions provided in this section.
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at Baseline. 
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
reproducible repeated measurements. Measurements must be provided for target measurable 
lesions.
Confirmation of response is not required, as response is not the primary endpoint of this 
study.
Disease Response Criteria for Target and Nontarget Lesions
Evaluation of target lesions
Complete Response:
Disappearance of all target lesions
Partial Response:
At least a 30% decrease in the sum of the LD of target lesions, taking as reference 
the baseline sum LD
Progressive Disease:
At least a 20% increase in the sum of the LD of target lesions, taking as reference 
the smallest sum LD recorded since the treatment started or the appearance of 
one or more new lesions
Stable Disease:
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum LD since the treatment started
Evaluation of nontarget lesions
Complete Response:
Disappearance of all nontarget lesions and normalization of tumor marker level
Incomplete Response/
Stable Disease: 
Persistence of one or more nontarget lesion(s) or/and maintenance of tumor 
marker level above the normal limits
Progressive Disease:
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 tumours: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45(2):228-47.[40]
Abbreviation: LD=longest diameter.
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The following table summarizes the overall response status calculation at each time point for 
patients who have measurable disease per RECIST at baseline.
Time Point Response: Patients With Target (Nontarget) Disease
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
NE
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 tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer 2009;45(2):228-47.[40]
Abbreviations: CR=complete response; NE=not evaluable; PD=progressive disease; PR=partial response; 
SD=stable disease.
The following table summarizes the overall response status calculation at each time point for 
patients who have nonmeasurable (therefore nontarget) disease at baseline.
Time Point Response: Patients With Nontarget Disease Only
Nontarget lesions
New lesions
Overall response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
Abbreviations: CR=complete response; NE=not evaluable; PD=progressive disease.
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14.4
Amendment 1 Summary of Changes
Rationale for Amendment 1
The primary purpose for this amendment is to shorten the time period during which urine is 
collected for postdose pharmacokinetic (PK) assessments of MLN2480 in the dose 
escalation phase. The originally planned 48-hour urine collection period after the Cycle 1, 
Day 21 dose will be shortened to an 8-hour urine collection period after the Cycle 1, Day 21 
dose. In order to ensure accurate quantitation of MLN2480 concentrations and determination 
of renal clearance, a detergent (3-[(3-cholamidopropyl)dimethylammonio]-1-
propanesulfonate [CHAPS]) must be added to each urine void to prevent nonspecific 
binding of MLN2480 to collection containers. It was not considered feasible for patients to 
add accurate volumes of CHAPS to urine voids collected at home. As a result, the collection 
period was condensed when patients are already at the study site so that appropriately 
trained staff can add an accurate volume of CHAPS to each urine void.
In addition to the above purpose for this amendment, skin punch biopsies will not be 
performed in this study and clarification has been added indicating that core or excisional 
biopsies are acceptable. Footnotes in the Schedules of Events were clarified. Section 7 was 
harmonized with the Schedules of Events and AE reporting language in the Schedules of 
Events was aligned with that in Section 9 and according to Millennium template standards. 
Nonclinical PK experience was updated to reflect content in Addendum 1 of the 
Investigator's Brochure (IB) unavailable at the time of the original protocol. The number of 
study centers was corrected for the Dose Expansion phase. The inclusion criterion was 
clarified to ensure that patients should have thyroid hormone tests consistent with stable 
thyroid function and allow patients with stable disease to be enrolled. Clarification was 
added to specify that based on data from the Dose Escalation phase, patients may be treated 
at the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D) in the 
Dose Expansion phase. Dose modification language was expanded to allow more 
conservative dose escalation, evaluation of intermediate doses, and expansion of an existing 
dose level for patient safety or a better understanding of the study drug. Reference to 
“Directions for Use” (as a standalone document) has been removed from the protocol as 
instructions for handling and administration of MLN2480 are contained in the Pharmacy 
Manual and handling of PK samples is in the Laboratory Manual. Instructions for 
dispensation and unused study drug destruction policies were clarified. Patient information 
will be captured and managed by study sites by Inform. Electrocardiogram (ECG) 
instructions were clarified and the time window for predose ECG was increased from 
30 minutes to 1 hour for all treatment cycles. Additional details for collection of blood and 
urine samples for PK analysis were specified and an option for unscheduled blood sample 
collection for plasma PK analysis at the time of a serious or unusual adverse event (AE) was 
added. Examples of cytochrome P450 (CYP) enzymes, which may be included in the 
pharmacogenomics assessment, were added. Serious pretreatment events will be reported to 
PPDI Pharmacovigilance. Administrative changes include, but are not limited to, updating 
the cover page with current signatories and assigning table numbers.
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Purposes for Amendment 1
The purposes of this amendment are to:

Update the cover page with current signatories

Align AE reporting language in the Schedules of Events and in Section 9 with the 
Millennium template standards

Clarify footnotes for vital sign measurements in the Schedules of Events and specify that 
blood pressure should be determined with the patient in a seated position after sitting 
quietly for 5 minutes

Remove the option to perform skin punch biopsies, clarify that core or excisional 
biopsies are allowed, and delete reference to the Study manual in the Schedules of 
Events. 

Clarify that the 48-hour postdose serum sample for biomarker analysis corresponds to 
the Cycle 2, Day 1 predose sample

Clarify that hematology and blood chemistry may be completed up to 72 hours prior to 
Day 1 to allow time for review of results prior to initiating another cycle according to the 
Schedules of Events

Align the Schedules of Events with Section 7.4.15 indicating that imaging and 
assessment may be conducted up to 3 days in advance of Day 21 (ie, Days 18 to 21)

Remove time window and clarify timing for single 12-lead ECGs for Treatment Cycle 3 
and Subsequent Cycles in the Schedules of Events 

Assign numbers to the supplemental Schedules of Events tables for Plasma 
Pharmacokinetic Assessment Time Points (Dose Escalation and Dose Expansion 
phases), provide time windows, and additional clarification for blood sample collection

Shorten the time period during which urine is collected for postdose PK assessments 
(Dose Escalation phase only) from a 48-hour to an 8-hour collection period after the 
Cycle 1, Day 21 dose, assign a number to the supplemental Schedule of Events table for 
Urine Samples for Pharmacokinetic Assessments, and provide additional clarification for 
urine sample collection

Align the nonclinical pharmacokinetics experience section with Addendum 1 of the IB 
unavailable at the time of protocol development

Clarify replacement procedures for patients discontinuing study treatment for reasons 
other than MLN2480-related toxicity

Correct the number of study centers from approximately 7 to 12 to approximately 8 to 13 
US and international sites for the Dose Expansion phase

Clarify that patients must return to the study site 30 days after administration of the last 
dose of study drug to complete the End of Study visit procedures

Clarify the inclusion criterion to ensure that patients have thyroid hormone tests 
consistent with stable thyroid function and that patients on a stable dose of thyroid 
replacement therapy are eligible. Additionally, remove reference to specific thyroid 
function tests as these are standard practice

Clarify that once the MTD has been identified, additional patients may be treated at the 
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MTD or at the RP2D in the Dose Expansion phase

Expand dose modification language to allow more conservative dose escalation, 
evaluation of intermediate doses, and expansion of an existing dose level for patient 
safety or a better understanding of MLN2480

As there is no long-term follow up in this study, after the End of Study visit, 
concomitant therapies and procedures or treatment of ongoing AEs will not be recorded

Remove reference to a specific “Directions for Use” document for instructions on 
handling, preparation, administration, and disposal of the study treatment; and refer 
study site staff to the Pharmacy Manual

Clarify instructions for dispensation of study drug

Remove reference to a specific “Directions for Use” document for instructions on study 
treatment storage and refer study sites to the Pharmacy Manual

Clarify unused study drug destruction policies 

Clarify that patient information will be captured and managed by study sites on 
electronic case report forms by Inform

Harmonize Section 7.4.8 with the Schedules of Events for the timing of serum 
pregnancy tests to be obtained for women of childbearing potential

Clarify time points for single ECG collection, update instructions for the collection of 
triplicate ECGs, and increase the time window for predose ECG assessments (single and 
triplicate) from 30 minutes to 1 hour for all treatment cycles and align the Schedules of 
Events with Section 7.4.13

Remove reference to the Study Manual for details regarding handling and shipping of 
the clinical laboratory samples since they are performed locally

Harmonize Section 7.4.14 with the Schedules of Events for absolute reticulocyte count

Clarify that PK samples for plasma and urine will be taken at prespecified time points 
predose and postdose

Provide the option for unscheduled PK blood sample collection at the time of a serious 
or unusual AE

Clarify that the number of PK samples will not be increased and that the timing of PK 
samples may be modified during the study conduct based on preliminary study results

Specify that the dates and times of dosing and PK sample collection will be recorded in 
the eCRF

Remove reference to the Study Manual for details regarding the collection, processing, 
storage, handling, and shipping of the PK samples, which are provided in the Laboratory 
Manual

Remove reference to the Pharmacy Manual for instructions on the pharmacodynamic 
assessment

Clarify that pharmacodynamic assessment includes tumor biopsies and specify that core 
and excision biopsies are acceptable

Provide specific examples of CYP enzymes known to exhibit genetic variation for 
potential pharmacogenomics assessment
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
Specify that serious pretreatment events will be reported to PPDI Pharmacovigilance

