Clinical trial NCT01318902
Conditions: Light-Chain Amyloidosis
Keywords: Drug therapy
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2011-04-27; Completion date: 2018-11-13
Enrollment: 27 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will include participants with previously treated systemic relapsed or refractory light-chain (AL) amyloidosis who require further therapy and will be aimed at determining the safety profile and the maximum tolerated dose/recommended phase 2 dose of MLN9078 (Ixazomib) administered orally.

Detailed description:

Arms: arm 1: Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles. arm 2: Ixazomib 5.5 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles. arm 3: Ixazomib 4.0 mg, capsule, orally, on Days 1, 8 and 15 during a 28-day treatment cycle until progressive disease (PD) or unacceptable toxicity, for participants with relapsed or refractory amyloidosis and who were not treated with any other proteasome inhibitor (PI). Duration of treatment was up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months. arm 4: Ixazomib 4.0 mg, capsule, orally, on Days 1, 8 and 15 during a 28-day treatment cycle until PD or unacceptable toxicity, for participants with relapsed or refractory amyloidosis and who were previously treated with any other PI. Duration of treatment was up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months.
Interventions: intervention 1: Ixazomib intervention 2: Dexamethasone
Intervention descriptions: intervention 1: Ixazomib capsules. intervention 2: Dexamethasone tablets.

Protocol documents:
Prot_001.pdf: 



Title: An Open-Label, Dose-Escalation, Phase 1 Study of the Oral Formulation of MLN9708 
Administered Weekly in Adult Patients With Relapsed or Refractory Light-Chain (AL) 
Amyloidosis Who Require Further Treatment
NCT Number: NCT01318902
Protocol Approve Date: 22 December 2014
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.


MLN9708
Clinical Study Protocol C16007 Amendment 6
EudraCT:  2010-022497-13
1
CLINICAL STUDY PROTOCOL C16007 AMENDMENT 6
MLN9708
An Open-Label, Dose-Escalation, Phase 1 Study of the Oral Formulation of MLN9708 
Administered Weekly in Adult Patients With Relapsed or Refractory Light-Chain (AL) 
Amyloidosis Who Require Further Treatment
Protocol Number:
C16007
Indication:
Amyloidosis
Phase:
1
Sponsor:
Millennium Pharmaceuticals, Inc.
EudraCT Number:
2010-022497-13
Therapeutic Area:
Oncology
Protocol History
Original
31 August 2010
Amendment 1
14 December 2010
Amendment 2
for use in Italy only
25 May 2011
Amendment 3
19 July 2011
Amendment 4
for use in Italy only
02 August 2011
Amendment 5
02 December 2014
Amendment 6
for use in Italy only
22 December 2014
Millennium Pharmaceuticals, Inc.
40 Landsdowne Street
Cambridge, MA USA 02139
Telephone: +1 (617) 679-7000
Note: If this document was approved electronically, the electronic approval signatures may 
be found at the end of the document.
Approved by:
PPD


MLN9708
Clinical Study Protocol C16007 Amendment 6
EudraCT:  2010-022497-13
2
Rationale for Amendment 6
This amendment allows for the following: a longer follow-up period for overall survival, an 
extension for a rollover study should one become available, and flexibility in laboratory 
evaluations as per standard of care.
Purposes for Amendment 6
The purposes of this amendment are to:

Update the cover page with current signatories.

Update the duration of the study and overall survival time point.

Update the hematology and chemistry laboratory evaluation schedule.

Update the SAE reporting contact information.

Update the product complaint reporting contact information.

Correct typographical errors, punctuation, grammar, and formatting.
For specific examples of changes in text and where the changes are located, see 
Section 15.12.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN9708
Clinical Study Protocol C16007 Amendment 6
EudraCT:  2010-022497-13
3
PROTOCOL SUMMARY
Study Title: An Open-Label, Dose-Escalation, Phase 1 Study of the Oral Formulation of MLN9708 
Administered Weekly in Adult Patients With Relapsed or Refractory Light-Chain (AL) Amyloidosis 
Who Require Further Treatment
Study Phase: 1
Number of Patients: Overall, as many as 50 patients will be enrolled in the study.
Study Objectives
Primary Objectives
!
To determine the safety, tolerability, and maximum tolerated dose (MTD) of oral MLN9708 
administered weekly in patients with previously treated relapsed or refractory light-chain (AL) 
amyloidosis
!
To determine the recommended phase 2 dose (RP2D) of oral MLN9708 administered weekly
Secondary Objectives
!
To characterize the plasma PK and whole blood pharmacodynamic effect of MLN9708 in this 
patient population 
!
To assess the rate of organ response and organ improvement according to standardized criteria
!
To assess overall hematologic response rate (complete response [CR], very good partial 
response [VGPR], and partial response [PR]) 
!
To assess time to hematologic and organ response, respectively
!
To assess duration of hematologic and organ response, respectively
!
To determine time to hematologic and organ disease progression, respectively
!
To assess progression free survival (PFS)
!
To assess overall survival including 1-year survival rate
Exploratory Objectives
Overview of Study Design: 
The study will include patients with previously treated systemic AL amyloidosis who require further 
therapy and will be aimed at determining the safety profile and the MTD/RP2D of MLN9708 
administered orally. A 3 + 3 dose-escalation scheme will be implemented. Patients will receive 
escalating doses of MLN9708 PO on Days 1, 8, and 15 in a 28-day cycle in the absence of disease 
progression or unacceptable toxicity. If there is no hematologic response (CR + VGPR + PR) after 
completion of 3 cycles of single-agent MLN9708, dexamethasone will be added on Days 1 to 4 of 
every cycle (Days1-4 every 28 days) beginning with Cycle 4. The patient’s response status will be 
reassessed after 3 additional cycles; if there is no hematologic response at that time, the patient will 
be removed from treatment and followed for survival.
The estimated safe starting dose of MLN9708 will be selected from the dose-escalation portion of 
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MLN9708
Clinical Study Protocol C16007 Amendment 6
EudraCT:  2010-022497-13
4
the C16004 study, a phase 1 study of weekly dosing in patients with relapsed and refractory multiple 
myeloma. The starting dose will be at least 1 dose level below the C16004 MTD (if it has been 
reached by the time this study starts) and, if not, then a dose level completed without documented 
dose-limiting toxicity (DLT).
DLTs will be assessed in Cycle 1 only. In the context of emerging clinical data of single-agent 
MLN9708, dose-escalation of MLN9708 will continue until the MTD has been identified or a 
maximum planned dose (MPD) is determined to be safe.
Once the MTD/RP2D has been established, 2 expansion cohorts of patients with relapsed or 
refractory amyloidosis, including approximately 10 proteasome inhibitor-naïve patients and 
approximately 16 proteasome inhibitor-exposed patients, will be treated at the MTD/RP2D to more 
fully characterize the safety, tolerability, and efficacy of MLN9708, and the PK and 
pharmacodynamics of MLN9708 in this patient population. As many as 30 patients will be enrolled 
in the dose-escalation portion of the study, and as many as 20 additional patients (26 in total, 
including 6 patients from the dose-escalation portion) will be enrolled in the expansion cohorts.
Toxicity will be evaluated according to the investigators’ documentation of adverse events (AEs) 
using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03.
AEs will be assessed, and laboratory values, vital signs, and ECGs will be obtained to evaluate the 
safety and tolerability of MLN9708.
Patients will be evaluated at scheduled visits over 4 study periods: Screening, Treatment, End of 
Treatment (EOT), and Follow-up (progression-free and overall survival). Patients will discontinue 
treatment if they experience PD or unacceptable toxicity. The maximum duration of treatment with 
either single-agent MLN9708 or MLN9708 plus dexamethasone, however, will be 12 cycles unless 
after discussion between the investigator and the sponsor, it is determined that a patient would derive 
benefit from continued therapy beyond 12 cycles.
The primary determinant of response for the purpose of continuing treatment is the hematologic 
response. Response will be determined according to standardized criteria. Hematologic response 
assessments are conducted after every cycle during treatment, at the end of treatment visit, and then 
every 6 weeks thereafter until disease progression or initiation of subsequent antineoplastic therapy.
A bone marrow aspirate and biopsy are to be obtained at the Screening visit and may be repeated at 
the discretion of the investigator as clinically indicated and if CR is documented by other parameters 
in the standardized criteria.
Amyloid-related organ assessments are to be performed for all patients at screening; after Cycles 3, 
6, 9, and 12; every 6 months thereafter until disease progression or the initiation of subsequent 
antineoplastic therapy; and at the End-of-Treatment visit. An evaluation of disease response 
according to standardized criteria will be performed at regular predefined intervals during treatment 
and then at regular intervals during follow up. Radiological evaluations (skeletal surveys, chest X-
rays, computed tomography [CT] scan, or magnetic resonance imaging [MRI]), echocardiograms, 
blood samples and 24-hour urine collections (M-protein quantification, serum free light chain assay, 
immunofixation of serum and urine, quantification of immunoglobulins, serum cardiac markers) and 
bone marrow biopsy and aspirates will be employed to assess the status of the patient’s disease 
response.
Quality of life (QOL) will be assessed only for patients in the expansion cohorts using the European 
Organization for Research and Treatment of Cancer QLQ-C30 (EORTC-QLQ-C30.
A blood sample will be collected for preparation of genomic deoxyribonucleic acid that will be used, 
as needed, to assess potential relationships 
 