Correct typographical errors, punctuation, grammar, abbreviations, and formatting
14.5
Amendment 2 Summary of Changes
Rationale for Amendment 2
The primary purpose for this amendment is to increase the frequency of dermatological 
examinations during the course of the study. Patients have presented with unexpected 
hyperpigmented lesions in Cycle 1 that differ from the expected keratoacanthomas or 
squamous cell carcinomas that may occur due to MLN2480’s mechanism of action. 
Although the lesions do not appear malignant at this time, additional monitoring for safety 
purposes will help to capture the onset and development of these hyperpigmented lesions. In 
addition, language allowing for the investigator/dermatologist’s discretion as whether to 
biopsy skin lesions that are not suspected keratoacanthomas or squamous cell carcinomas 
has been added. 
Other updates to the study have been made, per the sponsor’s current practices. 
Purposes for Amendment 2
The purposes of this amendment are to:

Update the cover page with current signatories

Clarify dermatological exam procedures and add exams to the following study visits:

Cycle 1: Day 1 (predose), Day 9, Day 15

Cycle 2: Day 1, Day 22

Cycle 3 and beyond: Day 21 (will coincide every third cycle with the 
dermatological exam already in the protocol)

Allow for investigator/dermatologist discretion as whether to biopsy skin lesions that are 
not suspected keratoacanthomas or squamous cell carcinomas

Replace the term medical monitor with project clinician to align with current company 
standards

Clarify that assessments to be performed at the End of Treatment visit are listed in the 
Schedule of Events

Update AE evaluation and analysis language, and clarify tables and listings of TEAEs to 
be provided

Delete redundant serious adverse event reporting language

Update language to current company standards and remove text regarding the start of 
antineoplastic or anticancer therapy as it relates to follow-up of AEs

Remove requirement to report medication errors to MedComm Solutions to reflect the 
sponsor's current practices

Correct typographical errors, punctuation, grammar, abbreviations, and formatting
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14.6
Amendment 3 Summary of Changes
Rationale for Amendment 3
The primary purposes for this amendment are to revise the details of the Dose Expansion 
phase of the study and to redefine the length of the dosing cycle from Q2D for 22 days to 
Q2D for 28 days. 
It is hypothesized that tumor genotype and treatment history may serve as a predictor of 
response for patients with melanoma, and 6 unique melanoma cohorts were added to the 
Dose Expansion phase to contextualize safety and preliminary antitumor activity.

Cohort 1: BRAF mutation-positive melanoma, naïve to prior therapy with 
vemurafenib, ipilimumab, and investigational RAF and MEK inhibitors

Cohort 2: BRAF mutation-positive melanoma, which in response to previous treatment 
with vemurafenib, ipilimumab, or investigational RAF or MEK inhibitors have 
1) relapsed following an objective response; 2) failed to demonstrate an objective 
response; and/or 3) could not tolerate such a regimen due to unacceptable toxicity

Cohort 3: NRAS mutation-positive melanoma, naïve to prior therapy with ipilimumab 
and investigational RAF and MEK inhibitors

Cohort 4: NRAS mutation-positive melanoma, which in response to previous treatment 
with ipilimumab and investigational RAF and MEK inhibitors have 1) relapsed 
following an objective response; 2) failed to demonstrate an objective response; and/or 
3) could not tolerate such a regimen due to unacceptable toxicity

Cohort 5: BRAF/NRAS mutation-negative melanoma (wild type), naïve to any prior 
anticancer therapy

Cohort 6: BRAF/NRAS mutation-negative melanoma (wild type), who have received 
at least 1 line of prior anticancer therapy
A seventh expansion cohort, the PK Expansion cohort, in patients with any advanced solid 
tumor (excluding lymphoma) was added to evaluate safety and preliminary antitumor 
activity of MLN2480 and further characterize the PK of MLN2480. 
This amendment redefines the cycle length for newly enrolling patients in the Dose 
Escalation phase and all patients in the Dose Expansion phase from 22 days (11 doses) to 
28 days (14 doses) to improve clinical feasibility and better facilitate future combination 
with other drugs. Regardless of the cycle length, MLN2480 is continuously dosed every
other day with no treatment-free period at the end of each cycle. 
Purposes for Amendment 3
The purposes of this amendment are to:

Update the cover page with current Global Clinical Lead signatory

Update the total number of patients in the study to reflect the 7 cohorts added to the 
Dose Expansion phase

Add details for 6 melanoma cohorts, based on prospectively analyzed genotype during 
Screening and treatment history, to the Dose Expansion phase
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
Add 1 PK cohort, consisting of patients with any advanced solid tumor (excluding 
lymphoma), to the Dose Expansion phase and present the modified dosing schedule for 
cycle 1 of the PK Expansion cohort

Clarify procedure for collecting tumor biopsies for genotyping and pharmacodynamic 
marker analysis

Extend the length of the dosing cycle for this Q2D continuously administered drug 
from 22 days (11 doses) to 28 days (14 doses) 

Add mandatory digital photographs for all patients at Screening and if any new or 
changes in skin lesions occur during the study

Add mandatory tumor biopsies for the melanoma cohorts of the Dose Expansion phase

Change serum samples to plasma samples for biomarker assessment and collection of 
circulating tumor DNA

Update currently approved standard of care therapies for melanoma based on recent 
approval of ipilimumab and vemurafenib

Clarify concomitant medications and exclusion criteria based on newly acquired 
in vitro metabolism information

Add detail to PK analysis section

Define the pharmacodynamic population

Define ECG collection and analysis

Define the pharmacogenomic analysis

Define the normal platelet count range and time frame to > 75,000/mm2 within 
48 hours of biopsy

Increase the number approximate number of study centers in the Expansion phase from 
8 to 13, to read 10 to 18.

Correct typographical errors, punctuation, grammar, and formatting
14.7
Amendment 4 Summary of Changes
Rationale for Amendment 4
The rationale for this amendment is to specify that individual Dose Expansion cohorts may 
be opened or closed sequentially or in parallel at the sponsor’s discretion. In addition, 
permitted and restricted prior anti-cancer therapies have been revised based on emerging 
response data. Ipilimumab was removed as an excluded medication for the treatment-naïve 
cohorts (Cohorts 1 and 3), and anti-PD-1 monoclonal antibodies (mAbs) were added as a 
restricted type of medication for all the melanoma expansion cohorts (Cohorts 1-6).
Other substantive changes include revising the definition of true abstinence, updating 
concomitant medications to be used cautiously, and clarifying the SAE reporting window. 
Clarifications to the study design and minor grammatical changes have also been 
incorporated.
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Purposes for Amendment 4
The purposes of this amendment are to:

Add anti-PD-1 mAbs to the background section describing current treatment options for 
melanoma

Clarify that the MTD and/or RP2D will be determined for the 28-day treatment cycle 
before starting the Dose Expansion phase

Specify that individual Dose Expansion cohorts may be opened or closed sequentially or 
in parallel at the sponsor’s discretion, on the basis of emerging data

Modify the cohort definitions by removing ipilimumab as a restricted anti-cancer therapy 
for the treatment-naïve melanoma Dose Expansion cohorts (Cohorts 1 and 3) and adding 
anti-PD-1 mAbs as a restricted anti-cancer therapy for all the melanoma Dose Expansion 
cohorts (Cohorts 1 through 6)

Add prior treatment with anti-PD-1 mAbs as an exclusion factor for patients in any of 
the 6 melanoma Dose Expansion cohorts

Allow a 72-hour window for performing the dermatological examination

Correct the frequency of disease assessments

Clarify that for patients undergoing biopsy procedures, prothrombin time and activated 
partial thromboplastin time must be within the normal range and platelet count should be 
75,000 within 48 hours before biopsy

Clarify that genotyping results from a fresh biopsy obtained during Screening are 
required for assignment of patients to 1 of the 6 melanoma cohorts in the Dose 
Expansion phase of the study

Clarify that the effect of MLN2480 
 

Modify contraception language regarding abstinence

Update concomitant medications to be used cautiously based on newly learned in vitro 
drug transporter information

Correct the storage temperature for MLN2480 tablets

Update the reporting period for SAEs to Millennium from 1 working day to 24 hours

Correct typographical errors, punctuation, grammar, and formatting
14.8
Amendment 5 Summary of Changes
Rationale for Amendment 5
The primary rationale for this amendment is to clarify procedures and recommendations 
related to the Dose Expansion phase of the study. Safety information has been added on the 
basis of observations thus far in the Dose Escalation phase, as well as known class effects of 
RAF kinase inhibitors. Modifications include the addition of photosensitivity language to 
the precautions and restrictions section; the insertion of management guidelines for ocular 
CCI
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disturbances, elevated creatinine kinase, and rash; and the addition of dose modification 
recommendations. 
The definitions of the 6 melanoma expansion cohorts have been modified to clarify 
permitted and/or restricted prior treatments. Changes include removal of the word 
‘investigational’ from Cohorts 1 through 4 to account for recent or anticipated regulatory 
agency approvals of RAF or MEK inhibitors, as well as permissibility of prior anti-PD-1 
usage in Cohorts 1 through 6 with a 6-week washout period. The exclusion criterion of 
prior anti-PD-1 usage has also been deleted.
Other substantive changes include clarifying tumor biopsy procedures for genotyping, 
expanding the duration of the Screening period from 21 to 28 days, adding the 
dermatological exam window to the Q2D 28-Day Treatment Cycle: Cycle 1 Schedule of 
Events table, clarifying that the Cycle 1, Day 1 pregnancy test can be urine or serum, and 
clarifying the statistical methods of analysis. 
The lettering of footnotes in the Q2D 28-Day Treatment Cycle: Cycle 1 Schedule of Events 
table has been updated to reflect the insertion of pregnancy footnote ‘m.’ 
Other minor clarifications to procedures are captured in the following bullets.
Purposes for Amendment 5
The purposes of this amendment are to:

Clarify the dermatological exam window in the Q2D 28-Day Treatment Cycle: Cycle 1 
Schedule of Events table

Add background information on other therapeutic agents that have reached late-stage 
development or approval for the treatment of metastatic melanoma

Clarify Screening tumor biopsy procedures

Clarify procedures for enrollment of patients into 1 of the 6 melanoma cohorts on the 
basis of genotype

Revise melanoma cohort definitions to remove redundancy and permit anti-PD-1 mAbs

Modify inclusion criterion to allow prior use of anti-PD-1 mAbs

Remove exclusion criterion for prior use of anti-PD-1 mAbs

Clarify dose modification procedures for the Dose Escalation and Dose Expansion 
phases

Add photosensitivity to the precautions and restrictions during the study

Add recommendations for management of clinical events during the Dose Expansion 
phase

Add text describing treatment group assignments for the Dose Expansion phase

Extend the Screening period from 21 to 28 days

Permit the Cycle 1, Day 1 pregnancy test to be serum or urine

Correct the assessment window for disease assessments

Add creatine kinase to the list of blood chemistry assessments

Clarify PK collection procedures
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
Clarify statistical methods of analysis for the Dose Escalation phase and Dose Expansion 
phase

Clarify demographic and baseline characteristics to be collected

Add SAE Reporting contact information for ex-US and Canada

Correct typographical errors, punctuation, grammar, and formatting
14.9
Amendment 6 Summary of Changes 
Rationale for Amendment 6
The purpose of this amendment is to introduce additional dose escalation cohorts that will 
evaluate the maximum tolerated dose (MTD) of MLN2480 administered on a weekly (QW) 
dosing schedule for the 28-day treatment cycle. The rationale for evaluation of weekly 
dosing as an alternate dosing schedule is as follows: Analysis of exposure-efficacy 
relationships in preclinical mouse xenograft models of tumor growth inhibition indicate that 
more robust mitogen-activated protein (MAP) kinase pathway inhibition may be required for 
antitumor activity in NRAS/ KRAS mutant tumors when compared to BRAF mutant tumors. 
A weekly dosing schedule can therefore be expected to achieve higher unit doses, which 
may allow achievement of higher MLN2480 concentrations, and therefore a higher degree 
of pathway inhibition for a window of time within the dosing interval, without 
compromising overall dose density. Once the MTD/ recommended phase 2 dose (RP2D) is 
established for the QW Dose Escalation phase, a QW Dose Expansion phase will test 
MLN2480 in 2 melanoma expansion cohorts.
Procedural information regarding the addition of the QW Dose Escalation and Dose 
Expansion phases has been added throughout the protocol. Other substantive changes 
include clarifying the melanoma cohort definitions, clarifying the dose modifications for 
toxicity, permitting intrapatient dose escalation for patients, and updating the SAE reporting 
contact information.
Other clarifications to procedures are captured in the following bullets.
Purposes for Amendment 6
The purposes of this amendment are to:

Increase the number of study centers to account for newly added QW dose cohorts

Add a QW dosing schedule to the study

Permit patients on the 22-day treatment cycle to switch to the 28-day treatment cycle

Add study procedures for a QW Dose Escalation phase

Add procedures for a QW Dose Expansion phase

Add alternative QW dosing schedules (BID and split over 2 days) to both the Escalation 
and Expansion phases, if necessary to increase systemic exposures

Clarify tumor tissue sampling requirements to include QW cohorts

Relocate the 22-Day Treatment Cycle SOE Tables to an appendix
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
Update scientific background to reflect that some RAF kinase inhibitors are 
commercially available

Add rationale for implementation of QW Dosing Schedule

Modify the primary objectives of the study to include QW dose schedule assessment

Update the number of patients in the study to reflect addition of QW Dose Escalation 
and Dose Expansion cohorts

Modify inclusion criteria to reflect Q2D or QW dose schedule and clarify melanoma 
cohort definitions

Clarify the inclusion criterion regarding previous chemotherapy, immunotherapy, and 
hormone therapy

Allow intrapatient dose escalation for patients in the Dose Escalation phase in dose 
cohorts below the MTD/RP2D

Clarify the dose modification guidelines

Update SAE Reporting Contact Information from PPDI to Cognizant

Correct typographical errors, punctuation, grammar, and formatting
14.10
Amendment 7 Summary of Changes
Rationale for Amendment 7
The primary purpose of this amendment is to add text detailing the management of cardiac 
events, based on an assessment of cardiac risk in patients treated with MLN2480 and on 
reports of cardiotoxicity associated with some BRAF inhibitors. To further evaluate this 
potential risk, ECHO and MUGA assessments have been added to the Schedules of Events.
This amendment redefines the eligibility criteria for Cohort 8 (QW Dose Expansion phase). 
The approximately 16-patient cohort will now be comprised of approximately 8 patients 
who are treatment naïve and approximately 8 patients who are relapsed and/or refractory to 
prior treatment with RAF inhibitors and/or MEK inhibitors. 
This amendment also clarifies the number of pharmacokinetic (PK) samples needed from 
patients on the QW dose schedule. A total of 16 evaluable patients are required for the QW 
schedule, inclusive of patients treated at the established maximum tolerated dose (MTD) / 
recommended phase 2 dose (RP2D) in the dose escalation phase and the dose expansion 
phase.
Purposes for Amendment 7
The purposes of this amendment are to:

Add collection of ECHO/MUGA assessments to the Schedules of Events

Increase the number (range) of study centers in the US for the QW Dose Escalation 
phase

Redefine the eligibility criteria for Cohort 4
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
Redefine the number of subjects and eligibility criteria for Cohort 8

Add a definition of the permitted LVEF, as measured by ECHO or MUGA, to the study 
inclusion criteria

Clarify the number of patients on the QW dose schedule who need a postdose fresh 
biopsy

Add recommendations for treatment should a patient experience a cardiac event during 
treatment with MLN2480

Add ECHO and MUGA assessments to the study procedures

Add thyroid function test to the list of blood chemistry evaluations

Correct typographical errors, punctuation, grammar, and formatting
14.11   Amendment 8 Summary of Changes
Rationale for Amendment 8
The primary purpose of this amendment is to provide notification that enrollment into 
Cohort 8 is discontinued as of this amendment (Amendment 8). 
Purposes for Amendment 8
The purposes of this amendment are to:

Clarify the description of dosing cohorts by removing the term “melanoma” expansion 
cohorts and replacing with “dose” expansion cohorts since not all cohorts are melanoma 
cohorts (ie, Cohort 7). 

Clarify procedures for pretreatment adverse event recording and reporting of suspected 
unexpected serious adverse reactions (SUSARS) to regulatory authorities.

Update section on monitoring of adverse events (AEs).

Clarify language regarding the recording of AEs during Screening.

Provide updated language that enrollment into Cohort 8 is discontinued as of this 
amendment (Amendment 8).

Revise language on the collection of tumor tissue samples to indicate that 
pharmacokinetic and correlative biomarker analysis will be conducted. 

Clarify procedures for obtaining archived / fresh tumor biopsies for genotyping in the 
Q2D and QW Expansion cohorts at Screening.

Revise timepoint from postdose to predose for collection of Day 22 plasma samples for 
biomarker assessment and circulating tumor DNA and retrieval of fresh tumor biopsy for 
QW 28-Day Treatment Cycle: Cycle 1 Schedule Treatment Cycle: Cycle 1 Schedule.

Clarify the Day 1 time window (± 2 days) for timing of procedures for the Q2D 28-Day 
Treatment Cycle: Cycle 2 Schedule, the QW 28-Day Treatment Cycle: Cycle 2 
Schedule, and the 22-Day Treatment Cycle: Cycle 2 Schedule.

Clarify footnotes that apply to the requirement for obtaining paired tumor biopsies.

Clarify footnote that describes the Q2D melanoma expansion cohorts during Q2D 28-
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
154
Day Treatment Cycle: Cycle 1 Schedule. 

Revise footnote to indicate that the timing of assessments during the Q2D 28-Day 
Treatment Cycle: Cycle 1 Schedule refers to pharmacokinetic assessments and not 
biomarker assessments. 

Revise language on once weekly (QW) dosing to indicate that melanoma or solid tumor 
patients may be enrolled in the QW Expansion cohorts.

Revise inclusion criteria to include patients with solid tumors.

Revise inclusion criteria to change the number of patients required to have paired 
biopsies from 16 to 8 patients. 

Remove inclusion criteria that indicate that patients in the melanoma expansion cohorts 
must have a fresh tumor biopsy at Screening. Language has been clarified throughout the 
protocol to indicate that archival tissue is acceptable where appropriate.

Update contraception language from 3 months to 120 days (4 months).

Update the time period allowed for archival of tissue or tumor biopsy samples from 
12 months to 24 months.

Correct the dose increase factor for the table on QW planned dose levels from 20% to 
25%.

Remove reference to the Pharmacy Manual in the section on study drug administration.

Update the section on study drug administration to remove the 5 mg tablet, to include the 
70 mg tablet and to provide additional details regarding the optimized formulation.

Clarify the three MLN2480 dosage strengths to be used in the study.

Remove the section on packaging and labeling as this section is contained in the revised 
section on study drug administration.

Provide updated contact information for product complaints.

Update contact information for the Global Clinical Lead.