, clinical response, and safety.
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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MLN9708
Clinical Study Protocol C16007 Amendment 6
EudraCT:  2010-022497-13
5
Electrocardiograms will be acquired on Day 1 of Cycles 1 through 12 and at EOT and a 24-hour 
Holter monitor will be used at screening.
Study Population:
Adult patients 18 years or older with biopsy-proven systemic AL amyloidosis with relapsed or 
refractory disease after at least 1 prior therapy that, in the investigator’s opinion, requires further 
treatment. If a patient has received a transplant as his/her first therapy, he/she must be at least 
3 months posttransplantation and recovered from the side effects of the stem cell transplant. Patients 
who were not candidates for high-dose therapy and were unable to tolerate an alkylating agent plus a 
corticosteroid (eg, melphalan plus prednisone) or patients who are intolerant to an alternative prior 
therapy after receiving at least 1 cycle of such therapy because of severe adverse events (eg, 
hypersensitivity reaction) can be considered for enrollment after discussion with the Millennium 
clinician.
Duration of Study: The duration of enrollment will be approximately 24 months.
It is anticipated that this study will last for approximately 84 months. The duration of follow-up for 
OS will be 60 months after the last patient enters treatment. Treatment may be continued in this 
study or in a MLN9708 rollover study, if and when such a study is made available, upon request by 
the investigator and agreement by the project clinician.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN9708
Clinical Study Protocol C16007 Amendment 6
EudraCT:  2010-022497-13
6
Study Overview Diagram 
Patient Cohort Assignment
MLN9708 PO Days 1, 8, 15  
Repeat q 28days 
Assess response after 3 cycles
No Hematologic Response
Discontinue study treatment 
and follow for survival 
Continue MLN9708 PO Days 1, 8, 15
Repeat q 28 days x 12 cycles maximum
or until PD or unacceptable toxicity which 
ever occurs first, then participate in PFS 
follow up and OS follow up
Hematology Response  (> PR)
No Hematologic Response
Continue MLN9708 Days 1, 8, 15 q28
Add Dexamethasone PO Days 1-4 q28
Assess response after 3 additional cycles
Hematologic Response (>PR)
Continue MLN9708 PO Days 1, 8, 15 + 
Dexamethasone PO Days 1-4 q28
Repeat q 28 days x 12 cycles maximum
or until PD or unacceptable toxicity 
which ever occurs first, then participate 
in PFS follow up and OS follow up
Patient Cohort Assignment
MLN9708 PO Days 1, 8, 15  
Repeat q 28days 
Assess response after 3 cycles
No Hematologic Response
Discontinue study treatment 
and follow for survival 
Continue MLN9708 PO Days 1, 8, 15
Repeat q 28 days x 12 cycles maximum
or until PD or unacceptable toxicity which 
ever occurs first, then participate in PFS 
follow up and OS follow up
Hematology Response  (> PR)
No Hematologic Response
Continue MLN9708 Days 1, 8, 15 q28
Add Dexamethasone PO Days 1-4 q28
Assess response after 3 additional cycles
Hematologic Response (>PR)
Continue MLN9708 PO Days 1, 8, 15 + 
Dexamethasone PO Days 1-4 q28
Repeat q 28 days x 12 cycles maximum
or until PD or unacceptable toxicity 
which ever occurs first, then participate 
in PFS follow up and OS follow up
No Hematologic Response
Discontinue study treatment 
and follow for survival 
Continue MLN9708 PO Days 1, 8, 15
Repeat q 28 days x 12 cycles maximum
or until PD or unacceptable toxicity which 
ever occurs first, then participate in PFS 
follow up and OS follow up
Hematology Response  (> PR)
Continue MLN9708 PO Days 1, 8, 15
Repeat q 28 days x 12 cycles maximum
or until PD or unacceptable toxicity which 
ever occurs first, then participate in PFS 
follow up and OS follow up
Hematology Response  (> PR)
No Hematologic Response
Continue MLN9708 Days 1, 8, 15 q28
Add Dexamethasone PO Days 1-4 q28
Assess response after 3 additional cycles
No Hematologic Response
Continue MLN9708 Days 1, 8, 15 q28
Add Dexamethasone PO Days 1-4 q28
Assess response after 3 additional cycles
Hematologic Response (>PR)
Continue MLN9708 PO Days 1, 8, 15 + 
Dexamethasone PO Days 1-4 q28
Repeat q 28 days x 12 cycles maximum
or until PD or unacceptable toxicity 
which ever occurs first, then participate 
in PFS follow up and OS follow up
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN9708
Clinical Study Protocol C16007 Amendment 6
EudraCT:  2010-022497-13
7
Schedule of Events
Study Procedures
Screeninga
Treatment Period
End of 
Treatmentd
Follow-up
CYCLES 1 -12b
Days
Days
PFSe
(± 1 wk)
OSf
(± 1 wk)
-28 to -1
1c
8
15
Rest Period 
22 to 28
Every 6 
weeks
Every 12 
weeks
Informed Consent
X
Inclusion/Exclusion criteria 
X
Demographics
X
Complete Medical History, including AL 
amyloidosis treatment history, neurologic 
history, and cardiac medical history
X
12-lead ECG (RR, PR, QRS, QT, QTc, and 
waveforms)
X
X
X
24-hour Holter monitorg
X
Physical Examination 
X
Xh
X
Per MD
practice
ECOG Performance Status 
X
Xi
X
Vital Signs
X
X
X
Per MD
practice
Height
X
Weight (kg) 
X
X
X
Pregnancy Testj
X
X
Hematologyk
X
X
X
X
X
X
Clinical Chemistryk
X
X
X
X
X
X
Urinalysis
X
X
24-hour urine collection for creatinine and total 
protein
X
Xl
X
Xl
Coagulation studies (PT/INR; PTT)m
X
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN9708
Clinical Study Protocol C16007 Amendment 6
EudraCT:  2010-022497-13
8
Study Procedures
Screeninga
Treatment Period
End of 
Treatmentd
Follow-up
CYCLES 1 -12b
Days
Days
PFSe
(± 1 wk)
OSf
(± 1 wk)
-28 to -1
1c
8
15
Rest Period 
22 to 28
Every 6 
weeks
Every 12 
weeks
Thyroid stimulating hormone (TSH); random 
cortisol level
X
Blood Sample for Genotyping
X
Neurologic examination
X
X
X
Xe
QOL Assessmentn
X
X
X
PK and Whole blood 20S proteasome activity
See table below for detailed sampling schedule 
Response Assessment
Hematological Disease Response Assessmento
X
X
X
2-microglobulin 
X
M-protein measurements (SPEP)
X
X
X
X
M-protein measurements (UPEP [24-hour urine 
collection])
X
X
X
X
Serum free light chain assay
X
X
X
X
Immunofixation - serum and urine
X
X
X
X
Quantification of Ig
X
X
X
X
Bone marrow biopsy/aspiration
Xp
Xq
X
Xq
Skeletal Surveyr
X
X
X
X
Amyloid-related organ assessments,t
X
Posteroanterior and lateral CXR
X
CT or MRI scans as indicated to assess organ 
involvement (eg, lung; liver)s,u
X
Echocardiograms
X
X
X
X
Estimates of interventricular septal and posterior 
wall thicknesss
X
X
X
X
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN9708
Clinical Study Protocol C16007 Amendment 6
EudraCT:  2010-022497-13
9
Study Procedures
Screeninga
Treatment Period
End of 
Treatmentd
Follow-up
CYCLES 1 -12b
Days
Days
PFSe
(± 1 wk)
OSf
(± 1 wk)
-28 to -1
1c
8
15
Rest Period 
22 to 28
Every 6 
weeks
Every 12 
weeks
Serum cardiac markers (NT-proBNP, BNP, 
troponin T or I)s
X
X
X
X
NYHA classification
X
X
X
X
Adverse Events
Recorded from the first dose of study drug through 30 
days after last dose of study drug or until the initiation 
of subsequent antineoplastic therapy
Serious Adverse Events
Recorded from the time informed consent is signed through 30 days after 
the last dose of study drug
Concomitant Medications/Procedures
Recorded from the first dose of study drug through 30 
days after last dose of study drug or until the intitiation 
of subsequent antineoplastic therapy
Study Drug Administration
MLN9708
X
X
X
Dexamethasone (only if no response after 
3 cycles of single-agent MLN9708)
X
Survival
X
Abbreviations: BNP = B-type natriuretic peptide; CT = computed tomography CXR = chest X-ray; ECG = electrocardiogram; ECOG = Eastern Cooperative 
Oncology Group; EMG = electromyography; EOT = end of treatment; Ig = immunoglobulin; INR = international normalized ration; MRI = magnetic 
resonance imaging; NT-proBNP = N-terminal proBNP; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PK = 
pharmacokinetics; PT = prothombin time; PTT = partial thromboplastin time; QOL = quality of life; SPEP = serum protein electrophoresis; UPEP = urine 
protein electrophoresis.
a Evaluations including CT scans, MRIs, and skeletal surveys may be performed within 8 weeks of the first dose of study drug.
b One complete cycle is 28 days. In order to begin a new cycle of treatment, certain criteria must be met (see Section 6.5.2). Patients who do not continue 
study treatment dosing after Cycle 1 must complete the EOT and follow-up assessments.
c All evaluations/procedures are to be conducted on Day 1 of the stated cycle before dosing or within 3 days before the first dose of drug unless otherwise 
specified.
d Patients who do not continue treatment must complete the EOT assessments, which should occur at least 30 days after the last dose of study drug or prior to 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN9708
Clinical Study Protocol C16007 Amendment 6
EudraCT:  2010-022497-13
10
Study Procedures
Screeninga
Treatment Period
End of 
Treatmentd
Follow-up
CYCLES 1 -12b
Days
Days
PFSe
(± 1 wk)
OSf
(± 1 wk)
-28 to -1
1c
8
15
Rest Period 
22 to 28
Every 6 
weeks
Every 12 
weeks
the initiation of subsequent antineoplastic therapy.
e Conducted from EOT until occurrence of PD or the initiation of subsequent antineoplastic therapy. If a patient comes off treatment due to PD, they should 
continue to be followed for OS long-term follow-up. Hematologic response assessments should be conducted every 6 weeks (± 1 week) during PFS follow-
up while amyloid organ response assessments should be conducted every 6 months, including a neurologic examination in patients with persistent 
neurologic symptoms and clinical examinations in patients with persistent symptoms thought by the investigator to be amyloid-disease related (see Section
7.5.12).
f
Conducted every 12 weeks (± 1 week) after PD or the initiation of subsequent antineoplastic therapy. Data may be collected by methods that include but are 
not limited to telephone, e-mail, mail, and social security indexes.
g 24-hour Holter monitor, to be performed at screening, and at any time the physician believes it is medically appropriate.
h A full physical exam will occur every 3 cycles. Symptom-directed assessments will be conducted per standard clinical practice.
i
Should occur every 3 cycles.
j
A serum pregnancy test will be performed for women of childbearing potential during screening and predose on Cycle 1, Day 1. The serum pregnancy test 
may be collected up to 3 days before dosing. The results must be available and negative before the first dose of MLN9708 is administered.
k Hematology and chemistry panels may be collected up to 3 days prior to dosing. Criteria for retreatment are provided in Section 6.5.2. After 24 cycles on 
treatment, hematology and chemistry laboratory evaluations may be done to monitor the patient according to standard clinical practice per the treating 
physician.
l
Repeat as clinically indicated by change in serum creatinine. Creatinine clearance will be calculated based on a 24-hour urine collection at screening. eGFR 
will be calculated according to the equations in Section 15.1. 24-hour urine for protein is required to assess amyloid renal involvement/ response.
m If abnormal, a diagnostic work up should be performed and the patient treated and stabilized before administering MLN9708. PT/INR and PTT may be 
repeated during the treatment period at the discretion of the investigator if bleeding occurs or as clinically indicated.
n Only for patients in the extension cohort after every cycle.
o Repeat every treatment cycle, at the EOT visit, and every 6 weeks during the PFS follow-up period.
p
q Bone marrow biopsy and aspirate should be repeated at the discretion of the investigator as clinically indicated and if response is documented by other 
parameters, and at EOT. Immunohistochemistry of dominant clonal plasma cells is recommended.
r
To be performed at screening and at any time the physician believes there are symptoms or signs that suggest increased or new bone lesions. Plain films of 
symptomatic sites for signs or symptoms of new bone lesions may be obtained instead of a full skeletal survey. A PET-CT may be done at screening in 
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MLN9708
Clinical Study Protocol C16007 Amendment 6
EudraCT:  2010-022497-13
11
Study Procedures
Screeninga
Treatment Period
End of 
Treatmentd
Follow-up
CYCLES 1 -12b
Days
Days
PFSe
(± 1 wk)
OSf
(± 1 wk)
-28 to -1
1c
8
15
Rest Period 
22 to 28
Every 6 
weeks
Every 12 
weeks
place of a skeletal survey provided that the same modality for assessment is used throughout the study. If results are interpreted as abnormal, then repeat at 
the discretion of the investigator as clinically indicated. The same imaging modality used at screening should be used for all follow-up assessments.
s At baseline, Cycles 3, 6, 9, and 12, and every 6 months thereafter until disease progression or the initiation of subsequent antineoplastic therapy.
t
The following tests should be included for organ assessments:
heart: NT-proBNP, BNP, troponin, echocardiography, physical examination; 
kidney: 24-hour urine proteinuria, serum creatinine, eGFR, serum albumin;
liver: alkaline phosphatase, ALT, ultrasound/CT scan/ MRI (as indicated); 
peripheral nervous system: patient reported symptoms, physical examination, electromyography (EMG; if indicated); 
autonomic nervous system: patient reported symptoms, determination of postural hypotension; 
gastrointestinal: patient reported symptoms;
soft tissue: physical examination, imaging as indicated
u If results are interpreted as abnormal, then repeat at the discretion of the investigator as clinically indicated except if being used to monitor amyloid liver 
involvement. The same imaging modality used at screening (CT/MRI) should be used for all follow-up assessments.
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MLN9708
Clinical Study Protocol C16007 Amendment 6
EudraCT:  2010-022497-13
12
Pharmacokinetic & Pharmacodynamic Sampling (Cycle 1)
Day 1a
Day 2
Day 8
Minutes
Hours
Predose (within 
1 hour of dosing)
MLN9708
30
(5)
1
(0.25)
2
(0.25)
4
(0.75)
6
(0.75)
24
(1.0)
168 (4.0) [prior to 
Day 8 dose]
PK (whole blood & plasma)
X
X
X
X
X
X
X
X
Whole blood 20S 
proteasome activity
X
X
X
X
X
X
X
X
Day 15
Day 16
Day 22
Minutes
Hours
Predose (within 
1 hour of dosing)
MLN9708
30
(5)
1
(0.25)
2
(0.25)
4
(0.75)
6
(0.75)
24
(1.0)
168 (4.0)
PK (whole blood & plasma)
X
X
X
X
X
X
X
X
Whole blood 20S 
proteasome activity
X
X
X
X
X
X
X
X
The following samples will be collected at each time point: 1 blood sample (3 mL) for the determination of plasma concentrations of MLN2238, 1 blood sample 
(3 mL) for the determination of whole blood concentrations of MLN2238, and 1 blood sample (1 mL) for the measurement of whole blood 20S proteasome 
activity.
a Day 1, 2 and 8 samples are ONLY collected at the MTD; however, Day 15, 16 and 22 are collected for all patients.
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TABLE OF CONTENTS
LIST OF TABLES.............................................................................................................16
LIST OF FIGURES............................................................................................................16
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ..........................................17
1. BACKGROUND AND STUDY RATIONALE..............................................................20
1.1 Scientific Background ..............................................................................................20
1.1.1 Disease Under Treatment...................................................................................20
1.1.2 Study Drug ........................................................................................................24
1.2 Preclinical Experience ..............................................................................................25
1.2.1 Nonclinical Pharmacology: In Vivo Studies.......................................................25
1.2.2 Drug Metabolism and Pharmacokinetics ............................................................25
1.2.3 In Vivo Toxicology in Rats and Dogs ................................................................27
1.3 Clinical Experience ..................................................................................................28
1.3.1 Pharmacokinetics and Pharmacodynamics .........................................................32
1.4 Study Rationale ........................................................................................................32
1.5 Rationale MLN9708 Dose and Schedule Selection ...................................................34
1.6 Rationale for Collection of PK and Pharmacodynamic Samples................................34
1.7 Rationale for Tumor Biomarker Assessment.............................................................35
1.8 Potential Risks and Benefits .....................................................................................35
2. STUDY OBJECTIVES ..................................................................................................35
2.1 Primary Objectives ...................................................................................................35
2.2 Secondary Objectives ...............................................................................................36
2.3 Exploratory Objectives .............................................................................................36
3. STUDY ENDPOINTS....................................................................................................37
3.1 Primary Endpoints....................................................................................................37
3.2 Secondary Endpoints................................................................................................37
3.3 Exploratory Endpoints..............................................................................................38
4. STUDY DESIGN...........................................................................................................38
4.1 Overview of Study Design........................................................................................38
4.2 Number of Patients...................................................................................................40
4.3 Duration of Study.....................................................................................................40
5. STUDY POPULATION.................................................................................................41
5.1 Inclusion Criteria......................................................................................................41
5.2 Exclusion Criteria.....................................................................................................44
6. DESCRIPTION OF TREATMENT................................................................................46
6.1 Study Drug...............................................................................................................46
6.2 Reference/Control Therapy.......................................................................................47
6.3 Definitions of Dose-Limiting Toxicity (DLT)...........................................................47
6.3.1 DLT Definitions.................................................................................................47
6.4 Dose-escalation Rules...............................................................................................49
6.5 Dose-Modification Guidelines..................................................................................52
6.5.1 Dose-Modification Guidelines ...........................................................................52
6.5.2 Criteria for Toxicity Recovery Before Beginning the Next Cycle of 
Treatment....................................................................................................53
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6.6 Criteria for Dose Modification (Delays, Reductions, and Discontinuations)..............54
6.6.1 MLN9708 Dose Adjustments for Hematologic Toxicity.....................................54
6.6.2 MLN9708 Dose Adjustments for Nonhematologic Toxicity...............................55
6.6.3 Dexamethasone–Related Treatment Modification ..............................................56
6.7 Excluded Concomitant Medications and Procedures.................................................57
6.8 Permitted Concomitant Medications and Procedures.................................................59
6.9 Precautions and Restrictions .....................................................................................60
6.10 Management of Clinical Events ..............................................................................60
6.11 Blinding and Unblinding ........................................................................................62
6.12 Description of Investigational and Noninvestigational Medicinal Agents................62
6.12.1 MLN9708: Investigational Medicinal Agent ....................................................62
6.12.2 Dexamethasone: Noninvestigational Medicinal Agent......................................63
6.13 Preparation, Reconstitution, and Dispensation ........................................................63
6.14 Packaging and Labeling..........................................................................................63
6.15 Storage, Handling, and Accountability....................................................................63
6.16 Other Protocol-Specified Materials.........................................................................65
7. STUDY CONDUCT ......................................................................................................65
7.1 Study Personnel and Organizations...........................................................................65
7.2 Arrangements for Recruitment of Patients ................................................................65
7.3 Treatment Group Assignments .................................................................................65
7.4 Enrollment................................................................................................................66
7.5 Study Procedures......................................................................................................66
7.5.1 Informed Consent ..............................................................................................66
7.5.2 Patient Demographics ........................................................................................66
7.5.3 Medical History.................................................................................................66
7.5.4 Physical Examination.........................................................................................66
7.5.5 Eastern Cooperative Oncology Group Performance Status.................................67
7.5.6 Vital Signs, Body Weight, and Height................................................................67
7.5.7 Pregnancy Test ..................................................................................................67
7.5.8 Electrocardiogram..............................................................................................67
7.5.9 Holter Cardiac Monitor......................................................................................67
7.5.10 Clinical Laboratory Evaluations.......................................................................68
7.5.11 Quality of Life Assessment (European Organization for Research and 
Treatment of Cancer) ..................................................................................69
7.5.12 Disease Assessments........................................................................................69
7.5.13 Pharmacokinetic and Pharmacodynamic Measurements...................................73
7.5.14 Germline DNA Measurements .........................................................................73
7.5.15 Concomitant Medications and Procedures........................................................74
7.5.16 Adverse Events................................................................................................74
7.5.17 Follow-Up Assessments (PFS and OS).............................................................74
7.6 Study Compliance ....................................................................................................75
7.7 Completion of Treatment..........................................................................................75
7.8 Completion of Study.................................................................................................75
7.9 Discontinuation of Treatment With Study Drug, and Patient Replacement................75
7.10 Withdrawal of Patients From Study ........................................................................76
8. STATISTICAL AND QUANTITATIVE ANALYSES ..................................................76
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8.1 Statistical Methods ...................................................................................................76
8.1.1 Determination of Sample Size............................................................................76
8.1.2 Randomization and Stratification .......................................................................77
8.1.3 Populations for Analysis ....................................................................................77
8.1.4 Procedures for Handling Missing, Unused, and Spurious Data...........................78
8.1.5 Demographic and Baseline Characteristics.........................................................78
8.1.6 Efficacy Analysis...............................................................................................79
8.1.7 Pharmacokinetics, Pharmacodynamics, and Exploratory Analyses.....................80
8.1.8 Safety Analysis ..................................................................................................81
8.1.9 Interim Analysis.................................................................................................83
9. STUDY COMMITTEES................................................................................................83
9.1 Steering Committee..................................................................................................83
9.1.1 Drug Safety Monitoring Board...........................................................................83
10. ADVERSE EVENTS ...................................................................................................84
10.1 Definitions..............................................................................................................84
10.1.1 Pretreatment Event Definition..........................................................................84
10.1.2 Adverse Event Definition.................................................................................84
10.1.3 Serious Adverse Event Definition ....................................................................84
10.2 Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events.................................................................................................85
10.3 Monitoring of Adverse Events and Period of Observation.......................................87
10.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events........87
11. ADMINISTRATIVE REQUIREMENTS .....................................................................88
11.1 Good Clinical Practice............................................................................................88
11.2 Data Quality Assurance ..........................................................................................88
11.3 Electronic Case Report Form Completion...............................................................88
11.4 Study Monitoring ...................................................................................................89
11.5 Ethical Considerations............................................................................................89
11.6 Patient Information and Informed Consent..............................................................89
11.7 Patient Confidentiality............................................................................................90
11.8 Investigator Compliance.........................................................................................90
11.9 On-site Audits ........................................................................................................90
11.10 Investigator and Site Responsibility for Drug Accountability................................90
11.11 Product Complaints ..............................................................................................91
11.12 Closure of the Study .............................................................................................91
11.13 Record Retention..................................................................................................92
12. USE OF INFORMATION............................................................................................92
13. INVESTIGATOR AGREEMENT................................................................................94
14. REFERENCES.............................................................................................................95
15. APPENDICES ...........................................................................................................101
15.1 Equation to Estimate Glomerular Filtration Rate (eGFR)......................................101
15.2 Amyloid Typing ...................................................................................................101
15.3 Eastern Cooperative Oncology Group Scale for Performance Status.....................103
15.4 New York Heart Association Classification of Cardiac Disease ............................103
15.5 Steroid Equivalent Doses......................................................................................104
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15.6 European Organization for Research and Treatment of Cancer (EORTC QLQ-
C30) Survey....................................................................................................105
15.7 Amyloid-Related Organ Involvement ...................................................................107
15.8 Assessment of Hematologic Disease Response .....................................................107
15.9 Criteria for Treatment Response of Amyloid-Related Organs ...............................109
15.10 Amendment 4 Rationale and Purposes................................................................111
15.11 Amendment 5 Rationale and Purposes................................................................112
15.12 Amendment 6 Detailed Summary of Changes.....................................................113
LIST OF TABLES 
Table 6-1
Planned Dose Levels...................................................................................51
Table 6-2
MLN9708 Dose Adjustments for Hematologic Toxicities ...........................54
Table 6-3
MLN9708 Dose Adjustments for Nonhematologic Toxicities......................55
Table 6-4
Dose Reduction Steps for Dexamethasone...................................................56
Table 6-5
Dexamethasone–Related Treatment Modification (Delays, Reductions, and 
Discontinuations) Guidelines Due to Adverse Events..................................56
Table 6-6
MLN9708 Capsules ....................................................................................62
LIST OF FIGURES 
Figure 6-1
Dose-escalation Algorithm..........................................................................50
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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
AE
adverse event
AL amyloidosis
primary systemic light chain amyloidosis
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC
area under the plasma concentration versus time curve
AUC0-24hr
area under the plasma concentration versus time curve zero to 24 hours
AUC0-tau
area under the plasma concentration versus time curve zero to next dose
AV
atrioventriculatar
BCRP
breast cancer resistance protein
BNP
B-type natriuretic peptide
BSA
body surface area
BUN
blood urea nitrogen
CBC
complete blood count
CL
clearance
CLb
blood clearance
CLP
plasma clearance
Cmax
maximum plasma concentration
CO2
carbon dioxide
CR
complete response
CT
computed tomography
CYP
cytochrome P450
DDI
drug-drug interaction
dFLC
serum differential free light chain concentration; difference between amyloid 
forming and non amyloid forming FLC
DLBCL
diffuse large B cell lymphoma
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate; eGFR according to the recently 
recommended CKD-EPI equation
Emax
maximum effect
EMG
electromyography
EORTC
European Organization for Research and Treatment of Cancer
EDC
electronic data capture
EOT
End of Treatment (visit)
F
bioavailability
FLC
free light chain
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
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Abbreviation
Term
GI
gastrointestinal
GLP
Good Laboratory Practices
GM-CSF
granulocyte macrophage-colony stimulating factor
hERG
human ether-à-go-go related gene
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
IC50
concentration producing 50% inhibition
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IMiDs
immunomodulatory drugs
IRB
Institutional Review Board
IV
intravenous; intravenously
Ki
inhibition constant
MedDRA
Medical Dictionary for Regulatory Activities
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
MPD
maximum planned dose
MR
minimal response
MRI
magnetic resonance imaging
MRP2
multidrug resistance associated protein
msec
millisecond
MTD
maximum tolerated dose
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NT-proBNP
N-terminal proBNP
NYHA
New York Heart Association
OS
overall survival
PD
progressive disease (disease progression)
PFS
progression free survival
P-gp
P-glycoprotein
PK
pharmacokinetic(s)
PO
per os; by mouth (orally)
PR
partial response
QD
quaque die; each day; once daily
QLQ
Quality of Life Questionnaire
QLQ-C30
EORTC Core Quality of Life Questionnaire
QOL
quality of life
QTc
rate-corrected QT interval (millisec) of electrocardiograph
RBC
red blood cell
RP2D
recommended phase 2 dose
SAE
serious adverse event
SCT
stem cell transplant
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Abbreviation
Term
t1/2
half-life
TEAE
treatment-emergent adverse event ; may or may not be treatment related
TEmax
time of occurrence of Emax
Tmax
first time to maximum plasma concentration
ULN
upper limit of the normal range
US
United States
VGPR
very good partial response
Vss
volume of distribution at steady state
WBC
white blood cell
WHO
World Health Organization
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1. BACKGROUND AND STUDY RATIONALE
1.1
Scientific Background
1.1.1 Disease Under Treatment
Primary systemic light chain (AL) amyloidosis is a progressive disorder caused by 
proteotoxic light chain proteins produced by a clonal plasma cell dyscrasia.(1, 2, 3) The plasma 
cell dyscrasia is characterized by monoclonal plasma cells in the bone marrow and the 
production of excess monoclonical immunoglobulin light-chains that tend to misfold, form 
aggregates, and deposit as unique amyloid fibrils in visceral organs. Tissue damage is 
caused when these light chain aggregates interact with cells and when they form large 
amounts of amyloid fibrils, insoluble pleated sheet filaments in fibrils that cause end-
organ dysfunction.(4) While the disease is a clonal plasma cell disease like multiple 
myeloma, the M-protein is often not an intact immunoglobulin and the clonal plasma cells 
are present at a low percentage in the bone marrow and are predominantly rather than 
restricted (-to-ratio is 1:4).(1, 5, 6)
Amyloidosis is a rare disease where early diagnosis and treatment are key to patient 
outcomes. Unfortunately, late diagnosis is still a major problem. Extracellular deposition of 
the fibrils ultimately results in an accumulation that disrupts normal tissue structure and 
function notably in the heart, kidneys, peripheral nervous system, and gastrointestinal tract 
with liver and soft tissues.(1) This progressive accumulation ultimately leads to organ 
dysfunction, organ failure, and finally death, often due to cardiac causes. The disease carries 
a poor prognosis which is predominantly influenced by the patient’s performance status and 
extent of organ involvement, particularly cardiac involvement, at diagnosis. One-fourth of 
patients present with clinical involvement of 1 organ; however, the majority present with 
clinical involvement of more than one.(1, 7) Renal dysfunction is the most common clinical 
manifestation while liver involvement is reported but not very common. The severity of the 
cardiac involvement ultimately dictates the prognosis. Notably the majority of patients with 
AL amyloidosis die from a cardiac death, which is often sudden.(8)
The incidence of systemic AL amyloidosis has been estimated at 8.9 per million 
person-years in the United States, similar to that of chronic myelogenous leukemia, which 
translates to approximately 2,225 new cases annually in the United States (US).(2, 9) It is 
about one-fifth as common as multiple myeloma; however, median survival time is shorter 
(13.2 months from the time of diagnosis compared to 47 months for multiple myeloma).(10, 
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11, 12) The natural history of AL amyloidosis includes progression to death within 2 years 
from diagnosis in about 80% of patients.(7)
The diagnosis of amyloidosis relies on the identification of amyloid deposits in tissues, eg, 
abdominal adipose aspiration, salivary glands, and organ biopsy.(13) The characterization of 
amyloidosis as AL type requires the demonstration of the underlying plasma cell clone.
Amyloid typing is necessary and demands adequate techniques. Current practice primarily 
involves Congo red (CR) staining and viewing under polarized light. Combination methods 
such as CR plus immunoelectron microscopy, immunofluorescence, immunoperoxidase, 
immunohistochemistry, mass spectrometry-based methods, and genetic testing play a major 
role in tissue typing.(14) The importance of these techniques is to enable differentiation of the 
various types of systemic amyloidosis, to identify specific mutation associated with 
hereditary forms,(13) and to confirm the diagnosis of AL amloidosis in certain instances.
Once the diagnosis of AL amyloidosis has been established, prompt initiation of treatment is 
required in order to inhibit growth of the malignant clone and to reduce the supply of the 
amyloidogenic light chains.
The death of the amyloidogenic plasma cells is the main goal of anti-AL amyloidosis 
therapy. Furthermore, the reduction or elimination of the amyloidogenic clone by 
chemotherapy has been shown to allow improvement of the function of affected organs.(3)
Currently, there are no treatment modalities that specifically target the amyloid deposits.
Therefore, the aim of therapy is to kill the underlying neoplastic plasma cell that produces 
the light chains which causes end organ dysfunction and significant toxicity for patients.
Supportive measures are additionally used to preserve organ function.
The regimens used to treat subjects with systemic AL amyloidosis are based on those used 
in multiple myeloma therapy. However, patients with AL amyloidosis not only have a 
hematologic malignancy, but also have progressive organ dysfunction often of more than 1 
organ. The amyloid deposits can cause symptoms that compromise the patient’s clinical 
course by rendering them particularly susceptible to the toxic effects of chemotherapy. A 
rapid response is essential in order to arrest the progressive organ damage and possibly 
rescue its function. Hematologic and organ responses predict survival.(8, 14, 15, 16, 17, 18, 19, 20)
However, given the potentially long delay in observing organ improvement, hematologic 
response is used as a short-term marker of treatment efficacy. Guidelines for the effective 
management of patients with systemic AL amyloidosis were published by the British 
Committee for Standards in Hematology (2004).(21) These 2004 guidelines have not been 
updated in recent years. According to the National Comprehensive Cancer Network 
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(NCCN), patients with AL amyloidosis should be treated on a clinical study as data are 
insufficient to identify an optimal treatment.(13)
As the approach to the treatment of multiple myeloma has evolved over the past decade, so 
has the approach to treatment of AL amyloidosis.(22, 23, 24) Treatments including steroids, 
alkylating agents, or stem cell transplant may achieve durable responses but few cures, with 
only about 5% of patients alive more than 10 years.(13, 25, 26, 27, 28, 29) For those considered 
transplant eligible, treatment generally involves high-dose melphalan followed by rescue 
with autologous stem cell transplantation (SCT). This approach is an aggressive treatment 
that can induce hematologic responses, prolonged survival, and reversal of organ disease.(30, 
31) However not all patients are able to tolerate this therapy and only about one-quarter of 
newly diagnosed AL patients are eligible.(28) For those ineligible for SCT, other treatment 
options include dexamethasone plus melphalan(32) or new agents such as the 
immunomodulatory drugs (IMiDs; lenalidomide, thalidomide, pomolidomide).(18, 19, 33, 34, 35, 
36, 37, 38, 39) Experience with IMiDs is also illustrative of the challenges encountered in the 
development of effective therapy. Dispenzieri, et al documented poor tolerance to high-dose 
(200 to 800 mg daily) thalidomide in a small phase 2 study involving 12 patients with 
systemic amyloidosis.(35) Within a median time on study of 72 days, 75% of patients 
developed progressive edema, cognitive difficulties, and constipation compared with the 
authors’ experience with similarly treated multiple myeloma patients. In addition, 50% of 
patients experienced dyspnea, dizziness, and rash. The same group noted similar challenges 
with pomalidomide.(19) Though the hematologic response rate was 35% (complete 
response/partial response [CR/PR]) and 47% (CR/PR/minimal response[MR]) with organ 
responses seen in 2 out of 19 patients, Grades 3 to 5 adverse events (AEs) possibly attributed 
to on-study therapy occurred in 56% of patients, with 1 death at Day 5 from cardiac 
amyloidosis. Though there has been some slow improvement over the last decade, no 
significant improvements in early mortality have been achieved likely reflecting the limited 
treatment tolerability in patients with advanced AL amyloidosis, especially those with 
cardiac involvement.(20)
Because lack of tolerance to treatment continues to be a common feature in this disease, a 
better understanding of the disease and new treatment options are needed, as those currently 
available are inadequate for most patients. Currently, no satisfactory therapy exists for 
patients with AL amyloidosis that has progressed despite previous chemotherapy including 
stem cell transplant; therefore, the recommendation of the NCCN is to treat patients on a 
clinical study.(13) Investigations in proteostasis and immunoglobulin production may lead to 
novel strategies to treat AL amyloidosis. Pengo, et al(40, 41) have reported that differentiating 
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plasma cells suffer from proteotoxicity with decreased proteasome capacity even with 
increased protein synthesis. This imbalance of the ubiquitin proteasome system results in the 
accumulation of ubiquitin-conjugates and apoptotic sensitization to proteasome inhibitors.(40, 
41) Amyloidosis is a protein misfolding disease and as such may be particularly sensitive to 
proteasome inhibition.
VELCADE (bortezomib), a selective protesome inhibitor effective in the treatment of 
relapsed/refractory multiple myeloma, has also been evaluated in patients with AL 
amyloidosis. Small retrospectivecase studies are suggestive of activity.(42, 43, 44) Most of the 
patients enrolled in these studies had failed previous therapies or were ineligible for SCT.
Treatment with VELCADE with or without dexamethasone was characterized by rapid 
response and high rates of hematologic and organ responses.(42, 43) Although treatment-
related mortality was uncommon in these studies, discontinuation of VELCADE due to 
adverse events was common.
Reece and colleagues reported on the first prospective study of single-agent VELCADE in 
relapsed amyloidosis.(45, 46) The primary objective of this phase 1/2 study was to determine 
the maximum tolerated dose (MTD) and evaluate safety. The determination of the 
hematologic response rate and duration of response at the MTD was a secondary objective, 
while assessment of organ response and overall survival were exploratory objectives. In the 
phase 1 portion of the study, VELCADE was generally well tolerated at doses of up to 
1.6 mg/m2 on a weekly schedule and 1.3 mg/m2 on a twice-weekly schedule. The MTD was 
not reached with either dosing schedule therefore the maximum planned dose (MPD) was 
evaluated in the phase 2 portion of the study. A total of 70 patients were enrolled in this 
study, 18 at 1.6 mg/m2 weekly, 34 at 1.3 mg/m2 twice weekly, and 18 at lower doses during 
dose-escalation. Best hematologic response (CR/PR) rates were 68.8% and 66.7% 
respectively for the weekly and twice-weekly dosing schedules with 78% overall of 
responders with a durable (> 1 year) response. Responses were more rapid with the twice-
weekly dosing schedule, but toxicity appeared lower with the weekly schedule. Overall, 
organ responses included 29% renal and 13% cardiac responses with organ response usually 
associated with hematologic response. Two patients had renal progression; however, no 
other organ disease progression was seen. The most common adverse events were fatigue, 
thrombocytopenia, vomiting, diarrhea, pneumonia, and syncope. Given the results of this 
study and activity reported in previously untreated patients,(47) 2 phase 3 studies are in 
development.
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Currently, no satisfactory therapy exists for patients with AL amyloidosis that has 
progressed despite previous chemotherapy including stem cell transplant. Amyloidosis is a 
protein misfolding disease and may therefore be particularly sensitive proteasome inhibition.
VELCADE, the first proteasome inhibitor, has been demonstrated to be safe and active in 
relapsed disease.(46) As a second generation selective reversible proteasome inhibitor with 
improved chemical properties, MLN9708 is a good candidate for development in AL 
amyloidosis. The main purpose of this clinical study is to determine the safety and activity 
of MLN9708 in patients with previously treated amyloidosis.
1.1.2 Study Drug
VELCADE, the first-in-class small molecule proteasome inhibitor developed by Millennium 
Pharmaceuticals, Inc (Millennium) validated the proteasome as a therapeutic oncology 
target. Recognizing that proteasome inhibition is an effective anticancer therapeutic 
approach, Millennium has developed MLN9708, a small-molecule 20S proteasome inhibitor 
that has shown an increased potency in preclinical studies, which could be translated to 
increase clinical efficacy.
MLN9708 rapidly hydrolyzes in plasma to MLN2238, the active form that potently, 
reversibly, and selectively inhibits the proteasome. MLN9708 is the citrate ester of the 
biologically active form, MLN2238. Like VELCADE, MLN9708 is a modified dipeptidyl 
boronic acid derived from leucine and phenylalanine. MLN9708 was identified in a screen 
for a small molecule proteasome inhibitor with improved preclinical antitumor activity and 
pharmacokinetic properties, and would be more convenient for clinical delivery. Both 
VELCADE and MLN2238 are reversible proteasome inhibitors. However, MLN9708 has a 
shorter proteasome dissociation half-life, which allows MLN2238 to reach equilibrium with 
its target more rapidly than VELCADE. As a consequence of these biochemical differences,
preclinical studies determined that MLN2238 could more easily move from the blood 
compartment to the tissue compartment, resulting in greater and more sustained 
pharmacodynamic effects in both bone marrow and tumor. The pharmacologic implications 
of this difference in binding kinetics and tissue distribution may in turn result in differences 
in safety and efficacy profiles in a broader range of tumors. The evidence therefore suggests 
that some proteasome inhibitors quickly bind to the immediately available proteasomes in 
the blood but then dissociate at differing rates, if at all, to the tissue.(48)
MLN2238 preferentially binds the 5 site of the 20S proteasome; at higher concentrations, it 
also inhibits the activity of the 1 and 2 sites. MLN2238 was selective for the proteasome 
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over a panel of several proteases (half-maximal inhibitory concentration [IC50] values 
between 20 and100 M), 103 kinases (IC50 values > 10 M), and receptors (IC50 values 
> 10 M). MLN2238 inhibited the cloned cardiac potassium human ether-à-go-go related 
gene (K+ hERG) channel with an IC50 value of 60 M. MLN2238 and VELCADE have 
different 5 proteasome dissociation half-lives (t1/2), reflecting differences in their on-off 
binding kinetics (the 5 proteasome dissociation t1/2 for MLN2238 and VELCADE are 18 
and 110 minutes, respectively).
1.2
Preclinical Experience
1.2.1 Nonclinical Pharmacology: In Vivo Studies
Antitumor activity was observed with MLN2238 in 4 xenograft models: CWR22 (a human 
prostate cancer cell line), WSU-DLCL2, OCI-Ly7-7D1-luc, and PHTX-22L (3 human 
lymphoma cell lines). In contrast, VELCADE demonstrated weaker antitumor activity in 
these latter 3 lymphoma models, demonstrating that MLN2238 has improved activity in 
nonclinical models compared to VELCADE. MLN2238 treatment demonstrated an 
improved tumor pharmacodynamic response compared to VELCADE in WSU-DLCL2 
human diffuse large B-cell lymphoma (DLBCL) xenografts. WSU-DLCL2 xenografts from 
MLN2238-treated mice displayed greater tumor 20S proteasome inhibition compared to 
xenografts from VELCADE-treated mice and demonstrated increased downstream 
biological effects, as determined by protein marker expression.
MLN2238-treated xenografts displayed higher and more sustained 20S proteasome 
inhibition and increased downstream biological effects as determined by Growth Arrest 
DNA Damage 34 (GADD34) and Activating Transcription Factor-3 (ATF-3 levels).
MLN2238 demonstrated both an improved efficacy profile and pharmacodynamic response 
compared to VELCADE.
1.2.2 Drug Metabolism and Pharmacokinetics
The pharmacokinetic (PK) properties of MLN2238 were studied in severe combined 
immunodeficient mice bearing human CWR22 tumor xenografts, Sprague-Dawley rats, 
beagle dogs, and cynomolgus monkeys. Because of the extensive red blood cell (RBC) 
partitioning of MLN2238, both blood and plasma PK parameters were determined in these 
studies. MLN2238 had a very low blood clearance (CLb) and a moderate blood volume of 
distribution at steady-state (Vss,b) after intravenous (IV) administration. The concentration-
versus-time curve of MLN2238 displayed a distinct bi-exponential profile with a steep 
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initial distribution phase and a long terminal t1/2 (24 hours) in all species tested. MLN2238 
had higher plasma clearance (CLp) and a larger plasma volume of distribution at steady-state 
(Vss,p) than in blood, largely because of the extensive RBC partitioning.
The PK properties of MLN2238 after oral (PO) administration were studied in rats and dogs.
The plasma oral bioavailability (F) was 41% in rats and nearly 100% in dogs. A clinical 
prototype formulation of the MLN9708 capsule demonstrated that MLN2238 had excellent 
oral F and an excellent absorption profile in dogs. In addition, after PO administration, 
interindividual variability (as measured by percent coefficient of variation) in maximum 
plasma concentration (Cmax) and area under the plasma concentration versus time curve zero 
to 24 hours (AUC0-24hr) was low to moderate, similar to that after IV administration. The 
terminal t1/2 after PO administration was also similar to that after IV administration.
MLN2238 is predicted to have very low CLb (0.0045 L/hr/kg) and a moderate Vss,b
(0.79 L/kg) with a long terminal t1/2 (24 hours) in humans. The human efficacious IV dose 
of MLN2238 is predicted to be 2.0 mg/m2 (0.054 mg/kg) twice weekly. The projected PO 
efficacious dose is between 2 and 5 mg/m2 twice weekly. It is anticipated that the plasma 
AUC at the PO efficacious dose will be similar to that at the IV efficacious dose 
(AUC0-24hr 143 hr ng/mL) and that the systemic effects are probably driven by plasma 
AUC.
Metabolism appears to be the major route of elimination for MLN2238 and urinary 
excretion of the parent drug is negligible (< 3% of dose). In vitro studies indicate that 
MLN2238 is metabolized by multiple cytochrome P450s (CYPs) and nonCYP 
enzymes/proteins. The rank order of relative biotransformation activity of the 5 major 
human cytochrome P450 (CYP) isozymes was 3A4 (34.2%) > 1A2 (30.7%) > 2D6 (14.7%) 
> 2C9 (12.1%) > 2C19 (< 1%). All metabolites observed in the human liver microsome 
studies were also found in the rat and dog, supporting the rat and dog as the species to be 
used for toxicology studies. MLN2238 is not an inhibitor of CYPs 1A2, 2C9, 2C19, 2D6, or 
3A4 (IC50 > 30 M, estimated Ki > 15 M) nor a time-dependent inhibitor of CYP3A4/5 (up 
to 30 M). The potential for MLN9708 treatment to produce drug-drug interactions (DDI) 
via CYP inhibition is inferred to be low. However, there may be a potential for DDIs with a 
concomitant strong CYP3A4 or CYP1A2 inhibitor because of the potential for first-pass 
metabolism when MLN2238 is administered via the PO route, and because of the moderate 
contribution of CYP3A4- and CYP1A2-mediated metabolism of MLN2238 in human liver 
microsomes. To ensure patient safety and minimize PK variability in this first-in-human 
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investigation of the PO formulation of MLN9708, strong inhibitors of CYPs 3A and 1A2 
and strong CYP3A inducers are identified as excluded concomitant medications.
MLN2238 may be a weak substrate of P-glycoprotein (P-gp), breast cancer resistance 
protein (BCRP), and multidrug resistance associated protein (MRP2) efflux pump 
transporters. MLN2238 is not an inhibitor of P-gp, BCRP, and MRP2 (IC50 > 100 M). The 
potential for DDI with substrates or inhibitors of P-gp, BCRP, and MRP2 is therefore 
inferred to be low.
1.2.3 In Vivo Toxicology in Rats and Dogs
Compromise of gastrointestinal (GI) and lymphoid systems led to dose-limiting toxicity in 
both rats and dogs. Additionally, at doses below those associated with dose-limiting toxicity, 
alterations in leukocyte and coagulation parameters consistent with an inflammatory 
response were seen in both rats and dogs. The toxicologic effects seen in rats in the Good 
Laboratory Practice (GLP)-compliant, 2-cycle, PO toxicology study (inhibition of 
erythropoiesis, thrombocytopenia, leukocyte and coagulation profile consistent with an 
inflammatory response, intestinal mucosal thickening and inflammation, thymus and lymph 
node lymphoid depletion, adrenal gland vacuolation) were largely consistent with the 
toxicologic effects seen in rats in the GLP-compliant, 2 cycle, IV toxicology study, for 
which the dosing schedule was identical. Differences of note between the IV and PO studies 
in rats included a trend towards leukocytosis in the PO study versus a trend toward 
leukopenia (with corresponding bone marrow hypocellularity) in the IV study, as well as 
histologic findings in the peripheral nervous system in the IV study, but not in the PO study.
In the rat IV study, leukocytosis was seen before leukopenia. Additionally, in early-death 
rats in the PO study, bone marrow hypocellularity was seen; had the rats survived, this 
would likely have resulted in peripheral cytopenias. Higher exposures were achieved in the 
IV study compared to the PO study, and differences seen in peripheral white blood cell 
(WBC) counts and bone marrow hypocellularity between the 2 studies may reflect 
differences in exposures. Similarly, the decreased exposures achieved after PO versus IV 
administration may account for the lack of peripheral nervous system effects seen in the PO 
study. The toxicologic effects seen in both of these studies are qualitatively similar to what 
was previously observed in rodents treated with VELCADE.(49)
Although the GI and lymphoid system compromise, as well as the leukocyte and coagulation 
profile consistent with an inflammatory response, was consistent between rats and dogs, 
there were differences in the toxicologic effects between these 2 species. Differences 
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included a much more profound effect on lymphoid tissues at dose-limiting toxicity in dogs 
as compared to rats, as well as toxicologic effects seen in the peripheral nervous system of 
dogs (peripheral ganglia neuronal degeneration with secondary axonal degeneration), but not 
of rats. In dogs, neuronal degeneration in peripheral autonomic ganglia likely contributed to 
functional GI effects. These differences are consistent with the differences observed 
previously in GLP-compliant studies in dogs and rats after IV administration of MLN9708.
Additionally, there were no significant findings at tolerated exposures in dogs observed after 
PO administration that were not seen after IV administration, and similar exposures were 
tolerated regardless of the route of administration. All of the effects seen in both dogs and 
rats at tolerated doses were reversible or reversing.
The potential risks identified from nonclinical studies in dogs and rats include:

GI toxicity that could result in nausea, vomiting, diarrhea, dehydration, electrolyte 
imbalance, bleeding, bowel obstruction including ileus and intussusception, and 
sepsis.