Correct typographical errors, punctuation, grammar, and formatting.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
155
14.12   Detailed Description of Amendments to Text
The primary section(s) of the protocol affected by the changes in Amendment No. 9 are 
indicated. The corresponding text has been revised throughout the protocol. 
Change 1: Changed the information for the signatories on the title page.
The primary change occurs on the Title Page:
Initial 
wording:
Amended
or new 
wording:
Rationale for Change:
Information was changed to reflect changes in Takeda processes and personnel.
PPD
PPD
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
156
Change 2: Added a Schedule of Events with reduced assessments (12-week [84-day] 
treatment cycle) for patients in the study for 4 years or longer.
The primary change occurs in the new Schedule of Events for the 12-Week (84-Day)
Treatment Cycle for Patients in the Study for 4 Years or Longer:
Description 
of change:
A new schedule of events was added showing assessments for the 12-week (84-
day) treatment cycle for patients who are in the study for 4 years or longer:

Physical examination and body weight at Day 1 ±14 days

Dermatological exam at Day 1 ±14 days

Vital signs (temperature, blood pressure, pulse rate) at Day 1 ±14 days

Laboratory tests (thyroid function, urinalysis, hematology, blood chemistry) 
at Day 1 ±14 days

Disease assessment, including CT or MRI scan every 6 months ±14 days

Creatine kinase every 6 months ±14 days

12-lead ECG every 6 months ±14 days

SAE reporting: SAEs will be collected from signing of informed consent 
form through 30 days after the last dose of study drug

MLN2480 Q2D administration: continuous dosing
Rationale for Change:
Many of the original assessments are no longer required for patients in the study for 4 years 
or longer and after the planned database lock for this study.
Change 3: Introduced TAK-580, the new product code for MLN2480.
The primary change occurs in Section 1.1 Scientific Background:
Added 
text:
MLN2480, currently known as TAK-580, is a potent, small molecule pan-RAF 
kinase inhibitor being developed for the treatment of solid tumors, including 
locally advanced, metastatic, and/or unresectable melanoma.
Rationale for Change:
The new product code is being introduced in clinical documents when they are updated.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
157
Change 4: Added that patients in the study for 4 years or longer will take MLN2480 every 
other day in 12-week (84-day) treatment cycles until disease progression, unacceptable 
toxicity, or the patient discontinues for any other reason.
The primary change occurs in Section 4.3 Duration of Study:
Added 
text:
During the Treatment period, patients will take MLN2480 orally Q2D in 22- or 
28-day treatment cycles or QW in 28-day treatment cycles until disease 
progression, unacceptable toxicity, or the patient discontinues for any other 
reason. The maximum duration of treatment will be 12 months unless it is 
determined that a patient would derive benefit from continued therapy beyond 12 
months. Patients in the study for 4 years or longer will take MLN2480 Q2D
in 12-week (84-day) treatment cycles until disease progression, unacceptable 
toxicity, or the patient discontinues for any other reason.
Rationale for Change:
The study duration for patients on 12-week treatment cycles was added for consistency with 
the text regarding patients on other dosing/treatment cycles.
Change 5: Added that when patients have been in the study for 4 years or longer, 
nonserious adverse events will no longer be reported.
The primary change occurs in Section 9.2 Procedures for Recording and Reporting Adverse 
Events and Serious Adverse Events:
Added 
text:
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 9.3 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. When patients have been 
in the study for 4 years or longer, nonserious AEs will no longer be 
recorded.
Rationale for Change:
Adequate nonserious AE data have been collected; therefore, only SAEs will be reported for 
these patients in accordance with the ICH-GCP and appropriate regulatory requirement(s).
Section 9.3 Monitoring of Adverse Events and Period of Observation also contains this 
change. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN2480 (TAK-580)
Clinical Study Protocol C28001 Amendment 9
158
Change 6: Changed the name and telephone number of the call center for product 
complaints.
The primary change occurs in Section 10.11 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,
For more information call 1-866-835-2233 
or email GlobalOncologyMedinfo@takeda.com
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 the Medical Information 
Call Center (Dohmen Life Science Services [DLSS]) (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,
For more information call 1-866-835-2233 1-844-ONC-TKDA (1-844-662-
8532)
or email GlobalOncologyMedinfo@takeda.com
Rationale for Change:
The name and telephone number of the call center have changed.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

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: An Open-Label, Phase 1, Dose Escalation Study of MLN2480 in Patients With Relapsed or 
Refractory Solid Tumors Followed by a Dose Expansion Phase in Patients With Metastatic 
Melanoma
NCT Number: NCT01425008
SAP Approve Date: 29 July 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.


MLN-2480
Statistical Analysis Plan, Study C28001
MLN2480C28001 SAP Version 2.0
1
STATISTICAL ANALYSIS PLAN
An Open-Label, Phase 1, Dose Escalation Study of MLN2480 in
Patients With Relapsed or Refractory Solid Tumors Followed by
a Dose Expansion Phase in Patients With Metastatic Melanoma
Protocol #: C28001
SAP Version:
Date of Statistical Analysis Plan:
Final
29July2016
Approval Signatures
PPD


MLN-2480
Statistical Analysis Plan, Study C28001
MLN2480C28001 SAP Version 2.0
2
TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.........................................4
1. INTRODUCTION............................................................................................................6
1.1 Study Design..............................................................................................................6
1.2 Study Objectives ........................................................................................................7
1.2.1 Primary Objectives ..............................................................................................7
1.2.2 Secondary Objectives...........................................................................................7
1.2.3 Exploratory Objectives ........................................................................................7
2. POPULATIONS FOR ANALYSIS..................................................................................8
2.1 DLT-evaluable population..........................................................................................8
2.2 Response-Evaluable Population..................................................................................8
2.3 Safety Population .......................................................................................................8
2.4 Pharmacokinetics evaluable Population ......................................................................8
2.5 Pharmacodynamics evaluable Population ...................................................................8
3. HYPOTHESES................................................................................................................8
4. INTERIM ANALYSIS.....................................................................................................9
4.1 Interim Analysis .........................................................................................................9
4.2 Data Safety Monitoring Board (DSMB)......................................................................9
5. STATISTICAL METHODOLOGY .................................................................................9
5.1 Sample Size Justification............................................................................................9
5.2 Randomization and Stratification................................................................................9
5.3 Unblinding ...............................................................................................................10
5.4 Data Handling ..........................................................................................................10
5.4.1 Methods for Handling Missing Data...................................................................10
5.4.2 Definition of Baseline Values ............................................................................11
5.4.3 Windowing of Visits..........................................................................................12
5.4.4 Justification of Pooling ......................................................................................12
5.4.5 Withdrawals, Dropouts, Loss to Follow-up ........................................................12
5.5 Patient Disposition ...................................................................................................12
5.6 Demographics and Baseline Disease Characteristics.................................................12
5.6.1 Demographics....................................................................................................12
5.6.2 Medical History.................................................................................................13
5.6.3 Baseline Disease Status......................................................................................13
5.7 Treatments and Medications.....................................................................................13
5.7.1 Concomitant Medications ..................................................................................13
5.7.2 Study Treatments...............................................................................................13
5.8 Efficacy Analyses.....................................................................................................14
5.9 Pharmacokinetic, Pharmacodynamic, and Pharmacogenetics Analysis......................14
5.9.1 Pharmacokinetic Analyses .................................................................................14
5.9.2 Pharmacodynamic Analyses...............................................................................19
5.9.3 Pharmacogenetics Analyses ...............................................................................20
5.10 Safety Analyses......................................................................................................20
5.10.1 Adverse Events................................................................................................20
5.10.2 Laboratory Data...............................................................................................22
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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5.7
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Statistical Analysis Plan, Study C28001
MLN2480C28001 SAP Version 2.0
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5.10.3 Electrocardiograms ..........................................................................................22
5.10.4 Vital Signs .......................................................................................................23
5.10.5 Other Safety Assessments ................................................................................23
6. CHANGES TO PLANNED ANALYSES FROM PROTOCOL .....................................23
7. PROGRAMMING CONSIDERATIONS .......................................................................23
7.1 Statistical Software...................................................................................................23
7.2 Rules and Definitions ...............................................................................................23
8. REFERENCES...............................................................................................................24
on-commercial use only and subject to the applicable Terms of Use
23
23
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24


MLN-2480
Statistical Analysis Plan, Study C28001
MLN2480C28001 SAP Version 2.0
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC
area under the plasma concentration versus time curve
BLQ
below level of quantification
CI
confidence interval
CLR
renal clearance
Cmax
maximum plasma concentration
CR
complete response 
Ctrough
trough concentration
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DLT
dose-limiting toxicity
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
ERK
extracellular signal-regulated kinase
 
IL
interleukin
Ki
Inhibition constant
LLOQ
lower limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
MTD
maximum tolerated dose
NALQ
number of observations above lower limit of quantitation
NCI
National Cancer Institute
ORR
overall response rate
PD
progressive disease (disease progression)
pERK
phosphorylated extracellular signal-regulated kinase
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
partial response
Q2D
every other day
QTc
rate-corrected QT interval (millisec) of electrocardiograph
QW
once weekly
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended phase 2 dose
SAE
serious adverse event
SD
stable disease
Property of Takeda: For non-commercial 
only and subject to the applicable Terms of Use
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MLN-2480
Statistical Analysis Plan, Study C28001
MLN2480C28001 SAP Version 2.0
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Abbreviation
Term
t1/2z
Terminal disposition phase half-life
Tmax
first time to maximum plasma concentration
TEAE
Treatment Emergent Adverse Event
TTR
time to response
on-commercial use only and subject to the applicable Terms of Use


MLN-2480
Statistical Analysis Plan, Study C28001
MLN2480C28001 SAP Version 2.0
6
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 a phase 1, multicenter, nonrandomized, open-label, dose escalation study. The study 
is conducted in 2 phases (dose escalation and dose expansion) and will test 2 dosing 
schedules (every other day (Q2D) and once weekly (QW)) of MLN2480 also known as 
TAK-580. 
In the Dose Escalation phase, a 3 + 3 dose escalation design is implemented to evaluate 
MLN2480 Q2D or QW in dose intervals with continuous dosing (no washout) prespecified
in the Dose Escalation Algorithm. Patients in the Dose Escalation cohorts are evaluated for 
dose-limiting toxicity (DLT) during the first cycle of treatment, and decisions regarding
escalation to the next dose level, expansion of a dose level, or evaluation of an intermediate
dose level are determined based on DLT evaluation. Patients in the Dose Escalation phase 
may continue treatment for additional cycles until disease progression, unacceptable
toxicity, or the patient discontinues for any other reason. The maximum duration of 
treatment will be 12 months unless it is determined that a patient would derive benefit from
continued therapy beyond 12 months.
The dose used for the Dose Expansion phase (MTD and/or RP2D) is selected based on data 
from the Dose Escalation phase at the corresponding dosing schedule (Q2D or QW). The 
Dose Expansion phase may commence before establishing the MTD/RP2D upon medical 
determination of a safe dose that is lower than MTD/RP2D. Patients fast (with the exception 
of water) for at least 2 hours before and at least 2 hours after taking their dose of MLN2480. 
Patients in the Dose Expansion phase take MLN2480 orally Q2D or QW in 28-day cycles 
until disease progression, unacceptable toxicity, or the patient discontinues for any other 
reason. The maximum duration of treatment will be 12 months unless it is determined that a 
patient would derive benefit from continued therapy beyond 12 months. 
Patients who discontinue study treatment during Cycle 1 for reasons other than 
MLN2480-related toxicity are replaced in the Dose Escalation phase of the study.
A total of approximately 198 patients with solid tumors will be enrolled in this study 
(approximately 54 patients in the Dose Escalation phase [Q2D and QW] and approximately 
144 patients in the Dose Expansion phase [Q2D and QW]). Of the approximately 
144 patients enrolled in the Dose Expansion phase, approximately 128 patients with locally 
advanced metastatic and/or unresectable melanoma (each cohort with a maximum of 
16 patients) and 16 patients with advanced solid tumors (excluding lymphona) will be 
enrolled.
on-co
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ommercial use only and subject to the applicable Terms of Use
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MLN-2480
Statistical Analysis Plan, Study C28001
MLN2480C28001 SAP Version 2.0
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When patients discontinue study treatment, they return to the study site 30 (! 10) days after 
administration of the last dose of study drug or the start of subsequent antineoplastic 
therapy, whichever occurs first, to complete the End of Study visit procedures. All 
MLN2480-related toxicities are followed until the End of Study visit or until the toxicities 
have resolved, stabilized, or returned to baseline, whichever occurs later.
1.2
Study Objectives
1.2.1 Primary Objectives
The primary objectives of the study are as follows:
∀
To evaluate the safety and tolerability of MLN2480 taken orally Q2D or QW by patients 
with relapsed or refractory solid tumors (Dose Escalation phase and Dose Expansion 
phase and Pharmacokinetic (PK) Expansion cohort) or locally advanced, metastatic, 
and/or unresectable melanoma (Dose Expansion phase).
∀
To determine the MTD of MLN2480 taken Q2D or QW by patients with relapsed or 
refractory solid tumors (Dose Escalation phase).
∀
To determine the recommended phase 2 dose (RP2D) of MLN2480 taken Q2D or QW 
by patients with relapsed or refractory solid tumors (Dose Escalation phase).
1.2.2
Secondary Objectives
The secondary objectives in this study population are as follows: 
∀
To evaluate the preliminary efficacy of MLN2480 as measured by Response Evaluation 
Criteria in Solid Tumors (RECIST), version 1.1.
∀
To evaluate the pharmacokinetics of MLN2480.
∀
To evaluate the effect of MLN2480 on pharmacodynamic markers in paired tumor 
biopsies.
1.2.3
Exploratory Objectives
on-commercial use only and subject to the applicable Terms of Use
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MLN-2480
Statistical Analysis Plan, Study C28001
MLN2480C28001 SAP Version 2.0
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2.
POPULATIONS FOR ANALYSIS
2.1
DLT-Evaluable Population
The DLT-evaluable population is defined as all patients in the Dose Escalation phase of the 
study who either experience DLT during Cycle 1 or complete at least 75% of the planned 
doses of MLN2480 and have sufficient follow-up data to allow the investigators and sponsor 
to determine whether DLT occurred. This population will be used for analysis of MTD.
2.2
Response-Evaluable Population 
The response-evaluable population is defined as all patients with measurable disease who 
receive any amount of MLN2480 and have at least 1 post baseline response assessment. This 
population will be used for response related analyses (eg, ORR, DOR, etc).
2.3
Safety Population
The safety population is defined as all patients who receive at least 1 dose of study drug 
(MLN2480). This population will be used for all safety analyses, as well as other analyses 
such as pharmacogenomic analyses except the response related analyses.
2.4
Pharmacokinetics Evaluable Population
The PK-evaluable population is defined as all patients who have sufficient dosing data and 
MLN2480 concentration-time data to permit calculation of any MLN2480 PK parameters.
Assessment of PK evaluability will be performed for patients undergoing serial PK sampling 
in dose escalation and PK expansion cohorts and will not include patients undergoing sparse 
PK sampling in melanoma expansion cohorts. The PK evaluable population will be used for 
the description of the serial PK profile of MLN2480 and for the estimation of PK parameters
via noncompartmental analysis. 
2.5
Pharmacodynamics Evaluable Population
The pharmacodynamic evaluable population is defined as all patients who have sufficient 
dosing data and pharmacodynamic data, collected within the protocol-specified window of 
sampling time. The pharmacodynamic evaluable population will be used for calculation of 
summary statistics and graphical analysis.
3.
HYPOTHESES 
Statistical analyses will be primarily descriptive and graphical in nature. No formal 
statistical hypothesis testing will be performed. 
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MLN-2480
Statistical Analysis Plan, Study C28001
MLN2480C28001 SAP Version 2.0
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4.
INTERIM ANALYSIS 
4.1
Interim Analysis
No formal interim analysis will be performed. Safety and available PK data will be reviewed 
jointly by sponsor and investigators on an ongoing basis for the purposes of safety 
monitoring and dose escalation decisions.
4.2
Data Safety Monitoring Board (DSMB)
There is no DSMB in this study.
5.
STATISTICAL METHODOLOGY
In general, 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 (of non-missing) per category for categorical data, unless specified 
otherwise. 
At the time of CSR database lock, all relevant data will be queried and cleaned; a database 
snapshot will be taken and used for the CSR. Additional treatment data will be entered into 
the database through study termination. Analyses may be updated based on additional 
information. An addendum to the CSR may be written if warranted based on these analyses 
at study termination.
Unless specified otherwise, all the summary tables will be presented by each dose level 
cohort at escalation, subtotal of Q2D patients at escalation, subtotal of QW patients at 
escalation, total at escalation, each expansion cohort, total at expansion, and if applicable,
subtotal of Q2D patients at expansion, subtotal of QW patients at expansion.
5.1
Sample Size Justification
The total sample size for the study will be approximately 198 patients (approximately 
54 patients in the Dose Escalation phases (Q2D and QW) and approximately 144 patients in 
the Dose Expansion phase [Q2D and QW]). In the Dose Escalation phase, a 3 + 3 dose
escalation design will be used; therefore, the sample size is dependent on the number of dose
escalation steps and the number of patients per cohort. To further evaluate the safety and
preliminary antitumor activity of the selected MLN2480 dose for the Dose Expansion phase, 
approximately 128 patients with locally advanced, metastatic, and/or unresectable melanoma
(each cohort will have a maximum of 16 evaluable patients) and 16 patients with advanced
solid tumors (excluding lymphoma) will be enrolled in the Dose Expansion phase (Q2D and
QW).
5.2
Randomization and Stratification
Randomization is not used in this study; however, patients are assigned to 1 of 8 Expansion 
cohorts based on tumor type, mutational status, and/or treatment history (see Section 5.1 of 
the protocol). No stratification is planned for this study. An interactive voice response
system is used for cohort management. Refer to the Study Manual for details.
on-commercial use only and subject to the applicable Terms of Use
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5.3
Unblinding
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 data will be presented. Data that are potentially spurious or erroneous will be 
examined under the auspices of standard data management operating procedures. No data 
imputation will be applied for missing values unless specified.
5.4.1.1
Missing/Partial Dates in Screening Visit
The following rules apply to dates recorded during the screening visits. 
1. If only the day-component is missing, the first day of the month will be used if the year 
and the month are the same as those for the first dose of study drug. Otherwise, the 15th 
will be used. 
2. If only the year is present, and it is the same as the year of the first dose of study drug, 
the 15th of January will be used unless it is later than the first dose, in which case the 
first of January will be used. 
3. If only the year is present, and it is not the same as the year of the first dose of study 
drug, the 15th of June will be used, unless other data indicates that the date is earlier.
5.4.1.2
Missing/Partial Dates in Adverse Events/Concomitant Therapies
5.4.1.2.1
Missing/Partial Dates in Adverse Events
Adverse events with stop dates that are completely or partially missing will be imputed as 
follows:
1. If the stop date has month and year but day is missing, the last day of the month will be 
imputed.
2. If the stop date has year, but day and month are missing, the 31st of December will be 
imputed.
After the imputation, the imputed dates will be compared against the date of death, if 