Reduced blood counts manifest as thrombocytopenia, neutropenia, and anemia.
Reticulocytopenia was described in animals and may be associated with anemia.
Reductions in blood counts may predispose to an increased susceptibility to 
infection, bleeding, and anemia.

Peripheral nerve ganglia effects that may be associated with peripheral neuropathy 
that includes pain, burning sensation, and numbness. Autonomic and motor 
neuropathy may be observed, as both have been reported for VELCADE.

Lymphoid cell depletion that may be associated with increased risk of infection, 
including re-activation of herpes zoster.

Acute phase response that may result in fever and metabolic changes.
Detailed information regarding the nonclinical pharmacology and toxicology of MLN9708
may be found in the Investigator’s Brochure (IB).
1.3
Clinical Experience
MLN9708 is a boronic acid proteasome inhibitor similar to VELCADE. Clinical studies 
with VELCADE have yielded a detailed understanding of its safety profile. For details, refer 
to the package insert for VELCADE.(50) MLN9708 is in the early stages of clinical 
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investigations in humans with safety, tolerability, PK, pharmacodynamics, 
electrocardiogram (ECG) parameters, and disease response assessed in each study.
MLN9708 is the first investigational proteasome inhibitor with substantial oral 
bioavailability in patients with MM.
As of 24 September 2010, 112 patients have been treated with single-agent MLN9708 
across 4 phase 1 studies (C16001, IV administration twice weekly in adult patients with 
advanced nonhematologic malignancies, n = 67; C16002, IV administration weekly in adult 
patients with advanced lymphoma, n = 11; C16003 and C16004 PO administration twice 
weekly and weekly, respectively, in adult patients with relapse or refractory multiple 
myeloma, n = 19 and 15, respectively). Regardless of the route of administration in the 
twice-weekly dosing schedule, MLN9708 is given on Days 1, 4, 8, and 11 of a 21-day cycle 
and, in the weekly dosing schedule, the drug is given on Days 1, 8, and 15 of a 28-day cycle.
In the 2 studies investigating PO MLN9708 in relapsed or refractory multiple myeloma, a 
total of 34 patients have been treated thus far at doses of 0.24 mg/m2 to 2.23 mg/m2 twice a 
week (C16003) and 0.24 mg/m2 to 1.68 mg/m2 weekly (C16004). To date in study C16003 
(PO, twice weekly), 6 patients have experienced treatment-related AE ≥Grade 3 
(thrombocytopenia [2 pts], neutropenia [2 pts], anemia [1 pt], rash [1 pt- DLT], oral 
candidiasis [1 pt], and 1 patient that experienced nausea, vomiting, abdominal and chest pain 
[non-cardiac] for which they were hospitalized), otherwise there have not been 
any drug-related serious adverse events (SAEs). In study C16004 (PO, weekly), there have
not been any treatment-related AEs ≥Grade 3 or any drug-related SAEs. In the study 
investigating IV MLN9708 in advanced lymphoma (C16002; IV weekly), a total of 11 
patients have been treated at doses ranging from 0.125 mg/m2 to 1.76 mg/m2 weekly 
with 2 treatment-related AEs ≥ Grade 3 occurring in 2 patients at any point during the 
course of therapy: 1 each Grade 3 neutropenia and Grade 4 neutropenia that lasted more than 
7 days (meeting the definition of a dose-limiting toxicity [DLT]), and 2 Grade 3 
thrombocytopenia with no drug-related SAEs.
In study C16001(IV, twice weekly), 67 evaluable patients with advanced nonhematologic 
malignancies have been treated across 7 dose levels, ranging from 0.125 mg/m2 to 
2.34 mg/m2 twice weekly. At the 1.0-mg/m2 dose level, 1 out of 6 patients experienced a 
DLT (transient Grade 3 rash); no drug-related SAEs reported. No additional DLTs were 
reported as the dose was escalated up to 1.76 mg/m2. At the 2.34-mg/m2 dose level, 3 out of 
3 patients were admitted to the hospital with DLTs (1 reversible Grade 3 acute renal failure, 
2 reversible Grade 4 thrombocytopenia). All 3 patients recovered; 1 patient, who had 
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experienced thrombocytopenia, continued on study at a reduced dose of MLN9708 for an 
additional 3 cycles before disease progression. Given these AEs, the MTD of IV MLN9708 
administered twice weekly is determined to be 1.76 mg/m2.
In contrast to the AEs experienced by the patients at the highest dose administered in 
C16001, 50 patients (6 in the dose escalation phase, 44 from the dose expansion phase) have 
been treated at the MTD of 1.76 mg/m2. In these patients fatigue, nausea, vomiting, diarrhea, 
anemia, thrombocytopenia, rash, constipation, fever, abdominal pain, back pain, cough, 
chills, headache, and dyspnea are the most common treatment-emergent AEs. One patient 
treated at the MTD had experienced renal toxicity, 1 patient experienced Grade 3 transient 
peripheral sensory neuropathy during Cycle 2, and 1 Grade 3 peripheral neuropathy at the 
end of treatment after completion of 3 cycles. Eleven SAEs have been reported in the 
1.76-mg/m2 dose cohort where the investigators considered MLN9708, as well as alternative 
etiologies, as a possible cause (1 each Grade 3 reversible: depressed level of consciousness, 
pneumonitis, pneumonia, rash, and ileus; 2 each Grade 3 reversible: fatigue and dehydration; 
1 Grade 2 shingles, 1 Grade 4 elevated creatinine).
During enrollment in the expansion cohort of Study C16001 (dosing at 1.76 mg/m2), 
1 patient (among 44 patients treated as of 24 September 2010) has experienced acute renal 
failure (NCI CTCAE [version 3.0] Grade 4 increased creatinine). Both cases of acute renal 
failure reported to date (the other patient was treated at the 2.34 mg/m2 dose level) share the 
following features: (1) a pre-existing kidney condition (status post nephrectomy due to 
kidney cancer and prior hydronephrosis due to disease progression); (2) prior exposure to 
other antineoplastic drugs associated with nephrotoxic potential; (3) diarrhea and/or poor 
oral intake; (4) use of nonsteroidal antiinflammatory drugs during the 24 to 48 hours before 
the onset of the AE; (5) the event occurred after a total of 4 doses of study drug had been 
administered (1 patient received all 4 doses within Cycle 1, while the second patient 
received them over the course of 2 treatment cycles); and (6) concomitant with event, the 
patient experienced thrombocytopenia.
One patient in Study C16001 received a dose of MLN9708 higher than was planned per 
protocol. The patient’s dose was calculated based on pounds when the reported weight was 
actually in kilograms, this resulted in the patient twice receiving a dose of MLN9708 
approximately 46% higher than was intended per the protocol. The patient experienced 
Grade 4 thrombocytopenia (nadir 22 k/uL), some liver function elevations, but no other 
issues including no elevation in creatinine. All laboratory abnormalities resolved 8 days after 
the overdose.
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Additional trials are planned or recently started enrollment, each of which will use the oral 
formulation of MLN9708 (Study C16005, PO weekly MLN9708 added to lenalidomide and 
dexamethasone in a 28 day cycle in patients with NDMM; Study C16006, phase 1/2, PO 
MLN9708 added to melphalan and prednisone in patients with newly diagnosed multiple 
myeloma [NDMM]; Study C16008, PO twice weekly administration in combination with 
lenalidomide and low-dose dexamethasone in adult patients with NDMM requiring systemic 
treatment every 21 days; and Study C16009, phase 1 study of oral MLN9708 to assess drug-
drug interaction with ketoconazole, relative bioavailability, food effect, and safety and 
tolerability in patients with advanced nonhematologic malignancies or lymphoma).
The emerging safety profile indicates that MLN9708 is generally well tolerated with 
manageable and reversible treatment-emergent adverse events (TEAEs) or adverse 
reactions. The most common treatment-related adverse drug reactions reported with 
MLN9708 use pooled from the 4 phase 1 early human studies (including both IV and oral 
formulations) include thrombocytopenia and maculopapular rash, with or without pruritus.
Other treatment-emergent side effects reported across these studies, which may have been 
due to either the patient’s disease of MLN9708 include nausea, vomiting, diarrhea, 
constipation, dehydration, anorexia, fatigue, anemia, fever, abdominal pain, peripheral 
edema, cough, headache, and insomnia. The most frequent (> 10%) TEAEs of any grade 
reported across the 2 phase 1 studies using the oral formulation, C16003 and C16004, 
irrespective of causality to MLN9708, include fatigue (44%), diarrhea (26%), nausea and 
anemia (19% each), cough (15%), and dyspnea (11%). Please refer to the IB and Safety 
Management Attachment for further details. The most frequent AEs were anticipated based 
on preclinical data and previous experience with VELCADE and are noted in the current IB, 
the Safety Management Attachment, and the informed consent documents. While the 
potential toxicities may be severe, they are managed by appropriate clinical monitoring and
standard medical interventions.
While safety, PK and pharmacodynamic objectives are the primary focus of the 4 phase 1 
studies currently enrolling patients, preliminary assessments of disease response are also 
being evaluated. The most common preliminary observation of response in these heavily-
pretreated patients (n 112 as of 24 September 2010) is stabilization of the underlying 
disease: 6 patients with various nonhematologic malignancies in Study C16001 which uses 
the IV formulation, including reported tumor reductions of 18and 22in 2 patients with 
renal cell carcinoma; 2 patients with lymphoma in Study C16002 which uses the IV 
formulation, including 1 patient with a reported 44reduction in tumor; and 2 patients with 
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relapsed/refractory MM in Study C16004 dosing oral MLN9708 weekly. In patients with 
relapsed or refractory MM in Study C16003, oral dosing twice-weekly, there has been 1 PR 
in a patient with relapsed disease after VELCADE treatment and 6 patients reported to have 
stable disease. The MTD has been established only in Study C16001 with dose-escalation 
continuing in the 3 other studies. Based on the proven utility of VELCADE in the treatment 
of MM and MCL and MLN9708’s increased tissue distribution as well as activity in several 
xenografts models, it is anticipated that MLN9708 directed against the same components of 
the ubiquitin-proteasome system (UPS) will prove efficacious in the treatment of similar if 
not additional malignancies.
1.3.1 Pharmacokinetics and Pharmacodynamics
MLN9708 completely hydrolyzes to the boronic acid MLN2238 in aqueous solutions.
MLN2238 is the only form of MLN9708 measurable in plasma or urine.
Based on preliminary clinical data from the first-in-human study of MLN9708 (C16001), 
following IV administration of MLN9708, MLN 2238 shows multi-exponential plasma 
disposition, characterized by a rapid initial disposition phase (t1/2 of < 0.25 hours), 1 or more 
intermediate disposition phases, and a slow terminal disposition phase (t1/2 of > 4 days). The 
Day 1 and Day 11 extrapolated immediate post-IV bolus plasma concentration of MLN2238 
(C0) and AUC show proportional increases with increasing dose. There is accumulation of 
MLN2238 with multiple dosing; AUCtau following the Day 11 dose of MLN9708 is an 
approximately 4-fold accumulation of MLN9708 by Day 11 on the biweekly schedule.
The pharmacodynamic effect being evaluated in the development of MLN9708 is red cell 
proteasome inhibition as measured by whole blood 20S proteasome activity. Based on 
preliminary clinical data from study C16001, following IV administration of MLN9708, 
maximum whole blood 20S proteasome inhibition occurs at the earliest sampled time points 
(0.8 or 0.25 hours) and increases with increasing dose over the dose range studied. Inhibition 
is short-lived (approximately 4 hours) following the Day 1 dose but is prolonged following 
the Day 11 dose.
Further details on these studies are provided in the IB.
1.4
Study Rationale
Amyloidosis is a protein conformational disease due to a clonal plasma cell dyscrasia that is
related to multiple myeloma.(45) Aggregation of normally soluble proteins into insoluble ß-
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sheet fibrils are deposited into target tissues causing progressive organ dysfunction that 
leads to organ failure and death. The neoplastic plasma cells that cause amyloidosis suffer 
from proteotoxicity resulting in an imbalance in the ubiquitin proteasome system and thus 
may be particular sensitive to proteasome inhibition.(40) VELCADE has validated the 
proteasome as a therapeutic target for hematologic malignancies, where it is now indicated 
in the treatment of multiple myeloma and mantle cell lymphoma. Recognizing that 
proteasome inhibition is an effective anticancer therapeutic approach, Millennium has 
developed MLN9708, a small-molecule, orally bioavailable 20S proteasome inhibitor, with 
the aim of improving the pharmacology of the agent thereby building on the efficacy seen 
with VELCADE, while improving drug administration. This study is proposed based on the 
results of VELCADE in previously treated amyloidosis(51) and the urgent need for better 
treatment options for this rare disease, especially in the relapsed setting where no standard 
treatment exists.
The purpose of this study is to determine the safety, MTD, and recommended phase 2 dose 
(RP2D) of MLN9708 treatment in patients with AL amyloidosis who have relapsed or 
experienced progressive disease (PD) despite prior therapy. The study will also include 
hematologic and organ efficacy assessments.
Given that AL amyloidosis can present in a variety of organs yet the most objective organ 
response criteria involve AL amyloidosis that affects the kidney and heart, patients eligible 
for this study must have amyloid involvement of at least one of those organs. Patients may 
present with amyloidosis involvement of additional organ systems, for example liver/ 
gastrointestinal and autonomic/ peripheral nervous system, but they must also have either 
kidney and/or heart involvement. However, patients with the poorest prognosis of cardiac 
status are excluded in order to ensure a comprehensive characterization of the safety profile 
and activity of MLN9708 in AL amyloidosis.
Further, because no approved therapy exists for patients with AL amyloidosis, experts, 
including the NCCN,(13) recommend treatment of patients on clinical studies. At relapse, 
given the limited treatment options, patients seek subsequent treatment even if it means 
exposure to an agent from the same drug class. MLN9708 is structurally similar to the first 
in class proteasome inhibitor VELCADE, which in some parts of the world is used to treat 
AL amyloidosis. It is unlikely that there will be significant differences in safety, based on 
the emerging safety data from ongoing Phase 1 studies in patients with relapsed or refractory 
multiple myeloma who have been previously treated with proteasome inhibitors, however 
there may be differences in activity. Therefore, patients are eligible regardless of prior 
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exposure to proteasome inhibition therapy in the dose escalation phase. Once the 
MTD/RP2D has been established, separate enrollment will begin for 2 expansion cohorts, 
(one for patients that are proteasome inhibitor-naïve and one for patients who have been 
exposed to proteasome-inhibitor therapy) in order to better understand the potential activity 
of MLN9708 in this patient population.
1.5
Rationale MLN9708 Dose and Schedule Selection
The schedule of MLN9708 is based on results of single-agent VELCADE from Reece, et 
al(51) where the hematologic response rate, duration of response, and organ response rate 
were similar between the weekly and twice-weekly schedules, but the toxicity appeared 
lower with the weekly dosing. The estimated safe starting dose of MLN9708 will be selected 
from the dose-escalation portion of the C16004 study, a phase 1 study of weekly dosing in 
patients with relapsed and refractory multiple myeloma. The starting dose will be at least 
1 dose level below the C16004 MTD if it has been reached by the time this study starts, and 
if not, then a dose level completed without reported DLTs when MLN9708 is administered 
weekly as a single agent (Section 1.3).
A population PK analysis was performed for MLN9708 to assess the feasibility of switching 
from body surface area (BSA)-based dosing to flat dosing. A population PK model was built 
using nonlinear mixed effects modeling in NONMEM VII software compiled with the Intel 
Fortran 9.2 compiler. Data from both the twice weekly and once weekly IV dosing regimens
were used in the analysis (N = 42). Population PK analysis showed that MLN9708 PK can 
be well described by a 3-compartment model with linear elimination. Race, sex, BSA, and/
or body weight do not appear to significantly affect clearance (CL) and volume of 
distribution (V1) in the central compartment. Clearance and volume of distribution in the 
central compartment are the PK parameters that will affect AUC and Cmax, respectively. CL 
and V1 are primary parameters that are independent of the route of administration of drug.
Therefore, BSA is not expected to affect Cmax or AUC after oral dosing, and thus flat dosing 
is appropriate for both oral and IV routes of administration.
1.6
Rationale for Collection of PK and Pharmacodynamic Samples
A limited number of PK and pharmacodynamic samples will be collected so that the PK and 
pharmacodynamics of MLN9708 can be characterized in this population. This evaluation is 
being undertaken to assess if chronic organ injury caused by amyloidosis affects the 
absorption or systemic disposition of MLN9708 and to assess if the disease state alters the 
whole blood pharmacodynamic effect of MN9708 treatment.
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1.7
Rationale for Tumor Biomarker Assessment
1.8
Potential Risks and Benefits
MLN9708 is a modified dipeptide boronic acid proteasome inhibitor similar to VELCADE, 
which has a known safety profile. The most frequent AEs reported to date in the ongoing 
MLN9708 phase 1 studies were anticipated based on preclinical data and previous 
experience with VELCADE, and are noted in the IB, the Safety Management Attachment, 
and the informed consent documents. However, it is possible that MLN9708 will have 
toxicities that were not previously observed in or predicted from such sources. Patients will 
be monitored closely for anticipated toxicities.
This study will be conducted in compliance with the protocol, good clinical practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines.
2. STUDY OBJECTIVES
2.1
Primary Objectives
!
To determine the safety, tolerability, and MTD of oral MLN9708 administered 
weekly in patients with previously treated relapsed/refractory AL amyloidosis
!
To determine the RP2D of oral MLN9708 administered weekly
CCI
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2.2
Secondary Objectives
!
To characterize the plasma PK and whole blood pharmacodynamic effect of 
MLN9708 in this patient population 
!
To assess the rate of organ response and organ improvement according to 
standardized criteria
!
To assess overall hematologic response rate (complete response [CR], very good 
partial response [VGPR], and partial response [PR]) 
!
To assess time to hematologic and organ response, respectively
!
To assess duration of hematologic and organ response, respectively
!
To determine time to hematologic and organ disease progression, respectively
!
To assess hematologic and organ disease progression free survival (PFS)
!
To assess overall survival including 1-year survival rate
2.3
Exploratory Objectives
CCI
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3. STUDY ENDPOINTS
3.1
Primary Endpoints
The primary endpoints include:

AEs, SAEs, assessments of clinical laboratory values, and neurotoxicity grading 
of oral MLN9708 administered once weekly in a 28-day cycle

MTD and RP2D of oral MLN9708 based on both toxicity and efficacy outcomes 
as above
3.2
Secondary Endpoints
The secondary endpoints include:

Single- (MTD cohort) and multiple-dose plasma PK after oral MLN9708

Whole blood 20S proteasome activity profile and inhibition parameters of 
multiple-dose oral MLN9708

Organ response and organ improvement according to standardized criteria 

Overall hematologic CR + VGPR + PR 

Time to organ or hematologic response, measured as the time from the first dose 
of MLN9708 to the date of first documentation of a confirmed organ or 
hematologic response, respectively

Duration of organ or hematologic response, measured as the time from the date 
of first documentation of a confirmed organ or hematologic response to the date 
of confirmed organ or hematologic disease progression, respectively

Time to organ and hematologic progression, measured as the time from the date 
of the first dose of MLN9708 to the date of first documented organ or
hematologic disease progression

Organ and hematologic disease PFS, defined as the time from the date of the first 
dose of MLN9708 to the date of confirmed organ or hematologic disease 
progression or death, respectively.
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!
One-year survival, defined as the patient survival probability at 1 year after the 
date of first dose of MLN9708
3.3
Exploratory Endpoints
4. STUDY DESIGN 
4.1
Overview of Study Design
This is a phase 1, open-label, multicenter clinical study using the oral formulation of 
MLN9708 in patients with previously treated systemic AL amyloidosis who require further 
therapy. As many as 30 patients will be enrolled in the dose-escalation portion of the study, 
and as many as 20 patients will be enrolled in the expansion cohorts. Overall, as many as 50 
patients will be enrolled.
The dose-escalation portion of the study will be aimed at determining the safety profile and 
the MTD/RP2D of MLN9708 administered weekly in patients with previously treated AL 
amyloidosis. Patients will receive escalating doses of MLN9708 PO on Days 1, 8, and 15 in 
a 28-day cycle in the absence of disease progression or unacceptable toxicity.
Once the MTD/RP2D has been established, 2 expansion cohorts of patients with relapsed or 
refractory amyloidosis, including approximately 10 proteasome inhibitor-naïve patients and 
approximately 16 proteasome inhibitor-exposed patients, will be treated at the MTD/RP2D 
to more fully characterize the safety, tolerability, and efficacy of MLN9708, and the PK and 
CCI
Property of Takeda: For non-commercial use only an
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pharmacodynamics of MLN9708 in this patient population. As many as 30 patients will be 
enrolled in the dose-escalation portion of the study, and as many as 20 additional patients 
(26 in total, including 6 patients from the dose-escalation portion) will be enrolled in the 
expansion cohorts.
The estimated safe starting dose of MLN9708 will be selected from the dose-escalation 
portion of the C16004 study, an ongoing phase 1 study of weekly dosing in patients with 
relapsed and refractory multiple myeloma. The starting dose will be at least 1 dose level 
below the C16004 MTD if it has been reached by the time this study starts, and if not, then a 
dose level completed without documented DLTs.
A 3 + 3 dose-escalation scheme will be implemented and dose intervals will follow those 
outlined in Section 6.4. Although DLTs may occur at any point during treatment, only DLTs 
occurring during Cycle 1 of treatment in the phase 1 portion will necessarily influence 
decisions regarding dose-escalation, expansion of a dose level, or evaluation of intermediate 
dose levels. In the context of emerging clinical data of single-agent MLN9708, dose-
escalation of MLN9708 will continue until the MTD has been identified or a maximum 
planned dose (MPD) is determined to be safe. Based on experience with other drugs in this 
condition, it is considered unlikely that patients with systemic AL amyloidosis will tolerate 
doses higher than those tolerated in other diseases, such as multiple myeloma. Therefore, the 
maximum dose in patients with systemic AL amyloidosis may be the MTD as recommended 
from the phase 1 single-agent study of weekly MLN9708 in relapsed/refractory multiple 
myeloma (C16004). For treatment Cycle 2 and beyond, doses of MLN9708 may be held or 
reduced in an attempt to manage toxicity according to the guidelines outlined in Section 6.6.
More conservative dose-escalation, evaluation of alternative dosing, 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 MLN9708.
Treatment repeats every 28 days for 3 cycles. If there is no hematologic response (PR, 
VGPR, or CR) after completion of 3 cycles of single-agent MLN9708, dexamethasone will 
be added at the initially recommended dose of 40 mg on Days 1 to 4 of every cycle (d1-4 
q28days), beginning in Cycle 4. For patients with fluid retention > 3% of body weight 
despite optimal diuretic therapy, a starting dose of dexamethasone 20 mg should be 
considered. The patient’s response status will be reassessed after 3 additional cycles; if there 
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is no hematologic response at that time, the patient will be removed from treatment and 
followed for survival.
If there is response with MLN9708 alone or dexamethasone and MLN9708, the patient may 
continue on study for up to 12 cycles of treatment in the absence of PD. Study treatment 
beyond 12 cycles is allowed only if clinical benefit is clearly indicated after a discussion 
between the Millennium clinician and the investigator treating the patient.
Radiological evaluations and serial blood/urine samples will be employed to assess the 
status of the patient’s amyloidosis. An evaluation of disease response using standardized 
criteria (53, 54) will be performed after each cycle during treatment and then at regular 
intervals during follow-up.
If patients are removed from treatment for unacceptable toxicity or reasons other than PD, 
they will continue in PFS follow-up until documented disease progression or the initiation of 
subsequent antineoplastic therapy. Once a patient experiences PD or starts subsequent 
antineoplastic therapy, they will proceed to the OS follow-up phase.
4.2
Number of Patients
As many as 50 patients will be enrolled in this study. As many as 30 patients will be 
enrolled in the dose-escalation portion of the study. Because approximately 6 patients in the 
dose-escalation part of the study will be included in the expansion cohort, approximately 20 
patients will be enrolled in the expansion part of this study after taking the dropout rate into 
consideration. Patients will be enrolled from approximately 10 centers in North America and 
Europe. Enrollment is defined as the time the patient receives the first dose of any study 
drug.
4.3
Duration of Study
The duration of enrollment will be approximately 24 months.
Patients who have a response to treatment may remain on treatment for a maximum of 
12 cycles or until the occurrence of PD or unacceptable toxicity, whichever occurs first.
Patients who stop treatment for any reason other than disease progression will continue in 
PFS follow-up and be seen every 6 weeks until documented disease progression. After 
disease progression, all patients will continue to the OS follow-up part of the study and will 
be contacted every 12 weeks.
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Delayed treatment-related AEs will be followed for 30 days after last dose of study drug or 
until initiation of subsequent antineoplastic therapy. The analyses for the clinical study 
report will be conducted after 75% of patients have PD or 12 months after last patient is 
enrolled, whichever occurs first in the study.
It is anticipated that this study will last for approximately 84 months. The duration of 
follow-up for overall survival will be 60 months after the last patient enters the study.
Treatment may be continued in this study or in a MLN9708 rollover study, if and when such 
a study is made available, upon request by the investigator and agreement by the project 
clinician.
5. STUDY POPULATION
Adult patients with biopsy-proven systemic AL amyloidosis with relapsed or progressive 
disease despite prior therapy will be enrolled.
5.1
Inclusion Criteria
1. Male or female patients 18 years or older.
2. Histologic diagnosis of AL amyloidosis, confirmed by pathology-positive Congo red 
stain with green birefringence on polarized light microscopy, with evidence of 
measurable clonal disease according to standardized criteria(54, 55, 56) that requires active 
treatment (see Section 15.2 for amyloid typing).
3. Patients will have a measurable disease as defined by serum differential free light chain 
concentration (dFLC, difference between amyloid forming and nonamyloid forming free 
light chain [FLC]) 40 mg/L.
4. Percentage of plasma cells < 30% in the bone marrow aspirate and biopsy.
5. Patients must have objective, measurable major organ (heart or kidney) involvement.
a.
renal: albuminuria higher than 0.5 g/day in 24-hour urine analysis.
b. cardiac: involvement is defined as the presence of a mean left ventricular wall 
thickness on echocardiogrammore than 12 mm in the absence of a history of 
hypertension or valvular heart disease, or unexplained low voltage (< 0.5 mV) on 
electrocardiogram; or NT-proBNP > 332 ng/L in the absence of renal failure 
(estimated glomerular filtration rate [eGFR] < 45 mL/min/1.73 m2).
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In addition, patients can also have amyloidosis organ involvement in such organ systems as 
liver/GI tract, peripheral nerves, or soft tissue. Skin purpura, carpal tunnel syndrome, or the 
presence of vascular amyloid on a bone marrow biopsy alone are not sufficient to meet 
criteria for “symptomatic organ involvement”. Patient may present with any of the 
following amyloid-related organ involvement as defined below:
a.
hepatic: hepatomegaly onphysical examination with alkaline phosphatase > 1.5 the 
upper limit of normal (ULN).
b. gastrointestinal: direct biopsy verification of amyloid involvement with symptoms 
such as gastrointestinal bleeding (confirmed by tissue biopsy) or diarrhea (at least 4 
stools per day). A positive GI biopsy change is not sufficient.
c.
autonomic or peripheral neuropathy: based on clinical history, autonomic 
dysfunction with orthostasis, symptoms of nausea or dysgeusia, gastric atony by 
gastric emptying scan, diarrhea or constipation, or abnormal sensory and/or motor
findings on neurologic examination.
d. soft tissue and lymphatic: based on physical examination findings (macroglossia, 
shoulder pad sign, raccoon eyes, carpal tunnel syndrome, synovial enlargement, or 
firm enlarged lymph nodes) or biopsy.
6. AL Amyloidosis Risk stage I or II disease.
Staging system defined by: NT-proBNP cut off of < 332 pg/mL and troponin T cut-off 
of 0.035 ng/mL as thresholds: Stage I, both under threshold; Stage II, either troponin or 
NT-proBNP [but not both] over threshold; if troponin T not available at local institution, 
troponin I may be used, but threshold is < 0.1 ng/mL.(57)
7. Must be relapsed or refractory after at least 1 prior therapy for AL amyloidosis and, in 
the investigator’s opinion, requires further treatment.
NOTE:
If a patient has received a transplant as his/her first therapy, he/she must be at 
least 3 months posttransplantation and recovered from the side effects of the 
stem cell transplant.
Any patient who was not a candidate for high-dose therapy and was unable to 
tolerate an alkylating agent plus a corticosteroid (eg, melphalan plus 
prednisone) or patients who are intolerant to an alternative prior therapy after 
receiving at least 1 cycle of such therapy because of severe adverse events 
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(eg, hypersensitivity reaction) also can be considered for enrollment after 
discussion with the Millennium clinician.
8. Patients must have an Eastern Cooperative Oncology Group (ECOG) status of 0 to 2 
(see Section15.3)
9. Clinical laboratory values as specified below within 3 days before the first dose of study 
drug (unless otherwise noted):
a.
echocardiographic ejection fraction 40% within 28 days before the first 
dose of study drug.
b. platelet count 75 109/L.
c.
neutrophil count 1.0 109/L.
d. total bilirubin 1.5 ULN.
e.
alkaline phosphatase 5 ULN.
f.
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
3 ULN.
g. eGFR 45 mL/min/1.73 m2 (see Section 15.1 for the Equation to Estimate 
Glomerular Filtration Rates).
10. Female patients who:

Are postmenopausal for at least 1 year before the screening visit, OR

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 30 days after the last dose of study drug, or agree to 
completely abstain from heterosexual intercourse.
11. Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study 
treatment period and through 4 months after the last dose of study drug, OR

Agree to completely abstain from heterosexual intercourse.
12. Voluntary written consent must be given before performance of any study-related 
procedure not part of standard medical care with the understanding that consent may be 
withdrawn by the patient at any time without prejudice to future medical care.
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5.2
Exclusion Criteria
1. Known allergy to any of the study medications, their analogues, or excipients in the 
various formulations.
2. Treatment with any investigational products within 28 days before the first dose of study 
drug.
3. Requirement for other concomitant chemotherapy, immunotherapy, radiotherapy, or any 
ancillary therapy considered to be investigational.
4. Failure to have fully recovered (ie, Grade 1 toxicity) from the effects of prior 
chemotherapy regardless of the interval since last treatment.
5. Cardiac system:
a.
QTc > 470 milliseconds (msec) on a 12 lead ECG obtained during the Screening 
period. If a machine reading is above this value, the ECG should be reviewed by 
a qualified reader and confirmed on a subsequent ECG.
b. AL Amyloidosis Risk Stage III disease. Staging defined by: NT-proBNP cut off 
of < 332 pg/mL and troponin T cut-off of 0.035 ng/mL as thresholds: stage III, 
both over threshold; if troponin T not available at local institution, troponin I 
may be used, but threshold is < 0.1 ng/mL(57)
c.
New York Heart Association (NYHA) classification III or IV. See Section 15.4
for criteria.
d. Enzyme-documented myocardial infarction within 6 months before enrollment.
e.
Chronic atrial fibrillation.
f.
Grade 2 or 3 atrioventricular (AV) block (Mobitz, Type I permitted).
g. Sustained (> 30 seconds) ventricular tachycardia, more than 1 episode of 
nonsustained ventricular tachycardia (defined as 3 consecutive ventricular beats), 
or frequent (> 20/24 hours) ventricular pairs, detected by 24-hour ambulatory 
electrocardiographic monitoring.
h. Supine systolic blood pressure < 90 mmHg, or symptomatic orthostatic 
hypotension, or a decrease in systolic blood pressure on standing of > 20 mm Hg 
in spite of being treated for orthostatic hypotension.
i.
History of a bleeding diathesis or currently receiving treatment with warfarin.
Patients are allowed to take aspirin.
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7. GI system:
a.
Severe diarrhea (≥ Grade 3) not controllable with medication (such as octreotide) 
or requires administration of total parenteral nutrition.
b. Known GI disease or GI procedure that could interfere with the oral absorption 
or tolerance of study drug, including difficulty swallowing.
8. Neurologic/ Social system:
a.
Patients with Grade 2 peripheral neuropathy or painful peripheral neuropathy 
on clinical examination will be excluded.
b. Previous or ongoing psychiatric illness and/or social situations that would limit 
compliance with study requirements.
9. Systemic infections:
a.
Known to be human immunodeficiency virus (HIV)-positive.
b. Known to be hepatitis B surface antigen-positive or has known or suspected 
active hepatitis C infection.
c.
Uncontrolled infection requiring systemic antibiotics.
10. Other malignant disease/s:
a.
Clinically overt multiple myeloma (bone marrow plasma cells ≥ 30%), and at 
least 1 of the following: bone lesions, anemia (< 100 g/L), and hypercalcemia.
b. Patients with amyloidosis due to mutations of the transthyretin gene (see Section
15.2).
c.
Patients with non-AL amyloidosis (see Section 15.2).
d. Presence of other active malignancy with the exception of nonmelanoma skin 
cancer, cervical cancer, treated early-stage prostate cancer provided that prostate-
specific antigen is within normal limit, or any completely resected carcinoma in 
situ.
11. Female patients who are lactating or pregnant.
12. Major surgery within 14 days before the first dose of study drug.
13. Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, 
ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, 
voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers 
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(rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of 
Ginkgo biloba or St. John’s wort within 14 days before the first dose of study treatment.
14. Any other serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol.
6. DESCRIPTION OF TREATMENT
6.1
Study Drug
The study drug will be administered at the Amyloidosis Research and Treatment Center.
The treatment schedule for each patient will be provided to the Intensive Care Department at 
least 1 week before commencing each treatment cycle. The Intensive Care Unit will grant 
availability on the days of MLN9708 administration, in the event that any adverse events 
occur that require emergency or intensive care.
All protocol-specific criteria for administration of study drug must be met and documented 
prior to drug administration. Study drug will be administered only to eligible patients under 
the supervision of the investigator or identified subinvestigator(s). Patients should be
monitored for toxicity as necessary and doses of MLN9708 should be modified as needed to
accommodate patient tolerance to treatment; this may include symptomatic treatment, dose
interruptions and adjustments of MLN9708 dose. All doses must be taken as outlined in the 
Schedule of Events. No doses should be missed or delayed during Cycle 1 due to patient 
scheduling. Following agreement between the investigator and the sponsor, eligible patients 
may take study drug at home as directed.
Refer to Study Manual for additional instructions regarding study drug administration.
MLN9708 Administration
The study drug should be taken on an empty stomach, at least 1 hour before or no sooner 
than 2 hours after a meal. The capsules should not be chewed, broken, or opened for 
administration. Each capsule should be swallowed separately with approximately 240 mL 
(ie, 8 oz) total of water with the full dose. MLN9708 will be given as a single daily oral 
dose. The dose will be assigned based on the dose-escalation methodology outlined in Table 
6-1. Administration of the capsules may be guided by the dosing tables included in the 
pharmacy manual.
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The prescribed administration of MLN9708 doses in this study is weekly x 3 followed by 
1 week without MLN9708 in a 28-day cycle. Missed doses can be taken as soon as the 
patient remembers as long as the next scheduled dose is 70-72 hours or more away. Patients 
who vomit after ingestion will not receive an additional dose, but should resume dosing at 
the time of the next scheduled dose.
Dexamethasone Administration
If a patient does not have a response after 3 cycles of MLN9708 treatment, dexamethasone 
will be added. Dexamethasone will be given as a single, oral dose of 40 mg/day on Days 1 
through 4 of a 28-day cycle beginning with Cycle 4. For patients with fluid retention > 3% 
of body weight despite optimal diuretic therapy a starting dose of dexamethasone 20 mg 
should be considered.
Dexamethasone should be taken at approximately the same time each day. Dexamethasone 
should be taken approximately 1 hour after MLN9708. Each dose of dexamethasone should 
be taken with food or milk.
If a dose of dexamethasone is missed, the dose should be taken as soon as the patient 
remembers it. A double dose should not be taken to make up for a missed dose. If the patient 
vomits after taking a dose, the patient should not repeat the dose but should resume dosing at 
the time of the next scheduled dose.
6.2
Reference/Control Therapy
There is no reference group in this study.
6.3
Definitions of Dose-Limiting Toxicity (DLT) 
6.3.1 DLT Definitions
Although DLTs may occur at any point during treatment, only DLTs occurring during 
Cycle 1 of treatment must influence decisions regarding dose-escalation, expansion of a 
dose level, or evaluation of intermediate dose levels. However, DLTs occurring in later 
cycles may be taken into consideration for dose-escalation decisions, at the discretion of the 
investigators and sponsors.
Toxicity will be evaluated according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), version 4.03.(58) Toxicity will be evaluated 
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according to the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE), version 4.03.(58) DLT will be defined as any of the following AEs 
that are considered by the investigator to be even possibly related to therapy with 
MLN9708:

Any Grade 4 thrombocytopenia (platelets < 25, 000/mm3) lasting at least 
7 days.

Grade 3 thrombocytopenia with clinically significant bleeding, where 
clinically significant bleeding is defined as a blood loss of > 100 cc or the 
requirement for a RBC transfusion.

A platelet count 10,000/mm3.

Any Grade 4 neutropenia (ANC < 500/mm3) lasting at least 7 days or 
Grade 3 febrile neutropenia with fever and/or infection where fever is 
defined as a temperature 38.5oC.

Grade 2 peripheral neuropathy with pain or Grade 3 or greater peripheral 
toxicity.

Any Grade 3 or higher nonhematologic toxicity (in particular, worsening 
neuropathy, diarrhea despite maximal supportive therapy, life-threatening 
ventricular arrhythmia or atrial arrhythmia with hemodynamic instability, 
fluid retention that does not resolve with 3 or 4 days of intravenous 
diuretic therapy and bedrest, symptomatic congestive heart failure, and 
hypotension); with the following exceptions: Grade 3 arthralgia/ myalgia 
and brief (< 1 week) Grade 3 fatigue.

Grade 3 or greater nausea and/or emesis despite the use of optimal anti-
emetic prophylaxis. Optimal anti-emetic prophylaxis is defined as an anti-
emetic regimen than employs 5-HT3 antagonist given according to 
standard practice.

A delay of more than 2 weeks in the initiation of Cycle 2 of treatment 
because of a lack of adequate recovery of MLN9708-related 
hematological or nonhematologic toxicities.
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
Other MLN9708-related nonhematologic toxicities Grade 2 or greater 
that, in the opinion of the investigator, requires discontinuation of therapy 
with MLN9708.
Patients who do not receive all doses of MLN9708 in Cycle 1 for reasons other than DLTs 
will be replaced within the cohort. Patients who receive all doses of MLN9708, yet for 
unforeseen circumstances recovery of toxicity is not available and safety in Cycle 1 cannot 
be fully evaluated may be replaced within the cohort.
6.4
Dose-escalation Rules
The dose intervals will follow the 3+3 traditional escalation rules, starting with the treatment 
of 3 patients at a planned dose level:
1. If 0 of 3 patients experiences DLT, dose-escalation will proceed to the next higher 
dose level at which 3 patients will be enrolled.
2. If 1 of 3 patients experiences DLT, 3 more patients will be enrolled at that same dose 
level.
3. Escalation will continue if 1 of 6 patients experiences DLT.
4. If 2 or more patients in any dose level experience DLT, dosing will stop, and the 
previous dose level may be considered the MTD or an alternative dose between this 
dose level and the previous dose level might be further explored.
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Figure 6-1
Dose-escalation Algorithm
1 has DLT
Enter 3
0 have DLT
2-3 have DLT
Escalate to 
next dose
Enter 3 at 
same dose
1of 6 have DLT
1 of 6 has DLT
STOP: 
Current dose = MTD
STOP: 
previous dose = MTD
Enter 3 at 
previous  dose
1 of 6 has DLT
1 of 6 have DLT
6 at previous dose level ?
Yes
No
Planned Dose Levels of MLN9708
The estimated safe starting dose of MLN9708 was selected from the dose-escalation portion 
of the C16004 study, a phase 1 study of weekly dosing in patients with relapsed and 
refractory multiple myeloma. The starting dose for Study C16007 was to be either at least 1 
dose level below the MTD from Study C16004 if it had been determined and, if not, then a 
dose level completed without DLTs. The starting dose of 4.0 mg (flat dose) is dose level 2 as 
seen in Table 6-1. This dose represents a dose completed without reported DLTs in Study 
C16004 since the MTD has not been determined in that study.
A population PK analysis was performed for MLN9708 to assess the feasibility of switching 
from BSA-based dosing to flat dosing. A population PK model was built using nonlinear 
mixed effects modeling in NONMEM VII software compiled with the Intel Fortran 9.2 
compiler. Data from both the twice weekly and once weekly IV dosing regimens were used 
in the analysis (N = 42). Population PK analysis showed that MLN9708 PK can be well 
described by a 3-compartment model with linear elimination. Race, sex, BSA, and/or body 
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weight do not appear to significantly affect clearance (CL) and volume of distribution (V1) 
in the central compartment. Clearance and volume of distribution in the central compartment 
are the PK parameters that will affect AUC and Cmax, respectively. CL and V1 are primary 
parameters that are independent of the route of administration of drug. Therefore, BSA is 
not expected to affect Cmax or AUC after oral dosing, and thus flat dosing is appropriate for 
both oral and IV routes of administration.
The planned dose levels of MLN9708 are shown in Table 6-1. The starting dose level in this 
study is Dose Level 2 (4.0 mg).
Table 6-1
Planned Dose Levels
Dose Level
Dose MLN9708 (mg)
1
3.0
2
4.0
3
5.5
4
7.0
5+
prior dose 1.33
Note: More conservative dose-escalation, evaluation of alternative 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 MLN9708. If emerging data from other MLN9708 phase 1 studies support it, 
consideration could be given to an alternative dosing schedule, eg, twice weekly, if such a measure is 
needed to better characterize safety and activity.
Note: The dose levels of MLN9708 shown in this table represent possible estimated doses planned in this 
study based on those already safely administered to patients treated to date in the C16004 study in which 
BSA dosing was used.
Based on experience with other drugs for this disease, it is considered unlikely that patients 
with systemic AL amyloidosis will tolerate doses higher than those tolerated in other 
diseases, such as multiple myeloma. Therefore, the MTD in patients with systemic 
AL amyloidosis may be the maximum dose as recommended from the phase 1 single-agent 
study of weekly MLN9708 in relapsed or refractory multiple myeloma (C16004).
More conservative dose-escalation, evaluation of alternative dosing, 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 MLN9708. If emerging data 
from other MLN9708 phase 1 studies support it, consideration could be given to an 
alternative dosing schedule, eg, twice weekly, if such a measure is needed to better 
characterize safety and activity.
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Recommendation of Phase 2 Dose
The RP2D estimation will be established following evaluation of the available data which 
will include, but is not limited to, toxicity characterization (Grade 3/4 AEs, SAEs, all grades 
peripheral neuropathy, and treatment discontinuation) with efficacy (hematologic and organ 
responses) also taken into consideration. The RP2D will require first cycle DLTs in not 
more than 0 in 3 or 1 in 6 DLT-evaluable patients enrolled in a single cohort. For the 
purpose of the RP2D estimation, Cycle 1 data from 6 evaluable patients will be used in 
addition to the available clinical data supporting tolerance over multiple treatment cycles.
AEs that meet DLT criteria in Cycle 2 and beyond will not necessarily influence dose-
escalation, but will be considered when determining the RP2D. Toxicities leading to dose 
modification in Cycle 2 and beyond will not necessarily influence dose-escalation, but will 
be considered when determining the RP2D.
Once the MTD/RP2D has been established, 2 expansion cohorts of patients with relapsed or 
refractory amyloidosis, including approximately 10 proteasome inhibitor-naïve patients and 
approximately 16 proteasome inhibitor-exposed patients, will be treated at the MTD/RP2D 
to more fully characterize the safety, tolerability, and efficacy of MLN9708, and the PK and 
pharmacodynamics of MLN9708 in this patient population. As many as 30 patients will be 
enrolled in the dose-escalation portion of the study, and as many as 20 additional patients 
(26 in total, including 6 patients from the dose-escalation portion) will be enrolled in the 
expansion cohorts.
6.5
Dose-Modification Guidelines
6.5.1 Dose-Modification Guidelines
During the study, the focus of the evaluations is on the assessment of toxicity to document 
the occurrence of DLT. Although DLTs may occur at any point during treatment, only DLTs 
occurring during Cycle 1 of treatment must influence decisions regarding dose-escalation, 
expansion of a dose level, or evaluation of intermediate dose levels. However, DLTs 
occurring in later cycles may be taken into consideration for dose-escalation decisions, at the 
discretion of the investigators and sponsors. Unless a DLT is documented to have occurred, 
no dose modification is allowed during Cycle 1. Dose-limiting toxicities (DLTs) are defined 
in Section 6.3.1. In the event that a patient experiences DLT during Cycle 1, treatment 
should be held and the event will be counted toward the assessment of MTD for the given 
cohort. Patients experiencing DLTs in Cycle 1 may be restarted following recovery from 
toxicity at the discretion of the investigator according to the guidelines provided in Section 
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6.5.2 and Section 6.6. If a decision is made to restart MLN9708 therapy following a DLT, 
the MLN9708 dose must be reduced 1 dose level.
The patient will be evaluated weekly for possible toxicities that may have occurred after the 
previous dose(s). Toxicities are to be assessed according to the NCI CTCAE, version 
4.03.(58) Prior to beginning the next cycle of treatment, refer to the guidelines in Sections 
6.5.2 and 6.6. Further clarification can be obtained in consultation with the Millennium 
clinician (or designee). If multiple toxicities are noted, the dose adjustments and/or delays 
should be made according to the most severe toxicity guidelines.
6.5.2 Criteria for Toxicity Recovery Before Beginning the Next Cycle of Treatment 
If a patient fails to meet the criteria outlined in the following sections for beginning the next 
cycle of treatment, initiation of the next cycle should be delayed for 1 week. At the end of 
that time, the patient should be re-evaluated to determine whether the criteria for retreatment 
have been met. If the start of the next cycle needs to be delayed for more than 2 weeks due 
to incomplete recovery from treatment-related toxicity, refer to the recommended dose 
modification guidelines provided in Section 6.6. The maximum delay before treatment 
should be discontinued will be 3 weeks (except in the case of investigator determined 
clinical benefit and discussion with the Millennium clinician).
NOTE: A delay of more than 2 weeks because of lack of adequate recovery of MLN9708-
related hematologic or nonhematologic toxicities occurring during Cycle 1 meets the 
criteria for a DLT in the given cohort (refer to Section 6.3). If the patient is to receive 
additional treatment despite a DLT, the dose of MLN9708 will be reduced by at least 
1 dose level (or by 33% if the patient is receiving the first dose level) upon resolution 
of toxicity (refer to Section 6.6).
6.5.2.1
Criteria for Hematologic and Nonhematologic Recovery 

Absolute neutrophil count (ANC) must be ≥ 1 109/L

Platelet count must be ≥ 75 109/L

All other nonhematologic toxicity (except for alopecia) must have 
resolved to ≤Grade 1 or to the patient’s baseline condition
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6.6
Criteria for Dose Modification (Delays, Reductions, and Discontinuations)
When possible, toxicities should be attributed to a specific study drug (MLN9708 or 
dexamethasone [as applicable]) so that dose modifications can be made rationally. If 
multiple toxicities are noted, the dose adjustments and/or delays should be made once per 
cycle according to the most severe toxicity guidelines.
6.6.1 MLN9708 Dose Adjustments for Hematologic Toxicity
Dosage adjustments for hematologic toxicity are outlined in Table 6-2.
Table 6-2
MLN9708 Dose Adjustments for Hematologic Toxicities
Criteria
Action
Within-Cycle Dose Modifications
If platelet count 30 109/L or ANC ≤ 0.75 109/L 
on a MLN9708 dosing day (other than Day 
1)
MLN9708 dose should be withheld. Complete blood 
count (CBC) with differential should be 
repeated at least every other day until the 
ANC and/or platelet counts have exceeded 
the prespecified values (see Section 6.5.2.1) 
on at least 2 occasions. In the event CBC 
cannot be repeated at least every other day, 
dose modifications should be made in 
consultation with sponsor. Upon recovery, 
MLN9708 may be reinitiated with 1 dose 
level reduction or by 33% if the patient is 
receiving the first dose level.
Dose Modifications for Subsequent Treatment 
Cycles
Delay of > 2 weeks in the start of a subsequent cycle 
due to lack of toxicity recovery as defined in 
Section 6.5.2:
-
ANC < 1.0 109/L, platelet count < 75 109/L, 
or other nonhematologic toxicities > Grade 1 or 
not to the patient’s baseline condition
- Hold MLN9708 until resolution as per criteria 
Section 6.5.2.
- Reduce MLN9708 1 dose level or 33% if the 
patient is receiving the first dose level.
- The maximum delay before treatment should be 
discontinued (except in the case of investigator 
determined clinical benefit and discussion with the 
Millennium clinician) will be 3 weeks.
Dose Modifications for Subsequent Treatment 
Cycles
All hematologic toxicities
For hematologic toxicity that occurs during a cycle 
but recover in time for the start of the next 
cycle, a dose level reduction will be made 
either based on within-cycle or for 
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Table 6-2
MLN9708 Dose Adjustments for Hematologic Toxicities
Criteria
Action
subsequent cycle criteria, but not for both 
from the same cycle.
6.6.2 MLN9708 Dose Adjustments for Nonhematologic Toxicity
Dosage adjustments for nonhematologic toxicity are outlined in Table 6-3.
Table 6-3
MLN9708 Dose Adjustments for Nonhematologic Toxicities
Criteria
Action
Peripheral Neuropathy:
Newly developed Grade 1 peripheral neuropathy with 
pain, Grade 2 peripheral neuropathy,
Reduce dose of MLN9708 to the previous dose level 
or by 33% if the patient is receiving the first 
dose level.
Grade 2 neuropathy with pain or Grade 3 peripheral 
neuropathy
Hold MLN9708 until toxicity resolves or returns to 
baseline. When toxicity resolves, re-initiate 
MLN9708 at the previous dose level or by 
33% if the patient is receiving the first dose 
level.
Grade 4 peripheral neuropathy
Discontinue MLN9708.
Peripheral neuropathy should be monitored until 
toxicity resolves or returns to baseline. Upon 
toxicity recovery, if the patient has received 
clinical benefit from therapy with MLN9708, 
the investigator and Millennium clinician
may consider restarting therapy.
All Other Grade ≥ 3 Nonhematological Toxicities, 
except:
-
Grade 3 nausea and/or vomiting in the absence 
of optimal anti-emetic prophylaxis (Section 6.10)
-
Hold MLN9708 until resolution to Grade < 1 or 
baseline.
-
Grade 3 diarrhea that occurs in the absence of 
optimal supportive therapy (Section 6.10)
- Reduce MLN9708 1 dose level or 33% if the 
patient is receiving the first dose level.
-
Grade 3 fatigue
-
Note, a dose level reduction will be made either 
based on within-cycle or for a subsequent cycle 
criteria, but not for both from the same cycle.
Grade 4 Nonhematologic Toxicities
Consider permanently discontinuing MLN9708.
Exception, in the case where the investigator 
determines the patient is obtaining a clinical 
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Table 6-3
MLN9708 Dose Adjustments for Nonhematologic Toxicities
Criteria
Action
benefit and has discussed this with the 
Millennium clinician.
Criteria for Retreatment and Cycle Delays
Both hematologic & nonhematologic recovery 
required
Delay therapy 1 week.
Re-evaluate patient; if still not resolved, delay therapy 
1 additional week.
If not resolved
If initiation of subsequent therapy needs to be delayed 
for more than 2 weeks because of incomplete 
recovery from treatment related toxicity, the 
dose of MLN9708 will be reduced by at least 
1 dose level when treatment resumes.
The maximum delay before treatment should be 
discontinued (except in the case of 
investigator-determined clinical benefit and 
discussion with the Millennium clinician) 
will be 3 weeks.
6.6.3
Dexamethasone–Related Treatment Modification 
Dosage adjustments for dexamethasone are outlined in Table 6-4. Dexamethasone dose 
treatment modifications are outlined in Table 6-5.
Table 6-4
Dose Reduction Steps for Dexamethasone
Starting Dose
First Dose Reduction
Second Dose Reduction
Third Dose Reduction
40 mg QD
20 mg QD
8 mg QD
Discontinue dexamethasone
Table 6-5
Dexamethasone–Related Treatment Modification (Delays, Reductions, 
and Discontinuations) Guidelines Due to Adverse Events
Adverse Event (Severity)
Action on Study Drug
Gastrointestinal
Dyspepsia, gastric, or duodenal ulcer, 
gastritis Grades 1-2 (requiring 
medical management)
Treat with histamine-2 blockers, sucralfate, 
or omeprazole. If symptoms persist 
despite these measures, decrease 
dexamethasone by 1 dose level.
> Grade 3 (requiring hospitalization or 
surgery)
Hold dexamethasone until symptoms 
adequately controlled. Restart and 
decrease 1 dose level of current 
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Table 6-5
Dexamethasone–Related Treatment Modification (Delays, Reductions, 
and Discontinuations) Guidelines Due to Adverse Events
Adverse Event (Severity)
Action on Study Drug
dose along with concurrent therapy 
with histamine-2 blockers, 
sucralfate, or omeprazole. If 
symptoms persist despite these 
measures, discontinue 
dexamethasone and do not resume.
Acute pancreatitis
Discontinue dexamethasone and do not 
resume.
Cardiovascular
Edema > Grade 2 (limiting function and 
unresponsive to therapy or 
anasarca)
Diuretics as needed and decrease 
dexamethasone by 1 dose level. If 
edema persists despite these 
measures, decrease dose another 
level. Discontinue dexamethasone 
and do not resume if symptoms 
persist despite second reduction.
Neurological
Confusion or mood alteration > Grade 2 
Hold dexamethasone until symptoms 
resolve. Restart with 1 dose level 
reduction. If symptoms persist 
despite these measures, discontinue 
dexamethasone and do not resume.
Musculoskeletal
Muscle weakness > Grade 2 (interfering 
with function interfering with 
activities of daily living)
Decrease dexamethasone dose by 1 dose 
level. If weakness persists despite 
these measures, decrease dose by 1 
dose level. Discontinue 
dexamethasone and do not resume 
if symptoms persist.
Metabolic
Hyperglycemia > Grade 3 or higher
Treatment with insulin or oral 
hypoglycemics as needed. If 
uncontrolled despite these 
measures, decrease dose by 1 dose 
level until levels are satisfactory.
Source: Package insert for DEXAMETHASONE Tablets USP, DEXAMETHASONE Oral Solution September 
2007, Roxane Laboratories, Inc, a division of Boehringer Ingelheim.(59)
6.7
Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited during the study.
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Systemic treatment with any of the following metabolizing enzyme inhibitors is not 
permitted during this study. The rationale for this is that in the event of a drug-drug 
interaction with an inhibitor, MLN9708 exposure would be increased leading to a high 
probability of an AE.