available. If the date is later than the date of death, the date of death will be used as the 
imputed date instead. 
If the stop date of an adverse event is completely missing, then this event will be regarded as 
ongoing and will be included in the summary table.
Adverse events with start dates that are completely or partially missing will be imputed as 
follows:
1. If the start date has month and year but day is missing.
a.
If the onset month and year are the same as that of first dose date, the first dose date 
will be used instead. If the onset month and year are different from that of the first 
dose date, then the first day of the month will be used.
be
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b. After imputation, the imputed dates will be compared against the stop date. If this 
date is later than the stop date (possibly imputed), then the stop date will be used 
instead.
2. If the start date has year, but day and month are missing.
a.
If the onset year is the same as that of first dose date, then the first dose date will be 
used instead
b. If onset year is different than that of the first dose date, the first of January of the 
year will be imputed.
c.
After the imputation, the imputed dates will be compared against the dose stop date. 
If this date is later than the stop date (possibly imputed), then the stop date will be 
used instead.
3. If the start date of an adverse event is completely missing, then it is imputed with the 
first dose date.
5.4.1.2.2
Missing/Partial Dates in Concomitant Therapies
Concomitant therapies with start dates that are completely or partially missing will be 
analyzed as follows:
1. If the start date has month and year but day is missing, the therapy will be included in 
the summary table if the month and year are: 
a.
On or after the month and year of the date of the first dose of study drug
and 
b. On or before the month and year of the date of the last dose of study drug plus 
30 days.
2. If the start date has year, but day and month are missing, the therapy will be included in 
the summary table if the year is:
a.
On or after the year of the date of the first dose of study drug
and 
b. On or before the year of the date of the last dose of study drug plus 30 days.
If the start date of concomitant therapies is completely missing and the stop date of 
concomitant therapies is prior to the date of the first dose of study drug, then this therapy 
will not be included in the summary table. 
If the start date of concomitant therapies is completely missing and the stop date of 
concomitant therapies is on or after the date of the first dose of study drug, then the therapy 
will be included in the summary table.
If the start date and stop date of concomitant therapies are completely missing, then the 
therapy will be included in the summary table.
5.4.2
Definition of Baseline Values
Unless otherwise specified, the baseline value is defined as the value collected at the time 
closest to, but prior to, the start of study drug administration. For the triplicate 
electrocardiogram (ECG) summaries in the Dose Escalation and PK Expansion cohorts, the 
on-commercial use only and subject to the applicable Terms of Use
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stop da
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MLN-2480
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baseline is defined as the average of the triplicate 12-lead ECG measurements recorded at 
2 to 5 minute intervals on Cycle 1, Day 1 before dosing (predose).
5.4.3
Windowing of Visits
All data will be categorized based on the scheduled visit at which it was collected. These 
visit designators are predefined values that appear as part of the visit tab in the eCRF. 
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. If differences between sites are noted through the 
review process, exploratory analysis may be performed to assess the differences.
5.4.5
Withdrawals, Dropouts, Lost to Follow-up
Patients will be replaced if they are not evaluable for DLT during cycle 1 in the Dose 
Escalation Phase. These additional patients will receive the same allocation of treatment as 
those whom they replaced.
Time to event parameters will be censored if patients withdraw, drop out, or are lost to 
follow-up before documentation of the events (progressive disease /death).
5.4.6
General Conventions for Determining Duration
The duration of an event is calculated as: date of end of the event – date of start of the event 
+1, eg, days on treatment = date of last dose – date of first dose + 1.
Time to event analyses such as survival time or time to tumor progression are calculated in a 
similar way. Table shells will specify if there are any exceptions
5.5
Patient Disposition
Disposition of patients includes the number and percentage of patients for the following 
categories: safety population, PK-evaluable population, pharmacodynamic-evaluable 
population, response-evaluable population, DLT-evaluable population. These categories will 
be summarized in each dose group and total for Dose Escalation phase, for the PK 
expansion and other expansion cohorts and the total for Expansion Phase. The primary 
reason for study discontinuation will also be summarized in this table. All percentages will 
be based on the number of patients in the safety population.
5.5.1Protocol Deviations
A listing of major protocol deviations will be provided.
5.6
Demographics and Baseline Disease Characteristics
5.6.1
Demographics
Demographics will be summarized for the safety population. Demographic data to be 
evaluated will include age, sex, race, ethnicity, height, weight, body surface area and other 
on-commercial use only and subject to the applicable Terms of Use
on will
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throu
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evalu
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MLN-2480
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parameters as appropriate. No inferential statistics will be carried out. Demographic data 
will also be presented in a by-patient listing.
Age is calculated from date of birth to date of informed consent.
Body surface area (m2) = {[height(cm) x weight(kg)]/3600}1/2
5.6.2
Medical History 
Medical history data will be presented in a by-patient listing, including medical and surgical 
history, date of onset and status (ongoing or resolved).
5.6.3
Baseline Disease Status 
Baseline disease characteristics consist of baseline Eastern Cooperative Oncology Group 
(ECOG) score, primary diagnosis, years since initial diagnosis, method of stage 
classification, disease stage at study entry and disease-specific markers. 
By-patient listings will also be presented for baseline disease characteristics.
A separate table will summarize the numbers and percentages of patients who had prior 
therapies, including prior antineoplastics, prior radiation therapy, prior surgery and best 
response to the last therapy. Separate by-patient listings will also be presented.
5.7
Treatments and Medications
5.7.1
Concomitant Medications and Procedures
Concomitant medications will be coded by preferred term using the World Health 
Organization (WHO) Drug Dictionary. The number and percentage of patients taking 
concomitant medications from the first dose date through 30 days after last dose data will be 
tabulated by the Anatomical Therapeutic Chemical (ATC) classification pharmacological 
subgroup and WHO drug generic term. Concomitant medications will also be presented in a 
by-patient listing.
Concomitant procedures will not be coded, but will be presented in a by-patient listing.
5.7.2
Study Treatments
MLN2480 is administered Q2D or QW. MLN2480 is formulated as an immediate release 
tablet for oral administration.
5.7.2.1
Extent of Exposure 
The exposure to study drug will be summarized by total amount of dose received (mg), total 
number of doses received, number of treated cycles, numbers and percentages of patients 
who had ≥1, ≥2, …, and ≥13 treated cycles, and relative dose intensity. 
A treated cycle is defined as a cycle in which the patient received any amount of study drug.
Planned dose is determined by the dose level to which a patient is enrolled at study entry.
Relative Dose intensity (%) is defined as 100 x (total dose received (mg)) / (planned total 
dose per day x planned total number of treated days per cycle x number of treated cycles).
on-commercial use only and subject to the applicable Terms of Use
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Dosing data will also be presented in by-patient listings.
The actions on study drug (Reduced, Increased, Held, Missed, Interrupted, Cycle Delay, 
Delayed within a Cycle, or Discontinued Permanently) will be summarized by treatment 
cycles (each of Cycle 1 through Cycle 6, Cycle 7-12, Cycle >=13, and total).
5.8
Efficacy Analyses
As this is a phase I study, analysis of efficacy measures will be descriptive. Antitumor 
activity of MLN-2480 will be based on the best overall response. Disease response will be 
determined by investigators at each time point. The best overall response is defined as the 
best response recorded from the start of the study treatment until the End of Study visit
using the RECIST guideline (version 1.1). The number and percentage of patients will be 
summarized by the best overall disease response category (ie, complete response [CR], 
partial response [PR], stable disease [SD], and progressive disease [PD]). Disease response 
category will also be presented in a by-patient listing.
Overall response rate (ORR) is defined as the proportion of patients whose best overall 
response is either CR or PR. ORR will be tabulated with point estimates. Confidence 
intervals (95% CIs) will be provided for each expansion cohort as well as the total for the 
expansion cohorts and total for the escalation cohorts.
Time to response (TTR) is defined as the time from the date of first dose of study treatment 
to the date of the first documentation of a PR or better response up to the alternative therapy 
in a patient who responded. TTR will be summarized and listed.
Duration of response (DOR) will be assessed from the date of first documented response 
(CR or PR) to the date of first documented PD and will be censored at the date of the last 
assessment for responders who die without documented PD and for responders who are still 
alive and have not progressed. DOR will be summarized and listed.
Progression-free survival (PFS) is defined as the time from the date of first study drug 
administration to the date of first documented PD or death due to any cause, whichever 
occurs first. PFS will be censored at the last response assessment that is SD or better for a 
patient that has not progressed and last known to be alive. Patients with no response 
assessment will be censored at the date of first dose. PFS will be summarized and listed.
Time-to-event data for each melanoma expansion cohort and the total of the expansion 
cohorts and total of the escalation cohorts will be analyzed by the Kaplan-Meier method and 
results will be summarized by 25th, 50th (median) and 75th percentiles with associated 
2-sided 95% CIs, as well as the percentage of censored observations.
5.9
PK, Pharmacodynamic, and Pharmacogenetics Analysis
5.9.1
PK Analyses
PK Assessments
Blood and urine samples will be collected for measurement of plasma and urine MLN2480
concentrations in patients in the escalation and expansion cohorts at time points designated 
in the protocol. Validated bioanalytical methods will be used for the determination of 
MLN2480 concentrations in plasma and urine.
on-commercial use only and subject to the applicable Terms of Use
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Methods for PK Data Handling
No data imputation will be applied for missing concentration values, with one exception. If 
the end of dosing interval (trough) plasma concentration value is missing after Cycle 1, 
Day 21 dosing, that concentration may be imputed at the discretion of the Clinical 
Pharmacologist for the purpose of calculating Cycle 1, Day 21 PK parameters (eg, Ctrough, 
PTR, AUCtau) that depend on the end of dosing interval plasma concentration. Additionally, 
if the time between Cycle 1, Day 21 dosing time and actual sample collection time for the 
Cycle 1, Day 21 end of dosing interval (trough) plasma sample is less than 40 hr 
(approximately 20% deviation from the scheduled sample collection time of 48 hr in the 
case of Q2D dosing), that concentration may be imputed at the discretion of the Clinical 
Pharmacologist for the purpose of calculating Cycle 1, Day 21 PK parameters that depend 
on the end of dosing interval plasma concentration. If imputation is performed, the end of 
dosing interval plasma concentration will be set equal to the pre-dose plasma concentration 
for the same dosing interval. Imputation will be performed only if it can be inferred that PK 
steady-state conditions are attained by Cycle 1, Day 21. 
Pharmacokinetic Profiles for MLN2480
The PK evaluable population will be used for the description of the serial PK profile of 
MLN2480.
For Dose Escalation and PK Expansion cohorts, plasma concentrations of MLN2480 will be 
summarized by time post-dose and grouped by dose group and dosing cycle and day. If the 
same dose is administered in a Dose Escalation and the PK Expansion cohort, the plasma 
concentration-time data will be summarized separately for the Escalation and PK Expansion 
cohorts, as well as using combined data from both the Dose Escalation and PK Expansion 
cohorts. For melanoma Expansion cohorts, plasma concentrations of MLN2480 will be 
summarized by time post-dose and grouped by cohort and dosing cycle and day.
Summary statistics will be reported at scheduled sampling times that have at least 2 patients 
in the PK evaluable population and the number of observations above the lower limit of 
quantitation (NALQ) is ≥50% of the number of patients. The summary statistics will consist 
of: N, arithmetic mean, standard deviation, coefficient of variation (CV), median, minimum, 
maximum, geometric mean, and NALQ. Arithmetic mean, geometric mean, median,
minimum, and maximum will be reported when there are at least 2 non-missing values, 
while the SD and CV will be reported when there are at least 3 non-missing values. For ease 
of presentation, scheduled sampling times will be used to present results in summary tables
and figures.
Concentrations that are below level of quantification (BLQ) will be set to zero for 
calculation of summary statistics, except for geometric means, where BLQ values will be 
excluded. Arithmetic mean, geometric mean, median, minimum and maximum values less 
than the lower limit of quantitation (LLOQ) will be displayed as BLQ in concentration 
summaries.
Concentration data that are considered anomalous may be excluded from the concentration 
summaries and plots. Evidence or explanations will be provided in the clinical study report
to justify the exclusion of data.
on-commercial use only and subject to the applicable Terms of Use
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MLN-2480
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For Dose Escalation and PK Expansion cohorts, population mean and individual plasma 
concentration-time data will be plotted by dose group and dosing cycle and day on linear 
and semi-logarithmic scales. Population mean and individual trough plasma 
concentration-time data will be plotted by dose group on a linear scale. Visual inspection of 
the trough plasma concentration-time plots will be used to make inferences regarding the 
attainment of PK steady-state. If the same dose is administered in a Dose Escalation and the 
PK Expansion cohort, the plasma concentration-time data will be plotted separately for the 
Escalation and the PK Expansion cohorts, as well as combined for both the Dose Escalation 
and PK Expansion cohorts. BLQ values will be plotted as zero on a linear scale and treated 
as missing on a semi-logarithmic scale.
Individual plasma concentration data, urine concentration data, and urine collection volume 
will be listed by time point or urine collection interval. Both scheduled and actual sampling 
times will be presented in the listings.
PK Parameters for MLN2480
The PK evaluable population will be used for the estimation of PK parameters via 
noncompartmental analysis. 
PK parameter determination in the dose escalation and PK expansion cohorts will be based 
on individual plasma and urine concentrations of MLN2480 collected at pre-specified times 
prior to and following MLN2480 administration. Actual sampling times will be used for the 
calculation of PK parameters. In the event that actual sampling times are either unreliable or 
missing, scheduled sampling times will be used.
For calculation of PK parameters, concentrations of MLN2480 that are BLQ will be treated 
as zero prior to Tmax, as missing between Tmax and the time of the last measurable 
concentration, and as zero after the last measurable concentration. If measurable 
concentrations are near the LLOQ or imbedded between BLQ concentrations, these values 
may be excluded at the discretion of the Clinical Pharmacologist.
Concentration data that are considered anomalous will not be used in the calculation of PK 
parameters. Evidence or explanations will be provided in the CSR to justify the exclusion of 
data.
on-commercial use only and subject to the applicable Terms of Use
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MLN-2480
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As data permit, the following PK parameters will be calculated for MLN2480 by 
noncompartmental analysis using Phoenix™WinNonlin® version 6.2 or higher: 
Parameter
Definition
Units
Cmax
Observed maximum plasma concentration
ng/mL
Tmax
First time Cmax is observed
hr
λz
Terminal disposition phase rate constant
1/hr
t1/2z
Terminal disposition phase half-life
hr
Ctrough
Observed plasma concentration at the end of a dosing interval
ng/mL
AUCt
Area under the plasma/blood/serum concentration-time curve from time 
0 to time of the last quantifiable concentration. using the linear-log 
trapezoidal method
hr*ng/mL
AUCtau
Area under the plasma concentration-time curve, time 0 to end of dosing 
interval, estimated using the linear-log trapezoidal method
hr*ng/mL
CL/F
Apparent clearance after extravascular administration, calculated as 
Dose/AUC∞ after a single dose and as Dose/AUCτ after multiple dosing 
(at steady state)
L/hr
PTR
Peak-trough ratio in the steady state
unitless
Rac(AUC)
Accumulation ratio (based on AUC), calculated as AUCτ at steady 
state/AUCτ after a single dose
unitless
Aet
Amount of MLN2480 excreted in the urine, collected from time 0 to 
time = 8 hours
mg
fe
Fraction of drug excreted in urine, calculated as (Aet/dose)×100.
%
CLR
Renal clearance, calculated as Aet/AUC(0-t)
L/hr
on-commercial use only and subject to the applicable Terms of Use
se
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ng/mL
ng/mL
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Term
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MLN-2480
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Different PK parameters will be estimated in the dose escalation and PK expansion cohorts 
for different dosing cycles and days, as follows:
Cohort(s)
Dosing Cycles and Day
Parameter
Dose Escalation& PK Expansion 
Cohort
Cycle 1, Day 1
Cmax
Tmax
Ctrough
AUCtau
Cycle 1, Day 9
Ctrough
Cycle 1, Day 15
Ctrough
Cycle 1, Day 21
Cmax
Tmax
Ctrough
AUCt
AUCtau
CL/F
PTR
Rac(AUC)
Aet
fet
CLR
PK Expansion Cohort Only
Cycle 1, Day 21
λz t1/2z
To report λz and t1/2z, the terminal disposition phase data time span must be greater than or 
equal to 1.5 and R2
adj must be greater than or equal to 0.8. In addition, a minimum of 
3 measurable concentrations must be present within the terminal disposition phase.
Cycle 1, Day 1 Ctrough and AUCtau will not be reported if the time between Cycle 1, Day 1 
dosing time and actual sample collection time for the end of dosing interval (trough) plasma 
sample is less than 40 hr (in the case of Q2D dosing). Cycle 1, Day 1 Ctrough also will not be 
reported if the end of dosing interval plasma sample is collected after start of the next dosing 
interval. Cycle 1, Day 9 Ctrough will not be reported if the time between Cycle 1, Day 7 
dosing time and actual sample collection time for the Cycle 1, Day 9 predose plasma sample 
is less than 40 hr, or if the Cycle 1, Day 9 predose plasma sample is collected after Cycle 1, 
Day 9 dosing. Cycle 1, Day 15 Ctrough will not be reported if the time between Cycle 1, Day 
13 dosing time and actual sample collection time for the Cycle 1, Day 15 predose plasma 
sample is less than 40 hr, or if the Cycle 1, Day 15 predose plasma sample is collected after 
Cycle 1, Day 15 dosing. Cycle 1, Day 21 Ctrough will not be reported if the end of dosing 
interval plasma sample is collected after start of the next dosing interval.
If the time between Cycle 1, Day 21 dosing time and actual sample collection time for the 
end of dosing interval (trough) plasma sample is less than 40 hr, and steady-state conditions 
are inferred, the end of dosing interval plasma concentration may be imputed at the 
discretion of the Clinical Pharmacologist for the purpose of calculating Cycle 1, Day 21 PK 
parameters (eg, Ctrough, PTR, and AUCtau) that are dependent on the end of dosing interval 
plasma concentration. If imputation is performed, the end of dosing interval plasma 
on-commercial use only and subject to the applicable Terms of Use
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concentration will be set equal to the pre-dose plasma concentration for the same dosing 
interval. 
For the Dose Escalation and PK expansion cohorts, PK parameters will be summarized and 
grouped by dose group and dosing cycle and day. If the same dose is administered in a Dose 
Escalation and the PK expansion cohort, PK parameters will be summarized separately for 
the Escalation and PK expansion cohorts, as well as combined for both the Dose Escalation 
and PK expansion cohorts. In addition, Cycle 1, Day 21 Tmax, AUCtau, CL/F, CLR, fet, PTR, 
Rac(AUC), and t1/2z will be summarized across all patients in the Dose Escalation and PK 
expansion cohorts., provided no apparent dose-dependency is observed for these PK 
parameters.