Strong inhibitors of CYP1A2: fluvoxamine, enoxacin, ciprofloxacin

Strong inhibitors of CYP3A: clarithromycin, telithromycin, itraconazole, 
voriconazole, ketoconazole, nefazodone, and posaconazole
Systemic treatment with any of the following metabolizing enzyme inducers should be 
avoided, unless there is no appropriate alternative medication for the patient’s use. The 
rationale for this (unlike with inhibitors) is that in the event of a drug-drug interaction with 
an inducer, MLN9708 exposure would be decreased, leading to a reduced chance of toxicity 
and potentially a reduced chance of efficacy.

Strong CYP3A inducers: rifampin, rifapentine, rifabutin, carbamazepine, 
phenytoin, and phenobarbital

ACE inhibitors (ACE inhibitors should be used with caution and requires 
consultation with the Millennium clinician. Patients with AL 
amyloidosis usually poorly tolerate ACE inhibitors, not due to possible 
interaction with MLN9708, but because of symptomatic hypotension due 
to an underlying involvement of the autonomic nervous system.
Therefore, ACE inhibitors should be excluded in patients with eGFR 
< 60mg/min/1.72 and in those whom orthostatic systolic blood pressure 
is < 100 mmHg.)

Excluded foods and dietary supplements include St. John’s wort and 
Ginkgo biloba

Warfarin (aspirin is allowed)
The following procedures are prohibited during the study:

Any antineoplastic treatment with activity against AL amyloidosis, other 
than study drugs
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
Radiation therapy (note that, in general, the requirement for local 
radiation therapy indicates disease progression)

Platelet transfusions to help patients meet eligibility criteria are not 
allowed within 3 days prior to study drug dosing
6.8
Permitted Concomitant Medications and Procedures
All necessary supportive care consistent with optimal patient care shall be available to 
patients as necessary.
The following are examples of those permitted during the study:
Growth factors (eg, granulocyte colony stimulating factor [G-CSF], granulocyte 
macrophage-colony stimulating factor [GM-CSF], recombinant erythropoietin) will not be 
allowed in Cycle 1, but may be considered in Cycle 2 and beyond although caution must be 
exercised.
Patients should be transfused with red cells and platelets as clinically indicated.
Antiviral therapy such as acyclovir may be considered.
Concomitant treatment with bisphosphonates will be permitted.
Patients who experience worsening neuropathy from baseline may be observed for recovery, 
and any supportive therapy or intervention may be initiated as appropriate at the discretion 
of the investigator. Dose reduction is suggested, when and if the patient resumes MLN9708 
therapy.
Standard amyloid supportive guidelines that should be considered include:
Patients who experience fluid retention or congestive heart failure (CHF) may be treated 
with intravenous diuretics.
Patients who experience life-threatening ventricular arrhythmias or atrial arrhythmias with 
hemodynamic instability should be treated according to standard clinical practice guidelines
Compression garments and midodrine for patients with symptomatic orthostasis
Note: Such adverse events may still qualify as a DLT depending on the severity and timing 
of their occurrence (see Section 6.3.1).
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6.9
Precautions and Restrictions 
It is not known what effects MLN9708 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

If they are of childbearing potential, agree to practice 2 effective methods of 
contraception, at the same time, from the time of signing the informed consent form 
through 30 days after the last dose of study drug, or agree to completely abstain from 
heterosexual intercourse
Male patients, even if surgically sterilized (ie, status postvasectomy), must agree to 1 of the 
following:

Agree to practice effective barrier contraception during the entire study treatment 
period and through 4 months after the last dose of study drug, OR

Agree to completely abstain from heterosexual intercourse
Additionally, volume depletion should be corrected before initiation of study drug.
NSAIDs should be avoided with impaired renal function given reported NSAID-induced 
renal failure in patients with decreased renal function.
6.10 Management of Clinical Events 
Prophylaxis Against Risk of Infection
If lymphopenia is noted, patients may be at an increased risk of infection. In particular, 
lymphopenia can be associated with reactivation of herpes zoster and herpes simplex 
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viruses. Antiviral therapy such as acyclovir or valacyclovir may be initiated at the onset of 
administration of MLN9708. Other antivirals are also acceptable.
Erythematous Rash With or Without Pruritus
As with VELCADE, rash with or without pruritus has been reported with MLN9708, 
primarily at the higher doses tested. The rash has been transient and has resolved either 
spontaneously or with standard symptomatic measures such as oral or topical antihistamines.
Prophylactic measures should also be considered if a patient develops a rash (eg, using a 
thick, alcohol-free emollient cream on dry areas of the body). In the case of rash, the use of a 
topical or oral steroid (eg, prednisone < 10 mg per day or equivalent [See Section 6.13]) is 
permitted. In the case of rash, punch biopsies for histopathological analysis are encouraged 
at the discretion of the investigator. In the event a skin biopsy specimen is collected, excess 
tissue should be sent to the sponsor (or designee). This tissue may be utilized for conducting 
additional histopathological analysis and/or pharmacodynamic assessments.
Nausea and/or Vomiting
Standard anti-emetics including 5 HT3 antagonists are recommended for emesis if it occurs 
once treatment is initiated; prophylactic anti-emetics may also be considered.
Dexamethasone should not be administered as an anti emetic. Volume depletion should be 
corrected before initiation of study drug.
Diarrhea
Prophylactic antidiarrheals will not be used in Cycle 1 of this protocol unless the patient has 
AL amyloidosis involving the GI tract (see Section 5.2). However, the administration of 
antidiarrheals once infectious causes are excluded may be considered. Fluid intake should be 
maintained to avoid dehydration. Volume depletion should be corrected before initiation of 
study drug.
Thrombocytopenia
Thrombocytopenia has been reported to date primarily at the higher doses tested. Blood
counts should be monitored regularly as outlined in each protocol with additional testing
obtained according to standard clinical practice. Thrombocytopenia may be severe but has
been manageable with platelet transfusions according to standard clinical practice.
Administration of MLN9708 should be modified as noted as per dose modification
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recommendations in each specific protocol when thrombocytopenia occurs. Therapy with
MLN9708 can be reinitiated at a reduced level upon recovery of platelet counts.
Volume Depletion 
Dehydration should be avoided. Two cases of acute renal failure have been reported in
patients treated at or above the MTD for IV MLN9708 (see Section 1.3). Volume depletion
should be corrected before initiation of study drug. Until further information is available,
intake of nonsteroidal anti-inflammatory drugs immediately prior to the administration of
MLN9708 should be discouraged and requires consultation with the Millennium clinician.
6.11 Blinding and Unblinding
This is an open-label study; no blinding methods will be employed.
6.12 Description of Investigational and Noninvestigational Medicinal Agents
6.12.1
MLN9708: Investigational Medicinal Agent
The drug product is MLN9708 capsules. The drug product is provided in strengths of 0.2-, 
0.5-, and 2.0-mg capsules as the active boronic acid.
The 3 different dose strengths are differentiated by both capsule size and color as described 
in Table 6-6.
Table 6-6
MLN9708 Capsules
Dose Strength
Capsule Size
Capsule Color
0.2 mg
Size 4
White opaque
0.5 mg
Size 3
Dark green
2.0 mg
Size 2
Swedish orange
For additional details, please see the MLN9708 IB and pharmacy manual.
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6.12.2
Dexamethasone: Noninvestigational Medicinal Agent
Dexamethasone is a standard agent. It is a commercially-available oral drug supplied as 
tablets.
6.13 Preparation, Reconstitution, and Dispensation
MLN9708
MLN9708 is an anticancer drug and as with other potentially toxic compounds caution 
should be exercised when handling MLN9708 capsules.
Dexamethasone
Dexamethasone is a standard agent and will be procured from commercial sources.
Additional details are provided in the package insert or SmPC as appropriate.
6.14 Packaging and Labeling
The study drug MLN9708 capsules will be provided by Millennium. The study drug will be 
labeled and handled as open-label material, and packaging labels will fulfill all requirements 
specified by governing regulations. The formulation consists of 0.2-, 0.5-, and 2.0-mg 
capsules for oral administration.
The capsules are individually packaged in blisters using cold form foil-foil with child 
resistant paper backing. The capsules are in 1 4 blister strips that are individually 
perforated. The strips (1 4) are placed in cartons containing 6 strips (24 total capsules) of 
the same strength.
6.15 Storage, Handling, and Accountability
Upon receipt at the investigative site, MLN9708 should remain in the blister and carton 
provided until use or until drug is dispensed. The container should be stored at the 
investigative site refrigerated (36°F to 46°F, 2°C to 8°C). All excursions should be brought 
to the sponsor’s attention for assessment and authorization for continued use. Ensure that the 
drug is used before the retest expiry date provided by Millennium. Expiry extensions will be 
communicated accordingly with updated documentation to support the extended shelf life.
In countries where local regulations permit, MLN9708 capsules dispensed to the patient for 
take-home dosing should remain in the blister packaging and refrigerated as noted above 
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until the point of use. The investigative site is responsible for providing the medication to 
the patient in the correct daily dose configurations. Approval for any patient for take-home 
medication must be discussed with Millennium in order to ensure the greatest conformity 
with repackaging, labeling, and patient compliance. Comprehensive instructions should be 
provided to the patient in order to ensure compliance with dosing procedures. Patients who 
are receiving take-home medication should be given only 1 cycle of medication at a time.
Patients should be instructed to store the medication refrigerated (36°F-46°F, 2°C-8°C) for 
the duration of each cycle. Patients should be instructed to return their empty blister packs to 
the investigative site, rather than discarding them. Reconciliation will occur accordingly 
when the patient returns for their next cycle of take-home medication. Any extreme in 
temperature should be reported as an excursion and should be dealt with on a case-by-case 
basis.
Because MLN9708 is an investigational agent, it should be handled with due care. Patients 
should be instructed not to chew, break, or open capsules. In case of contact with broken 
capsules, raising dust should be avoided during the clean-up operation. The product may be 
harmful by inhalation, ingestion, or skin absorption. Gloves and protective clothing should 
be worn during cleanup and return of broken capsules and powder to minimize skin contact.
The area should be ventilated and the site washed with soap and water after material pick-up 
is complete. The material should be disposed of as hazardous medical waste in compliance 
with federal, state, and local regulations.
In case of contact with the powder (eg, from a broken capsule), skin should be washed 
immediately with soap and copious amounts of water for at least 15 minutes. In case of 
contact with the eyes, copious amounts of water should be used to flush the eyes for at least 
15 minutes. Medical personnel should be notified. Patients are to be instructed on proper 
storage, accountability, and administration of MLN9708, including that MLN9708 is to be 
taken as intact capsules.
Please refer to the pharmacy manual for additional instructions.
Dexamethasone
Dexamethasone tablets should be stored in accordance with the package insert or SmPC.
requirements.
Dexamethasone will be made available in an amount sufficient for each treatment cycle.
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6.16 Other Protocol-Specified Materials
No other drugs or ancillary material are supplied for use in this study.
7. STUDY CONDUCT
7.1
Study Personnel and Organizations
The contact information for the central laboratory and any additional clinical laboratories 
may be found in the Study Manual.
Emergency contact information for the study’s medical monitors is provided below with 
additional information also in the Study Manual:
EU: +371 6709 5803
US and Canada: +1 888-723-9952
For use in Italy only
Emergency contact numbers for the study doctors will be provided to patients in the Subject 
Information Sheet Informed Consent Form (SISICF). Additionally emergency contact 
numbers are provided in the study manual.
7.2
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. If advertisements become 
part of the recruitment strategy, they will be reviewed by the institutional review board 
(IRB)/independent ethics committee (IEC). It is not envisioned that prisoners (or other 
populations that might be subject to coercion or exploitation) will be enrolled into this study.
7.3
Treatment Group Assignments 
During the dose escalation phase of the study patients will be assigned to a dose level based 
on the dose-escalation methodology as described in Section 6.4. All patients in the 
expansion portion will be assigned the same initial dose level.
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7.4
Enrollment
Enrollment in this study is defined as the time the patient receives the first dose of study 
drug.
Procedures for completion of the enrollment information are described in the Study Manual.
7.5
Study Procedures
Patients will be evaluated at scheduled visits over 4 study periods: Screening, Treatment, 
End of Treatment (EOT), and Follow-Up (progression-free and overall survival). Refer to 
the Schedule of Events for the timing of all procedures.
Additional details are provided as necessary in the sections that follow.
7.5.1 Informed Consent
Each patient must provide written informed consent before any study-required procedures 
are conducted, unless those procedures are performed as part of the patient’s standard care.
7.5.2 Patient Demographics
The age, race, ethnicity, and sex of the patient are to be recorded during screening.
7.5.3 Medical History
During the Screening period, a complete medical history will be compiled for each patient.
A complete medical history is to be obtained at screening, including AL amyloidosis
diagnosis, staging (cardiac biomarkers and NYHA classification), AL amyloidosis organ 
involvement, treatment history, neurologic medical history, and cardiac medical history. The 
history should include a review of all current medications and the patient’s current smoking 
status.
7.5.4 Physical Examination
A complete physical examination is to be conducted at the Screening visit and at the time 
points specified in the Schedule of Events. A neurologic examination is to be conducted to 
assess both amyloid-related clinical findings and treatment emergent adverse events; 
Symptom-directed assessments will be conducted per standard clinical practice to include 
but not limited to visits for response assessment.
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7.5.5 Eastern Cooperative Oncology Group Performance Status
Performance status will be assessed using the ECOG scale (see Section 15.3) at the time 
points specified in the Schedule of Events.
7.5.6 Vital Signs, Body Weight, and Height
Measurement of vital signs will include temperature, blood pressure, and heart rate.
Consideration should be given to determining orthostatic hypotension in patients with 
amyloid nerve involvement.
Body weight will be determined at the Screening visit and the time points specified in the
Schedule of Events. Height will be measured at the Screening visit only.
7.5.7 Pregnancy Test
A serum pregnancy test will be performed for all women of childbearing potential at the 
Screening visit; Cycle 1, Day 1 (predose). The Cycle 1, Day 1 pregnancy test may be 
collected up to 3 days before dosing. The results must be available and negative before the 
first dose of MLN9708 is administered.
Pregnancy tests may also be repeated during the study as per request of IEC/IRBs or if
required by local regulations.
7.5.8 Electrocardiogram
A 12-lead ECG will be conducted at screening and at the times outlined in the Schedule of 
Events. It may be repeated as clinically indicated during the study at the discretion of the 
investigator. ECG data to be obtain include intervals RR, PR, QRS, QT, and QTc and 
waveforms.
7.5.9
Holter Cardiac Monitor
Continuous cardiac monitoring will be conducted for 24 hours during screening using a 
Holter Monitor. It may be repeated as clinically indicated during the study at the discretion 
of the investigator.
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7.5.10
Clinical Laboratory Evaluations
Handling of clinical laboratory samples will be outlined in the Study Manual. Decisions 
regarding eligibility for this study may be made using local laboratory determinations. For 
dosing decisions, local hematology and chemistry laboratory results may be used.
Hematology and chemistry panels may be collected up to 72 hours prior to dosing. Criteria 
for retreatment are provided in Section 6.6.
Clinical Chemistry and Hematology
Blood samples for analysis of the following clinical chemistry and hematological parameters 
will be obtained as specified in the Schedule of Events. After 24 cycles on treatment, 
hematology and chemistry laboratory evaluations may be done to monitor the patient 
according to standard clinical practice per the treating physician.
Hematology

Hemoglobin

Hematocrit

Platelet count 

WBC count with differential
Serum Chemistry

Blood urea nitrogen 
(BUN)

Creatinine

Total bilirubin

Uric acid

Lactate dehydrogenase

Alkaline phosphatase 

AST

ALT 

Albumin

Glucose 

Sodium

Potassium 

Chloride

CO2

Magnesium

Calcium

Phosphate
Urinalysis

Appearance and color

pH

Specific gravity

Protein

Ketones

Bilirubin

Blood 

Nitrite

Urobilinogen

Glucose

Leukocytes

Microscopic 
assessment
24-Hour Urine Collection

Total protein 

Creatinine
Coagulation Studies
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
Prothrombin time and 
international 
normalized ratio 

Activated partial 
thromboplastin time
Hormones

Thyrotropin (TSH)

Cortisol
Other

Cardiac Markers: 
BNP, NT-ProBNP, and troponin 
T or I 

2-microglobulin
7.5.11
Quality of Life Assessment (European Organization for Research and 
Treatment of Cancer)
For Patients Enrolled in the Expansion Cohort Only
The QOL Assessment (EORTC-QLQ-C30; see Section 15.6) will be completed by the 
patient at screening and at the time points specified in the Schedule of Events.
7.5.12
Disease Assessments
7.5.12.1 Hematologic Disease Assessments
The primary determinant of response for the purpose of continuing treatment is the 
hematologic response. Response will be determined according to standardized criteria using 
a central laboratory. A bone marrow aspirate and biopsy are to be obtained at the Screening 
visit and may be repeated at the discretion of the investigator as clinically indicated and at 
the EOT. Immunohistochemistry of dominant clonal plasma cells is recommended. The 
response assessment is to be done during the rest cycle period (Days 22 through 28)
Quantitative Immunoglobulins, Serum M-protein, Urine M-protein, and Serum Free 
Light Chains
Serum specimens will be analyzed for quantitative immunoglobulins at screening, and if 
abnormal at screening, this test is to be repeated during Days 22 through 28 of each 
treatment cycle, and at the EOT visit. If the patient comes off treatment, but has not yet 
progressed it should be conducted every 6 weeks until disease progression.
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Analysis for serum and urine M-protein and immunofixation is to be performed at screening, 
during Days 22 through 28 of each treatment cycle, and at the EOT visit. If the patient 
comes off treatment, but has not yet progressed it should be conducted every 6 weeks until 
disease progression.
Serum free light chain assay and ratio is to be performed at screening, during Days 22 
through 28 of each treatment cycle, and at the EOT visit. If the patient comes off treatment, 
but has not yet progressed it should be conducted every 6 weeks until disease progression.
The definition of hematologic response to treatment is based on the difference between the 
concentration of amyloid forming (involved) and uninvolved free light chain (dFLC). To be 
measurable dFLC must be at least 50 mg/L. Patients with dFLC < 50 mg/L are eligible for 
clinical studies but are evaluable only for complete remission.(55, 56)
7.5.12.2 Amyloid-Related Organ Assessments
Amyloid-related organ assessments (see Section 15.7) are to be performed for all patients at 
screening; after Cycles 3, 6, 9, and 12; every 6 months thereafter until disease progression; 
and at the End-of-Study visit (as outlined in the Schedule of Events).
The following procedures/ tests should be included at a minimum to assess amyloid-related 
organ involvement. If clinically indicated, additional assessments may be performed at the 
discretion of the investigator.(23, 54, 55, 56)
Heart: NT-proBNP, BNP, troponin, echocardiography, physical examination
Kidney: 24-hour urine proteinuria, serum creatinine, eGFR, serum albumin
Liver: alkaline phosphatase, ALT, ultrasound/CT scan/ MRI (as indicated)
Peripheral nervous system: patient reported symptoms, physical examination, 
electromyography (EMG) (if indicated)
Autonomic nervous system: patient reported symptoms, determination of postural 
hypotension
Soft tissue: physical examination, imaging as indicated
These assessments include relevant AEs and patient-reported symptoms, physical findings, 
and special laboratory tests for individual organ sites. In addition, radiographic, CT, MRI, 
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and ultrasound techniques may be performed as indicated to assess organ involvement. In 
some cases, tissue sampling may be necessary. Detailed cardiac evaluations are planned. At 
each staging evaluation, the organ response/improvement will be assessed relative to 
baseline.
Cardiac Assessments
Cardiac assessments are to be performed for all patients as outlined in the Schedule of 
Events.
The assessments include, but are not limited to:

Relevant AEs and clinical findings, such as dyspnea, fluid retention, fatigue 

Cardiac markers (NT-proBNP and troponin T or I)

Blood pressure

NYHA classification determination (see Section 15.4)

Echocardiogram at baseline; Cycles 3, 6, 9, and 12; and every 6 months thereafter 
until disease progression
The following data may be collected: 2D-guided M-Mode (wall thickness and chamber 
diameters), short-axis, long-axis, apical 4-chamber and 2-chamber video clips (5 beats each), 
transmitral, transaortic, transtriscupidal, and pulmonary vein Doppler studies, mitral and 
tricuspidal annulus longitudinal excursion, tissue Doppler imaging for systolic and diastolic 
wall velocities. Strain and strain rate analyses -may also be analyzed off-line from the short-
axis and 4-chamber video clips at the discretion of the investigator.
Note: The average of the estimates of the interventricular septal and posterior 
wall thickness yields the mean ventricular wall thickness.
Note: If CT or MRI cardiac assessments are clinically indicated, then a record of the 
findings will be made.
Renal Assessment: 

24-hour urine collection (total protein, M-protein quantification, and 
immunofixation)

eGFR assessment
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
Serum creatinine

Serum albumin
Renal assessments are to be performed in all patients as outlined in the Schedule of Events.
Hepatic Assessment

Alkaline phosphatase

Clinical examination, or

Abdominal ultrasound, or

CT or MRI scans at the discretion of the investigator as clinically indicated.
Hepatic assessments are to be performed in all patients as outlined in the Schedule of 
Events. The same evaluation (physical examination or radiography [and the same imaging 
modality]) must be used consistently in individual patients throughout the study for all 
follow-up assessments.
Neurologic Assessments
Assessments are to be performed in all patients as outlined in the Schedule of Events.

Patient-reported gastrointestinal and neurologic symptoms

Clinical examination

Neurologic examination, including sensory and/or motor findings

Nerve conduction studies, if indicated (including electromyography, if necessary)

Detection and measures of postural hypotension
Soft Tissue or Lymph Node
Assessments are to be performed in all patients as outlined in the Schedule of Events.

CT or MRI scans at the discretion of the investigator as clinically indicated. The 
same imaging modality used at screening (CT/MRI) should be used for all follow-up 
assessments

Recording of any abnormalities on physical examination
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!
Patient reported symptoms
The investigator will evaluate each patient for response to therapy according to the response 
criteria presented in Sections 15.8 and 15.9. At each staging evaluation, the organ response 
will be assessed relative to baseline.
7.5.13
Pharmacokinetic and Pharmacodynamic Measurements
The timing of the PK and pharmacodynamic blood specimens may be changed if emerging 
data indicate that an alteration in the sampling scheme is needed to better characterize the 
PK or pharmacodynamics of MLN9708. The number of specimens may also change, but the 
number will not increase.
Plasma concentrations of the complete hydrolysis product of MLN9708 (ie, MLN2238) will 
be measured using a GLP-validated liquid chromatography/tandem mass spectrometry 
assay. Whole blood concentrations of MLN2238 will be measured using a fit-for-purpose 
liquid chromatography/tandem mass spectrometry assay.
Details regarding the preparation, handling, and shipping of the PK and pharmacodynamic 
samples are provided in the Study Manual.
The sampling scheme is outlined in the Pharmacokinetic & Pharmacodynamic Sampling 
(Cycle 1). One blood sample (3 mL) for the determination of plasma concentrations of 
MLN2238, 1 blood sample (3 mL) for the determination of whole blood concentrations of 
MLN2238, and 1 blood sample (1 mL) for the measurement of whole blood 20S proteasome 
activity will be collected at each time point. Blood samples are to be collected during Cycle 
1 at the following time points before and after the administration of MLN9708 on Day 1 
(MTD cohort patients only) and Day 15 (all patients enrolled in the study): predose (within 1 
hour before dosing), and postdose: 30 (± 5) minutes, 1 (± 0.25) hour, 2 (± 0.25) hours, 4 (± 
0.75) hours, 6 (± 0.75) hours, 24 (± 1.0) hours (Days 2 and 16), and 168 (± 4.0) hours (Days 
8 and 22). If feasible, a blood sample for plasma concentration should also be obtained at the 
time of any drug-related SAE.
7.5.14
Germline DNA Measurements 
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Details regarding the preparation, handling, and shipping of samples are provided in the 
Study Manual.
7.5.14.1
Tumor Biomarkers Assessment
7.5.15
Concomitant Medications and Procedures
Concomitant medications and therapy will be recorded as specified in the Schedule of 
Events. See Section 6.7 for a list of prohibited concomitant medications and therapies and 
Section 6.8 for a list of allowed concomitant medications and therapies.
7.5.16
Adverse Events
Monitoring of AEs, both nonserious and serious, will be conducted throughout the study as 
specified in the Schedule of Events. See Section 10.1 for details regarding definitions, 
documentation, and reporting of pretreatment events, AEs, and SAEs.
7.5.17
Follow-Up Assessments (PFS and OS) 
Patients who do not develop PD will continue to have PFS follow-up visits. The 
hematologic PFS follow-up should occur every 6 weeks from the EOT until the occurrence 
of progression or the start of subsequent antineoplastic therapy. A bone marrow aspirate and 
biopsy may be repeated at the discretion of the investigator as clinically indicated, but is not 
required during this follow-up period. The amyloid-organ PFS follow-up assessments should 
occur every 6 months from the EOT until the occurrence of progression (including 
hematologic progression) or the start of subsequent antineoplastic therapy. Refer to the 
Schedule of Events and Section 7.5.12 for appropriate assessments.
After the occurrence of PD or the initiation of subsequent antineoplastic therapy, patients 
will continue to have OS follow-up visits. The OS follow-up visits should be conducted 
every 12 weeks after documented PD or until the initiation of subsequent antineoplastic 
therapy. Data may be collected by methods that include, but are not limited to, telephone, 
e-mail, mail, and social security indexes. The duration of follow-up for OS will be 60 
months after the last patient starts treatment.
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7.6
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision 
of the investigator or identified sub-investigator(s). The appropriate study personnel will 
maintain records of study drug receipt and dispensing.
7.7
Completion of Treatment
Patients will be considered to have completed study treatment if they meet any of the 
following criteria:

Have received at least 6 cycles of treatment

PD after at least 28 days of Cycle 1
7.8
Completion of Study
Patients will be considered to have completed the study if they complete treatment according 
to the criteria outlined in Section 7.7 and complete 6 months of follow up (after the last dose 
of MLN9708).
7.9
Discontinuation of Treatment With Study Drug, and Patient Replacement
For patients who did not complete treatment by meeting 1 or more of the criteria outlined 
above, treatment may be discontinued permanently if any of the following criteria are met:

AE

Protocol violation

Study terminated by sponsor

Withdrawal by patient

Lost to follow-up

PD

Initiation of subsequent therapies 

Progression of amyloid markers (hematologic), see Section 15.9.