Except for Tmax, the summary statistics will consist of: N, mean, SD, CV, median, min, max, 
and geometric mean. The summary statistics for Tmax will consist of: N, median, min, and
max. Summary statistics of parameter data will be reported for doses with at least 2 patients 
in the PK parameter population and ≥50% of patients have available PK parameter values.
Scatter plots will be generated for Cycle 1, Day 1 and Day 21 Cmax versus dose, Cycle 1, 
Day 1 and Day 21 AUCtau versus dose. 
Individual PK parameter data will be listed.
Provisional Assessment of Dose Proportionality
If data permit, a regression analysis may be used to assess the dose proportionality of Cycle 
1, Day 21 AUCtau. If the same dose is administered in a Dose Escalation and the PK 
Expansion cohort, only the above PK parameters from the escalation cohort will be include 
in the regression analysis.
Dose proportionality will be assessed using a power model, described by the following 
equation:
ln (PK parameter/dose) = ln (a) + b * ln(dose),
where a and b are the estimated parameters of the model. The 95% confidence interval of the 
estimate of b will be provided. 
Population PK Analysis
MLN2480 plasma concentration-time data collected in this study, together with data 
collected from future studies, may contribute to population PK analysis. Patients undergoing 
serial or sparse PK sampling will contribute to population PK analysis. The objectives of 
this analysis are to understand potential sources of PK variability, including patient-specific 
covariates (eg, age, gender, weight, renal and hepatic function), and to enable exploratory 
analysis of the relationships between PK and pharmacodynamic effects, efficacy, and safety.
If applicable, the specifics of the population PK modeling approaches will be described 
separately in a population PK analysis plan and the results will be reported separately from 
the CSR.
5.9.2
Pharmacodynamic Analyses
The pharmacodynamic evaluable population will be used for the PD analysis.
on-commercial use only and subject to the applicable Terms of Use
TR,
TR,
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Summary and percent change from baseline of the PD biomarkers will be tabulated with 
descriptive statistics (N, mean, standard deviation, median, min, and max).
The PD biomarkers in the tumor immunohistochemistry (IHC) will include, but not be 
limited to the direct pathway marker of Raf inhibition (pERK), proliferation marker (Ki67) 
and apoptotic marker (Bim-1).
Relationships between response and PD biomarkers may be explored graphically.
The relationship between MLN2480 exposures and tumor PD biomarkers may also be 
explored.
Individual PD data will be presented in a by-patient listing.
5.9.3
Pharmacogenetics Analyses
Individual patient DNA genotype (BRAF, NRAS, and others) will be listed with clinical 
response.
If applicable, drug metabolizing enzyme and/or transporter genotypes will be listed by 
patient. Descriptive statistics and graphical methods may be used to explore the relationship 
between these genotypes and selected PK parameters of MLN2480.
5.10
Safety Analyses
Safety evaluations will be based on the incidence, intensity, and type of AEs and on 
clinically significant changes in the patient’s vital signs, weight and clinical laboratory 
results. Safety variables will be tabulated and presented for the safety population. The 
incidence of DLT will be presented in a listing.
These analyses will be performed using the safety population.
5.10.1
Adverse Events
5.10.1.1
Adverse Events
Adverse events will be coded using MedDRA Version 16.0. All AEs will be presented in a 
by-patient listing. Treatment-emergent AEs (TEAEs) will be tabulated. A TEAE 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 medication, 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 or is subsequently considered drug-related by the investigator.
Patients with the same AE occurring more than once will have that AE counted only once 
within each body system, each high level term, and each preferred term. TEAEs will be 
tabulated by system organ class, high level term and preferred term for the following 
categories:
∀
TEAEs.
∀
Drug-related TEAEs.
∀
Grade 3 or higher TEAEs.
∀
Grade 3 or higher drug-related TEAEs.
on-commercial use only and subject to the applicable Terms of Use
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∀
The most commonly reported TEAEs (ie, those events reported by #10% of all patients 
in the safety population).
∀
TEAEs by maximum intensity (CTCAE grade).
∀
Drug-related TEAEs by maximum intensity (CTCAE grade).
∀
TEAEs resulting in study drug discontinuation.
∀
TEAEs resulting in study drug dose6 reduction.
TEAEs will be tabulated by system organ class, preferred term, and highest intensity. Most 
commonly reported (at least 10% of all subjects) TEAEs will be presented by preferred term 
only.
AEs will be summarized by the National Cancer Institute Common Toxicity Criteria for 
Adverse Events (NCI CTCAE) version 4.03. Patients with the same AE occurring more than 
once will have the maximum intensity of that AE counted once within each body system, 
high level term and preferred term. 
An overall summary AE table will include numbers and percentages of patients who had any 
AE, drug-related AE, grade 3 or higher AE, grade 3 or higher drug-related AE, serious AE 
(SAE), drug-related SAE, AE resulting in treatment discontinuation, AE resulting in dose 
reduction, AE resulting in dose modification (defined as delay, reduction or 
discontinuation), and on-study deaths. On-study death is defined as the death that occurs 
between the first dose of study drug and 30 days of the last dose.
Additionally, by-patient listings of the AE of special interest will be presented including 
rash or others as appropriate.
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 primary system organ class, high level term, 
and preferred term. A drug-related SAE summary will also be produced.
In addition, a by-patient listing of the SAEs will be presented (the patient listing will contain 
all SAEs regardless of treatment-emergent status).
5.10.1.3
Deaths
A by-patient listing of the on-study deaths will be presented. 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
A by-patient listing of TEAEs resulting in discontinuation of study drug will be presented. 
The number and percentage of patients experiencing at least one AE resulting in 
discontinuation of study drug will be summarized by MedDRA system organ class, high 
level term, and preferred term.
on-commercial use only and subject to the applicable Terms of Use
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5.10.1.5 Adverse Events Resulting in Dose Reduction
A by-patient listing of TEAEs resulting in dose reduction of study drug will be presented. 
The number and percentage of patients experiencing at least one AE resulting in dose 
reduction will be summarized by MedDRA system organ class, high level term, and 
preferred term.
5.10.1.6
Dose Limiting Toxicities (DLTs)
A by-patient listing of DLTs that occur during Cycle 1 of treatment will be presented for 
patients from dose escalation. 
5.10.2
Laboratory Data
For the purposes of summarization in both the tables and listings, all laboratory values will 
be converted to standard 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 summary statistics, ignoring the non-numeric qualifier. If there are 
multiple values with the same date at a visit for any patient, the average of those values will 
be used. If there are multiple values with different dates for the same visit, then the latest 
value will be used.
Shift tables of the change in National Cancer Institute Common Terminology Criteria for 
(NCI CTC) for toxicity from baseline to the post baseline worst CTC grade will be 
generated for relevant parameters. Scatter plots of baseline versus worst post-baseline values
will be generated. Parameters to be tabulated will include:
∀
Hematology: ANC, hemoglobin, platelets, WBC.
∀
Clinical chemistry: ALT, AST, alkaline phosphatase, creatinine, total bilirubin, calcium, 
CO2, potassium, glucose, albumin and sodium.
All hematology and clinical chemistry data will be also presented in by-patient listings, 
respectively.
5.10.3
Electrocardiograms
For the triplicate 12-lead electrocardiogram (ECG) summaries, the baseline is defined as the 
average of the triplicate 12-lead ECG measurements recorded at 2 to 5 minute intervals on 
Cycle 1, Day 1 before dosing (predose).
A summary of ECG abnormalities will be presented by visit. The ECG intervals, including 
QT, QT adjusted by an appropriate correction (QTcB and QTcF [Bazett and Fridericia]), 
PR, QRS, and RR, will be summarized at each scheduled time point, along with change 
from baseline to each post-treatment time point.
QTc (Bazett) = QT / (RR0.5)
QTc (Fridericia) = QT / (RR0.33)
where RR = 60 / heart rate (bpm)
on-commercial use only and subject to the applicable Terms of Use
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The number and percent of patients with QTc falling into the following categories: ≤450, 
>450-480, >480–500, and > 500 msec, will be summarized at each scheduled time point as
well as the number and percent of patients with changes from baseline of ≥30 msec and
≥60 msec. A similar summary will also be presented for maximum QTc (maximum over all
time points) using the same categories.
Individual ECG data will be presented in by-patient listings.
In addition, the relationship between MLN2480 plasma concentrations and select ECG 
parameters (eg, change in QTc from baseline) may be evaluated using data from this and 
other studies using a population concentration-effect analysis approach. If conducted, this 
analysis will be reported separately from the CSR.
5.10.4
Vital Signs
The actual values of vital sign parameters, including oral temperature, heart rate, weight and 
systolic and diastolic blood pressure, will be summarized over time. Summary of change 
from baseline will also be presented. A by-patient listing will be presented. 
5.10.5
Eastern Cooperative Oncology Group Performance Status
Eastern Cooperative Oncology Group (ECOG) performance status over time will be 
summarized. Shifts from baseline to the worst post-baseline over time will be summarized.
A by-patient listing will also be presented.
5.10.6
Other Safety Assessments
A listing of DLTs occurring in Cycle 1 will be presented.
A listing of dermatology exam results and percent change from baseline in size will be 
presented.
Additional safety analyses may be determined at any time without prejudice to enumerate 
rates of toxicities and to further define the safety profile of study drugs. 
6.
CHANGES TO PLANNED ANALYSES FROM PROTOCOL
There is no change made to the planned analyses from the protocol.
Reference materials for this statistical plan include Clinical Study Protocol C28001 
Amendment 8 (dated 22 July 2015).
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.
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Treatment emergent AEs are defined as in Section 5.10.1.1.
8.
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.
on-commercial use only and subject to the applicable Terms of Use