Clinically important decrease in ECOG performance status with organ function 
deterioration
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
Other
At the time of study drug discontinuation, all study procedures outlined for the EOT visit 
will be completed. The primary reason for study drug discontinuation will be recorded on 
the electronic case report form (eCRF). Patients who do not meet the DLT-evaluable criteria 
in the dose-escalation part of the study may be replaced. See Section 8.1.3 for definitions of 
patient populations of the study.
Patients who are withdrawn from treatment during Cycle 1 for reasons other than DLT may 
be replaced.
7.10 Withdrawal of Patients From Study
A patient may also be withdrawn from the study for any of the following reasons:

Study terminated by sponsor

Initiation of subsequent therapies

Withdrawal by patient

Lost to follow-up

Death

Other
The consequence of study withdrawal is that no new information will be collected from that 
patient and added to the existing data or any database. However, every effort will be made to 
follow all patients for safety.
8. STATISTICAL AND QUANTITATIVE ANALYSES
8.1
Statistical Methods
8.1.1 Determination of Sample Size
A 3 + 3 dose-escalation scheme will be conducted, with 3 to 6 DLT-evaluable patients 
evaluated at each dose level. It is expected that as many as 30 patients will be enrolled in the 
dose-escalation part of this study.
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Once the MTD/R2PD has been established, the following 2 expansion cohorts will be 
treated at the MTD or RP2D.
1. Proteasome inhibitor-naive expansion cohort including approximately 8 organ 
response-evaluable patients. There will be approximately 83% probability of 
observing at least 2 patients with organ responses among 8 patients based on the 
binomial probability calculation if the overall organ response rate is 35% for this 
population. Approximately 10 patients will be enrolled to obtain 8 response-
evaluable patients.
2. Proteasome inhibitor-exposed expansion cohort including approximately 14 organ 
response-evaluable patients. There will be approximately 80% probability of 
observing at least 2 patients with organ responses among 14 patients based on the 
binomial probability calculation if the overall organ response rate is 20% for this 
population. Approximately 16 patients will be enrolled to obtain 14 organ response-
evalauble patients.
Because approximately 6 patients in the dose-escalation part of the study will be included in 
the expansion cohorts, approximately 20 patients will be enrolled in the expansion part of 
this study.
Overall, as many as 50 patients will be enrolled in this study.
8.1.2 Randomization and Stratification
No randomization or stratification will be performed in this study. All patients from all sites 
will be pooled for analysis.
8.1.3 Populations for Analysis
The populations used for analysis will include the following:
Safety Population: Patients who receive at least 1 dose of MLN9708. The safety population 
will be used for safety analyses.
DLT-evaluable Population: Patients who receive all Cycle 1 doses of MLN9708 or 
experience a DLT in Cycle 1. The DLT-evaluable population will be used to determine the 
MTD.
Organ Response-Evaluable Population: The organ response-evaluable population is defined 
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as patients who receive at least 1 cycle of MLN9708, have amyloid involvement of at least 
kidney or heart at baseline, and at least 1 post-baseline organ response assessment.
Hematologic Response-Evaluable Population: The hematologic response-evaluable 
population is defined as patients who receive at least 1 cycle of MLN9708, have measurable 
disease at baseline, and at least 1 post-baseline hematologic response assessment.
Plasma PK Analysis Population: Patients who: 
a.
Receive full doses of MLN9708 during Cycle 1 without dose reduction or 
interruptions through the completion of PK sampling
b. Do not receive any excluded concomitant medications 
c.
Have sufficient plasma MLN2238 concentration-time data to permit reliable 
estimation of plasma PK parameters
Pharmacodynamic Analysis Population: Patients who:
a.
Receive full doses of MLN9708 during Cycle 1 without dose reduction or 
interruptions 
b. Do not receive any excluded concomitant medications through the completion of 
pharmacodynamic sampling
c.
Have sufficient whole blood 20S proteasome inhibition-time data to permit 
reliable estimation of pharmacodynamic parameters
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
Demographic and baseline characteristics will be summarized by dose levels of MLN9708 
and expansion cohorts. Data to be evaluated will include at least age, sex, race, weight, 
height, etc. Components of disease severity assessment in addition to relevant patient and 
disease assessments and laboratory parameters will be presented if appropriate.
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8.1.6 Efficacy Analysis
Standard response criteria will be used in this study.(53, 54) The patients treated at doses other 
than the dose in the expansion cohorts may be combined together for analysis and for 
presentation in the tables and figures.
The efficacy parameters include the organ response rate and organ improvement rate, overall 
hematologic response rate, time to hematologic and organ response, duration of hematologic 
and organ response, time to hematologic and organ response, hematologic and organ disease 
free progression, and 1-year survival rate.
The organ response and improvement rate will be analyzed based on the organ response-
evaluable population. Estimates of the organ response rate will be presented with 2-sided 
95% exact binomial confidence intervals.
The hematologic response rate will be analyzed based on the hematologic response-
evaluable population and presented with 2-sided 95% exact binomial confidence interval.
Time to organ or hematologic response is defined as the time from the date of the first dose 
of MLN9708 to the date of first documentation of a confirmed organ or hematologic 
response, respectively.
Duration of organ or hematologic response is defined as the time from the date of first 
documentation of a confirmed organ or hematologic response to the date of confirmed organ 
or hematologic disease progression, respectively.
Time to organ or hematologic disease progression is defined as the time from the date of the 
first dose of MLN9708 to the date of first documented organ or hematologic disease 
progression.
Organ or hematologic disease progression free survival is defined as the time from the date 
of the first dose of MLN9708 to the date of confirmed organ or hematologic disease 
progression or death, respectively.
One-year survival is defined as the patient survival probability at 1 year after the date of first 
dose of MLN9708.
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Time to response, duration of response, time to progression, PFS, and survival may be 
analyzed using standard survival analysis techniques based on Kaplan-Meier estimates if 
appropriate.
8.1.6.1
Exploratory Efficacy Endpoints and Analysis
8.1.7 Pharmacokinetics, Pharmacodynamics, and Exploratory Analyses
Pharmacokinetic Analysis
PK analysis will be based on concentrations of MLN2238, the complete hydrolysis product 
of MLN9708.
Individual and mean plasma and whole blood concentration data will be plotted over time.
Summary tables will be presented for the plasma and whole blood concentration data.
Plasma and whole blood PK parameters will be estimated using noncompartmental analysis 
methods. The PK parameters calculated for individual plasma MLN2238 concentration-time 
data and whole blood MLN2238 concentration-time data will include, but are not limited to:
Cmax, Tmax, and AUCtau. PK parameters will be summarized using descriptive statistics.
Pharmacodynamic Analysis
Individual and mean whole blood 20S proteasome inhibition data will be plotted over time.
Summary tabulations will be presented for the whole blood 20S proteasome inhibition data.
Pharmacodynamic parameters of whole blood 20S proteasome inhibition will be estimated 
using noncompartmental analysis methods. The pharmacodynamics parameters calculated 
for individual whole blood 20S proteasome inhibition-time data will include, but are not 
limited to: maximum inhibition (Emax) and time of occurrence of Emax (TEmax).
Pharmacodynamic parameters will be summarized using descriptive statistics.
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Tumor Biomarker Analysis
8.1.8 Safety Analysis
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 percent per category for categorical data.
The incidence of DLT may be tabulated for each dose group. In addition, to assess the 
relationship between toxicities and MLN9708 dose, the preferred term of individual 
toxicities may be summarized by their frequency and intensity for each dose group. The 
DLT-evaluable population will be used for the analysis of DLT. DLT will also be listed for 
each dose group.
Safety will also be evaluated by the incidence of treatment emergent AEs, severity and type 
of AEs, and by changes from baseline in the patient’s vital signs, weight, and clinical 
laboratory results using the population evaluable for safety. Exposure to study drug and 
reasons for discontinuation will be tabulated.
Treatment-emergent events will be tabulated. Treatment emergent is defined as any AE that 
occurs after administration of the first dose of study drug 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. AEs will be 
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tabulated according to the Medical Dictionary for Regulatory Activities (MedDRA) by 
system organ class, high-level terms, and preferred terms and will include the following 
categories: 

Treatment-emergent AEs

Drug-related treatment-emergent AEs

Grade 3 or higher treatment-emergent AEs

Grade 3 or higher drug-related treatment-emergent AEs

Treatment-emergent AEs resulting in study drug reduction

Treatment-emergent AEs resulting in study drug discontinuation

SAEs
The most commonly reported treatment-emergent AEs (ie, those events reported by 10% 
of all patients) will be tabulated by high level term and preferred term.
Descriptive statistics for the actual values and/or change from baseline of clinical laboratory 
parameters will be presented for all scheduled measurements over time. Mean laboratory 
values over time will be plotted for key laboratory parameters.
Descriptive statistics for the actual values and changes from baseline of vital signs, weight, 
and ECOG scores will be tabulated by scheduled time point.
Shift tables for laboratory parameters will be generated based on changes in NCI CTCAE 
Grade from baseline to the worst post baseline value. Graphical displays of key safety 
parameters, such as scatter plots of baseline versus worst post baseline values, may be used 
to understand the MLN9708 safety profile.
All concomitant medications collected from screening through the study period will be 
classified to preferred terms according to the World Health Organization (WHO) drug 
dictionary.
Additional safety analyses may be performed to most clearly enumerate rates of toxicities 
and to further define the safety profile of MLN9708.
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8.1.9 Interim Analysis
No formal interim analysis will be conducted in this study.
9. STUDY COMMITTEES 
9.1
Steering Committee
A steering committee that includes a subset of investigators in this study and representatives 
from Millennium will be formed to advise on the conduct of the study and development of 
publications and presentations (see also Section 12).
9.1.1 Drug Safety Monitoring Board
In accordance with Millennium standard procedures each clinical trial is evaluated to 
determine if a Drug Safety Monitoring Board (DSMB) should be convened. Applicable 
regulation and guidance (including the guidance set forth by the FDA as described in the 
Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data 
Monitoring Committees, 
(http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127073.pdf ) are 
used to evaluate each trial in terms of potential confounding factors that complicate 
evaluation of the study safety and/ or efficacy data, and potential risks of the study design or 
treatment to study participants. A DSMB is not indicated at this time for this study given 
that Millennium's standards and processes, which include continuous review and evaluation 
of safety data reported from all participating sites through the conduct of the study, are 
appropriate for the ongoing monitoring of patient safety and data integrity. Further, as 
described in Section 9.1, a Steering Committee has been formed to advise on the conduct of 
the study. However, taking into consideration the evolving benefit/ risk profile of 
MLN9708, the decision to convene a DSMB could be taken any time during the conduct of 
study C16007.
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10.
ADVERSE EVENTS
10.1 Definitions
10.1.1
Pretreatment Event Definition
A pretreatment event is any untoward medical occurrence in a patient or subject who has 
signed informed consent to participate in a study but before administration of any study 
medication; it does not necessarily have to have a causal relationship with study 
participation.
10.1.2
Adverse Event Definition
Adverse event (AE) means any untoward medical occurrence in a patient or subject 
administered a pharmaceutical product; the untoward medical occurrence does not 
necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product whether 
or not it is related to the medicinal product. This includes any newly occurring event, or a 
previous condition that has increased in severity or frequency since the administration of 
study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline.
10.1.3
Serious Adverse Event Definition
Serious AE (SAE) means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the 
time of the event. It does not refer to an event which hypothetically might have 
caused death if it were more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization
(see clarification in the paragraph below on planned hospitalizations).
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
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.(58) Clarification should be made between a serious AE 
(SAE) and an AE that is considered severe in intensity (Grade 3 or 4), because the terms 
serious and severe are NOT synonymous. The general term severe is often used to describe 
the intensity (severity) of a specific event; the event itself, however, may be of relatively 
minor medical significance (such as a Grade 3 headache). This is NOT the same as serious, 
which is based on patient/event outcome or action criteria described above, and is usually 
associated with events that pose a threat to a patient’s life or ability to function. A severe AE 
(Grade 3 or 4) does not necessarily need to be considered serious. For example, a white 
blood cell count of 1000/mm3 to less than 2000 is considered Grade 3 (severe) but may not 
be considered serious. Seriousness (not intensity) serves as a guide for defining regulatory 
reporting obligations.
10.2 Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events
All AEs spontaneously reported by the patient and/or in response to an open question from 
study personnel or revealed by observation, physical examination, or other diagnostic 
procedures will be recorded on the appropriate page of the eCRF (see Section 10.3 for the 
period of observation). Any clinically relevant deterioration in laboratory assessments or 
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other clinical finding is considered an AE. When possible, signs and symptoms indicating a 
common underlying pathology should be noted as 1 comprehensive event.
All SAEs and serious pretreatment events (as defined in Section 10.1) must be reported (see 
Section 10.3 for the period of observation) by the investigator to the Millennium Department 
of Pharmacovigilance or designee (contact information provided below) by faxing the SAE 
Form within 1 working day after becoming aware of the event. All SAEs and serious 
pretreatment events (which include all deaths) must be reported whether or not considered 
causally related to the study drug or study procedures. The SAE Form, created specifically 
by Millennium, will be provided to each clinical study site. A sample of the SAE Form may 
be found in the Study Manual. Follow-up information on the SAE or serious pretreatment 
event may be requested by Millennium. SAE report information must be consistent with the 
data provided on the eCRF.
SAE Reporting Contact Information*
Planned hospital admissions or surgical procedures for an illness or disease that existed 
before the patient was enrolled in the study 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).
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.(58) The criteria are provided in the Study Manual and also are 
available online at http://ctep.cancer.gov/reporting/ctc.html.
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Relationship to study drug administration will be determined by the investigator responding 
yes or no to this question: Is there a reasonable possibility that the AE is associated with the 
study drug?
10.3 Monitoring of Adverse Events and Period of Observation
AEs, both nonserious and serious (which include all deaths), will be monitored throughout 
the study as follows:

AEs will be reported from 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.

Serious pretreatment events will be reported to Millennium Pharmacovigilance or 
designee from the time of the signing of the informed consent form (ICF) up to first 
dose of study drug, but will not be recorded in the eCRF.

SAEs will be reported to Millennium Pharmacovigilance or designee from 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). Any SAE that occurs at any time after completion of the 
study and the designated follow-up period that the investigator considers to be 
related to study drug must be reported to the Millennium Department of 
Pharmacovigilance.
10.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this 
study, she must inform the investigator immediately and permanently discontinue study 
drug. The sponsor must also be contacted immediately by faxing a completed Pregnancy 
Form to the Millennium Department of Pharmacovigilance (see Section 10.2). The 
pregnancy must be followed for the final pregnancy outcome.
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If a female partner of a male patient becomes pregnant during the male patient’s 
participation in this study, the sponsor must also be contacted immediately by faxing a 
completed Pregnancy Form to the Millennium Department of Pharmacovigilance (see 
Section 10.2). Every effort should be made to follow the pregnancy for the final pregnancy 
outcome.
11.
ADMINISTRATIVE REQUIREMENTS
11.1 Good Clinical Practice
The study will be conducted in accordance with the ICH-GCP and the appropriate regulatory 
requirement(s). The investigator will be thoroughly familiar with the appropriate use of the 
study drug as described in the protocol and the IB.
11.2 Data Quality Assurance
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
patient. Study data will be entered into an eCRF by site personnel using a secure, validated, 
web-based electronic data capture (EDC) application. Millennium will have access to all 
data upon entry in the EDC application.
Study monitors will discuss instances of missing or uninterpretable data with the 
investigator for resolution. Any changes to study data will be made to the eCRF and 
documented via an electronic audit trail associated with the affected eCRF.
11.3 Electronic Case Report Form Completion 
Millennium or designee will provide the study sites with secure access to and training on the 
EDC application, sufficient to permit site personnel to enter or correct information in the 
eCRFs for the patients for whom they are responsible.
eCRFs will be completed for each study patient. It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the 
patient’s eCRF.
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The investigator, or designated representative, should complete the eCRF as soon as 
possible after information is collected.
The investigator must provide through the EDC application formal approval of all the 
information in the eCRFs and changes to the eCRFs to endorse the final submitted data for 
the patients for which he or she is responsible. The audit trail entry will show the user’s 
identification information and the date and time of the correction.
Millennium, or a designee, will retain the eCRF data and corresponding audit trails. A copy 
of the final archival eCRF in the form of a compact disk (CD) or other electronic media will 
be placed in the investigator’s study file.
11.4 Study Monitoring
Monitoring and auditing procedures developed or approved by Millennium will be followed 
to comply with GCP guidelines.
All information recorded on the eCRFs for this study must be consistent with the patient’s 
source documentation. During the course of the study, the study monitor will make study 
site visits to review protocol compliance, verify eCRFs against source documentation, assess 
drug accountability, and ensure that the study is being conducted according to pertinent 
regulatory requirements. The review of medical records will be performed in a manner that 
ensures that patient confidentiality is maintained.
11.5 Ethical Considerations
The study will be conducted in accordance with applicable regulatory requirement(s) and 
will adhere to GCP standards. The IRB/IEC will review all appropriate study documentation 
to safeguard the rights, safety, and well-being of the patients. The study will be conducted 
only at sites where IRB/IEC approval has been obtained. The protocol, IB, ICF, 
advertisements (if applicable), written information given to the patients (including diary 
cards), safety updates, annual progress reports, and any revisions to these documents will be 
provided to the IRB/IEC by the investigator or the sponsor, as allowed by local regulations.
11.6 Patient Information and Informed Consent
After the study has been fully explained, written informed consent will be obtained from 
either the patient or his/her guardian or legal representative before study participation. The 
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method of obtaining and documenting the informed consent and the contents of the consent 
must comply with the ICH-GCP and all applicable regulatory requirements.
11.7 Patient Confidentiality
To maintain patient privacy, all eCRFs, study drug accountability records, study reports, and 
communications will identify the patient by initials where permitted and/or by the assigned 
patient number. The patient’s confidentiality will be maintained and will not be made 
publicly available to the extent permitted by the applicable laws and regulations.
11.8 Investigator Compliance
The investigator will conduct the 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.
11.9 On-site Audits
Regulatory authorities, the IEC/IRB, and/or Millennium may request access to all source 
documents, eCRFs, and other study documentation for on-site audit or inspection. Direct 
access to these documents must be guaranteed by the investigator, who must provide support 
at all times for these activities.
11.10
Investigator and Site Responsibility for Drug Accountability
Accountability for the study drug at the 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 
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the drug, if approved by Millennium) will be maintained by the clinical site. Millennium or 
its designee will review drug accountability at the site on an ongoing basis.
All material containing study drug will be treated and disposed of in accordance with 
governing regulations.
11.11
Product Complaints
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals 
who identify a potential product complaint situation should immediately contact PPD (see 
below) and report the event. Whenever possible, the associated product should be 
maintained in accordance with the label instructions pending further guidance from a 
Millennium quality representative.
For Product Complaints, call PPD at
1-877-TAKEDA7 (1-877-825-3327)
or 1-919-666-9442
E-mail: medicalinformation@tpna.com
Product complaints in and of themselves are not AEs. If a product complaint results in an 
SAE, an SAE form should be completed and sent to 
(refer to section 10.2).
11.12
Closure of the Study
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 
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
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
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.
11.13
Record Retention
The investigator will maintain all study records according to the ICH-GCP and applicable 
regulatory requirement(s). Records will be retained for at least 2 years after the last 
marketing application approval or 2 years after formal discontinuation of the clinical 
development of the investigational product or according to applicable regulatory 
requirement(s). If the investigator withdraws from the responsibility of keeping the study 
records, custody must be transferred to a person willing to accept the responsibility and 
Millennium notified.
12.
USE OF INFORMATION
All information regarding MLN9708 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 
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toward the development of MLN9708 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.
A Steering Committee that includes a subset of investigators in this study and 
representatives from Millennium will be formed to advise on the conduct of the study and 
development of publications and presentations. This policy may be changed with the 
agreement of both the investigators and Millennium.
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13.
INVESTIGATOR AGREEMENT
I have read Protocol C16007, Amendment 6: An Open-Label, Dose-Escalation, Phase 1 
Study of the Oral Formulation of MLN9708 Administered Weekly in Adult Patients With 
Relapsed or Refractory Light-Chain (AL) Amyloidosis Who Require Further Treatment
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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14.
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refractory multiple myeloma. J Clin Oncol 2008;26(29):4777-83.
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in patients with relapsed or refractory multiple myeloma. Eur J Med Res 
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Ikhlaque N, Seshadri V, Kathula S, Baumann MA. Efficacy of prophylactic warfarin 
for prevention of thalidomide-related deep venous thrombosis. American Journal of 
Hematology 2006;81(6):420-2.
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Baz R, Li L, Kottke-Marchant K, Srkalovic G, McGowan B, Yiannaki E, et al. The 
role of aspirin in the prevention of thrombotic complications of thalidomide and 
anthracycline-based chemotherapy for multiple myeloma. Mayo Clinic Proceedings 
2005;80(12):1568-74.
35.
Dispenzieri A, Lacy MQ, Rajkumar SV, Geyer SM, Witzig TE, Fonseca R, et al. 
Poor tolerance to high doses of thalidomide in patients with primary systemic 
amyloidosis. Amyloid 2003;10(4):257-61.
36.
Seldin DC, Choufani EB, Dember LM, Wiesman JF, Berk JL, Falk RH, et al. 
Tolerability and efficacy of thalidomide for the treatment of patients with light 
chain-associated (AL) amyloidosis. Clinical Lymphoma 2003;3(4):241-6.
37.
Palladini G, Perfetti V, Perlini S, Obici L, Lavatelli F, Caccialanza R, et al. The 
combination of thalidomide and intermediate-dose dexamethasone is an effective but 
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toxic treatment for patients with primary amyloidosis (AL). Blood 
2005;105(7):2949-51.
38.
Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. 
Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and 
dexamethasone in systemic AL amyloidosis. Blood 2007;109(2):457-64.
39.
Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, et 
al. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a 
phase 2 trial. Blood 2007;109(2):492-6.
40.
Pengo N, Oliva C, Palladini G, Merlini A, Fontana F, Pasqualetto E, et al. Adaptive 
autophagy in normal and neoplastic plasma cells. Amyloid 2010;17(suppl 1):60-61; 
abstr OP-043.
41.
Bianchi G, Oliva L, Cascio P, Pengo N, Fontana F, Cerruti F, et al. The proteasome 
load versus capacity balance determines apoptotic sensitivity of multiple myeloma 
cells to proteasome inhibition. Blood 2009;113(13):3040-9.
42.
Kastritis E, Wechalekar AD, Dimopoulos MA, Merlini G, Hawkins PN, Perfetti V, 
et al. Bortezomib with or without dexamethasone in primary systemic (light chain) 
amyloidosis. Journal of Clinical Oncology 2010;28(6):1031-7.
43.
Kastritis E, Anagnostopoulos A, Roussou M, Toumanidis S, Pamboukas C, Migkou 
M, et al. Treatment of light chain (AL) amyloidosis with the combination of 
bortezomib and dexamethasone. Haematologica 2007;92(10):1351-8.
44.
Wechalekar AD, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Efficacy of 
bortezomib in systemic AL amyloidosis with relapsed/refractory clonal disease. 
Haematologica 2008;93(2):295-8.
45.
Reece DE, Sanchorawala V, Hegenbart U, Merlini G, Palladini G, Fermand JP, et al. 
Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: 
results of a phase 1 dose-escalation study. Blood 2009;114(8):1489-97.
46.
Reece D, Hegenbart U, Sanchorawala V, Merlini G, Blade J, Liu K, et al. Weekly 
and twice-weekly bortezomib in AL amyloidosis: Results of a phase II study. J Clin 
Oncol (ASCO Meeting Abstracts) 2010;28(15s):abstr 8023.
47.
Zonder J, Sanchorawala V, Snyder R, Matous J, Terebelo H, Janakiraman N, et al. 
Melphalan and Dexamethasone Plus Bortezomib Induces Hematologic and Organ 
Responses in AL-Amyloidosis with Tolerable Neurotoxicity. Blood (ASH Annual 
Meeting Abstracts) 2009;114:abstr 746.
48.
Dick LR, Fleming PE. Building on bortezomib: second-generation proteasome 
inhibitors as anti-cancer therapy. Drug Discov Today 2010.
49.
Bross PF, Kane R, Farrell AT, Abraham S, Benson K, Brower ME, et al. Approval 
summary for bortezomib for injection in the treatment of multiple myeloma. Clinical 
Cancer Research 2004;10(12 Pt 1):3954-64.
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50.
VELCADE (bortezomib) for Injection [package insert]. Cambridge, MA: 
Millennium Pharmaceuticals, Inc.; 2009.
51.
Reece DE, Sullivan D, Lonial S, Mohrbacher AF, Chatta G, Shustik C, et al. 
Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients 
with relapsed multiple myeloma. Cancer Chemotherapy & Pharmacology 
2011;67(1):57-67.
52.
Soverini S, Cavo M, Cellini C, Terragna C, Zamagni E, Ruggeri D, et al. Cyclin D1 
overexpression is a favorable prognostic variable for newly diagnosed multiple 
myeloma patients treated with high-dose chemotherapy and single or double 
autologous transplantation. Blood 2003;102(5):1588-94.
53.
Fonseca R, Bergsagel PL, Drach J, Shaughnessy J, Gutierrez N, Stewart K, et al. 
International Myeloma Working Group molecular classification of multiple 
myeloma: spotlight review. Leukemia 2009;23:2210-2221.
54.
Gertz MA, Comenzo R, Falk RH, Fermand JP, Hazenberg BP, Hawkins PN, et al. 
Definition of organ involvement and treatment response in immunoglobulin light 
chain amyloidosis (AL): a consensus opinion from the 10th International Symposium 
on Amyloid and Amyloidosis, Tours, France, 18-22 April 2004. American Journal of 
Hematology 2005;79(4):319-28.
55.
Merlini G. Discussion: New developments in amyloidosis. In: ASCO Annual 
Meeting; 2010 4-8 June; Chicago, IL.
56.
Palladini G, Dispenzieri A, Gertz M, Wechalekar A, Hawkins P, Schonland S, et al. 
Validation of the Criteria of Response to Treatment In AL Amyloidosis. Blood (ASH 
Annual Meeting Abstracts) 2010;116(21):abstr 1364.
57.
Dispenzieri A, Gertz MA, Kyle RA, Lacy MQ, Burritt MF, Therneau TM, et al. 
Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging 
system for primary systemic amyloidosis. Journal of Clinical Oncology 
2004;22(18):3751-7.
58.
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.
59.
DEXAMETHASONE Tablets USP, DEXAMETHASONE Oral Solution [package 
insert]. Columbus, OH: Roxane Laboratories, Inc, a division of Boehringer 
Ingelheim; September 2007.
60.
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. 
A new equation to estimate glomerular filtration rate. Annals of Internal Medicine 
2009;150(9):604-12.
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61.
Lachmann HJ, Booth DR, Booth SE, Bybee A, Gilbertson JA, Gillmore JD, et al. 
Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. New England 
Journal of Medicine 2002;346(23):1786-91.
62.
Comenzo RL, Zhou P, Fleisher M, Clark B, Teruya-Feldstein J. Seeking confidence 
in the diagnosis of systemic AL (Ig light-chain) amyloidosis: patients can have both 
monoclonal gammopathies and hereditary amyloid proteins. Blood 
2006;107(9):3489-91.
63.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. 
American Journal of Clinical Oncology 1982;5(6):649-55.
64.
Knoben J, Anderson P. Handbook of Clinical Drug Data, 6th ed.: Drug Intelligence 
Pub, Inc.; 1988.
65.
U.S. Department of Health and Human Services, National Institutes of Health 
National Cancer Institute. Common Terminology Criteria for Adverse Events 
(CTCAE). Version 4.02. 28 May 2009.
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15.
APPENDICES
15.1 Equation to Estimate Glomerular Filtration Rate (eGFR)
Race and Sex
Serum Creatinine Level
mol/L (mg/dL)
Equation
Black
Female
62 (0.7)
GFR = 166 (SCR/0.7)-0.329 (0.993)age
> 62 (> 0.7)
GFR = 166 (SCR/0.7)-1.209 (0.993)age
Male
80 (0.9)
GFR = 163 (SCR/0.9)-0.411 (0.993)age
> 80 (> 0.9)
GFR = 163 (SCR/0.9)-1.209 (0.993)age
White or Other
Female
62 (0.7)
GFR = 144 (Scr/0.7)-0.329 (0.993)age
> 62 (> 0.7)
GFR = 144 (Scr/0.7)-1.209 (0.993)age
Male
80 (0.9)
GFR = 141 (Scr/0.9)-0.411 (0.993)age
> 80 (> 0.9)
GFR = 141 (Scr/0.9)-1.209 (0.993)age
Source: Levey et al, 2009 (60)
CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration; GFR – glomerular filtration rate
Expressed for specified race, sex, and serum creatinine level. To convert GFR from mL/min/1.73 m2 to 
mL/sec/1.73 m2, multiply by 0.0167. We derived equation coefficients from pooled development and 
internal validation sets. The CKD-EPI equation, expressed as a single equation, is GFR = 141 
min(Scr/,1)max(Scr/,1)-1.209 0.993age 1.018 [if female] 1.159 [if black], where Scr is serum 
creatinine, is 0.7 for females ans 0.9 for males, is -0.329 for females and -0.411 for males, and min 
indicates the minimum of Scr/or 1, and max indicates the maximum of Scr/or 1. In this table, the 
multiplication factors for race and sex are incorporated into the intercept, which results in different 
intercepts for age and sex combinations.
15.2 Amyloid Typing
Because clinical presentations are similar for the common types of systemic amyloidosis, the 
stigmata of organ involvement do not enable one to deduce the type of amyloid in a given 
patient.(61)
Two potential precursor proteins can co-exist in a patient, making it perplexing as to which 
type the patient has, a happenstance particularly relevant to 3 situations: 
1. African-Americans who have higher rates of monoclonal gammopathies and a 4% 
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incidence of an hereditary ATTR variant (Val122Ile);(61, 62)
2. Patients presenting with peripheral neuropathy as the only clinical feature of organ 
involvement and a monoclonal gammopathy; peripheral nervous system involvement is 
a common presentation of hereditary disease;(62)
3. Elderly men who also have higher rates of both monoclonal gammopathies and 
wild-type ATTR.(62)
For diagnosis, tissue biopsy, either of an involved organ or a surrogate site (eg, abdominal 
fat), must demonstrate amyloid deposition by classic Congo red staining or electron 
microscopy.
For typing, immunohistochemical staining is frequently unreliable and inaccurate, and 
immunogold electron microscopy (IEM) reliable but limited by serologic dependence.(62)
DNA sequencing of genes related to hereditary variants is useful for typing, particularly in 
African-Americans and patients with peripheral neuropathy as above (situations 1 and 2 
where sequencing the transthyretin gene is indicated), or if adequate biopsy material for 
proteomic studies cannot be obtained. DNA sequencing is also useful for confirming 
proteomic findings and for subsequent screening of kin.(62)
Proteomics employing mass spectrometry with customized bioinformatic assessment of the 
constituents of the Congophilic deposits is now the gold standard for typing amyloid, 
enabling precise identification of type. It is specifically indicated for typing in cases where 
two potential amyloid precursor proteins may be present in a patient as in situation 3 above.
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15.3 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.(63)
15.4 New York Heart Association Classification of Cardiac Disease
The following table presents the New York Heart Association classification of cardiac 
diseases.
Class
Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting limitations of 
physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea, or anginal pain.
No objective evidence of 
cardiovascular disease.
II
Patients with cardiac disease resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary 
physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain.
Objective evidence of 
minimal cardiovascular 
disease.
III
Patients with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than 
ordinary activity causes fatigue, palpitation, dyspnea, or anginal 
pain.
Objective evidence of 
moderately severe 
cardiovascular disease.
IV
Patients with cardiac disease resulting in inability to carry on 
any physical activity without discomfort. Symptoms of heart 
failure or the anginal syndrome may be present even at rest. If 
any physical activity is undertaken, discomfort is increased.
Objective evidence of 
severe cardiovascular 
disease.
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15.5 Steroid Equivalent Doses
Approximately equivalent doses:
Steroid
Glucocorticoid
Anti-inflammatory
(mg)
Mineralicorticoid
(mg)
Half-life
(hours)
Cortisone
100
100
812
Hydrocortisone
80
80
812
Prednisone
20
100
1236
Prednisolone
20
100
1236
Methylprednisolone
16
no effect
1236
Dexamethasone
2
no effect
3672
Source: Knoben JE, Anderson PO. Handbook of Clinical Drug Data, 6th ed. Drug Intelligence Pub, Inc.
1988.(64)
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CCI
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CCI
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15.7 Amyloid-Related Organ Involvement
Renal
Albuminuria >0.5 g/day in a 24-hour urine collection
Cardiac
The presence of a mean left ventricular wall thickness on 
echocardiogram >12 mm in the absence of a history of 
hypertension or valvular heart disease, or of unexplained low 
voltage (<0.5 mV) on the electrocardiogram; or
NT-proBNP > 332 ng/L in the absence of renal failure (eGFR 
<45 mL/min/1.73 m2).
Clinical status is based on history, physical examination, and New 
York Heart Association (NYHA) heart failure class.
Patients who are NYHA class 1 with evidence of cardiac 
amyloid by echocardiogram or electrocardiogram are 
categorized as having asymptomatic cardiac instability.
Patients who are NYHA class 2 or higher with evidence of 
cardiac instability are categorized as having dominant 
cardiac instability (amyloid cardiomyopathy).
Hepatic and gastrointestinal
Hepatic involvement is defined as hepatomegaly on physical 
examination with an alkaline phosphatase value >1.5 
ULN. Gastrointestinal involvement is defined as direct 
biopsy verification of amyloid with symptoms such as 
gastrointestinal bleeding confirmed by tissue biopsy and 
diarrhea > 4 stools/ day over patient’s baseline.
Autonomic and/or peripheral 
neuropathy
Neuropathic involvement is defined based on clinical history, 
autonomic dysfunction with orthostasis, symptoms of 
nausea or dysgeusia, gastric atony by gastric emptying scan, 
diarrhea or constipation, or abnormal sensory or motor 
findings, or both, on neurological examination.
Soft tissue and lymphatic
Involvement may be ascertained based on classic physical 
examination findings (macroglossia, shoulder pad sign, 
raccoon eyes, carpal tunnel syndrome, synovial enlargement, 
firm enlarged lymph nodes) or biopsy.
15.8 Assessment of Hematologic Disease Response
The definition of hematologic response to treatment is based on the difference between the 
concentration of amyloid forming (involved) and uninvolved free light chain (dFLC).
To be measurable dFLC must be at least 50 mg/L. Patients with dFLC < 50 mg/L are 
eligible for clinical studies but are evaluable only for complete remission.
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Complete Response (CR)
Serum and urine negative for monoclonal 
protein by immunofixation; or free 
light chain ratio normal.
<5% plasma cells in bone marrow without 
clonal dominance
Very Good Partial Response (VGPR)
dFLC < 40 mg/L
Partial Response (PR)
Reduction in dFLC > 50% 
Progressive Disease (PD)
Is a 50% increase in serum M-protein to 
>0.5 g/dL from nadir/baseline, or 50% 
increase in urine M-protein to >200 
mg/24 hours with a visible peak 
present; free light chain increase of 
50% from nadir or baseline to >10 
mg/dL (100 mg/L)
Following a response of CR, the appearance of 
any detectable monoclonal protein by 
immunofixation, or abnormal free light 
chain ratio (light chain must double)
Source: Gertz et al. Definition of organ involvement and treatment response in immunoglobulin light chain 
amyloidosis (AL): A consensus opinion from the 10th International Symposium on amyloid and 
amyloidosis (54)
Modified criteria proposed by the 2010 International Society of Amyloidosis Consensus (55, 56)
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15.9 Criteria for Treatment Response of Amyloid-Related Organs
Response
Disease Progressiona
Heart
NT-proBNP reduction ≥30% and ≥300 ng/L in patients with eGFR 
≥45 mL/min/1.73 m2; baseline NT-proBNP must be at least 
650 ng/L to be measurable, or
A decrease in mean interventricular septal thickness by 2 mm, or
20% improvement in ejection fraction, or
Improvement in NYHA classification by 2 classes without an increase 
in diuretic use, and no increase in wall thickness
NT-prBNP increase ≥30% and ≥300 ng/L in patients with 
eGFR ≥45 mL/min/1.73 m2 , or
An increase in interventricular septal thickness by 2 mm 
compared with baseline, or
An increase in NYHA classification by 1 class with a decrease 
in ejection fraction of at least 10%
Kidney
At least a 50% decrease in 24-hour urine total protein (urine protein 
must be > 0.5 g/24 hours before treatment) in the absence of a
reduction 25% in eGFR and a 0.5 mg/dL increase in serum 
creatinine
50% increase (at least 1 g/day) in 24-hour urine total protein to 
> 1.0 g/24 hours or
25% worsening of serum creatinine or creatinine clearance (or 
eGFR).
Liver
At least a 50% decrease in abnormal alkaline phosphatase value
Decrease in liver size of at least 2 cm assessed in individual patients 
either by physical exam or radiographically. (Note: The same 
evaluation [physical examination or radiography] must be 
used consistently in individual patients throughout the study)
50% increase in alkaline phosphatase value as compared with 
the lowest value, or
An increase in liver size by at least 2cm (radiographic 
determination)
Nerve
No reliable method for defining peripheral and autonomic nervous 
system response.
Improvement in clinical examination findings
Decrease in the reported Neurotoxicity scorea
Improvement in orthostatic blood pressure
Improvement in any symptoms and/or signs related to peripheral 
Progressive neuropathy (peripheral, cranial or autonomic) not 
attributable to MLN9708 in the opinion of the 
investigator
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110
neuropathy, cranial neuropathy, or other autonomic 
dysfunction
Decrease is neuropathic pain
GI
Reduction of diarrhea to less than 50% of previous movements/day or 
decrease in fecal fat excretion by 50%
Worsening of diarrhea with increase > than 50% of previous 
movements/ day not attributable to MLN9708 in the 
opinion of the investigator or fecal fat by 50%
Source: Gertz et al. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): A consensus opinion 
from the 10th International Symposium on amyloid and amyloidosis. Am J Hematol 2005; 79: 319-328(54)
Modified criteria proposed by the 2010 International Society of Amyloidosis Consensus.(55)
a Organ progression can occur in an organ that has not been involved at baseline.
b Based on NCI CTC Version 4.02 criteria.(65)
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15.10
Amendment 4 Rationale and Purposes
Rationale for Amendment 4
The purpose of this amendment is to provide information relevant to allowing patients to 
take study drug at home. Following agreement between the investigator and the sponsor, 
eligible patients may take study drug at home as directed.
An additional purpose of this amendment is to clarify male contraceptive requirements 
following the last dose of MLN9708. Previously, the protocol indicated that 30 days was a 
sufficient period of time for males to use effective methods of contraception. Considering 
spermatogenesis is 90 days and the half life of MLN9708, the sponsor advises male patients 
to practice effective barrier contraception or abstinence during the entire study treatment 
period and through 4 months after the last dose of study drug.
This amendment also provides additional revisions and corrections made to clarify the initial 
intent of sections as detailed below.
Purposes:
!
Provide information relevant to allowing eligible patients to take study drug at home as 
directed
!
Update male contraceptive requirements
!
Clarify pharmacokinetic and pharmacodynamic sampling language
!
!
Update the anticipated duration of study based upon current patient accrual data
!
Clarify the starting dose level
!
Revise planned Dose Level 3 from 5.2 mg to 5.5 mg
!
Add information to the clinical experience summary regarding a patient in Study 
C16001 who received a dose of MLN9708 higher than was planned per protocol
!
Add prophylaxis against risk of infection to the management of clinical events 
recommendations
!
Clarify that a bone marrow aspirate and biopsy may be repeated at the discretion of the 
investigator as clinically indicated, but is not required during the follow-up period
!
Distinguish between investigational (ie, MLN9708) and noninvestigational (ie,
dexamethasone) medicinal agents
!
Update reference to the Millennium clinician (previously referred to as medical 
monitor)
!
Correct typographical errors, punctuation, grammar, and formatting
CCI
Property of Takeda: For non-commercial use
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15.11
Amendment 5 Rationale and Purposes
Rationale for Amendment 5
This amendment allows for the following: a longer follow-up period for overall survival, an 
extension for a rollover study should one become available, and flexibility in laboratory 
evaluations as per standard of care.
Purposes for Amendment 5
The purposes of this amendment are to:

Update the cover page with current signatories

Update the duration of the study and overall survival time point

Update the hematology and chemistry laboratory evaluation schedule

Update the SAE reporting contact information

Update the product complaint reporting contact information

Correct typographical errors, punctuation, grammar, and formatting
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15.12
Amendment 6 Detailed Summary of Changes
THE PRIMARY SECTION(S) OF THE PROTOCOL AFFECTED BY THE CHANGES 
IN AMENDMENT 6 ARE INDICATED. THE CORRESPONDING TEXT HAS BEEN 
REVISED THROUGHOUT THE PROTOCOL.
Purpose: Update the cover page with current signatories.
The primary change occurs on the cover page:
Formerly 
read:
Chair, Clinical Review Board (or designee)
Vice President, Oncology Clinical Research (or designee)
Now 
reads:
Purpose: Update the duration of the study and overall survival time point.
The primary change occurs in Section 4.3, Duration of Study:
Formerly 
read:
It is anticipated that this study will last for approximately 48 months. The 
duration of follow-up for overall survival will be 2 years after the last patient 
enters the study.
Now 
reads:
It is anticipated that this study will last for approximately 84 months. The 
duration of follow-up for overall survival will be 60 months after the last 
patient enters the study. Treatment may be continued in this study or in a 
MLN9708 rollover study, if and when such a study is made available, 
upon request by the investigator and agreement by the project clinician.
Sections that also contain this change are:
!
PROTOCOL SUMMARY
!
Section 7.5.17, Follow-Up Assessments (PFS and OS)
PPD
Property of Takeda: For non-commercial use only and 
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Purpose: Update the hematology and chemistry laboratory evaluation schedule.
The primary change occurs in Section 7.5.10, Clinical Laboratory Evaluations:
Added 
text:
After 24 cycles on treatment, hematology and chemistry laboratory 
evaluations may be done to monitor the patient according to standard 
clinical practice per the treating physician.
The Schedule of Events also contains this change.
Purpose: Update the SAE reporting contact information.
The primary change occurs in Section 10.2, Procedures for Recording and Reporting 
Adverse Events and Serious Adverse Events:
Formerly 
read:
SAE Reporting Contact Information*
PPDI Pharmacovigilance (US and Canada)
24-hour helpline: 800-201-8725
Fax: 888-488-9697
PPDI Pharmacovigilance (Central and South America)
24-hour helpline: +55 11 4504 4801
Fax: +55 11 4504 4802
PPDI Pharmacovigilance (All other countries)
24-hour helpline: +44 (0) 1223 374240
Fax: +44 1223 374102
Now 
reads:
SAE Reporting Contact Information*
Section 11.11, Product Complaints, also contains this change.
CCI
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MLN9708
Clinical Study Protocol C16007 Amendment 6
EudraCT:  2010-022497-13
115
Purpose: Update the product complaint reporting contact information.
The primary change occurs in Section 11.11, Product Complaints:
Formerly 
read:
A product complaint is a verbal, written, or electronic expression that 
implies dissatisfaction regarding the identity, strength, purity, quality, or 
stability of a drug product. Individuals who identify a potential product 
complaint situation should immediately contact 
(see 
below) and report the event. Whenever possible, the associated product 
should be maintained in accordance with the label instructions pending 
further guidance from a Millennium quality representative.
Now 
reads:
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 PPD (see below) and report 
the event. Whenever possible, the associated product should be maintained 
in accordance with the label instructions pending further guidance from a 
Millennium quality representative.
For Product Complaints, call PPD at
1-877-TAKEDA7 (1-877-825-3327) 
or 1-919-666-9442 
E-mail: medicalinformation@tpna.com
Purpose: Correct typographical errors, punctuation, grammar, and formatting.
These changes are not listed individually.
CCI
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Property of Takeda: For non-commercial use only and subject to
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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, Dose-Escalation, Phase 1 Study of the Oral Formulation of MLN9708 
Administered Weekly in Adult Patients With Relapsed or Refractory Light-Chain (AL) 
Amyloidosis Who Require Further Treatment
NCT Number: NCT01318902
SAP Approve Date: 06 November 2012
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.


P P D
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e


MLN9708
Study C16007 Statistical Analysis Plan
2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
ALT
alanine aninotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC
area under the  concentration versus time curve
AUCtau
area under the concentration-time curve, time 0 to end of dosing interval, estimated using 
the linear-log  trapezoidal method
AUE
area under the effect versus time curve
BLQ
below limit of quantification
CL
clearance
Cmax
maximum concentration
CSR
clinical study report
Ctrough
predose concentration
CR
complete response
CRF
case report form
CV
coefficient of variation
CYP
cytochrome P450
dFLC
serum differential free light chain concentration; difference between amyloid forming 
and non amyloid forming FLC
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EORTC-QLQ-C30
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30
EOS
end of study
EOT
end of treatment visit
Emax
maximum observed inhibition value
FLC
free light chain
Ht
height
Hr
hour
INR
international normalized ratio
IV
intravenous; intravenously
z
terminal disposition rate constant
LLOQ
lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
MLN2238
the complete hydrolysis product of MLN9708 to the boronic acid
MTD
maximum tolerated dose
NC
no change
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
ORR
overall response rate
PD
progressive disease (disease progression)
PK
pharmacokinetic(s)
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MLN9708
Study C16007 Statistical Analysis Plan
3
Abbreviation
Term
PR
partial response
PT
prothrombin time
PTT
partial thromboplastin time
QTc
rate-corrected QT interval (millisecond) of electrocardiograph
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
t1/2
terminal disposition half-life
TEmax
time of occurrence of Emax
US
United States
VGPR
very good partial response
WBC
white blood cell
WHO
World Health Organization
Wt
weight
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MLN9708
Study C16007 Statistical Analysis Plan
4
TABLE OF CONTENTS
1. INTRODUCTION................................................................................................................6
1.1 Study Design...................................................................................................................6
1.2 Study Objectives.............................................................................................................7
1.2.1 Primary Objective....................................................................................................7
1.2.2 Secondary Objectives ..............................................................................................7
1.2.3 Exploratory Objectives ............................................................................................7
2. POPULATIONS FOR ANALYSIS .....................................................................................8
2.1 Safety Population and Enrolled Patients ........................................................................8
2.2 DLT-Evaluable Population.............................................................................................8
2.3 Organ Response-Evaluable Population ..........................................................................8
2.4 Hematological Response Evaluable Population.............................................................8
2.5 Pharmacokinetic Analysis Population............................................................................8
2.6 Pharmacodynamic Analysis Population .........................................................................8
2.7 Protocol Deviation..........................................................................................................8
3. HYPOTHESES AND DECISION RULES..........................................................................9
4. INTERIM ANALYSIS.........................................................................................................9
5. STATISTICAL METHODOLOGY.....................................................................................9
5.1 Sample Size Justification................................................................................................9
5.2 Randomization and Stratification .................................................................................10
5.3 Unblinding....................................................................................................................10
5.4 Data Handling...............................................................................................................11
5.4.1 Methods for Handling Missing Data .....................................................................11
5.4.2 Definition of Baseline Values................................................................................11
5.4.3 Windowing of Visits..............................................................................................11
5.4.4 Justification of Pooling..........................................................................................11
5.5 Patient Disposition........................................................................................................12
5.6 Demographics and Baseline Disease Characteristics ...................................................12
5.6.1 Demographics........................................................................................................12
5.6.2 Medical History .....................................................................................................12
5.7 Treatments and Medications.........................................................................................13
5.7.1 Concomitant Medications......................................................................................13
5.7.2 Study Treatments...................................................................................................13
5.8 Efficacy Endpoints and Analyses.................................................................................13
5.8.1 Efficacy Endpoints.................................................................................................14
5.8.2 Efficacy Analyses ..................................................................................................16
5.9 Pharmacokinetic, Pharmacodynamic, and Exploratory Analysis.................................17
5.9.1 Pharmacokinetic Analyses.....................................................................................17
5.9.2 Pharmacodynamic Analyses..................................................................................19
5.9.3 Exploratory Analysis .............................................................................................20
5.10 Safety Analyses ..........................................................................................................21
5.10.1 Adverse Events ....................................................................................................21
5.10.2 Laboratory Data...................................................................................................23
5.10.3 Echocardiogram...................................................................................................25
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MLN9708
Study C16007 Statistical Analysis Plan
5
5.10.4 Electrocardiogram................................................................................................25
5.10.5 Vital Signs and Eastern Cooperative Oncology Group Performance Status.......25
5.10.6 Pregnancy Test, Substance Use Data, and Other Data ........................................26
6. CHANGES TO PLANNED ANALYSES FROM THE PROTOCOL ..............................26
7. PROGRAMMING CONSIDERATIONS ..........................................................................26
7.1 Statistical Software.......................................................................................................26
7.2 Rules and Definitions ...................................................................................................26
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN9708
Study C16007 Statistical Analysis Plan
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 an open-label, multicenter, phase 1, dose-escalation study of MLN9708 in adult 
patients with previously treated systemic light-chain (AL) amyloidosis.  A 3 + 3 dose-
escalation scheme will be implemented.  Patients will receive escalating doses of MLN9708 
orally (PO) on Days 1, 8, and 15 in a 28-day cycle in the absence of disease progression
(PD) or unacceptable toxicity.  If there is no hematologic response (complete response 
[CR], very good partial response [VGPR], or partial response [PR]) after completion of 3 
cycles of single-agent MLN9708, dexamethasone will be added on Days 1 to 4 of every 
cycle (Days1-4 every 28 days) beginning with Cycle 4.  The patient’s response status will be 
reassessed after 3 additional cycles; if there is no hematologic response at that time, the 
patient will be removed from treatment and followed for survival.
Once the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) has been 
established, 2 expansion cohorts of patients with relapsed or refractory amyloidosis, 
including approximately 10 proteasome inhibitor-naïve patients and approximately 16 
proteasome inhibitor-exposed patients, will be treated at the MTD/RP2D to more fully 
characterize the safety, tolerability, and efficacy of MLN9708, quality of life (QOL), and the 
pharmacokinetics (PK) and pharmacodynamics of MLN9708 in this patient population.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


M L N 9 7 0 8
St u d y C 1 6 0 0 7 St atistic al A n al ysis Pl a n
7
1. 2   
St u d y O bjecti ves
1. 2. 1  
Pri m ar y O bjecti ve

T o deter mi ne t he safet y, t olera bilit y , a n d M T D of P O M L N 9 7 0 8 a d mi nistere d 
wee kl y i n patie nts wit h pre vi o usl y treate d rela pse d or refract or y A L a m yl oi d osis

T o deter mi ne t he R P 2 D of P O M L N 9 7 0 8 a d mi nistere d wee kl y
1. 2. 2  
Sec o n d ar y O bjecti ves

T o c haracterize t he plas ma P K a n d w h ole bl o o d p har mac o d y n a mic effect of 
M L N 9 7 0 8 i n t his patie nt p o p ulati o n

T o assess t he rate of or ga n res p o nse a n d or ga n i m pr o ve me nt acc or di n g t o 
sta n dar dize d criteria

T o assess o verall he mat ol o gic res p o nse rate ( C R, V G P R, a n d P R)

T o assess ti me t o he mat ol o gic a n d or ga n res p o nse

T o assess d urati o n of he mat ol o gic a n d or ga n res p o nse

T o deter mi ne ti me t o he mat ol o gic a n d or ga n disease pr o gressi o n

T o assess pr o gressi o n -free s ur vi val ( P F S)

T o assess o verall s ur vi val i ncl u di n g 1- ye ar s ur vi val rate
1. 2. 3  
E x pl or at or y O bjecti ves
C CI
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e


MLN9708
Study C16007 Statistical Analysis Plan
8
2.  
POPULATIONS FOR ANALYSIS
2.1  
Safety Population and Enrolled Patients
The Safety population is defined as patients who receive at least 1 dose of MLN9708.  The 
Safety population will be used for all safety analyses. In this study, the enrolled patients are 
the patients who received at least 1 dose of MLN9708. 
2.2  
DLT-Evaluable Population
The Dose-Limiting Toxicity (DLT)Evaluable population is defined as patients who receive 
all Cycle-1 doses of MLN9708 or experience a DLT in Cycle 1 of the dose-escalation phase.  
The DLT-evaluable population will be used to determine the MTD.
2.3  
Organ Response-Evaluable Population
The Organ Response-Evaluable population is defined as patients who receive at least 1 cycle 
of MLN9708, have amyloid involvement of at least kidney or heart at baseline, and have at 
least 1 postbaseline organ response assessment.
2.4  
Hematological Response Evaluable Population
The Hematologic Response-Evaluable population is defined as patients who receive at least 
1 cycle of MLN9708, have measurable disease at baseline, and have at least 1 post-baseline 
hematologic response assessment.
2.5  
Pharmacokinetic Analysis Population
The PK Analysis population is defined as patients who receive at least 1 dose of MLN9708
and have sufficient MLN2238 concentration-time data and dosing data to permit the 
calculation of PK parameters.
2.6  
Pharmacodynamic Analysis Population
The Pharmacodynamic Analysis population is defined as patients who receive at least 1 dose 
of MLN9708 and have sufficient whole blood 20S proteasome inhibition-time data to permit 
the calculation of pharmacodynamic parameters.
2.7  
Protocol Deviation
A listing will be generated for major programmable protocol deviations. It will not affect 
analysis population definitions.
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MLN9708
Study C16007 Statistical Analysis Plan
9
3.  
HYPOTHESES AND DECISION RULES
Not applicable for a phase 1 study
4.  
INTERIM ANALYSIS
As this is a phase 1 study, there is not a formal interim analysis.  There will be an ongoing 
review of safety data with the medical monitor and study investigators.
5.  
STATISTICAL METHODOLOGY
Analyses will be primarily descriptive in nature. No formal statistical tests will be 
performed. Summary tabulations will be presented that display the number of observations,
mean, standard deviation, median, minimum, and maximum for continuous variables, and 
the number and percentage (calculated using nonmissing values) per category for categorical 
data, unless specified otherwise.
Patients will be analyzed at the dose level to which they were originally assigned, including 
those who receive subsequent treatment at a lower dose level.
The analyses for the clinical study report (CSR) will be conducted after 75% of patients 
have PD or 12 months after last patient is enrolled, whichever occurs first in the study. At 
that time, all relevant data will be queried and cleaned; a database snapshot will be taken and 
used for the CSR. Additional follow-up 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.  If deemed 
appropriate, however, the sponsor may decide to perform the analyses for CSR at the end of 
the study (EOS), which is approximately 2 years after the last patient is enrolled.
5.1  
Sample Size Justification
A 3 + 3 dose-escalation scheme will be conducted, with 3 to 6 DLT-evaluable patients 
evaluated at each dose level.  It is expected that as many as 30 patients will be enrolled in 
the dose-escalation part of this study.
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MLN9708
Study C16007 Statistical Analysis Plan
10
Once the MTD/R2PD has been established, the following 2 expansion cohorts will be 
treated at the MTD or RP2D:
1. Proteasome inhibitor-naive expansion cohort including approximately 8 organ 
response-evaluable patients.  There will be approximately 83% probability of 
observing at least 2 patients with organ responses among 8 patients based on the 
binomial probability calculation if the overall organ response rate is 35% for this 
population.  Approximately 10 patients will be enrolled to obtain 8 response-
evaluable patients.
2. Proteasome inhibitor-exposed expansion cohort including approximately 14 organ 
response-evaluable patients.  There will be approximately 80% probability of 
observing at least 2 patients with organ responses among 14 patients based on the 
binomial probability calculation if the overall organ response rate is 20% for this 
population.  Approximately 16 patients will be enrolled to obtain 14 organ response-
evaluable patients.
Proteasome inhibitor-naïve patients are the patients who have not received any prior 
bortezomib contained therapy and the roteasome inhibitor-exposed patients are the patients 
who received at least one prior bortezomib contained therapy. Because approximately 6 
patients in the dose-escalation part of the study will be included in the expansion cohorts, 
approximately 20 patients will be enrolled in the expansion part of this study. Please note 
that this is only for sample size justification, and the sponsor can stop the study enrollment 
for expansion cohorts at any time if deemed appropriate.
Overall, as many as 50 patients will be enrolled in this study.
5.2  
Randomization and Stratification
No randomization or stratification will be performed in this study. Patients will be enrolled 
in successive dose cohorts during dose escalation.  For the MTD disease expansion cohorts, 
patients will be enrolled in 1 of 2 expansion cohorts based on whether they have received a 
proteasome inhibitor-containing therapy.
5.3  
Unblinding
As this is an open-label study; no unblinding methodology is required.
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MLN9708
Study C16007 Statistical Analysis Plan
11
5.4  
Data Handling
5.4.1  
Methods for Handling Missing Data
Decisions regarding eligibility for this study may be made using local laboratory 
determinations in the dose-escalation segment of this study.  For dosing decisions, local 
hematology and chemistry laboratory results may be used.
All available efficacy and safety data will be included in data listings. For summary tables, 
laboratory test results from the central laboratory will be used when they are available. 
Laboratory test results from local laboratories will be used only when no central laboratory 
test results exist at the same scheduled sample collection time point and when the local 
laboratory results support an adverse event (AE), dose modification, or other medical 
decision.
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 before, the start of study drug administration.
5.4.3  
Windowing of Visits
All data will be categorized based on the scheduled visit at which they were collected.  
These visit designators are predefined values that appear as part of the visit tab in the 
electronic case report form (eCRF).
Refer to protocol Section 7.4.14 for details about the PK and pharmacodynamic sample 
collection windows.
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.
Due to the use of modified accelerated titration design for dose escalation, at a minimum, 1
patient will be dosed at any given dose level.  Data may be pooled across dose levels for 
summary purposes.  When appropriate, data will be summarized for patients at each dose 
level and pooled dose levels during dose escalation, patients at each expansion cohort
(including the patients at MTD during dose escalation), all patients enrolled at the MTD
dose level, and all patients overall.
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MLN9708
Study C16007 Statistical Analysis Plan
12
5.5  
Patient Disposition
A tabulation of patient disposition data will include a summary of the number of patients in 
the Safety, PK, and Pharmacodynamic analysis population, the DLT-Evaluable population, 
the Response-Evaluable population, and the primary reasons for study discontinuation.  
Patients will be considered to have completed the study if they:

Have received at least 6 cycles of treatment, or

Experience PD after completing at least 28 days of Cycle 1
5.6  
Demographics and Baseline Disease Characteristics
5.6.1  
Demographics
Demographic data (including age at date of informed consent, sex, race, ethnicity, height, 
and weight) will be summarized.
5.6.2  
Medical History
5.6.2.1  
General Medical History
Medical history findings will be presented in by-patient listings.
5.6.2.2  
Disease Specific History
Baseline disease characteristics (such as amyloid involvement at study entry, cardiac 
biomarker stage at study entry, substance usage, Eastern Cooperative Oncology Group 
[ECOG] performance status, amyloidosis disease-related cardiac status, and amyloidosis 
disease-related neurologic status) will be summarized. Disease-specific history at initial 
diagnosis (time since  initial diagnosis to first dose of MLN9708, amyloid involvement, 
cardiac biomarker stage, New York Heart Association classification) and the prior therapies
(number of patients with prior therapy, lines of prior therapies, months from last dose of 
prior therapy to the first dose, best hematological response to prior therapy, and best organ 
response to prior therapy, type of prior therapy in the format of therapy contained, number 
of  patients refractory to VELCADE, number of  patients received VELCADE at last line of 
prior therapy, number of  patients refractory to any line of prior therapy, number of  patients 
refractory to last line of prior therapy) will be summarized.
All disease-specific characteristics, including agents received as prior therapy, will be 
presented in by-patient listings.
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MLN9708
Study C16007 Statistical Analysis Plan
13
5.7  
Treatments and Medications
5.7.1  
Concomitant Medications
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary.  The number and percentage of patients taking concomitant medications from 
the first dosing date through the end of the on-study period will be tabulated by Anatomical 
Therapeutic Chemical (ATC) classification therapeutic subgroup and WHO drug preferred 
term.
Concomitant medication and procedures will be presented in by-patient listings.
5.7.2  
Study Treatments
5.7.2.1  
Extent of Exposure
A patient is considered to have been treated in a cycle as long as this patient receives any 
amount of study drug. A treatment cycle is defined as a cycle in which the patient received 
any amount of study drug.
Overall treatment duration will be summarized. The extent of exposure to MLN9708 will be 
summarize treatment duration, the number of cycles, total amount of dose taken in mg, total 
number of doses taken, dose intensity, relative dose intensity. The extent of exposure to 
dexamethasone will summarize the number of treatment cycles. The extent of exposure will 
be summarized by dose level, disease groups, and for all patients. Dose intensity (mg/cycle) 
will be calculated on a per-cycle basis, which equals the sum of total doses (mg) received in 
all cycles divided by the number of treatment cycles. Relative dose intensity is defined as 
100*(Total amount of dose taken / Total prescribed dose over treated cycles), where total 
prescribed dose equals [dose prescribed at enrollment * number of prescribed doses per 
cycle * the number of treated cycles].
5.7.2.2  
Dose Modifications
The modification actions on study drug will be summarized by dose level, disease groups, 
and for all patients, and by cycle if there are sufficient data for analysis.
5.8  
Efficacy Endpoints and Analyses
Standard response criteria will be used in this study.  The efficacy parameters include 
hematologic response rate, organ response rate, time to hematologic response, time to organ 
response, duration of hematologic response, duration of organ response, time to hematologic 
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MLN9708
Study C16007 Statistical Analysis Plan
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disease progression, time to organ disease progression, hematologic disease PFS, organ 
disease PFS, and 1-year overall survival (OS) rate.  The response assessment criteria are
defined in the study protocol appendices.
5.8.1  
Efficacy Endpoints
Best overall hematologic response is defined as the best hematologic response over time. It
will be calculated and summarized in 2 time frames: (1) Up to the End of Treatment (EOT) 
visit; and (2) Up to the initiation of alternative antineoplastic therapy or EOS.
Hematologic objective response rate (ORR) is defined as the proportion of patients who 
achieved a PR or better response as best overall response in the Hematological Response-
Evaluable population. Additional hematologic response rates are defined in the following 
table in the Hematological Response-Evaluable population.  All the hematologic response 
rates will be calculated and summarized in 2 time frames: (1) Up to the EOT visit; and (2) 
Up to the initiation of alternative antineoplastic therapy or EOS.
Hematologic Response 
Rate:
Proportion of Patients in the Hematological Response-Evaluable Population 
Whose Best Overall Responses Are:
CR Rate
CR
VGPR Rate
VGPR
PR Rate
PR
No Change (NC) Rate
No Change (NC)
PD Rate
PD
ORR
PR or VGPR or CR
VGPR or better
VGPR or CR
Vital organ response is defined as the best response of either heart or kidney over time. 
Organ-specific response is defined as the best response of each defined organ over time. 
Organ response rate is defined as the proportion of patients who achieved certain response 
(including response, no change, and PD) in the Organ Response-Evaluable population.
Organ-specific response rate will be calculated in the subgroup of the Organ Response-
Evaluable population with amyloid involvement of the specific organ at baseline. All the 
above organ response rates will be calculated and summarized in 2 time frames: (1) Up to 
the EOT visit; and (2) Up to the initiation of alternative antineoplastic therapy or EOS.
Time to hematologic response is defined as the time from the date of the first dose of 
MLN9708 to the date of first documentation of a hematologic response (PR or better).  Time 
to vital organ response is defined as the time from the date of the first dose of MLN9708 to 
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MLN9708
Study C16007 Statistical Analysis Plan
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the date of first documentation of an organ response of either heart or kidney. In addition, 
time to best hematologic response is defined as the time from the date of the first dose of 
MLN9708 to the date of first documentation of the best hematologic response for each 
patient. The time-to-response endpoints apply only to the responders; therefore, there is no 
censoring. Hematologic responder is defined as a patient whose best hematologic response 
is PR or better.  Vital organ responder is defined as a patient who demonstrates vital organ 
response.  In addition, the responders will be determined in 2 time frames: (1) Up to the 
EOT visit; and (2) Up to the initiation of alternative antineoplastic therapy or EOS.
Duration of hematologic response is defined as the time from the date of first documentation 
of a hematologic response (PR or better) to the date of hematologic PD. Duration of vital
organ response is defined as the time from the date of first documentation of an organ 
response of either heart or kidney to the date of organ PD. The duration-of-response 
endpoints apply only to the responders. However, the responders will be determined in two 
time frames: (1) Up to the EOT visit; and (2) Up to the initiation of alternative 
antineoplastic therapy or EOS. Patients will be censored in any of the following scenarios:

If the patient starts an alternative antineoplastic therapy before the documentation of 
PD, then he or she will be censored at the date of the last available response 
assessment before the alternative antineoplastic therapy.

If the patient has no documented PD and has not started alternative antineoplastic 
therapy and is still alive at the time of analysis, he or she will be censored at the date 
of the last available response assessment.

If the patient died before the documentation of PD and had not started any alternative
antineoplastic therapy, he or she will be censored at the date of the last available
response assessment.
Time to hematologic disease progression is defined as the time from the date of the first 
dose of MLN9708 to the date of first documented hematologic PD. Time to organ disease 
progression is defined as the time from the date of the first dose of MLN9708 to the date of 
first documented organ PD. Patients will be censored in any of the following scenarios:

If the patient starts an alternative antineoplastic therapy before the documentation of 
PD, then he or she will be censored at the date of the last available response 
assessment before the alternative antineoplastic therapy.
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MLN9708
Study C16007 Statistical Analysis Plan
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
If the patient has no documented PD and has not started alternative antineoplastic 
therapy and is still alive at the time of analysis, he or she will be censored at the date 
of the last available response assessment.

If the patient died before the documentation of PD and had not started any alternative 
antineoplastic therapy, he or she will be censored at the date of the last available
response assessment.
Hematologic disease PFS is defined as the time from the date of the first dose of MLN9708 
to the date of documented hematologic PD or any death. Organ disease PFS is defined as 
the time from the date of the first dose of MLN9708 to the date of documented organ PD or 
any death.  Patients will be censored in any of the following scenarios:

If the patient starts an alternative antineoplastic therapy before the documentation of 
PD, then he or she will be censored at the date of the last available response 
assessment prior to the alternative antineoplastic therapy.

If the patient has no documented PD and has not started alternative antineoplastic 
therapy and is still alive at the time of analysis, he or she will be censored at the date 
of the last available response assessment.
OS is defined as the time from the date of the first dose of MLN9708 to the date of death. 
Patients without documentation of death at the time of analysis will be censored at the date 
last known to be alive. One-year OS rate is defined as the patient survival rate at 1 year 
after the date of the first dose of MLN9708.
5.8.2  
Efficacy Analyses
The hematologic response (CR, VGPR, PR, no change [NC], PD) rate will be tabulated and 
analyzed based on the Hematologic Response-Evaluable population and presented with a 2-
sided 95% exact binomial confidence interval.  In addition, the overall hematologic response 
rates up to the end of Cycle 3 and up to the end of Cycle 6 will also be tabulated and 
analyzed in a similar way.
Vital organ response rate will be tabulated and analyzed based on the Organ Response-
Evaluable population. Organ-specific response rate will be tabulated and analyzed based on 
in the subgroup of the Organ Response-Evaluable population with amyloid involvement of 
the specific organ at baseline. Estimates of the organ response rate will be presented with 2-
sided 95% exact binomial confidence intervals.
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MLN9708
Study C16007 Statistical Analysis Plan
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Best hematologic response, time to hematologic response, time to best hematologic 
response, duration of hematologic response, time to hematologic PD, hematologic PFS, and 
OS will be presented in a by-patient listing.  Vital organ response, organ-specific response,
time to vital organ response, duration of vital organ response, time to organ PD, organ PFS, 
and OS will be presented in a by-patient listing.
Time to hematologic response, time to best hematologic response, duration of hematologic 
response, time to hematologic PD, hematologic PFS, and OS (1-year OS rate) will be 
analyzed using standard survival analysis techniques based on Kaplan-Meier estimates, if 
appropriate.
Raw values of serum M-protein, urine M-protein, serum free light chain (FLC), and the 
difference between amyloid-forming and nonamyloid-forming free light chain (dFLC), as 
well as the change from baseline, will be presented in by-patient listings. A waterfall plot 
will be generated to display the maximum change from baseline in dFLC.
QOL will be assessed for patients in the expansion cohorts only using the European 
Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 
(EORTC-QLQ-C30, multiple myeloma module).  Descriptive statistics will be presented for 
both the actual values and the changes from baseline in EORTC-QLQ-C30 assessment over 
time.  EORTC-QLQ-C30 assessments will be analyzed to determine if hematologic response 
to therapy is accompanied by measurable improvement in QOL.
5.9   
Pharmacokinetic, Pharmacodynamic, and Exploratory Analysis
5.9.1   
Pharmacokinetic Analyses
The PK Analysis population will be used for the description of the PK profile and for the 
estimation of PK parameters.
PK evaluation will be based on concentrations of MLN2238, the complete hydrolysis 
product of MLN9708, in specimens collected at prespecified times before and after drug 
administration.  Actual sample collection times will be used for the calculation of PK 
parameters. In the event that actual collection times are either unreliable or missing, 
scheduled collection times will be used. For ease of presentation, scheduled collection times 
will be used to present results in tables and figures. Both scheduled and actual collection
times will be presented in listings.
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MLN9708
Study C16007 Statistical Analysis Plan
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Concentrations of MLN2238 that are below the limit of quantification (BLQ) will be treated 
as zero. Concentration data that are considered anomalous may be excluded from the 
concentration summaries and plots and will not be used in the calculation of PK parameters. 
Evidence or explanation will be provided to justify the exclusion of data.
When summarizing concentrations or PK parameters, a minimum of 2 values is required to 
show the mean and geometric mean, and at least 3 values are required to show the standard 
deviation and coefficient of variation (CV). Summary statistics will be reported only if the 
calculated mean value is greater than the lower limit of quantification (LLOQ) and at least 
50% of the values are nonzero.
5.9.1.1   
Plasma and Whole Blood Pharmacokinetic Profiles
Individual patient plasma and whole blood concentration data will be listed. Concentrations 
will be summarized (N, mean, standard deviation, CV, geometric mean, median, min, and 
max) according to dose cohort and dosing cycle and day. Population mean and individual 
plasma and whole blood concentration-time data will be plotted by dose cohort and dosing 
cycle and day.
5.9.1.2   
Plasma and Whole Blood Pharmacokinetic Parameters
The following PK parameters will be calculated by noncompartmental methods, as data 
permit, from concentration-time data:
Parameter
Definition
Units
Cmax
Observed maximum concentration
ng/mL
Tmax
First time Cmax is observed
hr
Ctrough
Observed concentration at the end of a dosing interval
ng/mL
AUCtau
Area under the concentration-time curve, time 0 to end of dosing interval, 
estimated using the linear-log trapezoidal method
hr*ng/mL
lambdaz
Terminal disposition phase rate constant
1/hr
t1/2
Terminal disposition phase half-life
hr
Rac
Accumulation ratio
unitless
Different PK parameters are to be estimated following dosing on Day 1 and Day 15. For 
some of the doses, concentration data is collected only on either Day 1 or on Day 15. PK 
parameters will be calculated accordingly. The PK parameters to be estimated for each day 
of dosing are as follows:
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MLN9708
Study C16007 Statistical Analysis Plan
19
PK Parameter
Dosing Day
1
15
Cmax
X
X
Tmax
X
X
Ctrough
X
X
AUCtau
X
tau = 168 hr
X
tau = 168 hr
lambdaz
X
t1/2
X
Rac
X
Individual patient parameter data will be listed. PK parameters will be summarized (N, 
mean, standard deviation, CV, geometric mean [as appropriate], median, min, and max) 
according to dose cohort and dosing cycle and day.
5.9.2   
Pharmacodynamic Analyses
The Pharmacodynamic Analysis population will be used for the description of the 
pharmacodynamic profile and for the estimation of pharmacodynamic parameters.
The pharmacodynamic measure that will be analyzed is whole blood 20S proteasome 
inhibition. The inhibition is defined as the postdose proteasome activity times divided by 
the baseline proteasome activity.  If the baseline proteasome activity is missing or is BLQ 
for a patient, then no inhibition will be calculated for that patient. Individual and mean 
whole blood 20S proteasome inhibition data will be plotted over time, and summary 
tabulations will be presented.
Actual specimen collection times will be used for the calculation of pharmacodynamic 
parameters. In the event that actual collection times are either unreliable or missing, 
scheduled collection times will be used. For ease of presentation, scheduled collection times 
will be used to present results in tables and figures. Both scheduled and actual collection 
times will be presented in listings.
Proteasome activity measurements that are BLQ will be treated as zero. Proteasome activity 
measurements that are considered anomalous may be excluded from data summaries and 
plots and will not be used in the calculation of pharmacodynamic parameters. Evidence or 
explanations will be provided to justify the exclusion of data.
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M L N 9 7 0 8
St u d y C 1 6 0 0 7 St atistic al A n al ysis Pl a n
2 0
W he n s u m marizi n g pr oteas o me i n hi biti o n or p har mac o d y na mic para meters, a mi ni m u m of 2 
val ues is re q uire d t o s h o w t he mea n, a n d at least 3 val ues are re q uire d t o s h o w t he sta n dar d 
de viati o n a n d C V. S u m mar y  statistics will be re p orte d o nl y if at least 5 0 % of t he val ues are 
n o nzer o.
5. 9. 2. 1    
P h ar m ac o d y n a mic Pr ofiles
I n di vi d ual patie nt pr oteaso me acti vit y  data a n d pr oteas o me i n hi biti o n data will be liste d. 
Pr oteas o me i n hi biti o n will be s u m marize d ( N, mea n, sta n dar d de viati o n, C V, me dia n, mi n, 
a n d ma x) acc or di n g t o d ose c o h ort a n d d osi n g c y cle a n d da y. P o p ulati o n mea n a n d 
i n di vi d ual pr oteas o me i n hi biti o n-ti me data will be pl otte d b y d ose c o h ort a n d d osi n g c ycle 
a n d da y.
5. 9. 2. 2    
P h ar m ac o d y n a mic P ar a meters
T he f oll o wi n g p har mac o d y na mic para meters will be calc ulate d b y  n o nc o m part me ntal 
met h o ds , as data per mit, fr o m pr oteas o me i n hi biti o n-ti me:
P a r a m eter
Defi niti o n
U nits
E ma x
O bser ve d ma xi m u m pr oteas o me i n hi biti o n
%
T E ma x
First ti me E ma x is o bser ve d
hr
A U E ta u
Area u n der t he i n hi biti o n -ti me c ur ve fr o m ti me 0 t o e n d of d osi n g i nter val ( 0-1 6 8 
h o urs) esti mate d usi n g t he li near tra pez oi dal r ule
hr * %
I n divi d ual patie nt para meter data will be liste d. P har mac o d y n a mic para meters will be 
s u m marize d ( N, mea n, sta n dar d de viati o n, C V, me dia n, mi n, a n d ma x) acc or di n g t o d ose 
c o h ort a n d d osi n g c ycle a n d da y.
I n a d diti o n t o t he n o nc o m part me ntal P K a n d p har mac o d y na m ic a nalys es descri be d i n 
Secti o n 5. 9. 1 a n d Secti o n 5. 9. 2 , P K a n d p har mac o d yna mic data c ollecte d i n t his st u d y  ma y 
be use d f or p o p ulati o n P K a n d P K/ p har mac o d y na mic m o d eli n g p ur p oses. T hese a nal y ses 
will be re p orte d se paratel y , as t he y will use P K a n d/ or p har mac o d y n a mic data c ollecte d i n 
ot her cli nical st u dies.
5. 9. 3   
E x pl or at or y A n al ysis
5. 9. 3. 1    
T u m or Bi o m ar ker A n al ysis
C CI
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e


M L N 9 7 0 8
St u d y C 1 6 0 0 7 St atistic al A n al ysis Pl a n
2 1
5. 9. 3. 2    
Ger mli ne D N A P ol y m or p his m A n al ysis
5. 1 0   
S afet y A n al yses
T hese a nal y ses will be perf or me d usi n g t he S afet y p o p ulati o n.
5. 1 0. 1   
A d verse E ve nts
5. 1 0. 1. 1   
A d verse E ve nts
A Es will be c o de d usi n g t he Me dical Dicti o nar y  f or Re g ulat or y Acti vities ( Me d D R A).
Treat me nt -e mer ge nt is defi ne d as a n y A E t hat occ urs after a d mi nistrati o n of t he first d ose of 
st u d y treat me nt a n d u p t hr o u g h 3 0 da ys after t he last d ose of stu d y  dr u g or u ntil start of 
s u bse q ue nt a nti ne o plastic t hera py; a n y e ve nt t hat is c o nsi dere d dr u g -relate d re gar dless of t he 
start date of t he e ve nt; or a n y  e ve nt t hat is prese nt at baseli ne b ut w orse ns i n se verity after 
baseli ne. Patie nts w h o e x perie nce t he sa me A E m ore t ha n o nce will ha ve t hat e ve nt c o u nte d 
o nl y  o nce wit hi n eac h b o d y sys te m, o nce wit hi n eac h H i gh L e vel T er m, a n d o nce wit hi n 
eac h P referre d T er m.
A Es will be ta b ulate d b y S ys te m O r ga n Class, H i g h L e vel T er m, a n d P referre d T er m.  
S u m mar y  ta b ulati o ns i ncl u de t he f oll o wi n g s u bsets:

Treat me nt -e mer ge nt A Es

Dr u g -relate d treat me nt-e mer ge nt A Es
C CI
C CI
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e


MLN9708
Study C16007 Statistical Analysis Plan
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
Grade 3 or higher treatment-emergent AEs

Grade 3 or higher drug-related treatment-emergent AEs

Grade 3 treatment-emergent AEs and Grade 4 treament-emergent AEs

Grade 3 drug-related treatment-emergent AEs and Grade 4 drug-related treament-
emergent AEs
Treatment-emergent AEs will be tabulated by System Organ Class, Preferred Term, and 
highest intensity.  The most commonly reported (at least 10% of all patients) 
treatment-emergent AEs will be presented by Preferred Term. In addition, a by-patient 
listing of the treatment-emergent AEs will be presented.
AEs with start dates that are completely or partially missing will be analyzed as follows:

If the start date has a month and year but the day is missing, the event will be 
considered treatment emergent if both the month and year of the start date of the 
event are on or after the month and year of the date of the first dose of MLN9708 
and on or before the month and year of the date of the last dose of MLN9708 plus 30 
days.

If the start date has a year, but the day and month are missing, the event will be 
considered treatment emergent if the year of the start date of the event is on or after 
the year of the date of the first dose of MLN9708 and on or before the year of the 
date of the last dose of MLN9708 plus 30 days.

If the start date of an event is completely missing, then the event is assumed to be 
treatment emergent.
5.10.1.2   
Serious Adverse Events
The number and percentage of patients experiencing at least 1 treatment-emergent serious 
AE (SAE) will be summarized by MedDRA System Organ Class, High Level Term, and 
Preferred Term. A similar table for drug-related SAEs will also be presented.
A by-patient listing of the SAEs will be presented (the listing will contain all SAEs 
regardless of treatment-emergent AE status).
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Study C16007 Statistical Analysis Plan
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5.10.1.3   
Deaths
A listing of on-study deaths will be presented. On-study death is defined as death events 
that occur within 30 days of the last dose of study drug.
5.10.1.4   
Adverse Events Resulting in Discontinuation of Study Drug or Study Drug 
Modification
A by-patient listing of AEs resulting in discontinuation of study drug will be presented.  The 
number and percentage of patients experiencing at least 1 AE resulting in discontinuation of 
study drug will be summarized by MedDRA System Organ Class, High Level Term, and 
Preferred Term.
A by-patient listing of AEs resulting in study drug modification will be presented.  The 
number and percentage of patients experiencing at least 1 AE resulting in study drug 
modification will be summarized by MedDRA System Organ Class, High Level Term, and 
Preferred Term.
All AEs resulting in discontinuation of study drug occurring on-study will be displayed.
5.10.1.5   
Dose Limiting Toxicities
A by-patient listing of DLTs that occur during Cycle 1 of treatment will be presented by 
dose level for all patients enrolled during the dose-escalation portion of this study. Patients
will be grouped by the dose level to which they were originally assigned, including those 
who receive subsequent treatment at a lower dose level.
5.10.2   
Laboratory Data
For hematology parameters and chemistry parameters, shift tables of the change in National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) from 
baseline to the worst postbaseline CTCAE grade will be generated.  If necessary, graphical 
displays will be used to show changes in laboratory measures over time for each individual 
patient by the line graphs of individual tests over time for each patient
In addition, the lines of mean estimates over time by linear mixed model may be graphed for 
a selected list of test parameters.
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Study C16007 Statistical Analysis Plan
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Panel
Test
CTCAE Shift 
Table
Line Graphs
Chemistry
Albumin
X
X
ALT
X
X
AST
X
X
Alkaline Phosphatase
X
X
Creatinine
X
X
Bilirubin
X
X
Phosphate
X
X
Uric Acid
X
Calcium
X
X
Magnesium
X
X
Potassium
X
Sodium
X
Glucose
X
Hematology
Platelet
X
X
Hematocrit
Hemoglobin
X
X
White Blood Cells (WBC)
X
Lymphocytes
X
X
Neutrophils (ANC)
X
X
Cardiac markers
NT-ProBNP
X
BNP
X
Troponin T
X
24 hours urine collection
Total protein
X
Creatinine Clearance
X
In addition, the coagulation parameters and urinalysis parameters will be presented in by-
patient listings and are listed below:

Coagulation (from patients in the tumor pharmacodynamic expansion cohort and in 
the MTD disease expansion cohort to undergo tumor biopsy): prothrombin time 
(PT), partial thromboplastin time (PTT), and international normalized ratio (INR).

Urinalysis: appearance and color, blood, pH, nitrite, specific gravity, urobilinogen, 
protein, glucose, ketones, leukocyte esterase, and bilirubin

Hormones: thyrotropin (TSH) and cortisol

β2-microglobulin
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Study C16007 Statistical Analysis Plan
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For the purposes of summarization in both the tables and listings, all laboratory values will 
be converted to standardized units.  If a lab value is reported using a nonnumeric 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 nonnumeric qualifier.
If a patient has repeated laboratory values for a given time point, the value from the last 
evaluation will be used.
5.10.3   
Echocardiogram
The values of mean left ventricular wall thickness (septum and posterior wall) and the left 
ventricular ejection fraction (LVEF), as well as their changes from baseline, will be 
presented in a listing.
5.10.4   
Electrocardiogram
Electrocardiogram (ECG) clinical results (within normal limits; abnormal, not clinically 
significant; abnormal, clinically significant) will be presented in a by-patient listing and in a 
summary table.
ECG intervals (PR interval and heart rate, and calculated corrected QT [QTc] intervals) will 
be summarized at each scheduled time point, along with mean change from baseline to each 
posttreatment time point.
QTc (Bazett [QTcB] and Fridericia [QTcF] corrections) will be calculated as follows:
R-R interval = 60 /heart rate
QTcF = QT Interval/(R-R Interval)1/3
QTcB = QT Interval/(R-R Interval)1/2
5.10.5   
Vital Signs and Eastern Cooperative Oncology Group Performance Status
Listings will be generated for displaying the vital sign parameters and ECOG performance 
status over time. The descriptive statistics for the actual values and changes from baseline 
in vital sign parameters over time will be summarized by scheduled time point.  A table of 
ECOG performance status shifts from baseline to worst post baseline assessment will be 
generated.
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Study C16007 Statistical Analysis Plan
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5.10.6   
Pregnancy Test, Substance Use Data, and Other Data
The pregnancy test, substance use and any other collected important data will be presented 
in by-patient listings.
6.   
CHANGES TO PLANNED ANALYSES FROM THE PROTOCOL
The definition of the PK-Evaluable popuplation and the Pharmacodynamics-Evaluable 
popuplation are to be changed to include all treated patients instead of patients receiving full 
doses during Cycle 1 and to remove the condition of “did not receive any excluded 
concomitant medications”.
The 2 major organs (heart and kidney) will be called vital organs in the SAP and analyses.
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.
Treatment-emergent AEs are defined in Section 5.10.1.1.
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